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Calm down kitty. I was never making that argument.
This stock has been pretty flat for the last 2 weeks,
mark it
You really don't think some traders took July 4th weekend off?
Okay.
by the way I don't know what this stock will do on Monday
but
mark it anyway
Cmon, you know folks are on vacation until Monday.
WOW Your calculations are still WAY OFF.
TODAY
IGLOW wrote:
"Just for your edification the 4% of the gross proceeds from the warrants - hold on here we go: Let's use your $0.20 number - (12,500,000 x 0.2) x 4% = $100,000!
Newbridge receives a unheard of finders fee of 2,500,00 x $0.20 = $500,000 Plus $375,000 Plus $100,000 ....
For a grand total of $975,000"
YESTERDAY
IGLOW wrote:
"Add in Newbridge where they received 2.5 million shares plus $375,000.
So OWCP paid ($575,000 + $375,000) + $10,925,000 = $11,875,000"
On page 1 of Form 424B3 in the Prospectus Summary it makes it very clear that Newbridge did NOT receive "2.5 million shares plus $375,000" as you claim.
THIS IS WHAT IT ACTUALLY SAYS IN THE ACTUAL DOCUMENT about what Newbridge received
"Newbridge Securities Corporation (“Newbridge”), through LifeTech Capital, acted as exclusive placement agent for the transaction and we paid Newbridge a cash fee of $375,000 and issued to them warrants to purchase 2.5 million shares of our common stock at an exercise price of $0.20 per share."
It appears your calculations are seriously lacking in the knowledge and understanding of Warrants and how they work.
I will explain it for you... again
Q: What is a 'Warrant'?
A: A warrant is a security that entitles the holder to buy the underlying stock of the issuing company at a fixed price called exercise price until the expiry date.
note: This is a simple definition from Google. If you don't know what a "security", or "underlying stock" is it may still be confusing.
Newbridge is issued warrants to purchase 2.5 million shares of OWCP common stock at an exercise price of $0.20 per share. What this means is that if they exercise the warrants, then OWCP will receive $500,000. This will make the $375,000 cash fee a wash with OWCP still having $125,000 to cover the warrants solicitation fee equal to 4% of the gross proceeds that OWCP will receive upon cash exercise of the Warrants.
This means that if Newbridge exercises the warrants to purchase 2.5 million shares of OWCP common stock from OWCP at an exercise price of $0.20 per share, then OWCP would end up having paid Newbridge ONLY 2.5 million shares of common stock, AND ZERO CASH. In fact OWCP will end up with $105,000.
2.5 million shares X .20 = $500,000 (Money paid to OWCP upon exercise of warrants)
So now that it is understood that it is OWCP that is receiving the .20/share and it is Newbridge that is paying the .20/share upon exercising the Warrants, let's finish calculating how this works out.
+$500,000 Proceeds paid to OWCP by Newbridge
-$375,000 Cash fee paid to Newbridge by OWCP
——————————————————————————————————
+$125,000 Remaining proceeds that were paid to OWCP from the Warrants
——————————————————————————————————
-$20,000 4% fee of the gross proceeds that OWCP will receive upon cash exercise of the Warrants
——————————————————————————————————
+$105,000 Remaining proceeds paid to OWCP by Newbridge (after Newbridge exercises Warrants)
So if Newbridge exercises the Warrants then their services would have cost OWCP
2.5 million shares of common stock; and actually OWCP will come out with $105,000 cash in addition to their services.
That's not a bad deal at all.
$OWCP
Yea, OWCP sold 500 Series A Preferred Shares for an aggregate of $5 Million.
It will result in dilution of UP TO 47,500,000 shares of our common stock.
That's not a bad deal at all, and since management are holders of OWCP common stock they have skin in the game and will be motivated to accelerate progress on R&D, Patents, and Consulting during this year.
$OWCP
Nope, they bought shares and Warrants, and OWCP has to pay a dividend.
OWCP doesn't get $5 Million for nothing.
I know all about the anti-dilution provision. 3-day average during previous 10 days is reasonable.
I don't believe you read all of "the 8-K - the S-1 - the S-1A and the 424B3..." but whatever.
The paragraph you keep posting says "up to 47,500,000 shares of our common stock"
as in UP TO...
12,500,000 of the 47,500,000 shares of common stock will be from the Warrants if Discover Growth Fund exercises the Warrants.
If they do exercise the Warrants then Discover Growth Fund will pay OWCP an additional $2,750,000
12,500,000 X .22 = $2,750,000
OWCP will then pay Newbridge a commission on the proceeds from exercised Warrants of 4% which is $110,000.
So OWCP will receive an additional $2.64 Million if Discover Growth Fund exercises the Warrants.
Now are you starting to kind of understand how Warrants work or no?
$OWCP looking good right now
YOU ARE WAY OFF ON YOUR CALCULATION... BY MILLIONS OF DOLLARS
You need to read them again.
You need to know what a Warrant is and how they work to fix your calculations. My gift to you for the day.
"(ii) 12,500,000 shares of our common stock currently issuable upon exercise of a warrants held by the selling stockholder (the “Warrants”)."
——————————————————————
Here is my previous post where I tried to explain to you what a Warrant is and how they work. Instead of searching for the meaning of what a Warrant is in Wikipedia as you claim you did, perhaps you should have tried to understand my brief lesson on what Warrants are and how they work, because your calculations are still reflecting a lack of knowledge about what Warrants are and how they work.
You never even thanked me by the way... just sayin'
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=142009469
Do you know what a Warrant is? Your calculations are completely wrong.
IGLOW wrote:
"The $5 million equity purchase agreement will cost OWCP/Shareholders over $11 million - that is a horrendous deal for shareholders."
Your above claim is completely FALSE.
Great find. 1. (US20180185324) NOVEL CANNABINOID COMBINATION THERAPIES FOR MULTIPLE MYELOMA (MM)
https://patentscope.wipo.int/search/en/detail.jsf?docId=US222841762&recNum=1&tab=NatCollDocuments&maxRec=32&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=%22one+world+cannabis%22;
This patent is very much in the works and will be HUGE if granted.
The chances of OWCP getting this patent granted are pretty good with Dr. Oron Yacoby Zeevi as the Chief Scientific Officer (CSO).
She's a super star with pharmaceutical patents.
Have a look at the very long list of her patent work:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=142011320
-OR-
Dr. Zeevi's Patent List source link:
https://patents.justia.com/inventor/oron-yacoby-zeevi
$OWCP
I bought today. Going to buy more before day's end.
$OWCP
tick tock
How many times did we hear those nonsense claims... over and over like a broken record.
So here we are... OWCP filed the S-1 and the SEC issued the "Notice of Effectiveness" on July 2, 2018.
Them conspiracy theories have been officially debunked by the SEC.
We are funded, Have the best research and patent team in MMJ, and now we have conducted consulting services in Hawaii and Pennsylvania.
"While continuing with scientific investigations into medical effects and benefits of cannabis, we anticipate that it will begin generating revenue through providing consulting services related to medical marijuana programs. As of the date of this filing, we have provided consulting services to a medical marijuana program with locations in Hawaii and Pennsylvania."
$OWCP is looking better than ever.
This PPS is way undervalued, but that will change, and when it does.... c-ya, those on the sidelines will have to chase.
OWC Pharmaceutical Research Corp. Appoints Dr. Oron Yacoby Zeevi as its Chief Scientific Officer
NEWS PROVIDED BY
OWC Pharmaceutical Research Corp.
Feb 20, 2018, 08:30 EST
RAMAT GAN, Israel, Feb. 20, 2018 /PRNewswire/ -- OWC Pharmaceutical Research Corp. (OTCQB: OWCP), ("OWC" or the "Company"), a developer of cannabinoid-based therapies targeting a variety of different medical conditions and disorders, today announced the appointment of Dr. Oron Yacoby Zeevi as its Chief Scientific Officer (CSO).
Dr. Yacoby Zeevi has more than 20 years of extensive scientific experience with both private and publicly listed companies in the biopharmaceutical industry. She joined Neuroderm (Nasdaq: NDRM), a clinical-stage pharmaceutical company developing next-generation treatments for central nervous system (CNS) disorders in 2008 as the Vice President of Research and was promoted to the position of VP R&D in 2010. From October 2016 until her recent departure, she served as Chief Scientific Officer. Neuroderm was sold to Mitsubishi Tanabe Pharma for US $1.1 billion in July 2017.
Dr. Yacoby Zeevi is the inventor of over 50 issued patents and pending patents. Her expertise lies in industry-oriented innovation and scientific research, accelerating and orchestrating the evolution of new ideas through R&D proof of concept, intellectual property development, chemistry and manufacturing controls (CMC), early efficacy and safety trials, regulatory affairs and market landscape mapping in fields of unmet medical needs. She earned her Ph.D. in microbiology and immunology from Ben Gurion University in Be'er Sheva, Israel and also holds a degree of Doctor in Veterinary Medicine from the Hebrew University of Jerusalem.
Dr. Yehuda Baruch who, will now assume the role of Chief Medical and Regulatory Officer of the OWC Pharmaceutical Research Corp. commented:
"I am very pleased that we have reached a stage in our development where we were able to recruit a scientist of the caliber and background of Dr. Yacoby Zeevi. Her past scientific experience and achievements will greatly benefit our endeavors."
Dr. Yacoby Zeevi commented, "I am very proud to join OWCP and cooperate with their excellent management team in order to advance the Company to the next level. The Company has achieved a great deal in its clinical development to date and I am sure I can help in accelerating its growth."
Mr. Mordechai Bignitz, Chief Executive Officer, commented on the appointment, "I am proud and honored to have Dr. Zeevi agree to join OWCP and assume the role of CSO. She brings with her immense pharmaceutical discovery and development knowledge, a unique set of skills and an exceptional track record, which contributed significantly to the success of her previous company. Her addition will complement our management team extremely well."
About OWC Pharmaceutical Research Corp.
OWC Pharmaceutical Research Corp., through its wholly-owned Israeli subsidiary, One World Cannabis Ltd., (collectively 'OWC' or the 'Company') conducts medical research and clinical trials to develop cannabis-based pharmaceuticals and treatments for conditions including multiple myeloma, psoriasis, fibromyalgia, PTSD, and migraines.
OWCP is also developing unique delivery systems for the effective delivery and dosage of medical cannabis. All OWCP research is conducted at leading Israeli hospitals and scientific institutions and led by internationally renowned investigators. The Company's Research Division is focused on pursuing clinical trials evaluating the effectiveness of cannabinoids and cannabis-based products for the treatment of various medical conditions, while its Consulting Division is dedicated to helping governments and companies navigate complex international cannabis regulatory frameworks.
For more information visit: http://www.owcpharma.com/.
Notice Regarding Forward-Looking Statements
This news release contains "forward-looking statements" as that term is defined in Section 27A of the United States Securities Act of 1933, as amended and Section 21E of the Securities Exchange Act of 1934, as amended. Statements in this press release, which are not purely historical, are forward-looking statements and include any statements regarding beliefs, plans, expectations or intentions regarding the future. Such forward-looking statements include, among other things, filing patent applications, product development, and business strategy. Actual results could differ from those projected in any forward-looking statements due to numerous factors. Such factors include, among others, the inherent uncertainties associated with new projects and development stage companies. These forward-looking statements are made as of the date of this news release, and we assume no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements. Although we believe that any beliefs, plans, expectations and intentions contained in this press release are reasonable, there can be no assurance that any such beliefs, plans, expectations or intentions will prove to be accurate. Investors should consult all of the information set forth herein and should also refer to the risk factors disclosure outlined in OWC Pharmaceutical Research Corp. (OTCQB: OWCP) periodic reports filed from time-to-time with the Securities and Exchange Commission.
Contact Information::
Mordechai Bignizt , Chief Executive Officer – OWC Pharmaceutical research crop,
Email: Mordechai.Bignitz@owcpharma.com
Tel: +972-(0)3-7582659
SOURCE OWC Pharmaceutical Research Corp.
Company website:
http://www.owcpharma.com
(source link):
https://www.prnewswire.com/news-releases/owc-pharmaceutical-research-corp-appoints-dr-oron-yacoby-zeevi-as-its-chief-scientific-officer-300601008.html
$OWCP
Dr. Zeevi's EXTENSIVE Patent experience - here's the list... it's very long going all the way back to the year 2000.
Dr. Yacoby Zeevi is the inventor of over 50 issued patents and pending patents. Her expertise lies in industry-oriented innovation and scientific research, accelerating and orchestrating the evolution of new ideas through R&D proof of concept, intellectual property development, chemistry and manufacturing controls (CMC), early efficacy and safety trials, regulatory affairs and market landscape mapping in fields of unmet medical needs.
Patent List source link:
https://patents.justia.com/inventor/oron-yacoby-zeevi
Patents by Inventor Oron Yacoby-Zeevi
Oron Yacoby-Zeevi has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
Compositions comprising apomorphine and organic acids and uses thereof
Patent number: 9999674
Abstract: The present invention provides stable liquid or semi-solid pharmaceutical compositions of apomorphine, more particularly composition comprising apomorphine and an organic acid, which are useful in treatment of neurological or movement diseases or disorders, e.g., Parkinson's disease, or conditions associated therewith.
Type: Grant
Filed: June 5, 2013
Date of Patent: June 19, 2018
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 9993451
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: July 1, 2015
Date of Patent: June 12, 2018
Assignee: NeuroDerm, LTD.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
OPIPRAMOL PATCH
Publication number: 20180140610
Abstract: Disclosed herein are compositions that are useful in effecting the transdermal delivery of active agents such as opipramol. More particularly, the disclosed transdermal compositions include an active agent; one or more plasticizers; one or more penetration enhancers; a pressure-sensitive adhesive; and may include one or more hydrophilic polymers.
Type: Application
Filed: September 18, 2015
Publication date: May 24, 2018
Applicant: NeuroDerm, Ltd.
Inventors: Oron YACOBY-ZEEVI, Mara NEMAS
CRYSTAL FORMS OF APOMORPHINE AND USES THEREOF
Publication number: 20170368052
Abstract: The present invention provides solid crystalline forms of apomorphine free base or a hydrate, solvate, or co-crystals thereof. Such crystalline forms may be advantageous over amorphous forms of apomorphine, e.g., amorphous salt forms such as acid addition salts of apomorphine, because of their increased/greater stability and/or improved pharmacological properties, e.g., decreased adverse reactions at the site of administration. The invention further provides liquid formulations obtained by dissolving said crystalline forms of apomorphine in a solvent, as well as a method for treatment of a neurological or movement disorder, e.g., Parkinson's disease, or a condition associated therewith, by administration of said liquid formulations.
Type: Application
Filed: December 23, 2015
Publication date: December 28, 2017
Inventors: Oron Yacoby-Zeevi, Mara Nemas, Jonathan Cummins, Petra Dieterich
PHARMACEUTICAL COMPOSITIONS COMPRISING LEVODOPA AMIDE AND USES THEREOF
Publication number: 20170296491
Abstract: The present invention discloses various aqueous pharmaceutical compositions comprising a levodopa amide compound, or a salt thereof, which are stable for at least 24 hours at room temperature, and use thereof in treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, e.g., Parkinson's disease.
Type: Application
Filed: November 23, 2016
Publication date: October 19, 2017
Inventors: Oron Yacoby-Zeevi, Mara Nemas, Eduardo Zawoznik, Irena Vainshtok, Einat Sela
Continuous Administration of Levodopa and/or Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20170196828
Abstract: Disclosed herein are for example, liquid aqueous compositions that include for example an ester or salt of levodopa, or an ester or salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome, dystonia, and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of levodopa and/or carbidopa or ester and/or salt thereof.
Type: Application
Filed: August 23, 2016
Publication date: July 13, 2017
Inventors: Oron Yacoby-Zeevi, Mara Nemas
CONTINUOUS ADMINISTRATION OF L-DOPA, DOPA DECARBOXYLASE INHIBITORS, CATECHOL-O-METHYL TRANSFERASE INHIBITORS AND COMPOSITIONS FOR SAME
Publication number: 20170157077
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Application
Filed: July 13, 2016
Publication date: June 8, 2017
Inventors: Oron Yacoby-Zeevi, Mara Nemas
COMPOSITIONS FOR TRANSDERMAL DELIVERY OF ACTIVE AGENTS
Publication number: 20170157076
Abstract: Disclosed herein are compositions that are useful in effecting the transdermal delivery of therapeutic agents. More particularly, the disclosed transdermal compositions may include a fatty alcohol (for example, octanol), a terpene (for example, limonene), and an active agent comprising an amine moiety.
Type: Application
Filed: July 8, 2016
Publication date: June 8, 2017
Inventors: Oron Yacoby-Zeevi, Mara Nemas, Eduardo Zawoznik
DOPA DECARBOXYLASE INHIBITOR COMPOSITIONS
Publication number: 20170157079
Abstract: Disclosed herein are formulations containing carbidopa and optionally levodopa, arginine, and other components that have reduced levels of impurities and toxins, particularly degradation productions. Also disclosed herein are methods of treatment diseases or conditions relating to a loss of dopamine or dopaminergic neurons using such formulations, methods of making such formulations, and kits that include such formulations.
Type: Application
Filed: February 21, 2017
Publication date: June 8, 2017
Inventor: Oron Yacoby-Zeevi
Continuous administration of L-dopa, dopa decarboxylase inhibitors, catechol-O-methyl transferase inhibitors and compositions for same
Patent number: 9421267
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Grant
Filed: November 15, 2011
Date of Patent: August 23, 2016
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Compositions for transdermal delivery of active agents
Patent number: 9415108
Abstract: Disclosed herein are compositions that are useful in effecting the transdermal delivery of therapeutic agents. More particularly, the disclosed transdermal compositions may include a fatty alcohol (for example, octanol), a terpene (for example, limonene), and an active agent comprising an amine moiety.
Type: Grant
Filed: November 15, 2011
Date of Patent: August 16, 2016
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas, Eduardo Zawoznik
Compositions comprising apomorphine and organic acids and uses thereof
Patent number: 9381249
Abstract: The present invention provides stable liquid or semi-solid pharmaceutical compositions of apomorphine, more particularly compositions comprising apomorphine and an organic acid, which are useful in treatment of neurological or movement diseases or disorders, e.g., Parkinson's disease, or conditions associated therewith.
Type: Grant
Filed: November 18, 2015
Date of Patent: July 5, 2016
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20160151317
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: July 1, 2015
Publication date: June 2, 2016
Inventors: Oron Yacoby-Zeevi, Mara Nemas
COMPOSITIONS COMPRISING APOMORPHINE AND ORGANIC ACIDS AND USES THEREOF
Publication number: 20160067339
Abstract: The present invention provides stable liquid or semi-solid pharmaceutical compositions of apomorphine, more particularly compositions comprising apomorphine and an organic acid, which are useful in treatment of neurological or movement diseases or disorders, e.g., Parkinson's disease, or conditions associated therewith.
Type: Application
Filed: November 18, 2015
Publication date: March 10, 2016
Inventors: Oron Yacoby-Zeevi, Mara Nemas
METHOD FOR TREATMENT OF PARKINSON'S DISEASE
Publication number: 20160022573
Abstract: The present invention provides a method for treatment of a neurological or movement disorder, e.g., Parkinson's disease, in an individual in need thereof, by parenteral administration of a composition comprising carbidopa and levopoda, or pharmaceutically acceptable salts thereof, and concomitant oral administration of a catechol-O-methyl transferase (COMT) inhibitor, e.g., entacapone or tolcapone.
Type: Application
Filed: March 13, 2014
Publication date: January 28, 2016
Applicant: NEURODERM, LTD.
Inventor: Oron Yacoby-Zeevi
DOPA DECARBOXYLASE INHIBITOR COMPOSITIONS
Publication number: 20150352212
Abstract: Disclosed herein are formulations containing carbidopa and optionally levodopa, arginine, and other components that have reduced levels of impurities and toxins, particularly degradation productions. Also disclosed herein are methods of treatment diseases or conditions relating to a loss of dopamine or dopaminergic neurons using such formulations, methods of making such formulations, and kits that include such formulations.
Type: Application
Filed: March 12, 2015
Publication date: December 10, 2015
Inventor: Oron Yacoby-Zeevi
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 9101663
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: December 7, 2010
Date of Patent: August 11, 2015
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
COMPOSITIONS COMPRISING APOMORPHINE AND ORGANIC ACIDS AND USES THEREOF
Publication number: 20150182523
Abstract: The present invention provides stable liquid or semi-solid pharmaceutical compositions of apomorphine, more particularly composition comprising apomorphine and an organic acid, which are useful in treatment of neurological or movement diseases or disorders, e.g., Parkinson's disease, or conditions associated therewith.
Type: Application
Filed: June 5, 2013
Publication date: July 2, 2015
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 9040589
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: May 13, 2014
Date of Patent: May 26, 2015
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of L-dopa, dopa decarboxylase inhibitors, catechol-O-methyl transferase inhibitors and compositions for same
Patent number: 9040578
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Grant
Filed: April 2, 2014
Date of Patent: May 26, 2015
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of L-dopa, dopa decarboxylase inhibitors, catechol-O-methyl transferase inhibitors and compositions for same
Patent number: 9040577
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Grant
Filed: April 2, 2014
Date of Patent: May 26, 2015
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 9040590
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: May 13, 2014
Date of Patent: May 26, 2015
Assignee: NeuroDerm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20140249230
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: May 13, 2014
Publication date: September 4, 2014
Applicant: NEURODERM, LTD.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
CONTINUOUS ADMINISTRATION OF L-DOPA, DOPA DECARBOXYLASE INHIBITORS, CATECHOL-O-METHYL TRANSFERASE INHIBITORS AND COMPOSITIONS FOR SAME
Publication number: 20140249228
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Application
Filed: April 2, 2014
Publication date: September 4, 2014
Applicant: NEURODERM, LTD.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
CONTINUOUS ADMINISTRATION OF L-DOPA, DOPA DECARBOXYLASE INHIBITORS, CATECHOL-O-METHYL TRANSFERASE INHIBITORS AND COMPOSITIONS FOR SAME
Publication number: 20140249229
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Application
Filed: April 2, 2014
Publication date: September 4, 2014
Applicant: NEURODERM, LTD.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20140249231
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: May 13, 2014
Publication date: September 4, 2014
Applicant: NEURODERM, LTD.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of L-Dopa, Dopa Decarboxylase Inhibitors, Catechol-O-Methyl Transferase Inhibitors and Compositions for Same
Publication number: 20140051755
Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof, comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and optionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is administered substantially continuously, and compositions that can be used in the disclosed methods.
Type: Application
Filed: November 15, 2011
Publication date: February 20, 2014
Applicant: Neuroderm LTD
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Compositions for Transdermal Delivery of Active Agents
Publication number: 20130338143
Abstract: Disclosed herein are compositions that are useful in effecting the transdermal delivery of therapeutic agents. More particularly, the disclosed transdermal compositions may include a fatty alcohol (for example, octanol), a terpene (for example, limonene), and an active agent comprising an amine moiety.
Type: Application
Filed: November 15, 2011
Publication date: December 19, 2013
Applicant: Neuroderm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas, Eduardo Zawozink
Continuous Administration of Levodopa and/or Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20130253056
Abstract: Disclosed herein are for example, liquid aqueous compositions that include for example an ester or salt of levodopa, or an ester or salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome, dystonia, and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of levodopa and/or carbidopa or ester and/or salt thereof.
Type: Application
Filed: March 12, 2013
Publication date: September 26, 2013
Applicant: Neuroderm, Ltd.
Inventors: Mara Nemas, Oron Yacoby-Zeevi
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 8193243
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: May 17, 2010
Date of Patent: June 5, 2012
Assignee: Neuroderm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20110269833
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: December 7, 2010
Publication date: November 3, 2011
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous administration of dopa decarboxylase inhibitors and compositions for same
Patent number: 7863336
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Grant
Filed: July 14, 2010
Date of Patent: January 4, 2011
Assignee: Neuroderm, Ltd.
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20100298429
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: July 14, 2010
Publication date: November 25, 2010
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Continuous Administration of Dopa Decarboxylase Inhibitors and Compositions for Same
Publication number: 20100298428
Abstract: Disclosed herein are compositions that include for example the arginine salt of carbidopa, and methods for treating neurological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, PSP, MSA, ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, using substantially continuous administration of carbidopa or salt thereof together with administration of levodopa.
Type: Application
Filed: May 17, 2010
Publication date: November 25, 2010
Inventors: Oron Yacoby-Zeevi, Mara Nemas
Heparanase activity neutralizing anti-heparanase monclonal antibody and other anti-heparanase antibodies
Publication number: 20060269552
Abstract: Specific anti-heparanase antibodies which bind specifically to heparanase having sequence homology to human heparanase, which can be used to treat and diagnose conditions associated with heparanase catalytic activity, for purification of heparanase, and for drug development in heparanase associated conditions are disclosed.
Type: Application
Filed: June 3, 2004
Publication date: November 30, 2006
Inventors: Oron Yacoby-Zeevi, Tuvia Peretz, Daphna Miron, Yinon Shlomi, Iris Pecker, Maty Ayal-Hershkovitz
Methods of and pharmaceutical compositions for improving implantation of embryos
Publication number: 20060008892
Abstract: Methods of improving embryo implantation are disclosed and comprise contacting a receptive uterus and/or an embryo with an effective amount of heparanase and implanting the embryo in the receptive uterus.
Type: Application
Filed: June 17, 2005
Publication date: January 12, 2006
Applicant: Insight Strategy & Marketing Ltd.
Inventor: Oron Yacoby-Zeevi
Therapeutic and cosmetic uses of heparanases
Publication number: 20050260187
Abstract: Methods and compositions for inducing and/or accelerating wound healing and/or angiogenesis via the catalytic activity of heparanase are disclosed.
Type: Application
Filed: April 15, 2005
Publication date: November 24, 2005
Inventors: Neta Ilan, Israel Vlodavsky, Oron Yacoby-Zeevi, Iris Pecker, Elena Feinstein
Heparanase activity neutralizing anti-heparanase monoclonal antibody and other anti-heparanase antibodies
Publication number: 20040213789
Abstract: Specific anti-heparanase antibodies which bind specifically to heparanase having sequence homology to human heparanase, which can be used to treat and diagnose conditions associated with heparanase catalytic activity, for purification of heparanase, and for drug development in heparanase associated conditions are disclosed.
Type: Application
Filed: August 22, 2003
Publication date: October 28, 2004
Inventors: Oron Yacoby-Zeevi, Tuvia Peretz, Daphna Miron, Yinon Shlomi, Iris Pecker, Maty Ayal-Hershkovitz, Elena Feinstein, Joel M. Van Gelder, Israel Vlodavsky, Yael Friedmann
Introducing a biological material into a patient
Publication number: 20040175371
Abstract: A biological preparation is provided and includes a biological material and a purified, natural or recombinant, extracellular matrix degrading enzyme being externally adhered thereto.
Type: Application
Filed: March 15, 2004
Publication date: September 9, 2004
Inventor: Oron Yacoby-Zeevi
Heparanase activity neutralizing anti-heparanase monoclonal antibody and other anti-heparanase antibodies
Publication number: 20040170631
Abstract: Specific anti-heparanase antibodies which bind specifically to heparanase having sequence homology to human heparanase, which can be used to treat and diagnose conditions associated with heparanase catalytic activity, for purification of heparanase, and for drug development in heparanase associated conditions are disclosed.
Type: Application
Filed: November 28, 2003
Publication date: September 2, 2004
Inventors: Oron Yacoby-Zeevi, Tuvia Peretz, Daphna Miron, Yinon Shlomi, Iris Pecker, Maty Ayal-Hershkovitz, Elena Feinstein, Joel M. Van Gelder, Israel Vlodavsky, Yael Friedmann
Therapeutic and cosmetic uses of heparanases
Publication number: 20040146497
Abstract: Methods and compositions for inducing and/or accelerating wound healing and/or angiogenesis via the catalytic activity of heparanase are disclosed.
Type: Application
Filed: February 20, 2004
Publication date: July 29, 2004
Inventors: Neta Ilan, Israel Vlodavsky, Oron Yacoby-Zeevi, Iris Pecker, Elena Feinstein
Methods and kits utilizing heparanase as a diagnostic marker for haemostatic disorders
Publication number: 20040132123
Abstract: Provided is a method of determining a presence, absence, or severity of a haemostatic disorder in a subject. The method is effected by determining a level of heparanase expression or activity in a biological sample obtained from the subject. Also provided are kits for use with the method.
Type: Application
Filed: October 23, 2003
Publication date: July 8, 2004
Inventor: Oron Yacoby-Zeevi
Use of ecm degrading enzymes for the improvement of cell transplantation
Publication number: 20040033218
Abstract: Cell preparations which comprise cells carrying an extracellular matrix degrading enzyme and methods of using such cell preparations for improving transplantation efficiency of such cells.
Type: Application
Filed: June 12, 2003
Publication date: February 19, 2004
Inventor: Oron Yacoby-Zeevi
Therapeutic and cosmetic uses of heparanases
Publication number: 20030161823
Abstract: Methods and compositions for inducing and/or accelerating wound healing and/or angiogenesis via the catalytic activity of heparanase are disclosed.
Type: Application
Filed: January 14, 2003
Publication date: August 28, 2003
Inventors: Neta Ilan, Israel Vlodavsky, Oron Yacoby-Zeevi, Iris Pecker, Elena Feinstein
Genetically modified cells and methods for expressing recombinant heparanase and methods of purifying same
Publication number: 20030068806
Abstract: A method of purifying a recombinant heparanase from overexpressing cells or growth medium which comprises adsorbing said recombinant heparanase on an ion-exchange column under low salt conditions, washing said column with low salt solution thereby eluting other proteins, and eluting the recombinant heparanase from said column by a salt gradient or higher salt concentration.
Type: Application
Filed: May 3, 2002
Publication date: April 10, 2003
Inventors: Maty Ayal-Hershkovitz, Iris Pecker, Oron Yacoby-Zeevi
Method of inducing bone formation
Publication number: 20030031660
Abstract: A method of inducing bone formation in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of heparanase. A pharmaceutical composition for inducing bone formation in a subject in need thereof, the pharmaceutical composition comprises, as an active ingredient, a therapeutically effective amount of heparanase, and a pharmaceutically acceptable carrier.
Type: Application
Filed: June 7, 2002
Publication date: February 13, 2003
Applicant: Insight Strategy & Marketing Ltd.
Inventor: Oron Yacoby-Zeevi
Genetically modified cells and methods for expressing recombinant heparanase and methods of purifying same
Patent number: 6475763
Abstract: Bacterial, yeast and animal cells and methods for overexpressing recombinant heparanase in cellular systems, methods of purifying recombinant heparanase therefrom and modified heparanase species which serve as precursors for generating highly active heparanase by proteolysis.
Type: Grant
Filed: January 19, 2000
Date of Patent: November 5, 2002
Assignee: Insight Strategy & Marketing Ltd.
Inventors: Maty Ayal-Hershkovitz, Haim Moskowitz, Daphna Miron, Ayelet Gilboa, Madlene Mimon, Hanna Ben-Artzi, Oron Yacoby-Zeevi, Iris Pecker, Yoav Peleg, Yinon Shlomi
Genetically modified cells and methods for expressing recombinant heparanase and methods of purifying same
Patent number: 6426209
Abstract: A preparation containing an enzymatically inactive form of heparanase, said enzymatically inactive form of heparanase being cleavable into an enzimatically active form of heparanase.
Type: Grant
Filed: August 10, 2000
Date of Patent: July 30, 2002
Assignee: Insight Strategy Marketing Ltd.
Inventors: Maty Ayal-Hershkovitz, Iris Pecker, Oron Yacoby-Zeevi
Compositions including glycosaminoglycans degrading enzymes and use of same against surface protected bacteria
Patent number: 6423312
Abstract: A method of rendering a surface protected bacteria more susceptible to an anti-bacterial agent effected by subjecting the bacteria to a glycosaminoglycans degrading enzyme.
Type: Grant
Filed: August 27, 1998
Date of Patent: July 23, 2002
Assignee: Insight Strategy & Marketing Ltd.
Inventor: Oron Yacoby-Zeevi
Methods of and pharmaceutical compositions for improving implantation of embryos
Publication number: 20020088019
Abstract: Methods of improving embryo implantation are disclosed and comprise contacting a receptive uterus and/or an embryo with an effective amount of heparanase and implanting the embryo in the receptive uterus.
Type: Application
Filed: October 17, 2001
Publication date: July 4, 2002
Inventor: Oron Yacoby-Zeevi
Therapeutic and cosmetic uses of heparanases
Publication number: 20020068054
Abstract: Methods and compositions for inducing and/or accelerating wound healing and/or angiogenesis via the catalytic activity of heparanase are disclosed.
Type: Application
Filed: December 4, 2000
Publication date: June 6, 2002
Applicant: Insight Strategy & Marketing Ltd. and Hadasit Medical Research Services and Development Ltd.
Inventors: Neta Ilan, Israel Vlodavsky, Oron Yacoby-Zeevi, Iris Pecker
COMPOSITIONS INCLUDING GLYCOSAMINOGLYCANS DEGRADING ENZYMES AND USE OF SAME AGAINST SURFACE PROTECTED BACTERIA
Publication number: 20020064858
Abstract: A method of rendering a surface protected bacteria more susceptible to an anti-bacterial agent effected by subjecting the bacteria to a glycosaminoglycans degrading enzyme.
Type: Application
Filed: August 27, 1998
Publication date: May 30, 2002
Inventor: ORON YACOBY-ZEEVI
Genetically modified cells and methods for expressing recombinant heparanase and methods of purifying same
Patent number: 6348344
Abstract: Bacterial, yeast and animal cells and methods for overexpressing recombinant heparanase in cellular systems, methods of purifying recombinant heparanase therefrom and modified heparanase species which serve as precursors for generating highly active heparanase by proteolysis.
Type: Grant
Filed: March 2, 1999
Date of Patent: February 19, 2002
Assignee: Insight Strategy & Marketing Ltd.
Inventors: Maty Ayal-Hershkovitz, Haim Moskowitz, Daphna Miron, Ayelet Gilboa, Madelene Mimon, Hanna Ben-Artzi, Oron Yacoby-Zeevi, Iris Pecker, Yoav Peleg, Yinon Schlomi
INTRODUCING A BIOLOGICAL MATERIAL INTO A PATIENT
Publication number: 20010006630
Abstract: A biological preparation is provided and includes a biological material and a purified, natural or recombinant, extracellular matrix degrading enzyme being externally adhered thereto.
Type: Application
Filed: March 2, 1999
Publication date: July 5, 2001
Inventor: ORON YACOBY-ZEEVI
Use of glycosaminoglycans degrading enzymes for management of airway associated diseases
Patent number: 6153187
Abstract: A method of managing a patient having an accumulation of mucoid, mucopurulent or purulent material containing glycosaminoglycans, the method comprising the step of administering at least one glycosaminoglycans degrading enzyme to the patient in an amount therapeutically effective to reduce at least one of the following: the visco-elasticity of the material, pathogens infectivity and inflammation. An article of manufacture comprising an inhaler including, as an active ingredient, at least one glycosaminoglycans degrading enzyme for generating aerosols including the enzyme for management a patient having an accumulation of mucoid, mucopurulent or purulent material containing glycosaminoglycans.
Type: Grant
Filed: March 25, 1998
Date of Patent: November 28, 2000
Assignee: Insight Strategy & Marketing Ltd.
Inventor: Oron Yacoby-Zeevi
Meet The Top 10 Most Influential Israelis In International Business, Science, and Culture in 2017
By Simona Shemer, NoCamels December 28, 2017
The Scientist: Dr. Oron Yacoby-Zeevi
Neuroderm Chief Scientist Officer Dr. Oron Yacoby-Zeevi may seem rather unassuming when compared to some of the other game-changers on this list, but there’s a very good reason she joins the other nine candidates. Israel’s Neuroderm, a clinical-stage pharmaceutical firm developing next-generation treatments for disorders of the central nervous system, was sold to Mitsubishi Tanabe Pharma for $1.1 billion in what is said to be Israel’s largest Pharma exit earlier this year. Yacoby-Zeevi, according to a report in Globes, had a hand in that exit, at least in part, because she is responsible for the company’s technological solution. NeuroDerm has developed a liquid version of a drug already in existence to treat Parkinson’s Disease. This groundbreaking achievement will certainly improve the lives of patients around the world who suffer from the disease, while also generating profits for the company.
source link:
http://nocamels.com/2017/12/influential-israelis-business-culture/
$OWCP
I have some really bad news - You are totally making that up.
If she was fired or dismissed as you say, then provide proof.
"Israeli company NeuroDerm was sold to Mitsubishi Tanabe Pharma for $1.1 billion in the largest-ever Israeli pharma exit. NeuroDerm has two important characteristics that enabled it to become a unicorn - a company with a value of over $1 billion. The first is a smoothly running management team that graduated from the Ofakim incubator in 2006, but which managed NeuroDerm like a large company, even when it had only a few employees.
The second element is the company's technological solution, for which chief science officer Oron Yacoby-Zeevi is responsible."
Read the whole article here:
http://en.globes.co.il/en/article-israeli-pharma-co-neuroderm-sold-for-11b-1001198365
How we achieved Israel's biggest-ever pharma exit
by Gali Weinreb, 7 Aug, 2017
CSO Dr. Oron Yacoby-Zeevi tells about the day Neuroderm almost closed down, and how Israeli venture capital funds missed the opportunity to invest.
Israeli company NeuroDerm was sold to Mitsubishi Tanabe Pharma for $1.1 billion in the largest-ever Israeli pharma exit. NeuroDerm has two important characteristics that enabled it to become a unicorn - a company with a value of over $1 billion. The first is a smoothly running management team that graduated from the Ofakim incubator in 2006, but which managed NeuroDerm like a large company, even when it had only a few employees.
The second element is the company's technological solution, for which chief science officer Oron Yacoby-Zeevi is responsible. NeuroDerm has developed a liquid formulation of an existing drug for the treatment of Parkinson's Disease. This breakthrough improves the lives of patients with the disease, while at the same time generating revenue for the company. Many companies have tried and failed to develop similar technology.
Yacoby-Zeevi tells "Globes" about the search for this liquid formulation, the unsuccessful trial that almost made the company close down, and the investors in Israel who almost completely missed the boat with NeuroDerm.
Yacoby-Zeevi, originally a veterinarian, has PhDs in microbiology and immunology. Before she was hired by NeuroDerm, she was R&D manager at InSight Biopharmaceuticals, which manufactures drugs, mainly generic ones, and chief scientist at Harlan Biotech, which provides development and pre-clinical trials services for pharma companies. "I came to NeuroDerm in 2008," she says, "after the company finished its period in the Ofakim incubator. I reached a watershed after leaving Harlan. On the one hand, I was contacted by NeuroDerm, while on the other hand, I had an offer to return to InSight. I chose to go back to InSight, but within 10 days, I saw that it was a mistake. I decided to resign and embark on an adventure with NeuroDerm.
"When I got to NeuroDerm, (CEO) Oded (Lieberman, G.W.) explained that the goal was to reach a fixed level of the Levodopa drug in the bloodstream in order to maximize the drug's effectiveness for patients with Parkinson's Disease, with as few side effects as possible, thereby greatly improving the quality of their lives. The patent is a method of administering the drug through the skin. What is involved is not the drug itself; it is a material that breaks down and turns into this drug when it reaches the bloodstream.
"When I arrived, the company had already conducted a small clinical trial that showed that the drug could be administered through the skin. The transition, however, caused real damage to the skin. For months, we developed other materials that break down into Levodopa in the bloodstream. We devised formulations of these materials, and tested their effect on the skin. After months of intensive work, we concluded that it was impossible to administer so much material through the skin without damaging it."
Yacoby-Zeevi presented the situation at a meeting she remembers as being dramatic. "NeuroDerm had 12 employees at that point. Ostensibly, we had a product at the clinical stage (human trials, G.W.), and all of sudden, the product didn't work."
Lieberman instructed Yacoby-Zeevi to try a different approach. In retrospect, she discovered that on that same day, Lieberman had met with the major investors in NeuroDerm, Robert Taub and Uwe Wascher, and told them that the company would have to close down. The investors and the CEO decided that NeuroDerm would become another entry on the list of scientific failures and would be shut down. Since the company still had a small amount of cash, it was decided to briefly delay closing the company down, and give the R&D team a chance to look for a new solution.
Yacoby-Zeevi says that she did not completely realize at the time how grave the situation was. "Oded constantly told me, 'Do what you do best, and I'll take care of the money'," she says. At the same time, both she and the other employees realized that NeuroDerm had turned from a company with one product into a company with no products. "For me, it was never the end of the story," she remembers. "In the R&D team, we said, 'If one way doesn't work, we'll think of another way. That's how we got the idea of delivering the material into the bloodstream using a pump. No company was working on such a product at the time."
"People aren't pigs"
The Levodopa drug was replaced by a drug that delays the breakdown of Levodopa in the body (Carbidopa) administered simultaneously with oral Levodopa. "With this product, we got amazing results without any damage to the skin. It was our first breakthrough," Yacoby-Zeevi says. The effect on animals was stunning, and then human trials began, where the effect was significantly smaller. "It seems that people are not pigs, after all," she says.
At this stage, the company stood at a crossroads. One possibility was to develop the combined product - oral Levodopa and Carbidopa with a pump. This alternative was relatively safe, but the change it could have made in the lives of Parkinson's patients was fairly limited. The second option, which involved a bigger risk, was to develop an integrated product administering both materials through the skin. The question was whether the Levodopa could be administered without causing damage.
"We thought at first that we wouldn't manage to solve the problem of administering Levodopa through the skin, and even if we succeeded, there might be severe side effects in the skin in the area of the infusion, so it was worthwhile to remain with a combination of Carbidopa and oral Levodopa - a bird in the hand. In opposition to the majority opinion in the company, and despite the many resources required, Oded decided to examine both options simultaneously - on the one hand to bring the Carbidopa product to clinical trials as a backup, while on the other hand developing the combined product, and as soon as its feasibility was proven, to abandon the Carbidopa product. That's what eventually happened. We succeeded in developing the combined product that delivers both Carbidopa and Levodopa directly into the bloodstream. The Carbidopa product that depended on giving oral Levodopa was abandoned."
The combined product causes fewer side effects in the skin in the area in which the needle is inserted than a product based solely on Levodopa. "We hypothesize that there will be patients for whom it will be unsuitable, just like any other drug, but we truly believe that for most patients, it will be the solution that they have hoped for and looked forward to - a game-changing solution that will change the way of treating the disease."
"Oded hurried to raise money"
Like most startups, NeuroDerm also suffered from a lack of cash. Yacoby-Zeevi says, "Only later did I learn that the company several times reached a situation in which it was not clear that it would be able to pay salaries. We scientists didn't know about it. Management wanted to protect us and keep us free for our work. We did see, however, that Oded went running all over looking for money every summer, instead of going on vacation."
Most of the investors were from Europe, and most were private investors who heard about the company from Robert Taub and Uwe Wascher, or through the connections with Lieberman, who previously worked in Europe. The sole significant Israeli investor was Prof. Shmuel Cabilly, an angel investor in many biomed companies.
Yacoby-Zeevi says, "Other than Robert Taub, most of our investors are non-Jews having no previous connection with Israel. Today, they say that a miracle happened for them in Israel, because it's one of their best-ever investments. In the financing round before the offering, a South Korean fund came in for which it was the first investment in Israel, and they made back their money six times over in less than two years. We also got support from the Chief Scientist and the Michael J. Fox Foundation for Parkinson's Research. Venture capital funds, on the other hand, didn't want to invest, especially the Israeli ones."
"Globes": What did they say?
Yacoby-Zeevi: "Not long ago, I heard Oded laugh about one of the potential investors telling him that the company had 'no exit strategy'."
"A bad period"
NeuroDerm tried to become a public company in 2010 through an IPO on the Tel Aviv Stock Exchange (TASE). One month before the offering, the company decided to call it off, a decision that in retrospect appears to have been wise. Although investment concerns in Israel did not understand NeuroDerm's potential, Capital Point Ltd. (TASE:CPTP), which became the franchise holder for the Ofakim incubator after NeuroDerm was founded, and obtained the incubator's shares in NeuroDerm, was the second significant Israeli shareholder in NeuroDerm. Since Capital Point is listed on the TASE, the Israeli public was able to invest indirectly in NeuroDerm by investing in Capital Point. Capital Point sold most of its holdings in NeuroDerm in 2016, and therefore did not benefit from the big exit, but nevertheless distributed a substantial dividend to its investors.
Four years after calling off its TASE IPO, NeuroDerm decided to try its luck on Nasdaq. More than 10 Israeli drug development companies held IPOs in 2014. "We came in at the end of that wave. It was a bad time for an offering. There was a problem with our bankers, who left two days before the offering (due to corruption and sex scandals, G.W.), and Israeli companies encountered various difficulties," Yacoby-Zeevi explains. The NeuroDerm IPO was held at a lower price and company value than that sought by the company, and the share lost 50% of its value in the first 45 days, as happened to most of the Israeli companies that held IPOs at the time.
In the final week of 2014, the company benefited from a positive coincidence, luck or good karma. NeuroDerm undertook to publish the results of its first clinical trial by the end of the year, but the results were delayed, and arrived on December 30, in the middle of the holiday season. The bankers funding the company claimed that there was no point in publishing the results - everyone was on vacation, and no one would see them.
Yacoby-Zeevi remembers, "It was important to Oded to keep his promise, so it was decided to publish the results during the vacation. So they were published on a day on which there was very little news, and they attracted a great deal of attention." The company doubled its market cap in a single day on a huge trading volume, and this fact attracted interest from investment concerns on Nasdaq that do not generally invest in small companies or health companies. In a single day, almost by chance, NeuroDerm made it to the big leagues.
The investors exposed to the company realized the product's advantages. On the one hand, the product had less regulatory risk. The drug was known, the trials showed that it could pass through the skin, and the chances of the company's trials being a colossal failure, which could happen with a new drug, were small.
On the other hand, the product was very promising - perhaps not as much as a completely new drug, but the company's formulation was patent-protected, just like a drug. The company had a real technological risk at the beginning, when the product did not work at all, but by the time it reached Nasdaq, the risk had been substantially reduced. In addition, during the time following the IPO, a surgical procedure was introduced designed to put Levodopa directly into the bloodstream - a treatment not linked to the company.
When the market discovered that NeuroDerm could replace an operation with a non-invasive pump, the share climbed again. "Some of the patients will be able to postpone the procedure for several years, while others will not need it at all," Yacoby-Zeevi says. NeuroDerm is currently conducting one trial in the US and another in Europe, so its product is not risk-free, but the investors in the company will soon receive the acquisition proceeds, and their exit is already guaranteed.
Did the IPO change NeuroDerm's organizational culture? All of a sudden, you had money.
"The company grew from 18 to 80 employees, and we moved to new offices, but we remained - I won't say modest, but we didn't start excessive spending. We did have expensive clinical trials facing us. My feeling is that despite the big changes, we preserved the organizational culture."
From 2008 until just before the IPO in 2014, a dozen employees worked at the company with almost no change. Yacoby-Zeevi managed half of them, and the rest worked in management, including Lieberman, COO Alon Yaar (Tami Yardeni currently fills this position), chemistry, manufacturing, and controls head Dr. Sharon Cohen-Vered, and CMO Dr. Sheila Oren.
"All of these people joined after the company had conducted only one small clinical trial. Most companies do not recruit managers in these areas at those stages, but already at that stage, Oded regarded NeuroDerm not as a startup, but as a small pharma company. He used to say that companies that do not take production, quality, and clinical trials into account at the R&D stage pay a heavy price later on. He also hired only people with experience," Yacoby-Zeevi says.
Explaining the importance of an experienced team at the company's initial stages, Yacoby-Zeevi says, "Because we had an experienced production manager (Cohen-Vered) already at the formulation development stage, there was no problem in replacing an element in the formulation with a better-known element. That saved us a lot of work.
"The company actually worked according to the book from the first day, both when we were in a state of economic strangulation and when things were less acute. The trials were well-ordered, with no shortcuts. Documentation was precise, production was at the best sites, and all communications were in English."
What are you doing now? Your important job ostensibly ended after you prepared the formulation.
"We went on improving the formulation between the trials. There were several changes along the way that made it exceptionally stable, and also made patent protection longer. The patents were all ours - NeuroDerm homemade. Today, we provide support for production and the integration between the formulation and the pump."
The IPO and the acquisition are amazing events, but this is also the end of NeuroDerm in its familiar format. Realizing a dream ends it.
"NeuroDerm brought me to completely new places. Inventing ideas, solving chemical problems, and writing patents is what I know, but bringing something to market that's real and useful to patients is the first time for me, and that's very exciting. I have many more ideas on paper. I only wish that the same thing happens with them.
"My hope for the company was for it to be acquired, mainly for the product, because an international marketer is the right entity to bring this product to the market in a way that maximizes its success potential. There's no doubt that the company has topnotch personnel able to operate well as a team. This is now one of the biggest and best budgeted groups around, and certainly the most experienced, working on Parkinson's Disease. Even in giant corporations, the group working on Parkinson's Disease is not necessarily larger. We don't know what will happen now."
The employee who joined at age 70 and died before the exit
One of the factors that contributed to NeuroDerm's success was the decision to look for experienced employees. One of the employees hired was Mara Nemas, who was 70 years old at the time.
Nemas worked many years at the company, and died a few months before the exit. "Mara was one of the most amazing chemists I have ever met," Yacoby-Zeevi says. "This formulation wouldn't have existed without her.
"When Mara arrived, she was working here part-time, then full-time. Then she got cancer, and when she recovered, she went back to work here two days a week, but even on this limited schedule, she contributed so much to us. Even when the cancer recurred, and up until the very final stage, including in her final weeks, she constantly read and thought and advised us. She was there in order to help us."
Yacoby-Zeevi adds, "We all shared a great love for Mara. She always thought about everyone, with something small and personal to give them. She was always smiling and enthusiastic about work, although she didn't have an easy life.
"She loved to do things with her own hands. She didn't give things to other people to do; she wanted to feel the work."
$OWCP looking real good!
We have such a strong team.
Awesome to see the OWCP website updated with Dr. Oron Yacoby Zeevi on there.
http://www.owcpharma.com/our-leadership-team/
$OWCP is looking good
Your calculations are WAY OFF. Do you know what a warrant is?
IGLOW wrote:
"Add in Newbridge where they received 2.5 million shares plus $375,000.
So OWCP paid ($575,000 + $375,000) + $10,925,000 = $11,875,000"
On page 1 of Form 424B3 in the Prospectus Summary it makes it very clear that Newbridge did NOT receive "2.5 million shares plus $375,000" as you claim.
THIS IS WHAT IT ACTUALLY SAYS IN TH ACTUAL DOCUMENT about what Newbridge received
"Newbridge Securities Corporation (“Newbridge”), through LifeTech Capital, acted as exclusive placement agent for the transaction and we paid Newbridge a cash fee of $375,000 and issued to them warrants to purchase 2.5 million shares of our common stock at an exercise price of $0.20 per share."
I will explain it for you
Q: What is a 'Warrant'?
A: A warrant is a security that entitles the holder to buy the underlying stock of the issuing company at a fixed price called exercise price until the expiry date.
Newbridge is issued warrants to purchase 2.5 million shares of OWCP common stock at an exercise price of $0.20 per share. What this means is that if they exercise the warrants, then OWCP will receive $500,000. This will make the $375,000 cash fee a wash with OWCP still having $125,000 to cover the warrants solicitation fee equal to 4% of the gross proceeds that OWCP will receive upon cash exercise of the Warrants.
This means that if Newbridge exercises the warrants to purchase 2.5 million shares of OWCP common stock from OWCP at an exercise price of $0.20 per share, then OWCP would end up having paid Newbridge ONLY 2.5 million shares of common stock, AND ZERO CASH. In fact OWCP will end up with $105,000.
2.5 million shares X .20 = $500,000 (Money paid to OWCP upon exercise of warrants)
So now that it is understood that it is OWCP that is receiving the .20/share and it is Newbridge that is paying the .20/share upon exercising the Warrants, let's finish calculating how this works out.
+$500,000 Proceeds paid to OWCP by Newbridge
-$375,000 Cash fee paid to Newbridge by OWCP
——————————————————————————————————
+$125,000 Remaining proceeds that were paid to OWCP from the Warrants
——————————————————————————————————
-$20,000 4% fee of the gross proceeds that OWCP will receive upon cash exercise of the Warrants
——————————————————————————————————
+$105,000 Remaining proceeds paid to OWCP by Newbridge (after Newbridge exercises Warrants)
So if Newbridge exercises the Warrants then their services would have cost OWCP
2.5 million shares of common stock; and actually OWCP will come out with $105,000 cash in addition to their services.
That's not a bad deal at all.
Here is the part I quoted in context in the Prospectus Summary:
PROSPECTUS SUMMARY
This summary highlights selected information contained elsewhere in this prospectus and does not contain all of the information that you should consider in making your investment decision. Before investing in our common stock, you should carefully read this entire prospectus, including our financial statements and the related notes thereto and the information set forth under the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of this prospectus.
Overview
We are an early stage medical cannabis research and development company that applies conventional pharmaceutical research protocols and disciplines to the field of medical cannabis with the objective of establishing a leadership position in the research and development of medical cannabis therapies, products and delivery technologies. We are currently engaged in the research and development and have conducted trials on the efficacy of cannabis-based medical products (the “Cannabis-Based Medical Products”) commencing with our cannabis-based topical ointment for the treatment of psoriasis. In addition, we also are pursuing the use of our Cannabis-Based Medical Products for the treatment of multiple myeloma, post-traumatic stress disorder (“PTSD”), chronic pain and fibromyalgia, and have made significant advancements in the development of a cannabis soluble tablet delivery system that could have applications for other indications. We are also capable of providing consulting and advisory services to governmental and private entities to assist them with developing and implementing tailor-made, comprehensive medical cannabis programs, although we have not generated any revenues from such services to date.
We have been engaged in research and development and consulting and advisory activities through our wholly-owned Israeli subsidiary, One World Cannabis Ltd., since July 2014. To date, we have entered into binding agreements with major hospitals and medical research facilities in Israel for the purpose of conducting research studies and trials related to the development and use of Cannabis-Based Medical Products for the treatment of multiple myeloma, psoriasis, PTSD, chronic pain and fibromyalgia, and for the development of a cannabis soluble tablet delivery system.
In February 2017, we announced promising pre-clinical results from the testing of our cannabis-based topical ointment for the treatment of psoriasis, an autoimmune disease that causes red, scaly patches to appear on the skin. Skin cells in patients with psoriasis grow at an abnormally fast rate, causing a buildup of lesions that tend to burn and itch. While the real cause of psoriasis is not known, genetics are believed to play a major role in its development. According to the American Academy of Dermatology, psoriasis affects approximately 3% of the world’s population and 7.5 million people in the United States.
Recent Developments
April 2018 Private Placement
On April 30, 2018, we entered into and consummated a Securities Purchase Agreement (the “Purchase Agreement”) with a non-US-based institutional investor (the “Investor”). Under the terms and conditions of the Purchase Agreement, we sold and the Investor bought, (i) 500 shares of our new series of preferred stock designated as Series A Preferred Stock (the “Series A Preferred Shares”), which, as of April 30, 2018, were convertible into 25,000,000 shares of our common stock at a conversion price of $0.20 per share, subject to adjustment pursuant to the anti-dilution provisions of the Preferred Shares, and (ii) warrants representing the right to acquire 12,500,000 shares of our common stock at an exercise price of $0.22 per share (the “Warrants”), subject to adjustment pursuant to the anti-dilution provisions of the Warrants, for an aggregate purchase price of $5,000,000. Newbridge Securities Corporation (“Newbridge”), through LifeTech Capital, acted as exclusive placement agent for the transaction and we paid Newbridge a cash fee of $375,000 and issued to them warrants to purchase 2.5 million shares of our common stock at an exercise price of $0.20 per share. The Warrants contain customary terms, including provisions for “cashless” exercise, change of control, price based anti-dilution, and customary demand or piggyback registration rights. In addition, we are obligated to pay Newbridge a warrants solicitation fee equal to 4% of the gross proceeds that we receive upon cash exercise of the Warrants.
The terms of the Preferred Shares contain conditional redemption provisions and a deemed liquidation preference feature. In addition, the terms of each of the Preferred Shares and Warrants provide for anti-dilution protection for issuances of shares of our common stock at a price per share less than a price equal to the conversion price or exercise price, as applicable and, that in the event of a “fundamental transaction” (as described in the Warrants), the Investor will have the right to receive the value of the Warrants as determined in accordance with the Black Scholes option pricing model.
In connection with the Purchase Agreement, we entered into a Registration Rights Agreement (the “Registration Rights Agreement”) with the Investor, pursuant to which, among other things, we have agreed to use our commercially reasonable best efforts to (i) prepare and file with the SEC within 60 calendar days of the offering a registration statement covering the shares of common stock underlying the Preferred Shares and Warrants and (ii) have the registration statement and any amendment thereto to be declared effective by the SEC within 90 calendar days from the date of the initial filing of such registration statement.
Our Study on Psoriasis
On June 28, 2018, we announced the successful completion of the first part of our Phase I, placebo controlled, maximal dose study (the “Psoriasis Study”) to determine the safety and tolerability of topical ointment containing medical grade cannabis (the “Topical Ointment”) in healthy volunteers. The completed part of our Psoriasis Study consisted of application of escalating doses of the Topical Ointment to healthy volunteers and was successfully completed with no adverse effects. After the completion of the second part of our Psoriasis Study, we plan to initiate a Phase II study to demonstrate the efficacy of the Topical Ointment in treating mild to moderate psoriasis and other inflammatory skin diseases.
1
——————————————————————
As for dilution, startup companies on OTC and big board markets have some dilution as they increase their Outstanding Shares. OWCP has a track record of NOT diluting. You can try to argue it all day but the very small increase in OS during the last 18 months clearly shows that OWCP management values their shares greatly and OWC management are also shareholders of OWCP common stock. There will be some dilution, OWCP doesn't receive $5 Million for nothing.
We are funded and the research and patent work is moving forward making progress.
$OWCP is looking good
“Safe Harbor" and "forward-looking" statements are extremely common and all legit companies include them in their releases.
In short, it means that you are investing in a stock and there are risk involved and no guarantees in life.
They all have these “Safe Harbor" and "forward-looking" statements, wether it's AAPL, NFLX, GPRO, IBM, or OWCP.
Here's one from Apple (AAPL) from the first release I quickly pulled up
PRESS RELEASE
MAY 1, 2018
Apple Reports Second Quarter Results
...
This press release contains forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include without limitation those about the Company’s estimated revenue, gross margin, operating expenses, other income/(expense), tax rate, and plans for return of capital. These statements involve risks and uncertainties, and actual results may differ. Risks and uncertainties include without limitation: the effect of global and regional economic conditions on the Company's business, including effects on purchasing decisions by consumers and businesses; the ability of the Company to compete in markets that are highly competitive and subject to rapid technological change; the ability of the Company to manage frequent product introductions and transitions, including delivering to the marketplace, and stimulating customer demand for, new products, services and technological innovations on a timely basis; the effect that product introductions and transitions, changes in product pricing and product mix, and increases in component and other costs could have on the Company’s gross margin; the dependency of the Company on the performance of distributors of the Company's products, including cellular network carriers and other resellers; the inventory and other asset risks associated with the Company’s need to order, or commit to order, product components in advance of customer orders; the continued availability on acceptable terms, or at all, of certain components, services and new technologies essential to the Company's business, including components and technologies that may only be available from sole or limited sources; the dependency of the Company on manufacturing and logistics services provided by third parties, many of which are located outside of the US and which may affect the quality, quantity or cost of products manufactured or services rendered to the Company; the effect of product and service quality problems on the Company’s financial performance and reputation; the dependency of the Company on third-party intellectual property and digital content, which may not be available to the Company on commercially reasonable terms or at all; the dependency of the Company on support from third-party software developers to develop and maintain software applications and services for the Company’s products; the impact of unfavorable legal proceedings, such as a potential finding that the Company has infringed on the intellectual property rights of others; the impact of changes to laws and regulations that affect the Company’s activities, including the Company’s ability to offer products or services to customers in different regions; the ability of the Company to manage risks associated with its international activities, including complying with laws and regulations affecting the Company’s international operations; the ability of the Company to manage risks associated with the Company’s retail stores; the ability of the Company to manage risks associated with the Company’s investments in new business strategies and acquisitions; the impact on the Company's business and reputation from information technology system failures, network disruptions or losses or unauthorized access to, or release of, confidential information; the ability of the Company to comply with laws and regulations regarding data protection; the continued service and availability of key executives and employees; war, terrorism, public health issues, natural disasters, and other business interruptions that could disrupt supply or delivery of, or demand for, the Company’s products; financial risks, including risks relating to currency fluctuations, credit risks and fluctuations in the market value of the Company’s investment portfolio; and changes in tax rates and exposure to additional tax liabilities. More information on these risks and other potential factors that could affect the Company’s financial results is included in the Company’s filings with the SEC, including in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of the Company’s most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings. The Company assumes no obligation to update any forward-looking statements or information, which speak as of their respective dates.
LOL... It's a direct quote from page 1 of Form 424B3.
IGLOW wrote:
"That isn't close to being accurate"
Here is the entire Prospectus Summary:
PROSPECTUS SUMMARY
This summary highlights selected information contained elsewhere in this prospectus and does not contain all of the information that you should consider in making your investment decision. Before investing in our common stock, you should carefully read this entire prospectus, including our financial statements and the related notes thereto and the information set forth under the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of this prospectus.
Overview
We are an early stage medical cannabis research and development company that applies conventional pharmaceutical research protocols and disciplines to the field of medical cannabis with the objective of establishing a leadership position in the research and development of medical cannabis therapies, products and delivery technologies. We are currently engaged in the research and development and have conducted trials on the efficacy of cannabis-based medical products (the “Cannabis-Based Medical Products”) commencing with our cannabis-based topical ointment for the treatment of psoriasis. In addition, we also are pursuing the use of our Cannabis-Based Medical Products for the treatment of multiple myeloma, post-traumatic stress disorder (“PTSD”), chronic pain and fibromyalgia, and have made significant advancements in the development of a cannabis soluble tablet delivery system that could have applications for other indications. We are also capable of providing consulting and advisory services to governmental and private entities to assist them with developing and implementing tailor-made, comprehensive medical cannabis programs, although we have not generated any revenues from such services to date.
We have been engaged in research and development and consulting and advisory activities through our wholly-owned Israeli subsidiary, One World Cannabis Ltd., since July 2014. To date, we have entered into binding agreements with major hospitals and medical research facilities in Israel for the purpose of conducting research studies and trials related to the development and use of Cannabis-Based Medical Products for the treatment of multiple myeloma, psoriasis, PTSD, chronic pain and fibromyalgia, and for the development of a cannabis soluble tablet delivery system.
In February 2017, we announced promising pre-clinical results from the testing of our cannabis-based topical ointment for the treatment of psoriasis, an autoimmune disease that causes red, scaly patches to appear on the skin. Skin cells in patients with psoriasis grow at an abnormally fast rate, causing a buildup of lesions that tend to burn and itch. While the real cause of psoriasis is not known, genetics are believed to play a major role in its development. According to the American Academy of Dermatology, psoriasis affects approximately 3% of the world’s population and 7.5 million people in the United States.
Recent Developments
April 2018 Private Placement
On April 30, 2018, we entered into and consummated a Securities Purchase Agreement (the “Purchase Agreement”) with a non-US-based institutional investor (the “Investor”). Under the terms and conditions of the Purchase Agreement, we sold and the Investor bought, (i) 500 shares of our new series of preferred stock designated as Series A Preferred Stock (the “Series A Preferred Shares”), which, as of April 30, 2018, were convertible into 25,000,000 shares of our common stock at a conversion price of $0.20 per share, subject to adjustment pursuant to the anti-dilution provisions of the Preferred Shares, and (ii) warrants representing the right to acquire 12,500,000 shares of our common stock at an exercise price of $0.22 per share (the “Warrants”), subject to adjustment pursuant to the anti-dilution provisions of the Warrants, for an aggregate purchase price of $5,000,000. Newbridge Securities Corporation (“Newbridge”), through LifeTech Capital, acted as exclusive placement agent for the transaction and we paid Newbridge a cash fee of $375,000 and issued to them warrants to purchase 2.5 million shares of our common stock at an exercise price of $0.20 per share. The Warrants contain customary terms, including provisions for “cashless” exercise, change of control, price based anti-dilution, and customary demand or piggyback registration rights. In addition, we are obligated to pay Newbridge a warrants solicitation fee equal to 4% of the gross proceeds that we receive upon cash exercise of the Warrants.
The terms of the Preferred Shares contain conditional redemption provisions and a deemed liquidation preference feature. In addition, the terms of each of the Preferred Shares and Warrants provide for anti-dilution protection for issuances of shares of our common stock at a price per share less than a price equal to the conversion price or exercise price, as applicable and, that in the event of a “fundamental transaction” (as described in the Warrants), the Investor will have the right to receive the value of the Warrants as determined in accordance with the Black Scholes option pricing model.
In connection with the Purchase Agreement, we entered into a Registration Rights Agreement (the “Registration Rights Agreement”) with the Investor, pursuant to which, among other things, we have agreed to use our commercially reasonable best efforts to (i) prepare and file with the SEC within 60 calendar days of the offering a registration statement covering the shares of common stock underlying the Preferred Shares and Warrants and (ii) have the registration statement and any amendment thereto to be declared effective by the SEC within 90 calendar days from the date of the initial filing of such registration statement.
Our Study on Psoriasis
On June 28, 2018, we announced the successful completion of the first part of our Phase I, placebo controlled, maximal dose study (the “Psoriasis Study”) to determine the safety and tolerability of topical ointment containing medical grade cannabis (the “Topical Ointment”) in healthy volunteers. The completed part of our Psoriasis Study consisted of application of escalating doses of the Topical Ointment to healthy volunteers and was successfully completed with no adverse effects. After the completion of the second part of our Psoriasis Study, we plan to initiate a Phase II study to demonstrate the efficacy of the Topical Ointment in treating mild to moderate psoriasis and other inflammatory skin diseases.
1
——————————————————————
As for dilution, startup companies on OTC and big board markets have some dilution as they increase their Outstanding Shares. OWCP has a track record of NOT diluting. You can try to argue it all day but the very small increase in OS during the last 18 months clearly shows that OWCP management values their shares greatly and OWC management are also shareholders of OWCP common stock. There will be some dilution, OWCP doesn't receive $5 Million for nothing.
We are funded and the research and patent work is moving forward making progress.
$OWCP
Conversion price is at 0.2 and 0.22.
April 2018 Private Placement
On April 30, 2018, we entered into and consummated a Securities Purchase Agreement (the “Purchase Agreement”) with a non-US-based institutional investor (the “Investor”). Under the terms and conditions of the Purchase Agreement, we sold and the Investor bought, (i) 500 shares of our new series of preferred stock designated as Series A Preferred Stock (the “Series A Preferred Shares”), which, as of April 30, 2018, were convertible into 25,000,000 shares of our common stock at a conversion price of $0.20 per share, subject to adjustment pursuant to the anti-dilution provisions of the Preferred Shares, and (ii) warrants representing the right to acquire 12,500,000 shares of our common stock at an exercise price of $0.22 per share (the “Warrants”), subject to adjustment pursuant to the anti-dilution provisions of the Warrants, for an aggregate purchase price of $5,000,000
$OWCP
You're welcome. Try double clicking on the link in your news window.
Form 424B3 OWC Pharmaceutical Research
http://archive.fast-edgar.com//20180703/AV2ZR22CZ22RLTTZ2U2R2ZX2RU4TZZ22ZBA2/
A lot of good stuff in there!
$OWCP Long and Strong
https://friendsofsheba.org/owc-looks-to-bring-pharma-grade-cannabis-therapeutics-to-market/
Friends of Sheba Medical Center is a branch of the Sheba organization.
$OWCP
The link to it was posted on this board multiple times.
LOL... why won't Sheba Medical Center post online all of the studies being conducted there, along with the coinciding Intellectual property owned by the companies having research done there?
Furthermore, why won't Sheba post the medical charts of the patients that are currently staying there..... is Sheba even a real hospital?
https://www.shebaonline.org/about-us/
Also, you're wrong again. Sheba did post an article on their website about OWCP.
Thanks for the reply. Would be great if this runs this week.
GLTA
Why did they do the reverse split again? Was that part of the shell clean up?
I z what you did there.
where is it made clear please ?
In your opinion, where do you think the PPS will go from here?
I agree!
$OWCP Long and Strong
For those wanting to sell..
This morning when it was getting close to peak, since I don't have the converted shares yet, I just did a short sell on SLDCD for the exact amount of shares coming to me in 2-4 days.
I've been holding this stock for 10 months, I averaged down yesterday, and was happy to get out at break even. I knew it was a risky long shot going into it 10 months ago with little info available.
Maybe the new company will be something legit, and I'm trying to find out more about the details of the reverse merger I've heard some mentioning.
Can anyone please post a link(s) to any info about the reverse merger?
You make some good points.
however, wouldn't the R/S ratio of 1:100 turn 43mil shares into 430,000 shares
Do you have any links to info about name change and reverse merger? (other than what's on FINRA)
There are rules and requirements that need to be met for the OTCQX and OTCQB markets.
The OTCQX and OTCQB markets are considered 'Established Public Markets' by the SEC for the purpose of determining the public market price when registering securities for resale with the SEC in equity line financings.
So it's not just marketing.
Basic stuff.
$OWCP: OTCQB market
It's now a three tier system of organization for the stocks quoted by OTC Markets: OTCQX, OTCQB, and OTCPink.
OWCP is on the OTCQB market and not a pink.
Basic stuff.
I understand what I posted is a Patent Pending with USPTO.
You asked for it, and by the way, there is more "scientific research that OWCP has published since 2014".
I-GLOW wrote:
"Why don't you post some of the scientific research that OWCP has published since 2014?"
So I posted the science behind this Patent Pending which was published on May 3, 2018.
United States Patent Application 20180116998
Kind Code A1
Sinai; Alon ; et al. May 3, 2018
USE OF CANNABIS TO TREAT FIBROMYALGIA, METHODS AND COMPOSITIONS THEREOF
Abstract
The present invention discloses a composition comprising cannabis natural extract, or synthetic cannabinoids, for use in treating a subject suffering from fibromyalgia. The present invention further discloses methods and uses of the aforementioned composition.
Inventors: Sinai; Alon; (Petach Tikva, IL) ; Turner; Ziv; (Petach Tikva, IL) ; Baruch; Yehuda; (Gedera, IL)
Applicant:
Name City State Country Type
ONE WORLD CANNABIS LTD
Petach Tikva
IL
Assignee: ONE WORLD CANNABIS LTD
Petach Tikva
IL
Family ID: 1000003097448
Appl. No.: 15/573687
Filed: May 11, 2016
PCT Filed: May 11, 2016
PCT NO: PCT/IL2016/050498
371 Date: November 13, 2017
Related U.S. Patent Documents
Application Number Filing Date Patent Number
62160609 May 13, 2015
Current U.S. Class: 1/1
Current CPC Class: A61K 31/352 20130101; A61K 31/05 20130101; A61P 25/04 20180101; A61K 36/185 20130101
International Class: A61K 31/352 20060101 A61K031/352; A61K 31/05 20060101 A61K031/05; A61P 25/04 20060101 A61P025/04; A61K 36/185 20060101 A61K036/185
Claims
1.-87. (canceled)
88. A composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
89. The composition of claim 88, wherein at least one of the following holds true: a) said Tetrahydrocannabinol (THC) or a derivative thereof, or said Cannabidiol (CBD) or a derivative thereof is from cannabis extract; b) said THC a derivative thereof is selected from the group consisting of THC, Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCA) and any combination thereof; c) said THC or a derivative thereof is selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof; d) said THC or a derivative thereof is extracted from cannabis; said cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof; e) said cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, cannabidivarin (CBDV), cannabidiolic acid (CBDA) and any combination thereof; f) said CBD or a derivative thereof is selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof; g) said CBD or a derivative thereof is extracted from cannabis; said cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof; h) the concentration of said THC is in the range of about 2% to about 85%; and i) the concentration of said CBD is in the range of about 2% to about 85%.
90. The composition of claim 88, further comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof of 4:1 or 5:1, respectively.
91. The composition of claim 88, wherein said composition is formulated for administration of at least one of: a) between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day; b) between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit; c) between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day; d) between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit; and e) about 1 to about 10 times per day.
92. The composition of claim 88, wherein at least one of the following holds true: a) said composition is administered in a manner selected from the group consisting of: intranasal, transdermal, topical, intravenous, oral, and any combination thereof; b) said composition is formulated in the form of drops; c) said composition is formulated in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof; and d) said composition is administered in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
93. The composition according to claim 92, wherein said composition provides a synergistic effect with respect to treatment of fibromyalgia when administered in combination with said therapeutic agent, as compared to the effect provided when said composition and said therapeutic agent administered separately.
94. The composition of claim 88, wherein at least one of the following holds true: a) said composition additionally comprises at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof; b) said composition further comprising flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof; c) said composition further comprising preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof; d) said composition is in a sustained release dosage form or in an immediate release dosage form; and e) said composition is in a sustained release dosage form selected from the group comprising of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
95. The composition of claim 88, wherein said composition is used for preventing the onset of a flareup of fibromyalgia symptoms in said subject.
96. The composition of claim 88, wherein said composition provides an improvement in fibromyalgia symptoms of said subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
97. The composition of claim 96, wherein at least one of the following holds true: a) said improvement in fibromyalgia symptoms is measured by an improvement in the subject's score of at least one point on said at least one pain severity scale, as compared to an established baseline or to a placebo; b) said at least one pain severity scale is selected from the group comprising of Brief pain inventory (BPI), Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD), fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HORS) and any combination thereof; c) said fibromyalgia symptoms are selected from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR and any combination thereof; and d) a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
98. The composition of claim 97, wherein said composition provides at least one of: a) an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5; b) a reduction in BPI score from baseline to endpoint; and c) a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
99. The composition of claim 88, wherein said composition provides at least one of: a) an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items; and b) improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
100. The composition of claim 99, Wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
101. A method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to said subject a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof in a therapeutically effective dosage.
102. The method of claim 101, additionally comprising at least one step selected from the group consisting of: a) formulating said composition to comprise a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; b) administering said THC or a derivative thereof in a dosage unit of between about 5 mg THC and about 20 mg THC, preferably about 10 mg THC per dosage unit; c) administering said CBD or a derivative thereof in a dosage of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day; d) administering said CBD or a derivative thereof in a dosage unit of between about 1 mg CBD and about 5 mg CBD, preferably about 2 mg CBD per dosage unit; e) formulating said composition in a dosage form of drops; f) preventing the onset of a fibromyalgia flareup in said subject; g) improving fibromyalgia symptoms of said subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo; h) providing an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5; i) providing a reduction in BPI score from baseline to endpoint; j) providing a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between; and k) providing an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
103. The method of claim 102, wherein at least one of the following folds true: a) the method additionally comprising steps of performing blood tests for CBD and THC 1 hour and 2 hours after said dosage unit intake; b) the method additionally comprising steps of selecting said fibromyalgia symptoms to be a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold; and c) said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
104. The method of claim 103, additionally comprising steps of providing improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
105. A composition comprising a therapeutically effective amount of cannabis formulation for use in relieving a subject suffering from fibromyalgia syndrome symptoms, wherein said cannabis formulation contains synthetic components of cannabis.
106. The composition of claim 105, wherein at least one of the following holds true: a) said synthetic components are synthetically produced tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; b) said composition comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; c) said composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day; and d) said composition is formulated for administration of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
107. A method for preventing the risk for the onset of a fibromyalgia flareup, wherein said method comprises steps of: a) formulating a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; and b) administering said composition to a subject in risk for suffering from a fibromyalgia flareup according to a predetermined protocol.
108. The method of claim 107, wherein at least one of the following holds true: a) said step of formulating further comprises formulating said composition comprises a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; b) said method additionally comprising steps of administering said THC or a derivative thereof in a dosage of about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day per day; and c) said method additionally comprising steps of administering said CBD or a derivative thereof in a dosage of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
Description
FIELD OF THE INVENTION
[0001] The current invention relates to a novel treatment for fibromyalgia. More specifically the invention pertains to a composition comprising cannabis extract or fractions thereof, or cannabis synthetic components, for treating fibromyalgia.
BACKGROUND OF THE INVENTION
[0002] Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Fibromyalgia syndrome is believed to be caused by amplified painful sensations caused by the way the brain processes pain signals. Symptoms sometimes begin after a physical trauma, surgery, infection or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event.
[0003] Women are much more likely to develop fibromyalgia than are men. Many people who have fibromyalgia also have tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety and depression.
[0004] While there is no cure for fibromyalgia, a variety of medications can help control symptoms, as well as alterations of lifestyle habits such as exercise, relaxation and stress-reduction measures. The exact onset trigger is unknown but is believed to involve psychological, genetic, neurobiological and environmental factors, which among them stress levels are highly prominent.
[0005] The central symptom of fibromyalgia, namely widespread pain, appears to result from neuro-chemical imbalances including activation of inflammatory pathways in the brain which results in abnormalities in pain processing (Clauw D J et al., 2011, "The science of fibromyalgia". Mayo Clin Proc 86 (9): 907-11). The brains of fibromyalgia patients show functional and structural differences from those of healthy individuals, but it is unclear whether the brain anomalies cause fibromyalgia symptoms or are the product of an unknown underlying common cause. Some research suggests that these brain anomalies may be the result of childhood stress, or prolonged or severe stress (Schweinhardt P et al., October 2008, "Fibromyalgia: a disorder of the brain?". Neuroscientist 14 (5): 415-21).
[0006] Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2-4% of the population, with 9:1 female-to-male incidence ratio. FMS is the second most common disorder, after osteoarthritis, observed by rheumatologists. The defining symptoms of FMS include chronic widespread pain, intense pain in response to tactile pressure (allodynia), prolonged muscle spasms, weakness in the limbs, nerve pain, muscle twitching, palpitations and diffuse tenderness, along with fatigue, sleep disturbance and cognitive impairments. These impairments include problems with short- and long-term memory, short-term memory consolidation, impaired speed of information processing, reduced attention span and limited multi-tasking performance. FMS is a persistent disorder with symptoms that have a devastating effect on people's lives, including limited ability to engage in everyday activities, limited ability to maintain outside work and difficulties to maintain normal relationships with family, friends and employers. These limitations can lead to the occurrence of anxiety and depression in many FMS patients.
[0007] FMS is not completely understood, in part because there is no evidence of a single event that "causes" fibromyalgia. Rather, many physical and/or emotional stressors may trigger or aggravate symptoms. Those have included certain infections, such as a viral illness or Lyme disease, as well as emotional or physical trauma. Establishing proper diagnostic criteria is also a challenge.
[0008] As with many other syndromes, there is no efficient cure for FMS and no agreed upon treatment--the suggested treatment depends on the classification of choice. Those who regard FMS as a neurological disorder advocate pharmacotherapy. All current treatments, such as prescribed medications, aerobic exercises and cognitive behavioral therapies, consist of symptom management. Integrated programs based on these treatments have been shown to alleviate pain and some other symptoms but with limited effectiveness.
[0009] Fibromyalgia is currently treated with pain and depression management drugs. However, due to the origins of the disorder in the brain, and its association with high stress levels, there is a call for a medication that will enable both stress reduction and brain function modification.
[0010] Previous trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities, particularly in the treatment of pain resistant to conventional pain therapies.
[0011] In view of the above there is a long felt and unmet need for a naturally originated pharmaceutical composition that is specifically useful for treatment of fibromyalgia and chronic pain symptoms.
SUMMARY OF THE INVENTION
[0012] It is thus one object of the present invention to provide a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0013] It is also an object of the present invention to provide the aforementioned composition, wherein said Tetrahydrocannabinol (THC) or a derivative thereof, or said Cannabidiol (CBD) or a derivative thereof is from cannabis extract.
[0014] It is also an object of the present invention to provide the aforementioned composition comprising a therapeutically effective amount of cannabis extract for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0015] It is also an object of the present invention to provide the aforementioned composition, wherein the cannabis extract contains tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0016] It is also an object of the present invention to provide the aforementioned composition, wherein the THC or a derivative thereof is selected from the group consisting of THC, Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCA) and any combination thereof.
[0017] It is also an object of the present invention to provide the aforementioned composition, further comprising THC or a derivative thereof selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof.
[0018] It is also an object of the present invention to provide the aforementioned composition, wherein the THC or a derivative thereof is extracted from cannabis; the cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0019] It is also an object of the present invention to provide the aforementioned composition, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, cannabidivarin (CBDV), cannabidiolic acid (CBDA) and any combination thereof.
[0020] It is also an object of the present invention to provide the aforementioned composition, further comprising CBD or a derivative thereof selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0021] It is also an object of the present invention to provide the aforementioned composition, wherein the CBD or a derivative thereof is extracted from cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0022] It is also an object of the present invention to provide the aforementioned composition, wherein the concentration of the THC is in the range of about 2% to about 85%.
[0023] It is also an object of the present invention to provide the aforementioned composition, wherein the concentration of the CBD is in the range of about 2% to about 85%.
[0024] It is also an object of the present invention to provide the aforementioned composition, further comprising a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0025] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day.
[0026] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit.
[0027] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
[0028] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit.
[0029] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 1 to about 10 times per day.
[0030] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is administered in a manner selected from the group consisting of: intranasal, topical, transdermal, intravenous, oral, and any combination thereof.
[0031] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated in the form of drops.
[0032] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof.
[0033] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is administered in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
[0034] It is also an object of the present invention to provide the aforementioned composition, wherein the composition provides a synergistic effect with respect to treatment of fibromyalgia when administered in combination with the therapeutic agent, as compared to the effect provided when the composition and the therapeutic agent administered seperately.
[0035] It is also an object of the present invention to provide the aforementioned composition, wherein the composition additionally comprises at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof.
[0036] It is also an object of the present invention to provide the aforementioned composition, further comprising flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof.
[0037] It is also an object of the present invention to provide the aforementioned composition, further comprising preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof.
[0038] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is in a sustained release dosage form or in an immediate release dosage form.
[0039] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is in a sustained release dosage form selected from the group comprising of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
[0040] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is used for preventing the onset of a flareup of fibromyalgia symptoms in the subject.
[0041] It is also an object of the present invention to provide the aforementioned composition, wherein the composition provides an improvement in fibromyalgia symptoms of the subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
[0042] It is also an object of the present invention to provide the aforementioned composition, wherein the improvement in fibromyalgia symptoms is measured by an improvement in the subject's score of at least one point on the at least one pain severity scale, as compared to an established baseline or to a placebo.
[0043] It is also an object of the present invention to provide the aforementioned composition, wherein the at least one fibromyalgia severity scale is selected from the group comprising of Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HDRS) and any combination thereof.
[0044] It is also an object of the present invention to provide the aforementioned composition, wherein the fibromyalgia symptoms are selected from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR, and any combination thereof.
[0045] It is also an object of the present invention to provide the aforementioned composition, wherein the fibromyalgia symptoms is a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
[0046] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5.
[0047] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides a reduction in BPI score from baseline to endpoint.
[0048] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
[0049] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
[0050] It is also an object of the present invention to provide the aforementioned composition, wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
[0051] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
[0052] It is another object of the present invention to disclose a method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to the subject a composition comprising cannabis extract in a therapeutically effective dosage.
[0053] It is still an object of the present invention to disclose a method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to said subject a composition comprising comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof in a therapeutically effective dosage.
[0054] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of providing said Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof derived from cannabis extract.
[0055] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of formulating the cannabis extract to contain tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0056] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of selecting the THC or a derivative thereof from the group consisting of THC, THCV, THCA and any combination thereof.
[0057] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of extracting the THC or a derivative thereof from Cannabis; the cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0058] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the cannabidiol (CBD) or a derivative thereof from the group consisting of CBD, CBDV, CBDA and any combination thereof.
[0059] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the CBD from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0060] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of extracting the CBD or a derivative thereof from Cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0061] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a synergistic effect with respect to treating fibromyalgia as compared to the effect provided by the THC or a derivative thereof and by the CBD or a derivative thereof when administered separately.
[0062] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition to comprise a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0063] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage of about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0064] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage unit of between about 5 mg THC and about 20 mg THC, preferably about 10 mg THC per dosage unit.
[0065] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
[0066] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage unit of between about 1 mg CBD and about 5 mg CBD, preferably about 2 mg CBD per dosage unit.
[0067] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition between about 1 to about 10 times through the day.
[0068] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition once, twice, three, four or five times through the day.
[0069] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition to the subject over a time period of about 1 day to about 6 months.
[0070] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of performing blood tests for CBD and THC 1 hour and 2 hours after said dosage unit intake.
[0071] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a dosage form of drops.
[0072] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof.
[0073] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
[0074] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a synergistic effect with respect to treatment of fibromyalgia when administering the composition in combination with the fibromyalgia therapeutic agent, as compared to the effect provided when the composition and the therapeutic agent are administered seperatly.
[0075] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition in a manner selected from the group consisting of: intranasal, transdermal, topical, intravenous, oral, and any combination thereof.
[0076] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof.
[0077] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof.
[0078] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof.
[0079] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a sustained release dosage form or in an immediate release dosage form.
[0080] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a sustained release dosage form; wherein the sustained release dosage form is selected from a group consisting of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
[0081] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of preventing the onset of a fibromyalgia flareup in the subject.
[0082] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of improving fibromyalgia symptoms of the subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
[0083] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of measuring the improvement in the fibromyalgia symptoms of the subject by an improvement in the subject's score of at least one point on the at least one pain severity scale, as compared to an established baseline or to a placebo.
[0084] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the pain severity scale from a group consisting of brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HDRS) and any combination thereof.
[0085] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the fibromyalgia symptoms from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR, and any combination thereof.
[0086] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the fibromyalgia symptoms to be a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
[0087] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5.
[0088] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a reduction in BPI score from baseline to endpoint.
[0089] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
[0090] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
[0091] It is still an object of the present invention to disclose the above mentioned method, wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
[0092] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
[0093] It is another object of the present invention to provide a use of a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof, in the manufacture of a medicament to treat fibromyalgia syndrome.
[0094] It is yet another object of the present invention to provide a composition comprising a therapeutically effective amount of cannabis formulation for use in relieving a subject suffering from fibromyalgia syndrome symptoms, wherein the cannabis formulation contains synthetic components of cannabis.
[0095] It is also an object of the present invention to provide the aforementioned composition, wherein the synthetic components are synthetically produced tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0096] It is also an object of the present invention to provide the aforementioned composition, further comprising a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0097] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0098] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
[0099] It is another object of the present invention to disclose a method for preventing the risk for the onset of a fibromyalgia flareup, wherein the method comprises steps of: formulating a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; and administering the composition to a subject in risk for suffering from a fibromyalgia flareup according to a predetermined protocol.
[0100] It is still an object of the present invention to disclose the aforementioned method, wherein the step of formulating further comprises formulating the composition to comprise a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0101] It is still an object of the present invention to disclose the aforementioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0102] It is lastly an object of the present invention to disclose the aforementioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0103] In the following detailed description of the preferred embodiments, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration specific embodiments in which the invention may be practiced. It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention. The present invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the present invention is not unnecessarily obscured.
[0104] The essence of the present invention is to provide a composition for treating fibromyalgia comprising cannabis extract, which may further contain tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof, or a synthetic cannabis composition, or a combination thereof.
[0105] Fibromyalgia patients frequently self-report using cannabis therapeutically to treat symptoms of the disease. To date however, there is still a need for clinical trials assessing the use of cannabinoids to treat the disease.
[0106] In a main embodiment, the present invention provides a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms. It is emphasised that the composition of the present invention is useful for treating chronic pain conditions such as fibromyalgia.
[0107] In a further embodiment, the composition of the present invention, comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof is useful for treating chronic pain.
[0108] Without wishing to be bound by theory, it is herein acknowledged that the principal active component in the complex mixture of cannabinoids present in the marijuana plant is D9-tetrahydrocannabinol (THC), which acts primarily as an agonist at the CB1 cannabinoid receptor. This receptor is found at high concentrations in the brain, including the basal ganglia and cerebellar regions, and also in the hippocampus and hypothalamus. THC has been shown to inhibit the release of a wide spectrum of neurotransmitters including L-glutamate, GABA, norepinephrine, dopamine, serotonin (5-HT), and acetylcholine (Schlicker and Kathmann, 2001).
[0109] It is further acknowledged that marijuana contains other compounds of interest, including cannabidiol (CBD), a constituent of marijuana that is not a CB1 or CB2 receptor agonist (Burstein and Zurier, 2009; Scuderi et al., 2009). An early safety study reported that CBD was tolerated when administered to humans for 30 days (Cunha et al., 1980).
[0110] It is further within the scope that cannabinoids also modulate GABAergic transmission and the release of cholecystokinin (CCK), a peptide that may contribute to both anxiolytic and anxiogenic effects of THC and endocannabinoids (Beinfeld and Connolly, 2001; Katona et al., 1999; Marsicano and Lutz, 1999; Onaivi et al., 1990). Furthermore, cannabinoids enhance the release of endogenous opioids, and these may be involved in the functional interplay between the endocannabinoid and the opioid system and the production of analgesic responses. It is hypothesized that the relationship between these two systems plays a role in antidepressant-like effects and in various addiction-related processes (Houser et al., 2000; Pugh et al., 1997; Zimmer et al., 2001). Studies in rodents suggest that cannabinoids and their interaction with endogenous opioids might also modulate anxiety (Pugh et al., 1997; Berrendero and Maldonado, 2002; Marin et al., 2003).
[0111] It is an object of the present invention to use pharmacological modulation of the endocannabinoid system in the treatment of fibromyalgia related symptoms.
[0112] The composition of the present invention mainly comprises of cannabis extract drops. Such cannabis drops essentially comprises the cannabinoid Tetrahydrocannabinol (THC). The cannabis oil of the composition of the present invention may also include cannabidiol (CBD) that is known to potentiate the activity of THC by increasing CB1 receptor density or through another CB1-related mechanism (Hayakawa et al., 2008). CBD may increase the efficiency of the composition as well as will enable using lower concentrations of THC. The cannabis drops may also be formulated out of synthetic cannabis components or a combination of synthetic and naturally extracted components of cannabis.
[0113] As used herein the term "about" denotes .+-.25% of the defined amount or measure or value.
[0114] The term "cannabis" refers hereinafter to a genus of flowering plants that includes three different species, Cannabis sativa, Cannabis indica and Cannabis ruderalis.
[0115] The term "cannabidiol (CBD)" refers hereinafter to one of at least 85 active cannabinoids identified in cannabis. Cannabidiol is a major phytocannabinoid, accounting for up to 40% of the plant's extract. CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol (THC). Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists. CBD may potentiate THC's effects by increasing CB1 receptor density or through another CB1-related mechanism. It is also an inverse agonist of CB2 receptors. CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion.
[0116] The term "Tetrahydrocannabinol (THC)" refers hereinafter to the principal psychoactive constituent (or cannabinoid) of the cannabis plant. THC has a partial agonist activity at the cannabinoid receptor CB1, and the CB2 receptor and is known to increase cortisol levels. THC may refer to delta-9-tetrahydrocannabinol, delta-6-tetrahydrocannabinol and delta-1-tetrahydrocannabinol.
[0117] The term "cannabinoid receptor" refers hereinafter to a class of cell membrane receptors under the G protein-coupled receptor superfamily. There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2. The CB 1 receptor is expressed mainly in the brain, but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly in the immune system and in hematopoietic cells.
[0118] The term "Cannabinoid receptor type 1 (CB1)" refers hereinafter to a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system. It is activated by the endocannabinoid neurotransmitters anandamide and 2-arachidonoyl glyceride (2-AG); by plant cannabinoids, such as the compound THC, an active ingredient of the psychoactive drug cannabis; and by synthetic analogues of THC.
[0119] The term "Cannabinoid receptor type 2 (CB2)" refers hereinafter to a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of Tetrahydrocannabinol, the active agent in marijuana, and other phytocannabinoids (natural cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG).
[0120] The term "fibromyalgia" as used herein refers to a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. It is acknowledged that women are more likely to develop fibromyalgia than men. It is noted that people who have fibromyalgia sometimes also have tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety and depression. It is within the scope that the term "fibromyalgia" further refers to chronic pain conditions and symptoms.
[0121] The term "chronic pain" as used herein refers a pain that lasts a long time. It is acknowledged that In medicine, the distinction between acute and chronic pain is sometimes determined by an arbitrary interval of time since onset; the two most commonly used markers being 3 months and 6 months since onset, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months. Others apply acute to pain that lasts less than 30 days, chronic to pain of more than six months duration, and subacute to pain that lasts from one to six months.[3] A popular alternative definition of chronic pain, involving no arbitrarily fixed duration, is "pain that extends beyond the expected period of healing". Epidemiological studies have found that 10.1% to 55.2% of people in various countries have chronic pain.
[0122] The term "sustained release dosage form" refers hereinafter to the release of a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects. This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates. Sustained release's definition is more akin to a "controlled release" rather than "sustained".
[0123] The term "fibromyalgia severity scale" refers hereinafter to rating and scales that are commonly used as measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients which exhibit fibromyalgia syndrome symptoms. The fibromyalgia severity scale may be selected from a few commonly used scales, which may include in a non-limiting example, pain severity scale, Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, and Hamilton Depression Rating Scale (HDRS).
[0124] The term "established baseline" or "control" or "placebo" refers hereinafter to the results obtained by a subject or group of subjects that was not administered or otherwise exposed to the composition of the present invention and used as a control for the clinical study. Specifically, the term "placebo" refers to a substance containing no medication and prescribed or given to reinforce a patient's expectation to get well. According to further aspects, a placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect. It is within the scope that in medical research, placebos are given as control treatments and depend on the use of measured suggestion. Examples of common placebos include inert tablets, vehicle infusions, sham surgery, and other procedures based on false information. The term "established baseline" refers hereinafter to data collected at the beginning of a clinical study for all participants and for each arm or comparison group. These data include demographics, such as age and gender, and study-specific measures (for example, systolic blood pressure, prior antidepressant treatment etc.).
[0125] The term "extract" refers hereinafter to any extract deriving from a plant, or fragment or fraction thereof.
[0126] Thus it is according to one embodiment of the present invention to provide a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof, for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0127] It is further within the scope of the present invention to disclose the composition as defined above, wherein the THC or a derivative thereof is selected from the group consisting of THC, THCV, THCA and any combination thereof.
[0128] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the THC or a derivative thereof is selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof.
[0129] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the THC or a derivative thereof is extracted from cannabis; the cannabis is selected from the group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0130] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition additionally comprising cannabidiol (CBD) or a derivative thereof.
[0131] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, CBDV, CBDA and any combination thereof.
[0132] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the CBD or a derivative thereof is selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0133] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the CBD or a derivative thereof is extracted from cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0134] It is well within the scope of the present invention to disclose a cannabis formulation for the treatment of fibromyalgia syndrome symptoms, containing only synthetic cannabis components, or a combination of synthetic cannabis components with naturally extracted cannabis components.
[0135] It is further within the scope of the present invention to disclose a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0136] It is further within the scope of the present invention to disclose the composition as defined in any of the above, further comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof of 4:1 or 5:1, respectively.
[0137] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day, more preferably between about 10 mg and about 20 mg THC per day.
[0138] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein said composition is formulated for administration of between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit.
[0139] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day, more preferably between about 2 mg and about 4 mg CBD per day.
[0140] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit.
[0141] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of about 1 to about 10 times per day.
[0142] In order to understand the invention and to see how it may be implemented in practice, a plurality of preferred embodiments will now be described, by way of non-limiting example only, with reference to the following examples.
EXAMPLE 1
[0143] Organic, mental and functional aspects of the fibromyalgia syndrome are assessed in patients treated with cannabis drops compared to placebo. The protocol-defined primary outcome measure is pain severity as measured by the self-reported Brief Pain Inventory (BPI) (short form) average pain severity score fibromyalgia impact questionnaire (which measures physical function, pain assessment, fatigue and distress).
[0144] Secondary endpoints include validated parameters that measure quality of life, quality of sleep, disability, depression and anxiety and the patient global impression of change and the fibromyalgia severity score. In addition changes of concurrent medications are recorded.
[0145] Sample Size: The study will include eighty patients.
[0146] Maximal Study Duration time: up to 7 visits in up to 23 weeks as follows: [0147] Screening phase--up to 3 weeks, 1 visit [0148] Treatment phase--16 weeks, 4 visits [0149] Follow-up phase--4 weeks, 2 visits
[0150] Study Design: The study will be randomized and double-blinded, and will compare addition of cannabis drops versus placebo to female patients with fibromyalgia. Female patients with primary fibromyalgia syndrome will be recruited after obtaining their signed informed consent. The patients will be randomized to receive cannabis drops on an escalating scale or a placebo. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner. The duration of the study will be 6 weeks. There will be 4 biweekly office visits throughout these 6 weeks preceded by a screening visit. The study drug will be provided as an "add on" format.
[0151] The patients will start with the following drop dosage; every day of the first week each patient will take 5 drops, increments by five drops will be allowed by weekly intervals. The maximal dose will be no more than up to 20 drops twice daily. Dosage will be given at a 4:1 ratio between THC and CBD, wherein THC ranges from about 20 mg and about 160 mg per day, and CBD ranges from about 5 mg and 40 mg per day.
[0152] Inclusion Criteria: individuals eligible to be enrolled into this protocol are participants who: [0153] 1. Women with established fibromyalgia syndrome confirmed by the 1990 ACR classification criteria who signed an informed consent form. [0154] 2. Women 18-75 years old. [0155] 3. The score on the average pain severity item of the BPI is >5 at randomization. [0156] 4. Women of fertile age will need to use birth control measures.
[0157] Exclusion Criteria: individuals not eligible to be enrolled into this protocol are those who: [0158] 1. Confirmed pregnancy [0159] 2. Breast feeding patients [0160] 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test. [0161] 4. Patients with congestive heart failure [0162] 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) [0163] 6. Patients with coexistent t rheumatic/inflammatory conditions [0164] 7. Patients with active gastrointestinal bleeding [0165] 8. Patients with renal failure [0166] 9. Patients with comorbid conditions causing significant disability [0167] 10. Patients with uncontrolled hypertension. [0168] 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). [0169] 12. A high level of suicidality (a score above 3 in the relevant Hamilton score). [0170] 13. Patients with current or past history of substance abuse. [0171] 14. Patients who are drivers of public transportation or heavy vehicles
Experimental Design:
[0172] All women will be assessed by several rheumatic and psychiatric scales as following:
[0173] Brief pain inventory--Pain severity as measured by the self-reported BPI (short form) average pain severity score, which assesses average pain severity during the past 24 hours (0-10 scale, where 0=no pain and 10=pain as bad as you can imagine). A sustained response will be defined as a 30% reduction from baseline to endpoint in the BPI with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between. The primary outcome variable will be reduction in BPI from baseline to endpoint.
[0174] Sleep history questionnaire (PSQI)--PSQI is a validated sleeping scoring that measures sleep quality, impact on function and well being. A final score result below 5 reflects poor quality of sleep.
[0175] SF-36 Quality of life assessment--A Hebrew translated and validated version of the SF-36 scale measured quality of life. The SF-36 contains eight subscales: physical functioning (PF), social functioning (SF), role limitations attributable to physical and emotional problems, mental health, vitality, bodily pain, and general health.
[0176] Fibromyalgia impact questionnaire (FIQ)--This scale commonly performed in patients with FIBROMYALGIA SYNDROME is regarded to be a reliable and valid variable. The FIQ is less affected by temporary alterations and fluctuations of the disease severity.
[0177] Mini International Neuropsychiatric Interview this tools provides rapid assessment for comorbid psychiatric conditions.
[0178] Fibromyalgia syndrome Tenderness Assessment--Tenderness assessment was performed manually in all subjects by a senior rheumatologist; a count of 18 tender points (TP) will be performed by thumb palpation as specified in the ACR 1990 classification criteria.
[0179] Hamilton Depression Rating Scale (HDRS)--Major depressive disorder severity was determined by using the Hamilton Depression Rating Scale (HDRS). The HDRS is a 17-item scale that measures the presence and severity of depression. The HDRS is a reliable gauge of the degree of symptom severity in depressed patients.
[0180] All adverse events will be recorded at every office visit. Every serious adverse events will recorded within 24 hours from occurrence and the local ethics committee will be notified immediately.
[0181] BMI--weight and height will be measured at the beginning and end of the study.
[0182] In addition a urine toxic screen will be taken every visit, the patients will be blinded to the results of this tests throughout the study.
[0183] Statistical analysis: Prospective results are detailed for all data.
[0184] Data analysis will be two folded: group comparisons and correlations. Differences between the two groups of patients for continuous variables will be analyzed using. For categorical variables, group comparisons will be performed with the chi square test. Correlations between TP and other dependent variables will be calculated using Pearson correlations. Scores measured at several time points will also be analyzed by repeated measures ANOVA, absolutely and as percentage of baseline values.
EXAMPLE 2
A Randomized Double-Blinded Study Comparing Treatment with the Cannabis Tablets of the Present Invention Versus Placebo in Female Patients with Fibromyalgia
Abbreviations:
[0185] AE Adverse Event
[0186] BP Blood Pressure
[0187] CBD Cannabidiol
[0188] CRF Case Report Form
[0189] DCF Data Correction Form
[0190] ECG Electrocardiogram
[0191] EC Ethics Committee
[0192] FMS Fibromyalgia symptoms
[0193] GCP Good Clinical Practice
[0194] HCG Human Chorionic Gonadotropin
[0195] HIV Human Immunodeficiency Virus
[0196] HR Heart Rate
[0197] PI Principal Investigator
[0198] SAE Serious Adverse Event
[0199] THC Tetrahydrocannabinol
1. Protocol Synopsis
TABLE-US-00001 [0200] Title A randomized double-blinded study comparing treatment with Cannabis tablets versus placebo in female patients with fibromyalgia Phase of Phase II Development Primary To evaluate the safety, tolerability and efficacy of Objectives cannabis tablets (10 mg THC and 2 mg of CBD in female patients with fibromyalgia. Primary Pain severity as measured by the self-reported BPI (short Outcome form) average pain severity score fibromyalgia impact Measures: questionnaire (which measures physical function, pain assessment, fatigue and distress). Secondary 1. Quality of life, quality of sleep, disability, Outcome depression and anxiety and the patient global Measures: impression of change and the fibromyalgia severity score. 2. Changes of concurrent medications will be recorded. Safety 1. Collecting information on tolerability through self- Outcome reported reactions and experiences. Measures: 2. Collection of Adverse events and Serious Adverse Events. 3. Laboratory testing. Study Design This is a single center, prospective, double-blind, placebo- controlled, randomized study. Study The subjects are screened against eligibility criteria and in Methods order to confirm eligibility, subject will be tested for pregnancy (urine or blood), urine Cannabinoids (to exclude substance abuse). Patients will be consented and the following procedures will be performed: Subjects will be randomized to one of the study arms (treatment or placebo). Documentation of Medical history and medication consumption (present and past) BP, Heart Rate, Blood testing (chemistry, blood count). Fibromyalgia Tender Points counts. BMI calculation Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). Based on the urine testing and questionnaires, eligibility confirmation will be performed and the patient will be asked to swallow a tablet. 1 hour and 2 hours after tablet intake Blood tests for CBD and THC will be performed. Patients will be instructed to start home use of a single tablet at night time with a possible bidaily increment up to a maximum dosage of 10 tablets. The increments will be done at night time and when needed the other half dose will be taken every morning. On the follow-up visits (including final visit) the following will be performed: Documentation medication consumption. Urine testing for pregnancy and Cannabinoids. BP, Heart Rate, Blood testing (chemistry, blood count). Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). At the final visit, the un-used tablets will be collected. In case of an Adverse Event, patients will be asked to contact the clinic immediately. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner Number of Single Site Sites Maximal 4 biweekly visits in 6 weeks as follows: Study Screening visit--Week 0 Duration Follow-up visit--Week 2 and Week 4 time: Final visit--week 6 Flexibility of .+-.2 days will be permitted Sample Size 80 female subjects Inclusion 1. Female with established FMS confirmed by the Criteria 1990 ACR 2. 18-75 years old 3. The score on the average pain severity item of the BPI is .gtoreq.5 at randomization 4. A female subject is eligible to participate if she is of non-childbearing potential (postmenopausal or pre-menopausal females with a documented tubal ligation or hysterectomy). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol. 5. Willing to sign an Informed Consent 6. Agree not to participate in any other interventional clinical trials during the study 7. Agree to follow study instructions meticulously Exclusion 1. Confirmed pregnancy Criteria 2. Breast feeding patients 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test 4. Patients with congestive heart failure 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) 6. Patients with coexistent t rheumatic/inflammatory conditions 7. Patients with active gastrointestinal bleeding 8. Patients with renal failure 9. Patients with comorbid conditions causing significant disability 10. Patients with uncontrolled hypertension. 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). 12. Usage of anti-epileptic drugs 13. A high level of suicidality (a score above 3 in the relevant Hamilton score). 14. Patients who are drivers of public transportation or heavy vehicles. 15. A history of drug or alcohol abuse, or a history of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mililiter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. 16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives (whichever is longer). 17. Have any current problem or a history of substance abuse which, in the opinion of the investigator, might interfere with participation in the protocol. 18. Have used marijuana within a month of starting the study.
Fibromyalgia Assessment Tools
[0201] The following questionnaires are used in the study. They are validated and commonly used.
[0202] Brief pain inventory--The Brief Pain Inventory (BPI) is a self-administered questionnaire developed to assess pain and the impact of pain. It was developed for use in cancer pain, but has also been used in other chronic pain conditions.
[0203] Sleep history questionnaire (PSQI)--PSQI is a validated sleeping scoring that measures sleep quality, impact on function and wellbeing. A final score result below 5 reflects poor quality of sleep.
[0204] SF-36 Quality of life assessment--A Hebrew translated and validated version of the SF-36 scale measured quality of life. The SF-36 contains eight subscales: physical functioning (PF), social functioning (SF), role limitations attributable to physical and emotional problems, mental health, vitality, bodily pain, and general health. Each scale is scored on a VAS (0 to 100) with a high score indicating better health and less body pain. The completion of this study was conducted with the aid of a senior psychiatrist.
[0205] Fibromyalgia impact questionnaire (FIQ)--This scale commonly performed in patients with FMS is regarded to be a reliable and valid variable. The FIQ is less affected by temporary alterations and fluctuations of the disease severity.
[0206] Mini International Neuropsychiatric Interview this tools provides rapid assessment for comorbid psychiatric conditions.
[0207] FMS Tenderness Assessment--Tenderness assessment will be performed manually in all subjects by a senior rheumatologist; a count of 18 tender points (TP) will be performed by thumb palpation as specified in the ACR 1990 classification criteria. The subject was asked to say "yes" when the sensation altered from pressure to definite pain. Patients will be considered to have FMS if he complied with the ACR criteria defining the FMS e.g., having widespread musculoskeletal pain with excess tenderness in at least 11 of 18 the predefined anatomic sites.
[0208] Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). These two scales are widely used to gauge the severity of anxiety and depression. The HAM-A consists of 14 items designed to assess the severity of a patient's anxiety. Each of the 14 items contains a number of symptoms, and each group of symptoms is rated on a scale of zero to four, with four being the most severe. The HDRS is a 17-item scale that measures the presence and severity of depression. The HDRS is a reliable gauge of the degree of symptom severity in depressed patients.
[0209] 1990 ACR--The American College of Rheumatology (ACR) classification criteria, developed in 1990, helped galvanize research on FMS. The criteria required the presence of widespread pain in combination with 11 or more of 18 specific tender point sites. Widespread pain was defined as "3 out of 4 quadrant" pain, including left- and right-sided and upper- and lower-segment pain, and axial pain.
3. Rationale
[0210] This study investigates the safety, tolerability and efficacy of cannabis tablets (10 mg THC and 2 mg of CBD) in female patients with fibromyalgia. The evaluation tools of the Fibromyalgia symptoms are commonly used and validated in multiple studies, thus, will allow investigating if the cannabis tablet is an efficient treatment.
4. Objectives
[0211] To evaluate the safety, tolerability and efficacy of cannabis tablets (10 mg THC and 2 mg of CBD) in female patients with fibromyalgia.
5. Risks and Benefits
[0212] Fibromyalgia symptoms, including pain, fatigue, sleep deprivation, and mood instability or depression, can be effectively treated with the use Cannabinoids from cannabis (Cannabis sativa) cannabinoids, mimic the body's own naturally produced endocannabinoids. The cannabinoids in cannabis bind to the same endocannabinoid receptors that are responsible for regulating body systems including pain, appetite, mood and memory.
[0213] There is an extensive literature on the risks of habitual marijuana use in humans, and a sizeable but considerably smaller literature on the acute effects of marijuana, including adverse events.
[0214] Most research examining risks of marijuana examine smoked marijuana, as vaporization is a relatively recent form of marijuana consumption. Thus most reported risks associated with ingesting or inhaling marijuana relate to its psychoactive effects, though marijuana can also produce acute effects on the cardiovascular system and continued use can produce effects on the pulmonary system.
[0215] In this study, the investigational product is in a tablet form and it is provided in escalating dose to prevent adverse events and undesired affects related to cannabis.
[0216] The controlled dosage of CBD and THC along with the strict patient monitoring, limit the risk to the participant.
6. Study Design
[0217] This is a single center, prospective, double-blind, placebo-controlled, randomized study.
TABLE-US-00002 TABLE 1 STUDY PROCEDURES PER VISIT Visit number 1 2 3 4 Time of Visit Week Week week week 1 2 4 6 Information & Informed consent x urine Cannabinoids & Pregnancy testing x x x x Epidemiological & Demographic data x x x x Medication Consumption x x x x BP, Heart Rate x x x x Blood testing (chemistry, blood count) x x x x Randomization x BMI x x Patient global impression of change x x x Brief pain inventory x x x x Tender point count x SF-36 x x Hamilton depression score x x Fibromyalgia impact questionnaire x X CBD and THC blood testing x * Adverse events x x x x Re-confirmation of patient eligibility Dispense study drug x x x collect *--on the baseline visit, one hour and 2 hours after tablet intake.
7. Study Population
[0218] Study population: 80 female subjects with established FMS confirmed by the 1990 ACR are enrolled after meeting the following inclusion and exclusion criteria:
7.1 Inclusion Criteria
[0219] Subjects must satisfy inclusion criteria to be enrolled into the study:
[0220] Individuals eligible to be enrolled into this protocol are participants who:
[0221] Female with established FMS confirmed by the 1990 ACR
[0222] 18-75 years old
[0223] The score on the average pain severity item of the BPI is .gtoreq.5 at randomization
[0224] A female subject is eligible to participate if she is of non-childbearing potential (postmenopausal or pre-menopausal females with a documented tubal ligation or hysterectomy). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol.
[0225] Willing to sign an Informed Consent
[0226] Agree not to participate in any other interventional clinical trials during the study
[0227] Agree to follow study instructions meticulously
7.2 Exclusion Criteria
[0228] 1. Confirmed pregnancy [0229] 2. Breast feeding patients [0230] 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test [0231] 4. Patients with congestive heart failure [0232] 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) [0233] 6. Patients with coexistent t rheumatic/inflammatory conditions [0234] 7. Patients with active gastrointestinal bleeding [0235] 8. Patients with renal failure [0236] 9. Patients with comorbid conditions causing significant disability [0237] 10. Patients with uncontrolled hypertension. [0238] 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). [0239] 12. Usage of anti-epileptic drugs [0240] 13. A high level of suicidality (a score above 3 in the relevant Hamilton score). [0241] 14. Patients who are drivers of public transportation or heavy vehicles. [0242] 15. A history of drug or alcohol abuse, or a history of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mililiter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. [0243] 16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives (whichever is longer). [0244] 17. Have any current problem or a history of substance abuse which, in the opinion of the investigator, might interfere with participation in the protocol.
8. Study Procedures
[0245] The subjects are screened against eligibility criteria and in order to confirm eligibility, subject will be tested for pregnancy, urine Cannabinoids (to exclude substance abuse). Patients will be consented and the following procedures will be performed: [0246] Subjects will be randomized to one of the study arms (treatment or placebo). [0247] Documentation of Medical history and medication consumption (present and past) [0248] BP, Heart Rate, Blood testing (chemistry, blood count). [0249] Fibromyalgia Tender Points counts. [0250] BMI calculation [0251] Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD).
[0252] Based on the urine testing and questionnaires, eligibility confirmation will be performed and the patient will be asked to swallow a tablet. 1 hour and 2 hours after tablet intake Blood tests for CBD and THC will be performed.
[0253] Patients are instructed to start home use of a single tablet at night time with a possible bidaily increment up to a maximum dosage of 10 tablets. The increments are done at night time and when needed the other half dose is taken every morning.
[0254] On the follow-up visits (including final visit) the following is performed: [0255] Documentation medication consumption. [0256] Urine testing for pregnancy and Cannabinoids. [0257] BP, Heart Rate, Blood testing (chemistry, blood count). [0258] Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD).
[0259] At the final visit, the un-used tablets are collected.
[0260] In case of an Adverse Event, patients will be asked to contact the clinic immediately. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner.
8.1 Unscheduled Visits
[0261] An unscheduled visit is a visit unrelated to the study visits. It should be distinguished from an "Out of Window" visit that was performed outside the .+-.2 day visit window allowed per protocol, but was planned. In case of an "Out of Window" visit, the data collected at the visit is recorded in the closest scheduled visit CRF pages.
9. Treatment Principles
9.1 Method of Subject Identification
[0262] Subjects signing the informed consent are assigned a unique screening identifying number (3 digits number) and additional unique randomization number.
9.2 Removal of Subjects from Therapy or Assessment
[0263] All subjects are free to withdraw from participation in the study at any time, for any reason, without prejudice. The investigator may terminate a subject from the study at any time for lack of therapeutic effect that is intolerable to the subject or otherwise considered unacceptable, for intolerable or unacceptable AE's, inter-current illness, noncompliance with study procedures, or in the investigator's opinion to protect the subject's best interest.
[0264] All subjects prematurely discontinuing the study must be seen for a final evaluation unless the subject withdrew consent. If a subject is withdrawn before completing the study, the date and reason for withdrawal are entered on the appropriate page of the case report form (CRF). If study withdrawal was due to an AE, the subject should be followed until resolution or until the principal investigator deems it to be no longer medically indicated.
[0265] The primary reason for a premature withdrawal will be selected from the following standard categories of early termination: Adverse Event (AEs): Clinical or laboratory events which occurred that in the medical judgment of the investigator for the best interest of the subject are grounds for discontinuation. This includes serious and non-serious AEs regardless of relation to the study product. [0266] 1. Death of the subject. [0267] 2. Withdrawal due to Pregnancy. [0268] 3. Withdrawal of Consent: The subject desired to withdraw from further participation in the study in the absence of a medical need to withdraw as determined by the investigator. If the subject gave a reason for this desire, this should be recorded in the CRF. [0269] 4. Protocol Violation: The subject's findings or conduct failed to meet the protocol entry criteria or failed to adhere to the protocol requirements (e.g. treatment noncompliance, failure to return for defined number of visits). The violation necessitated premature termination from the study. [0270] 5. Lost to Follow-Up: The subject stopped coming for visits and study personnel were unable to contact the patient. 6. Other: The subject was terminated for a reason other than those listed above (e.g., termination of study by Principal Investigator). The actual reason should be entered into the CRF.
9.3 Concomitant Therapy
[0271] Medications, not allowed prior to the start of the study, are listed in the exclusion criteria.
[0272] In case of new medications or changes in dosing of existing medications, the drug, reason for use, dose and dosage regimen must be recorded in the Case Report Form.
[0273] Females must continue the use of contraceptives. These must be recorded in the Case Report Form.
[0274] For any concomitant therapy given as a treatment for a new condition or a worsening of an existing condition, the condition must be documented on the Adverse Event Form of the CRF.
9.4 Laboratory Tests
[0275] Blood samples for biochemistry, serology and haematology including and a urine sample for urinalysis and drugs screen are taken as defined in the protocol and as per PI decision.
[0276] Female subjects will provide a urine sample for a pregnancy test during the screening visit.
[0277] The Medical Center local laboratory test results will be transferred to the CRF. The lab report must be interpreted, signed and dated by the principal investigator or his/her designee; any clinically significant changes occurring during the study must be recorded on the AE Form of the CRF.
9.4.1 Chemistry:
[0278] Glucose, Urea, Creatinine, Sodium, Potassium, Chloride, Calcium, Phosphorus, Uric Acid, AST (SGOT), ALT (SGPT), Gamma GT, LDH, Alkaline Phosphatase, Total Bilirubin, Direct Bilirubin, Total Protein, Albumin, Total Cholesterol, HDL, LDL, Trig
9.4.2 Hematology:
[0279] Haemoglobin, Haematocrit, RBC, MCV, WBC, White differential blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), Platelets count, MPV.
9.4.3 Urinalysis
[0280] A 20 ml midstream urine sample must be provided for urinalysis for Cannabinoids.
9.5 Vital Signs
[0281] Blood pressure and heart rate measurements are assessed either manually by a sphygmomanometer or by an automated blood pressure device.
[0282] Heart rate and blood pressure are obtained at specified time points after subject has been in a supine position for 5 minutes.
10. Investigational Product (MGC, Ointment)
[0283] The principal investigator must maintain an adequate record of the receipt, distribution and return or destruction of all MGC tubes using an appropriate accountability forms provided for the study by the Sponsor. These forms must be available for inspection at any time.
10.1 Packing and Labelling
[0284] All tablets are packed and labeled in compliance with the EUROPEAN COMMISSION, Good Manufacturing Practice, Annex 13 (Brussels, 3 Feb. 2010) and according to the Israeli Guidelines for Clinical Trials in Human Subjects, 2006 (section 11 from December 2008).
11. Statistical Methods
11.1 Sample Size Justification
[0285] A sustained response is defined as a 30% reduction from baseline to endpoint in the BPI with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between. The primary outcome variable is the reduction in BPI from baseline to endpoint.
12. Adverse Events
12.1 Definitions
12.1.1 Adverse Event (AE):
[0286] Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device.
12.1.2 Serious Adverse Event (SAE):
[0287] Adverse event that [0288] a) Led to death, [0289] b) Led to serious deterioration in the health of the subject, that either resulted in [0290] 1) A life-threatening illness or injury, or [0291] 2) A permanent impairment of a body structure or a body function, or [0292] 3) In-patient or prolonged hospitalization, or [0293] 4) Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, [0294] c) Led to fetal distress, fetal death or a congenital abnormality or birth defect Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration in health, is not considered a serious adverse event.
12.1.3 Unexpected Adverse Event
[0295] An adverse event of which the nature or severity of which is not consistent with the applicable product information.
12.1.4 Life-Threatening
[0296] Any event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
12.1.5 Adverse Event Severity
[0297] The investigator rates the severity of an adverse event as follows: [0298] Grade 1--Mild AE [0299] Grade 2--Moderate AE [0300] Grade 3--Severe AE [0301] Grade 4--Life threatening or disabling AE [0302] Grade 5--Death related to AE
12.1.6 Adverse Event Attribution
[0303] Attribution definitions are in accordance with the NCI-CTEP guidelines for adverse events reporting.
[0304] An adverse event is considered associated with the use of the MGC ointment if the attribution is possible, probable or definite.
[0305] Adverse event attribution categories:
[0306] Unrelated--The AE is clearly not related to the use of the MGC ointment.
[0307] Unlikely--The AE is doubtfully related to the use of the MGC ointment.
[0308] Possible--The AE may be related to the use of the MGC ointment.
[0309] Probable--The AE is likely related to the use of the MGC ointment.
[0310] Definite--The AE is clearly related to the use of the MGC ointment.
12.1.7 Adverse Event Reporting
[0311] Adverse events or baseline signs and symptoms that occur during the screening period, between signing of the Informed Consent and actual MGC ointment treatment will be documented as part of the applicable medical history page(s) and adverse events pages of the CRF which will allow for designation of the event/symptom as a baseline event/symptom.
[0312] Adverse events occurring after the MGC ointment treatment will be reported on the adverse events CRF page and followed to satisfactory resolution. New adverse events will be recorded 1 week post end of MGC ointment active treatment visit.
[0313] SAEs should be reported by the investigator to the sponsor within 24 hours of their occurrence by telephone, facsimile (fax) or e-mail. The principal investigator must provide the minimal information: i.e. study number, subject's initials and date of birth, investigational product code number, period of administration, nature of the adverse event and the principal investigator's opinion of the attribution of a MGC to the SAE. This report of an SAE by telephone must always be confirmed by a written, more detailed report on the provided SAE reporting forms.
[0314] The Investigator shall report immediately, within 48 hours of actual knowledge of the event, to the chairman of the Institutional Ethics Committee, the following events: [0315] death; [0316] unexpected SAE when a connection between the event and use of the investigational product cannot be excluded; [0317] any malfunction in an investigational product that can compromise the safety and efficacy of the investigational product.
[0318] The Investigator shall issue the report on the provided SAE reporting form.
[0319] New SAEs will be reported up to 2 weeks following the end of active treatment visit.
[0320] Follow up of ongoing adverse events will continue until resolution or until the principal investigator deems them to be no longer medically indicated.
[0321] Mortality will be reported as an SAE. The date of death, cause of death of the subject in a clinical study, whether the event is expected or associated with the investigational agent and autopsy findings if applicable will be recorded in the CRF.
[0322] Pregnancies occurring during clinical study must be reported to Sponsor/EC within 24 hours using the provided reporting form. The outcome of the pregnancy must also be reported to Sponsor/EC.
[0323] Appropriate reporting of adverse events to the regulatory authorities will be performed. All serious adverse events that are unexpected and associated with the use of MGC to the principal investigator(s) will be reported.
[0324] Unexpected Serious Adverse Effect that somehow related to treatment with the investigational product occurring in sites in Israel, shall be report to the Ministry of Health, the Investigators and all the parties involved in the trial, according to the following timetable: [0325] A. Cases of death or life-threatening events shall be reported within 7 days of the Sponsor's actual knowledge of the event. [0326] B. All other events shall be reported within 15 days of the Sponsor's actual knowledge of the event.
[0327] It is the principal investigator's responsibility to report such adverse events to the Local Ethics Committee (EC) which has approved the protocol unless otherwise required and documented by the EC.
[0328] Each subject will be provided with a "study card" indicating the name of the MGC ointment and indication, the study number, the principal investigator's name, the site's name and a 24-hour emergency contact number.
13. Study Closure Considerations
[0329] Reasons for closure of the investigational site(s) or termination of the study by the sponsor may include: [0330] 1. Successful completion of the study at the center; [0331] 2. The required number of subjects for the study has been recruited; [0332] 3. Failure of the principal investigator to comply with the protocol or GCP guidelines; [0333] 4. Safety concerns; [0334] 5. Sufficient data suggesting lack of efficacy; [0335] 6. Inadequate recruitment of subjects by the principal investigator(s)
14. Ethics and Regulations
[0336] This study is conducted in accordance with the following guidelines and regulations: [0337] Declaration of Helsinki 2008: Sixth revision, 59th Meeting, Seoul, [0338] Public Health Regulations: Clinical Trials in Human Subjects, Israel Ministry of Health, 1980 [0339] Guidelines for Clinical Trials in Human Subjects, Israel Ministry of Health, 2014.
[0340] These standard and guidelines addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety or efficacy for regulatory purposes.
[0341] Compliance with this standard provides public assurance that the rights, safety and well-being of study subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical study data are credible.
15. Study Materials And Documentation
[0342] The principal investigator acknowledges that the study medications is an investigational and as such must be handled strictly in accordance with the protocol and the container label. Study medication must be verified upon receipt and retained in a safe, secure location and stored under the appropriate conditions as specified on delivery. Study medication should be dispensed under the supervision of the principal investigator's designee such as the medical center pharmacist (if applicable). All dispensing must be performed by the site recorded on the Investigator's Statement.
15.1 Subject Information and Informed Consent
[0343] The informed consent process will be conducted in accordance with "Good clinical practice". Prior to entry in the study, the principal investigator or his/her designee must explain to potential subjects the study and the implications of participation. Subjects will be informed that their participation is voluntary and that they may withdraw consent to participate at any time. They will be informed that choosing not to participate will not impact on the care that the subject will receive for the treatment of his/her disease. Subjects will be told that alternative treatments are available if they refuse to take part and that such refusal will not prejudice future treatment. Finally, they will be told that their records may be accessed by competent authorities and CRO without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) and/or regulations. By signing the Informed Consent Form (ICF) the subject is authorizing such access.
[0344] After this explanation and before entry to the study, written, dated and signed informed consent should be obtained from the subject or legally acceptable representative.
[0345] The subject will be given sufficient time to read the Informed Consent Form and to ask questions. After this explanation and before entry to the study, consent should be appropriately recorded by means of both the subject's dated signature and the principal investigator's designee who conducted the informed consent discussion. After having obtained the consent, a copy of the Informed Consent must be given to the subject.
[0346] The informed consent form will contain contact details for the subject in case of pertinent questions about subject rights and in case of research related injury.
[0347] In case the subject is unable to read, an impartial witness must attest the informed consent. Subjects who are unable to comprehend the information provided are unable to be enrolled.
15.2 Source Data & Source Documents
[0348] If data are inadvertently recorded directly into the CRF, there should be, at a minimum, an entry in the medical record that each of the assessments was done, by whom, and the date it was done.
[0349] The nature and location of all source documents will be identified to ensure that all sources of original data required to complete the CRF are known to the company and investigational staff and are accessible for verification by the monitor. If electronic records are maintained, the method of verification must be discussed between the investigational staff and the monitor.
[0350] Source documents should include the following information for each subject: [0351] subject identification (name, date of birth, gender) [0352] documentation that subject meets eligibility criteria, i.e., history, physical examination, and confirmation of diagnosis (to support inclusion and exclusion criteria) [0353] participation in the study (including study number) [0354] study discussed and informed consent forms [0355] dates of visits [0356] documentation that protocol specific procedures were performed [0357] results of efficacy parameters, as required by the protocol [0358] Investigational product start and end date [0359] record of all adverse events and other safety parameters [0360] concomitant medication [0361] date of study completion and reason for early discontinuation, if applicable
[0362] Each laboratory test will be reviewed for clinical significance, signed and dated by the Principal Investigator's designees/Co-PI.
15.3 Case Report Form
[0363] All data relating to the study must be recorded on CRFs. These CRFs are to be completed in a timely fashion, with the exception of results of tests performed outside the investigator's office, so that they always reflect the latest observations on the subjects participating in the study.
[0364] The CRF will be compared with the source documents to ensure that there are no discrepancies between data. All entries, corrections and alterations are to be made by the principal investigator's designees.
15.4 Subject Identification Log
[0365] In order to permit easy identification of the individual subject during and after the study, the principal investigator is responsible for keeping an updated Subject Identification Log. The Subject Identification Log records the personal identification of all subjects that have signed the informed consent form. This document will be reviewed by the monitor for completeness. However, in order to ensure subject confidentiality, no copy will be made.
15.5 Archiving
[0366] The principal investigator shall maintain the study documents. Study document include those listed in "Good clinical practice" and any additional documents required by the applicable regulatory requirement(s). The principal investigator should take measures to prevent accidental or premature destruction of these documents.
[0367] Essential documents should be retained until at least 2 years after the last approval of a marketing application and until there are no pending or contemplated marketing applications, or at least until 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements.
[0368] If it becomes necessary for the appropriate Regulatory Authority to review any documentation relating to this study, the principal investigator must permit access to such reports.
15.6 Protocol Modification
[0369] Any protocol modification must be documented in writing. Any change in the research activity, except that necessary to remove an apparent immediate hazard to the patient, must be reviewed and approved by the local ethics committee before implementation and submitted to the regulatory authorities.
15.7 Privacy of Personal Data
[0370] The processing of personal data in pursuit of this study will be limited to those data that are reasonably necessary to investigate the efficacy, safety, quality and utility of the investigational product(s) used in this study.
[0371] These data will be processed with adequate precautions to ensure confidentiality.
[0372] It is ensured that the personal data are: [0373] 1. Collected for a specified and legitimate purpose [0374] 2. Processed fairly and lawfully [0375] 3. Accurate and up to date
[0376] Explicit consent for the processing of personal data will be obtained from the participating subject (or his/her legally acceptable representative) prior to any processing of personal data.
[0377] This confidentiality will be maintained throughout the complete data processing.
* * * * *
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20180116998.PGNR.&OS=DN/20180116998&RS=DN/20180116998
$OWCP
United States Patent Application 20180116998
Kind Code A1
Sinai; Alon ; et al. May 3, 2018
USE OF CANNABIS TO TREAT FIBROMYALGIA, METHODS AND COMPOSITIONS THEREOF
Abstract
The present invention discloses a composition comprising cannabis natural extract, or synthetic cannabinoids, for use in treating a subject suffering from fibromyalgia. The present invention further discloses methods and uses of the aforementioned composition.
Inventors: Sinai; Alon; (Petach Tikva, IL) ; Turner; Ziv; (Petach Tikva, IL) ; Baruch; Yehuda; (Gedera, IL)
Applicant:
Name City State Country Type
ONE WORLD CANNABIS LTD
Petach Tikva
IL
Assignee: ONE WORLD CANNABIS LTD
Petach Tikva
IL
Family ID: 1000003097448
Appl. No.: 15/573687
Filed: May 11, 2016
PCT Filed: May 11, 2016
PCT NO: PCT/IL2016/050498
371 Date: November 13, 2017
Related U.S. Patent Documents
Application Number Filing Date Patent Number
62160609 May 13, 2015
Current U.S. Class: 1/1
Current CPC Class: A61K 31/352 20130101; A61K 31/05 20130101; A61P 25/04 20180101; A61K 36/185 20130101
International Class: A61K 31/352 20060101 A61K031/352; A61K 31/05 20060101 A61K031/05; A61P 25/04 20060101 A61P025/04; A61K 36/185 20060101 A61K036/185
Claims
1.-87. (canceled)
88. A composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
89. The composition of claim 88, wherein at least one of the following holds true: a) said Tetrahydrocannabinol (THC) or a derivative thereof, or said Cannabidiol (CBD) or a derivative thereof is from cannabis extract; b) said THC a derivative thereof is selected from the group consisting of THC, Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCA) and any combination thereof; c) said THC or a derivative thereof is selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof; d) said THC or a derivative thereof is extracted from cannabis; said cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof; e) said cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, cannabidivarin (CBDV), cannabidiolic acid (CBDA) and any combination thereof; f) said CBD or a derivative thereof is selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof; g) said CBD or a derivative thereof is extracted from cannabis; said cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof; h) the concentration of said THC is in the range of about 2% to about 85%; and i) the concentration of said CBD is in the range of about 2% to about 85%.
90. The composition of claim 88, further comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof of 4:1 or 5:1, respectively.
91. The composition of claim 88, wherein said composition is formulated for administration of at least one of: a) between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day; b) between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit; c) between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day; d) between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit; and e) about 1 to about 10 times per day.
92. The composition of claim 88, wherein at least one of the following holds true: a) said composition is administered in a manner selected from the group consisting of: intranasal, transdermal, topical, intravenous, oral, and any combination thereof; b) said composition is formulated in the form of drops; c) said composition is formulated in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof; and d) said composition is administered in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
93. The composition according to claim 92, wherein said composition provides a synergistic effect with respect to treatment of fibromyalgia when administered in combination with said therapeutic agent, as compared to the effect provided when said composition and said therapeutic agent administered separately.
94. The composition of claim 88, wherein at least one of the following holds true: a) said composition additionally comprises at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof; b) said composition further comprising flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof; c) said composition further comprising preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof; d) said composition is in a sustained release dosage form or in an immediate release dosage form; and e) said composition is in a sustained release dosage form selected from the group comprising of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
95. The composition of claim 88, wherein said composition is used for preventing the onset of a flareup of fibromyalgia symptoms in said subject.
96. The composition of claim 88, wherein said composition provides an improvement in fibromyalgia symptoms of said subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
97. The composition of claim 96, wherein at least one of the following holds true: a) said improvement in fibromyalgia symptoms is measured by an improvement in the subject's score of at least one point on said at least one pain severity scale, as compared to an established baseline or to a placebo; b) said at least one pain severity scale is selected from the group comprising of Brief pain inventory (BPI), Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD), fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HORS) and any combination thereof; c) said fibromyalgia symptoms are selected from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR and any combination thereof; and d) a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
98. The composition of claim 97, wherein said composition provides at least one of: a) an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5; b) a reduction in BPI score from baseline to endpoint; and c) a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
99. The composition of claim 88, wherein said composition provides at least one of: a) an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items; and b) improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
100. The composition of claim 99, Wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
101. A method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to said subject a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof in a therapeutically effective dosage.
102. The method of claim 101, additionally comprising at least one step selected from the group consisting of: a) formulating said composition to comprise a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; b) administering said THC or a derivative thereof in a dosage unit of between about 5 mg THC and about 20 mg THC, preferably about 10 mg THC per dosage unit; c) administering said CBD or a derivative thereof in a dosage of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day; d) administering said CBD or a derivative thereof in a dosage unit of between about 1 mg CBD and about 5 mg CBD, preferably about 2 mg CBD per dosage unit; e) formulating said composition in a dosage form of drops; f) preventing the onset of a fibromyalgia flareup in said subject; g) improving fibromyalgia symptoms of said subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo; h) providing an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5; i) providing a reduction in BPI score from baseline to endpoint; j) providing a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between; and k) providing an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
103. The method of claim 102, wherein at least one of the following folds true: a) the method additionally comprising steps of performing blood tests for CBD and THC 1 hour and 2 hours after said dosage unit intake; b) the method additionally comprising steps of selecting said fibromyalgia symptoms to be a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold; and c) said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
104. The method of claim 103, additionally comprising steps of providing improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
105. A composition comprising a therapeutically effective amount of cannabis formulation for use in relieving a subject suffering from fibromyalgia syndrome symptoms, wherein said cannabis formulation contains synthetic components of cannabis.
106. The composition of claim 105, wherein at least one of the following holds true: a) said synthetic components are synthetically produced tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; b) said composition comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; c) said composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day; and d) said composition is formulated for administration of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
107. A method for preventing the risk for the onset of a fibromyalgia flareup, wherein said method comprises steps of: a) formulating a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; and b) administering said composition to a subject in risk for suffering from a fibromyalgia flareup according to a predetermined protocol.
108. The method of claim 107, wherein at least one of the following holds true: a) said step of formulating further comprises formulating said composition comprises a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof, of 4:1 or 5:1, respectively; b) said method additionally comprising steps of administering said THC or a derivative thereof in a dosage of about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day per day; and c) said method additionally comprising steps of administering said CBD or a derivative thereof in a dosage of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
Description
FIELD OF THE INVENTION
[0001] The current invention relates to a novel treatment for fibromyalgia. More specifically the invention pertains to a composition comprising cannabis extract or fractions thereof, or cannabis synthetic components, for treating fibromyalgia.
BACKGROUND OF THE INVENTION
[0002] Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Fibromyalgia syndrome is believed to be caused by amplified painful sensations caused by the way the brain processes pain signals. Symptoms sometimes begin after a physical trauma, surgery, infection or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event.
[0003] Women are much more likely to develop fibromyalgia than are men. Many people who have fibromyalgia also have tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety and depression.
[0004] While there is no cure for fibromyalgia, a variety of medications can help control symptoms, as well as alterations of lifestyle habits such as exercise, relaxation and stress-reduction measures. The exact onset trigger is unknown but is believed to involve psychological, genetic, neurobiological and environmental factors, which among them stress levels are highly prominent.
[0005] The central symptom of fibromyalgia, namely widespread pain, appears to result from neuro-chemical imbalances including activation of inflammatory pathways in the brain which results in abnormalities in pain processing (Clauw D J et al., 2011, "The science of fibromyalgia". Mayo Clin Proc 86 (9): 907-11). The brains of fibromyalgia patients show functional and structural differences from those of healthy individuals, but it is unclear whether the brain anomalies cause fibromyalgia symptoms or are the product of an unknown underlying common cause. Some research suggests that these brain anomalies may be the result of childhood stress, or prolonged or severe stress (Schweinhardt P et al., October 2008, "Fibromyalgia: a disorder of the brain?". Neuroscientist 14 (5): 415-21).
[0006] Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2-4% of the population, with 9:1 female-to-male incidence ratio. FMS is the second most common disorder, after osteoarthritis, observed by rheumatologists. The defining symptoms of FMS include chronic widespread pain, intense pain in response to tactile pressure (allodynia), prolonged muscle spasms, weakness in the limbs, nerve pain, muscle twitching, palpitations and diffuse tenderness, along with fatigue, sleep disturbance and cognitive impairments. These impairments include problems with short- and long-term memory, short-term memory consolidation, impaired speed of information processing, reduced attention span and limited multi-tasking performance. FMS is a persistent disorder with symptoms that have a devastating effect on people's lives, including limited ability to engage in everyday activities, limited ability to maintain outside work and difficulties to maintain normal relationships with family, friends and employers. These limitations can lead to the occurrence of anxiety and depression in many FMS patients.
[0007] FMS is not completely understood, in part because there is no evidence of a single event that "causes" fibromyalgia. Rather, many physical and/or emotional stressors may trigger or aggravate symptoms. Those have included certain infections, such as a viral illness or Lyme disease, as well as emotional or physical trauma. Establishing proper diagnostic criteria is also a challenge.
[0008] As with many other syndromes, there is no efficient cure for FMS and no agreed upon treatment--the suggested treatment depends on the classification of choice. Those who regard FMS as a neurological disorder advocate pharmacotherapy. All current treatments, such as prescribed medications, aerobic exercises and cognitive behavioral therapies, consist of symptom management. Integrated programs based on these treatments have been shown to alleviate pain and some other symptoms but with limited effectiveness.
[0009] Fibromyalgia is currently treated with pain and depression management drugs. However, due to the origins of the disorder in the brain, and its association with high stress levels, there is a call for a medication that will enable both stress reduction and brain function modification.
[0010] Previous trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities, particularly in the treatment of pain resistant to conventional pain therapies.
[0011] In view of the above there is a long felt and unmet need for a naturally originated pharmaceutical composition that is specifically useful for treatment of fibromyalgia and chronic pain symptoms.
SUMMARY OF THE INVENTION
[0012] It is thus one object of the present invention to provide a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0013] It is also an object of the present invention to provide the aforementioned composition, wherein said Tetrahydrocannabinol (THC) or a derivative thereof, or said Cannabidiol (CBD) or a derivative thereof is from cannabis extract.
[0014] It is also an object of the present invention to provide the aforementioned composition comprising a therapeutically effective amount of cannabis extract for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0015] It is also an object of the present invention to provide the aforementioned composition, wherein the cannabis extract contains tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0016] It is also an object of the present invention to provide the aforementioned composition, wherein the THC or a derivative thereof is selected from the group consisting of THC, Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCA) and any combination thereof.
[0017] It is also an object of the present invention to provide the aforementioned composition, further comprising THC or a derivative thereof selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof.
[0018] It is also an object of the present invention to provide the aforementioned composition, wherein the THC or a derivative thereof is extracted from cannabis; the cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0019] It is also an object of the present invention to provide the aforementioned composition, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, cannabidivarin (CBDV), cannabidiolic acid (CBDA) and any combination thereof.
[0020] It is also an object of the present invention to provide the aforementioned composition, further comprising CBD or a derivative thereof selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0021] It is also an object of the present invention to provide the aforementioned composition, wherein the CBD or a derivative thereof is extracted from cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0022] It is also an object of the present invention to provide the aforementioned composition, wherein the concentration of the THC is in the range of about 2% to about 85%.
[0023] It is also an object of the present invention to provide the aforementioned composition, wherein the concentration of the CBD is in the range of about 2% to about 85%.
[0024] It is also an object of the present invention to provide the aforementioned composition, further comprising a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0025] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day.
[0026] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit.
[0027] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
[0028] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit.
[0029] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 1 to about 10 times per day.
[0030] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is administered in a manner selected from the group consisting of: intranasal, topical, transdermal, intravenous, oral, and any combination thereof.
[0031] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated in the form of drops.
[0032] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof.
[0033] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is administered in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
[0034] It is also an object of the present invention to provide the aforementioned composition, wherein the composition provides a synergistic effect with respect to treatment of fibromyalgia when administered in combination with the therapeutic agent, as compared to the effect provided when the composition and the therapeutic agent administered seperately.
[0035] It is also an object of the present invention to provide the aforementioned composition, wherein the composition additionally comprises at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof.
[0036] It is also an object of the present invention to provide the aforementioned composition, further comprising flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof.
[0037] It is also an object of the present invention to provide the aforementioned composition, further comprising preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof.
[0038] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is in a sustained release dosage form or in an immediate release dosage form.
[0039] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is in a sustained release dosage form selected from the group comprising of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
[0040] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is used for preventing the onset of a flareup of fibromyalgia symptoms in the subject.
[0041] It is also an object of the present invention to provide the aforementioned composition, wherein the composition provides an improvement in fibromyalgia symptoms of the subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
[0042] It is also an object of the present invention to provide the aforementioned composition, wherein the improvement in fibromyalgia symptoms is measured by an improvement in the subject's score of at least one point on the at least one pain severity scale, as compared to an established baseline or to a placebo.
[0043] It is also an object of the present invention to provide the aforementioned composition, wherein the at least one fibromyalgia severity scale is selected from the group comprising of Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HDRS) and any combination thereof.
[0044] It is also an object of the present invention to provide the aforementioned composition, wherein the fibromyalgia symptoms are selected from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR, and any combination thereof.
[0045] It is also an object of the present invention to provide the aforementioned composition, wherein the fibromyalgia symptoms is a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
[0046] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5.
[0047] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides a reduction in BPI score from baseline to endpoint.
[0048] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
[0049] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
[0050] It is also an object of the present invention to provide the aforementioned composition, wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
[0051] It is also an object of the present invention to provide the aforementioned composition, wherein said composition provides improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
[0052] It is another object of the present invention to disclose a method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to the subject a composition comprising cannabis extract in a therapeutically effective dosage.
[0053] It is still an object of the present invention to disclose a method for treating a subject suffering from fibromyalgia syndrome comprising steps of administering to said subject a composition comprising comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof in a therapeutically effective dosage.
[0054] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of providing said Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof derived from cannabis extract.
[0055] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of formulating the cannabis extract to contain tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0056] It is still an object of the present invention to disclose the above mentioned method, additionally comprising a step of selecting the THC or a derivative thereof from the group consisting of THC, THCV, THCA and any combination thereof.
[0057] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of extracting the THC or a derivative thereof from Cannabis; the cannabis is selected from the group comprising of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0058] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the cannabidiol (CBD) or a derivative thereof from the group consisting of CBD, CBDV, CBDA and any combination thereof.
[0059] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the CBD from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0060] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of extracting the CBD or a derivative thereof from Cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0061] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a synergistic effect with respect to treating fibromyalgia as compared to the effect provided by the THC or a derivative thereof and by the CBD or a derivative thereof when administered separately.
[0062] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition to comprise a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0063] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage of about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0064] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage unit of between about 5 mg THC and about 20 mg THC, preferably about 10 mg THC per dosage unit.
[0065] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage of about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
[0066] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage unit of between about 1 mg CBD and about 5 mg CBD, preferably about 2 mg CBD per dosage unit.
[0067] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition between about 1 to about 10 times through the day.
[0068] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition once, twice, three, four or five times through the day.
[0069] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition to the subject over a time period of about 1 day to about 6 months.
[0070] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of performing blood tests for CBD and THC 1 hour and 2 hours after said dosage unit intake.
[0071] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a dosage form of drops.
[0072] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a dosage form selected from the group consisting of oil, liquid, solid, gas, oral, pill, tablet, capsule, buccal, sub-lingual, orally-disintegrating, thin film, liquid solution, suspension, powder or liquid or solid crystals, pastes, inhalational, aerosol, inhaler, nebulizer, smoking, vaporizer, parenteral, intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, topical, cream, gel, liniment or balm, lotion, ointment, drops, skin patch, vaginal, suppository, pessary, rectal and any combination thereof.
[0073] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition in combination with at least one therapeutic agent selected from the group comprising of dypirone, pregabalin, duloxetine, milnacipran, tricyclic antidepressants, amitriptyline, gabapentin, paracetamol, tramadol, codeine, growth hormone, sodium oxybate, cyclobenzaprine, tizanidine, pramipexole, ropinirole, quercetin and any combination thereof.
[0074] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a synergistic effect with respect to treatment of fibromyalgia when administering the composition in combination with the fibromyalgia therapeutic agent, as compared to the effect provided when the composition and the therapeutic agent are administered seperatly.
[0075] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of administering the composition in a manner selected from the group consisting of: intranasal, transdermal, topical, intravenous, oral, and any combination thereof.
[0076] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one carrier or excipient selected from the group consisting of diluents, antiadherents, binders, coatings, disintegrants, surfactants, dissolving agents, solubilising agents, bioadhesive agents, polysaccharides, polymers, copolymers, fast dissolving tablet (FDT) type excipient, bioavailability enhancing agent, Thin Film type excipient, PharmFilm type excipient, mucoadhesive type excipient, acidifying agents, probiotic agents, protective agents, antioxidants, effervescent excipient, dispersing agents flavours, colours, lubricants, glidants, sorbents, preservatives, sweeteners, and any combination thereof.
[0077] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one flavoring agents, selected from the group consisting of sugar, sucrose, sorbitol, sucralose, saccharin sodium, sodium cyclamate, aspartame, neotame, acesulfame potassium, stevioside, sodium chloride, D-limonene, citric acid and any combination thereof.
[0078] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition with at least one preservatives, selected from the group consisting of methylparabens, ethylparabens, propylparabens, butylparabens, sorbic acid, acetic acid, propionic acid, sulfites, nitrites, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzonate, potassium benzonate, calcium benzonate, sodium metabisulfite, propylene glycol, benzaldehyde, butylated hydroxytoluene, butylated hydroxyanisole, formaldehyde donors, essential oils, monoglyceride, phenol, mercury components and any combination thereof.
[0079] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a sustained release dosage form or in an immediate release dosage form.
[0080] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of formulating the composition in a sustained release dosage form; wherein the sustained release dosage form is selected from a group consisting of liposomes, drug polymer conjugates, microencapsulation, controlled-release tablet coating, and any combination thereof.
[0081] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of preventing the onset of a fibromyalgia flareup in the subject.
[0082] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of improving fibromyalgia symptoms of the subject as measured by at least one pain severity scale, compared to an established baseline, control or placebo.
[0083] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of measuring the improvement in the fibromyalgia symptoms of the subject by an improvement in the subject's score of at least one point on the at least one pain severity scale, as compared to an established baseline or to a placebo.
[0084] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the pain severity scale from a group consisting of brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, Hamilton Depression Rating Scale (HDRS) and any combination thereof.
[0085] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the fibromyalgia symptoms from the group comprising of widespread pain, chronic pain, cognitive difficulties, chronic muscle pain, muscle spasms, muscle tightness, fatigue, insomnia, stiffness, fibro fog, abdominal pain, bloating, nausea, constipation, diarrhea, headache, jaw and facial tenderness, anxiety, depression, numbness or tingling in the limbs, irritable bladder, feeling of swelling, painful menstruation, restless leg, dizziness, female or subject with established FMS confirmed by the 1990 ACR, and any combination thereof.
[0086] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of selecting the fibromyalgia symptoms to be a sensitivity to at least one of the following: odors, noise, bright lights, medications, certain foods, and cold.
[0087] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing an improvement in fibromyalgia symptoms of said subject measured by a score on the average pain severity item of the BPI scale of above 5.
[0088] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a reduction in BPI score from baseline to endpoint.
[0089] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing a sustained response defined as a 30% reduction from baseline to endpoint in the BPI score with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between.
[0090] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing an improvement in pain severity as measured by the self-reported Brief Pain Inventory (short form) average pain severity score fibromyalgia impact questionnaire items.
[0091] It is still an object of the present invention to disclose the above mentioned method, wherein said pain severity score fibromyalgia impact questionnaire items comprising items which measure physical function, pain assessment, fatigue and distress.
[0092] It is still an object of the present invention to disclose the above mentioned method, additionally comprising steps of providing improvement in measures selected from the group consisting of: quality of life, quality of sleep, disability, depression, anxiety and the patient global impression of change and the fibromyalgia severity score.
[0093] It is another object of the present invention to provide a use of a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof, in the manufacture of a medicament to treat fibromyalgia syndrome.
[0094] It is yet another object of the present invention to provide a composition comprising a therapeutically effective amount of cannabis formulation for use in relieving a subject suffering from fibromyalgia syndrome symptoms, wherein the cannabis formulation contains synthetic components of cannabis.
[0095] It is also an object of the present invention to provide the aforementioned composition, wherein the synthetic components are synthetically produced tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof.
[0096] It is also an object of the present invention to provide the aforementioned composition, further comprising a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0097] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0098] It is also an object of the present invention to provide the aforementioned composition, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg CBD and about 20 mg CBD per day.
[0099] It is another object of the present invention to disclose a method for preventing the risk for the onset of a fibromyalgia flareup, wherein the method comprises steps of: formulating a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof; and administering the composition to a subject in risk for suffering from a fibromyalgia flareup according to a predetermined protocol.
[0100] It is still an object of the present invention to disclose the aforementioned method, wherein the step of formulating further comprises formulating the composition to comprise a ratio of the THC, or a derivative thereof, to the CBD, or a derivative thereof, of 4:1 or 5:1, respectively.
[0101] It is still an object of the present invention to disclose the aforementioned method, additionally comprising steps of administering the THC or a derivative thereof in a dosage of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg THC and about 100 mg THC per day.
[0102] It is lastly an object of the present invention to disclose the aforementioned method, additionally comprising steps of administering the CBD or a derivative thereof in a dosage of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0103] In the following detailed description of the preferred embodiments, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration specific embodiments in which the invention may be practiced. It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention. The present invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the present invention is not unnecessarily obscured.
[0104] The essence of the present invention is to provide a composition for treating fibromyalgia comprising cannabis extract, which may further contain tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination thereof, or a synthetic cannabis composition, or a combination thereof.
[0105] Fibromyalgia patients frequently self-report using cannabis therapeutically to treat symptoms of the disease. To date however, there is still a need for clinical trials assessing the use of cannabinoids to treat the disease.
[0106] In a main embodiment, the present invention provides a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms. It is emphasised that the composition of the present invention is useful for treating chronic pain conditions such as fibromyalgia.
[0107] In a further embodiment, the composition of the present invention, comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof is useful for treating chronic pain.
[0108] Without wishing to be bound by theory, it is herein acknowledged that the principal active component in the complex mixture of cannabinoids present in the marijuana plant is D9-tetrahydrocannabinol (THC), which acts primarily as an agonist at the CB1 cannabinoid receptor. This receptor is found at high concentrations in the brain, including the basal ganglia and cerebellar regions, and also in the hippocampus and hypothalamus. THC has been shown to inhibit the release of a wide spectrum of neurotransmitters including L-glutamate, GABA, norepinephrine, dopamine, serotonin (5-HT), and acetylcholine (Schlicker and Kathmann, 2001).
[0109] It is further acknowledged that marijuana contains other compounds of interest, including cannabidiol (CBD), a constituent of marijuana that is not a CB1 or CB2 receptor agonist (Burstein and Zurier, 2009; Scuderi et al., 2009). An early safety study reported that CBD was tolerated when administered to humans for 30 days (Cunha et al., 1980).
[0110] It is further within the scope that cannabinoids also modulate GABAergic transmission and the release of cholecystokinin (CCK), a peptide that may contribute to both anxiolytic and anxiogenic effects of THC and endocannabinoids (Beinfeld and Connolly, 2001; Katona et al., 1999; Marsicano and Lutz, 1999; Onaivi et al., 1990). Furthermore, cannabinoids enhance the release of endogenous opioids, and these may be involved in the functional interplay between the endocannabinoid and the opioid system and the production of analgesic responses. It is hypothesized that the relationship between these two systems plays a role in antidepressant-like effects and in various addiction-related processes (Houser et al., 2000; Pugh et al., 1997; Zimmer et al., 2001). Studies in rodents suggest that cannabinoids and their interaction with endogenous opioids might also modulate anxiety (Pugh et al., 1997; Berrendero and Maldonado, 2002; Marin et al., 2003).
[0111] It is an object of the present invention to use pharmacological modulation of the endocannabinoid system in the treatment of fibromyalgia related symptoms.
[0112] The composition of the present invention mainly comprises of cannabis extract drops. Such cannabis drops essentially comprises the cannabinoid Tetrahydrocannabinol (THC). The cannabis oil of the composition of the present invention may also include cannabidiol (CBD) that is known to potentiate the activity of THC by increasing CB1 receptor density or through another CB1-related mechanism (Hayakawa et al., 2008). CBD may increase the efficiency of the composition as well as will enable using lower concentrations of THC. The cannabis drops may also be formulated out of synthetic cannabis components or a combination of synthetic and naturally extracted components of cannabis.
[0113] As used herein the term "about" denotes .+-.25% of the defined amount or measure or value.
[0114] The term "cannabis" refers hereinafter to a genus of flowering plants that includes three different species, Cannabis sativa, Cannabis indica and Cannabis ruderalis.
[0115] The term "cannabidiol (CBD)" refers hereinafter to one of at least 85 active cannabinoids identified in cannabis. Cannabidiol is a major phytocannabinoid, accounting for up to 40% of the plant's extract. CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol (THC). Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists. CBD may potentiate THC's effects by increasing CB1 receptor density or through another CB1-related mechanism. It is also an inverse agonist of CB2 receptors. CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion.
[0116] The term "Tetrahydrocannabinol (THC)" refers hereinafter to the principal psychoactive constituent (or cannabinoid) of the cannabis plant. THC has a partial agonist activity at the cannabinoid receptor CB1, and the CB2 receptor and is known to increase cortisol levels. THC may refer to delta-9-tetrahydrocannabinol, delta-6-tetrahydrocannabinol and delta-1-tetrahydrocannabinol.
[0117] The term "cannabinoid receptor" refers hereinafter to a class of cell membrane receptors under the G protein-coupled receptor superfamily. There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2. The CB 1 receptor is expressed mainly in the brain, but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly in the immune system and in hematopoietic cells.
[0118] The term "Cannabinoid receptor type 1 (CB1)" refers hereinafter to a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system. It is activated by the endocannabinoid neurotransmitters anandamide and 2-arachidonoyl glyceride (2-AG); by plant cannabinoids, such as the compound THC, an active ingredient of the psychoactive drug cannabis; and by synthetic analogues of THC.
[0119] The term "Cannabinoid receptor type 2 (CB2)" refers hereinafter to a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of Tetrahydrocannabinol, the active agent in marijuana, and other phytocannabinoids (natural cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG).
[0120] The term "fibromyalgia" as used herein refers to a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. It is acknowledged that women are more likely to develop fibromyalgia than men. It is noted that people who have fibromyalgia sometimes also have tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety and depression. It is within the scope that the term "fibromyalgia" further refers to chronic pain conditions and symptoms.
[0121] The term "chronic pain" as used herein refers a pain that lasts a long time. It is acknowledged that In medicine, the distinction between acute and chronic pain is sometimes determined by an arbitrary interval of time since onset; the two most commonly used markers being 3 months and 6 months since onset, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months. Others apply acute to pain that lasts less than 30 days, chronic to pain of more than six months duration, and subacute to pain that lasts from one to six months.[3] A popular alternative definition of chronic pain, involving no arbitrarily fixed duration, is "pain that extends beyond the expected period of healing". Epidemiological studies have found that 10.1% to 55.2% of people in various countries have chronic pain.
[0122] The term "sustained release dosage form" refers hereinafter to the release of a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects. This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates. Sustained release's definition is more akin to a "controlled release" rather than "sustained".
[0123] The term "fibromyalgia severity scale" refers hereinafter to rating and scales that are commonly used as measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients which exhibit fibromyalgia syndrome symptoms. The fibromyalgia severity scale may be selected from a few commonly used scales, which may include in a non-limiting example, pain severity scale, Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, fibromyalgia syndrome Tenderness Assessment, and Hamilton Depression Rating Scale (HDRS).
[0124] The term "established baseline" or "control" or "placebo" refers hereinafter to the results obtained by a subject or group of subjects that was not administered or otherwise exposed to the composition of the present invention and used as a control for the clinical study. Specifically, the term "placebo" refers to a substance containing no medication and prescribed or given to reinforce a patient's expectation to get well. According to further aspects, a placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect. It is within the scope that in medical research, placebos are given as control treatments and depend on the use of measured suggestion. Examples of common placebos include inert tablets, vehicle infusions, sham surgery, and other procedures based on false information. The term "established baseline" refers hereinafter to data collected at the beginning of a clinical study for all participants and for each arm or comparison group. These data include demographics, such as age and gender, and study-specific measures (for example, systolic blood pressure, prior antidepressant treatment etc.).
[0125] The term "extract" refers hereinafter to any extract deriving from a plant, or fragment or fraction thereof.
[0126] Thus it is according to one embodiment of the present invention to provide a composition comprising tetrahydrocannabinol (THC) or a derivative thereof, or cannabidiol (CBD) or a derivative thereof, or a combination thereof, for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0127] It is further within the scope of the present invention to disclose the composition as defined above, wherein the THC or a derivative thereof is selected from the group consisting of THC, THCV, THCA and any combination thereof.
[0128] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the THC or a derivative thereof is selected from the group consisting of natural THC or a derivative thereof produced in the body of humans and animals, THC or a derivative thereof extracted from plants, synthetic THC or a derivative thereof, and any combination thereof.
[0129] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the THC or a derivative thereof is extracted from cannabis; the cannabis is selected from the group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0130] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition additionally comprising cannabidiol (CBD) or a derivative thereof.
[0131] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the cannabidiol (CBD) or a derivative thereof is selected from the group consisting of CBD, CBDV, CBDA and any combination thereof.
[0132] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the CBD or a derivative thereof is selected from the group consisting of natural CBD or a derivative thereof produced in the body of humans and animals, CBD or a derivative thereof extracted from plants, synthetic CBD or a derivative thereof, and any combination thereof.
[0133] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the CBD or a derivative thereof is extracted from cannabis; the cannabis is selected from a group consisting of: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any combination thereof.
[0134] It is well within the scope of the present invention to disclose a cannabis formulation for the treatment of fibromyalgia syndrome symptoms, containing only synthetic cannabis components, or a combination of synthetic cannabis components with naturally extracted cannabis components.
[0135] It is further within the scope of the present invention to disclose a composition comprising a therapeutically effective amount of Tetrahydrocannabinol (THC) or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a combination thereof for use in relieving a subject suffering from fibromyalgia syndrome symptoms.
[0136] It is further within the scope of the present invention to disclose the composition as defined in any of the above, further comprising a ratio of said THC, or a derivative thereof, to said CBD, or a derivative thereof of 4:1 or 5:1, respectively.
[0137] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 10 mg THC and about 160 mg THC per day, preferably between about 10 mg and about 100 mg THC per day, more preferably between about 10 mg and about 20 mg THC per day.
[0138] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein said composition is formulated for administration of between about 5 mg THC and about 20 mg THC per dosage unit, preferably about 10 mg THC per dosage unit.
[0139] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 2 mg CBD and about 40 mg CBD per day, preferably between about 2 mg and about 20 mg CBD per day, more preferably between about 2 mg and about 4 mg CBD per day.
[0140] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of between about 1 mg CBD and about 5 mg CBD per dosage unit, preferably about 2 mg CBD per dosage unit.
[0141] It is further within the scope of the present invention to disclose the composition as defined in any of the above, wherein the composition is formulated for administration of about 1 to about 10 times per day.
[0142] In order to understand the invention and to see how it may be implemented in practice, a plurality of preferred embodiments will now be described, by way of non-limiting example only, with reference to the following examples.
EXAMPLE 1
[0143] Organic, mental and functional aspects of the fibromyalgia syndrome are assessed in patients treated with cannabis drops compared to placebo. The protocol-defined primary outcome measure is pain severity as measured by the self-reported Brief Pain Inventory (BPI) (short form) average pain severity score fibromyalgia impact questionnaire (which measures physical function, pain assessment, fatigue and distress).
[0144] Secondary endpoints include validated parameters that measure quality of life, quality of sleep, disability, depression and anxiety and the patient global impression of change and the fibromyalgia severity score. In addition changes of concurrent medications are recorded.
[0145] Sample Size: The study will include eighty patients.
[0146] Maximal Study Duration time: up to 7 visits in up to 23 weeks as follows: [0147] Screening phase--up to 3 weeks, 1 visit [0148] Treatment phase--16 weeks, 4 visits [0149] Follow-up phase--4 weeks, 2 visits
[0150] Study Design: The study will be randomized and double-blinded, and will compare addition of cannabis drops versus placebo to female patients with fibromyalgia. Female patients with primary fibromyalgia syndrome will be recruited after obtaining their signed informed consent. The patients will be randomized to receive cannabis drops on an escalating scale or a placebo. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner. The duration of the study will be 6 weeks. There will be 4 biweekly office visits throughout these 6 weeks preceded by a screening visit. The study drug will be provided as an "add on" format.
[0151] The patients will start with the following drop dosage; every day of the first week each patient will take 5 drops, increments by five drops will be allowed by weekly intervals. The maximal dose will be no more than up to 20 drops twice daily. Dosage will be given at a 4:1 ratio between THC and CBD, wherein THC ranges from about 20 mg and about 160 mg per day, and CBD ranges from about 5 mg and 40 mg per day.
[0152] Inclusion Criteria: individuals eligible to be enrolled into this protocol are participants who: [0153] 1. Women with established fibromyalgia syndrome confirmed by the 1990 ACR classification criteria who signed an informed consent form. [0154] 2. Women 18-75 years old. [0155] 3. The score on the average pain severity item of the BPI is >5 at randomization. [0156] 4. Women of fertile age will need to use birth control measures.
[0157] Exclusion Criteria: individuals not eligible to be enrolled into this protocol are those who: [0158] 1. Confirmed pregnancy [0159] 2. Breast feeding patients [0160] 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test. [0161] 4. Patients with congestive heart failure [0162] 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) [0163] 6. Patients with coexistent t rheumatic/inflammatory conditions [0164] 7. Patients with active gastrointestinal bleeding [0165] 8. Patients with renal failure [0166] 9. Patients with comorbid conditions causing significant disability [0167] 10. Patients with uncontrolled hypertension. [0168] 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). [0169] 12. A high level of suicidality (a score above 3 in the relevant Hamilton score). [0170] 13. Patients with current or past history of substance abuse. [0171] 14. Patients who are drivers of public transportation or heavy vehicles
Experimental Design:
[0172] All women will be assessed by several rheumatic and psychiatric scales as following:
[0173] Brief pain inventory--Pain severity as measured by the self-reported BPI (short form) average pain severity score, which assesses average pain severity during the past 24 hours (0-10 scale, where 0=no pain and 10=pain as bad as you can imagine). A sustained response will be defined as a 30% reduction from baseline to endpoint in the BPI with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between. The primary outcome variable will be reduction in BPI from baseline to endpoint.
[0174] Sleep history questionnaire (PSQI)--PSQI is a validated sleeping scoring that measures sleep quality, impact on function and well being. A final score result below 5 reflects poor quality of sleep.
[0175] SF-36 Quality of life assessment--A Hebrew translated and validated version of the SF-36 scale measured quality of life. The SF-36 contains eight subscales: physical functioning (PF), social functioning (SF), role limitations attributable to physical and emotional problems, mental health, vitality, bodily pain, and general health.
[0176] Fibromyalgia impact questionnaire (FIQ)--This scale commonly performed in patients with FIBROMYALGIA SYNDROME is regarded to be a reliable and valid variable. The FIQ is less affected by temporary alterations and fluctuations of the disease severity.
[0177] Mini International Neuropsychiatric Interview this tools provides rapid assessment for comorbid psychiatric conditions.
[0178] Fibromyalgia syndrome Tenderness Assessment--Tenderness assessment was performed manually in all subjects by a senior rheumatologist; a count of 18 tender points (TP) will be performed by thumb palpation as specified in the ACR 1990 classification criteria.
[0179] Hamilton Depression Rating Scale (HDRS)--Major depressive disorder severity was determined by using the Hamilton Depression Rating Scale (HDRS). The HDRS is a 17-item scale that measures the presence and severity of depression. The HDRS is a reliable gauge of the degree of symptom severity in depressed patients.
[0180] All adverse events will be recorded at every office visit. Every serious adverse events will recorded within 24 hours from occurrence and the local ethics committee will be notified immediately.
[0181] BMI--weight and height will be measured at the beginning and end of the study.
[0182] In addition a urine toxic screen will be taken every visit, the patients will be blinded to the results of this tests throughout the study.
[0183] Statistical analysis: Prospective results are detailed for all data.
[0184] Data analysis will be two folded: group comparisons and correlations. Differences between the two groups of patients for continuous variables will be analyzed using. For categorical variables, group comparisons will be performed with the chi square test. Correlations between TP and other dependent variables will be calculated using Pearson correlations. Scores measured at several time points will also be analyzed by repeated measures ANOVA, absolutely and as percentage of baseline values.
EXAMPLE 2
A Randomized Double-Blinded Study Comparing Treatment with the Cannabis Tablets of the Present Invention Versus Placebo in Female Patients with Fibromyalgia
Abbreviations:
[0185] AE Adverse Event
[0186] BP Blood Pressure
[0187] CBD Cannabidiol
[0188] CRF Case Report Form
[0189] DCF Data Correction Form
[0190] ECG Electrocardiogram
[0191] EC Ethics Committee
[0192] FMS Fibromyalgia symptoms
[0193] GCP Good Clinical Practice
[0194] HCG Human Chorionic Gonadotropin
[0195] HIV Human Immunodeficiency Virus
[0196] HR Heart Rate
[0197] PI Principal Investigator
[0198] SAE Serious Adverse Event
[0199] THC Tetrahydrocannabinol
1. Protocol Synopsis
TABLE-US-00001 [0200] Title A randomized double-blinded study comparing treatment with Cannabis tablets versus placebo in female patients with fibromyalgia Phase of Phase II Development Primary To evaluate the safety, tolerability and efficacy of Objectives cannabis tablets (10 mg THC and 2 mg of CBD in female patients with fibromyalgia. Primary Pain severity as measured by the self-reported BPI (short Outcome form) average pain severity score fibromyalgia impact Measures: questionnaire (which measures physical function, pain assessment, fatigue and distress). Secondary 1. Quality of life, quality of sleep, disability, Outcome depression and anxiety and the patient global Measures: impression of change and the fibromyalgia severity score. 2. Changes of concurrent medications will be recorded. Safety 1. Collecting information on tolerability through self- Outcome reported reactions and experiences. Measures: 2. Collection of Adverse events and Serious Adverse Events. 3. Laboratory testing. Study Design This is a single center, prospective, double-blind, placebo- controlled, randomized study. Study The subjects are screened against eligibility criteria and in Methods order to confirm eligibility, subject will be tested for pregnancy (urine or blood), urine Cannabinoids (to exclude substance abuse). Patients will be consented and the following procedures will be performed: Subjects will be randomized to one of the study arms (treatment or placebo). Documentation of Medical history and medication consumption (present and past) BP, Heart Rate, Blood testing (chemistry, blood count). Fibromyalgia Tender Points counts. BMI calculation Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). Based on the urine testing and questionnaires, eligibility confirmation will be performed and the patient will be asked to swallow a tablet. 1 hour and 2 hours after tablet intake Blood tests for CBD and THC will be performed. Patients will be instructed to start home use of a single tablet at night time with a possible bidaily increment up to a maximum dosage of 10 tablets. The increments will be done at night time and when needed the other half dose will be taken every morning. On the follow-up visits (including final visit) the following will be performed: Documentation medication consumption. Urine testing for pregnancy and Cannabinoids. BP, Heart Rate, Blood testing (chemistry, blood count). Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). At the final visit, the un-used tablets will be collected. In case of an Adverse Event, patients will be asked to contact the clinic immediately. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner Number of Single Site Sites Maximal 4 biweekly visits in 6 weeks as follows: Study Screening visit--Week 0 Duration Follow-up visit--Week 2 and Week 4 time: Final visit--week 6 Flexibility of .+-.2 days will be permitted Sample Size 80 female subjects Inclusion 1. Female with established FMS confirmed by the Criteria 1990 ACR 2. 18-75 years old 3. The score on the average pain severity item of the BPI is .gtoreq.5 at randomization 4. A female subject is eligible to participate if she is of non-childbearing potential (postmenopausal or pre-menopausal females with a documented tubal ligation or hysterectomy). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol. 5. Willing to sign an Informed Consent 6. Agree not to participate in any other interventional clinical trials during the study 7. Agree to follow study instructions meticulously Exclusion 1. Confirmed pregnancy Criteria 2. Breast feeding patients 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test 4. Patients with congestive heart failure 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) 6. Patients with coexistent t rheumatic/inflammatory conditions 7. Patients with active gastrointestinal bleeding 8. Patients with renal failure 9. Patients with comorbid conditions causing significant disability 10. Patients with uncontrolled hypertension. 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). 12. Usage of anti-epileptic drugs 13. A high level of suicidality (a score above 3 in the relevant Hamilton score). 14. Patients who are drivers of public transportation or heavy vehicles. 15. A history of drug or alcohol abuse, or a history of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mililiter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. 16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives (whichever is longer). 17. Have any current problem or a history of substance abuse which, in the opinion of the investigator, might interfere with participation in the protocol. 18. Have used marijuana within a month of starting the study.
Fibromyalgia Assessment Tools
[0201] The following questionnaires are used in the study. They are validated and commonly used.
[0202] Brief pain inventory--The Brief Pain Inventory (BPI) is a self-administered questionnaire developed to assess pain and the impact of pain. It was developed for use in cancer pain, but has also been used in other chronic pain conditions.
[0203] Sleep history questionnaire (PSQI)--PSQI is a validated sleeping scoring that measures sleep quality, impact on function and wellbeing. A final score result below 5 reflects poor quality of sleep.
[0204] SF-36 Quality of life assessment--A Hebrew translated and validated version of the SF-36 scale measured quality of life. The SF-36 contains eight subscales: physical functioning (PF), social functioning (SF), role limitations attributable to physical and emotional problems, mental health, vitality, bodily pain, and general health. Each scale is scored on a VAS (0 to 100) with a high score indicating better health and less body pain. The completion of this study was conducted with the aid of a senior psychiatrist.
[0205] Fibromyalgia impact questionnaire (FIQ)--This scale commonly performed in patients with FMS is regarded to be a reliable and valid variable. The FIQ is less affected by temporary alterations and fluctuations of the disease severity.
[0206] Mini International Neuropsychiatric Interview this tools provides rapid assessment for comorbid psychiatric conditions.
[0207] FMS Tenderness Assessment--Tenderness assessment will be performed manually in all subjects by a senior rheumatologist; a count of 18 tender points (TP) will be performed by thumb palpation as specified in the ACR 1990 classification criteria. The subject was asked to say "yes" when the sensation altered from pressure to definite pain. Patients will be considered to have FMS if he complied with the ACR criteria defining the FMS e.g., having widespread musculoskeletal pain with excess tenderness in at least 11 of 18 the predefined anatomic sites.
[0208] Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD). These two scales are widely used to gauge the severity of anxiety and depression. The HAM-A consists of 14 items designed to assess the severity of a patient's anxiety. Each of the 14 items contains a number of symptoms, and each group of symptoms is rated on a scale of zero to four, with four being the most severe. The HDRS is a 17-item scale that measures the presence and severity of depression. The HDRS is a reliable gauge of the degree of symptom severity in depressed patients.
[0209] 1990 ACR--The American College of Rheumatology (ACR) classification criteria, developed in 1990, helped galvanize research on FMS. The criteria required the presence of widespread pain in combination with 11 or more of 18 specific tender point sites. Widespread pain was defined as "3 out of 4 quadrant" pain, including left- and right-sided and upper- and lower-segment pain, and axial pain.
3. Rationale
[0210] This study investigates the safety, tolerability and efficacy of cannabis tablets (10 mg THC and 2 mg of CBD) in female patients with fibromyalgia. The evaluation tools of the Fibromyalgia symptoms are commonly used and validated in multiple studies, thus, will allow investigating if the cannabis tablet is an efficient treatment.
4. Objectives
[0211] To evaluate the safety, tolerability and efficacy of cannabis tablets (10 mg THC and 2 mg of CBD) in female patients with fibromyalgia.
5. Risks and Benefits
[0212] Fibromyalgia symptoms, including pain, fatigue, sleep deprivation, and mood instability or depression, can be effectively treated with the use Cannabinoids from cannabis (Cannabis sativa) cannabinoids, mimic the body's own naturally produced endocannabinoids. The cannabinoids in cannabis bind to the same endocannabinoid receptors that are responsible for regulating body systems including pain, appetite, mood and memory.
[0213] There is an extensive literature on the risks of habitual marijuana use in humans, and a sizeable but considerably smaller literature on the acute effects of marijuana, including adverse events.
[0214] Most research examining risks of marijuana examine smoked marijuana, as vaporization is a relatively recent form of marijuana consumption. Thus most reported risks associated with ingesting or inhaling marijuana relate to its psychoactive effects, though marijuana can also produce acute effects on the cardiovascular system and continued use can produce effects on the pulmonary system.
[0215] In this study, the investigational product is in a tablet form and it is provided in escalating dose to prevent adverse events and undesired affects related to cannabis.
[0216] The controlled dosage of CBD and THC along with the strict patient monitoring, limit the risk to the participant.
6. Study Design
[0217] This is a single center, prospective, double-blind, placebo-controlled, randomized study.
TABLE-US-00002 TABLE 1 STUDY PROCEDURES PER VISIT Visit number 1 2 3 4 Time of Visit Week Week week week 1 2 4 6 Information & Informed consent x urine Cannabinoids & Pregnancy testing x x x x Epidemiological & Demographic data x x x x Medication Consumption x x x x BP, Heart Rate x x x x Blood testing (chemistry, blood count) x x x x Randomization x BMI x x Patient global impression of change x x x Brief pain inventory x x x x Tender point count x SF-36 x x Hamilton depression score x x Fibromyalgia impact questionnaire x X CBD and THC blood testing x * Adverse events x x x x Re-confirmation of patient eligibility Dispense study drug x x x collect *--on the baseline visit, one hour and 2 hours after tablet intake.
7. Study Population
[0218] Study population: 80 female subjects with established FMS confirmed by the 1990 ACR are enrolled after meeting the following inclusion and exclusion criteria:
7.1 Inclusion Criteria
[0219] Subjects must satisfy inclusion criteria to be enrolled into the study:
[0220] Individuals eligible to be enrolled into this protocol are participants who:
[0221] Female with established FMS confirmed by the 1990 ACR
[0222] 18-75 years old
[0223] The score on the average pain severity item of the BPI is .gtoreq.5 at randomization
[0224] A female subject is eligible to participate if she is of non-childbearing potential (postmenopausal or pre-menopausal females with a documented tubal ligation or hysterectomy). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol.
[0225] Willing to sign an Informed Consent
[0226] Agree not to participate in any other interventional clinical trials during the study
[0227] Agree to follow study instructions meticulously
7.2 Exclusion Criteria
[0228] 1. Confirmed pregnancy [0229] 2. Breast feeding patients [0230] 3. Patients with active coronary artery disease with documented myocardial ischemia proven by coronary angiography, thallium scan or exercise stress test [0231] 4. Patients with congestive heart failure [0232] 5. Patients with coexistent neoplastic conditions (not including basal cell carcinoma) [0233] 6. Patients with coexistent t rheumatic/inflammatory conditions [0234] 7. Patients with active gastrointestinal bleeding [0235] 8. Patients with renal failure [0236] 9. Patients with comorbid conditions causing significant disability [0237] 10. Patients with uncontrolled hypertension. [0238] 11. Patients with significant psychiatric conditions (excluding depression and anxiety disorders). [0239] 12. Usage of anti-epileptic drugs [0240] 13. A high level of suicidality (a score above 3 in the relevant Hamilton score). [0241] 14. Patients who are drivers of public transportation or heavy vehicles. [0242] 15. A history of drug or alcohol abuse, or a history of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mililiter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. [0243] 16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives (whichever is longer). [0244] 17. Have any current problem or a history of substance abuse which, in the opinion of the investigator, might interfere with participation in the protocol.
8. Study Procedures
[0245] The subjects are screened against eligibility criteria and in order to confirm eligibility, subject will be tested for pregnancy, urine Cannabinoids (to exclude substance abuse). Patients will be consented and the following procedures will be performed: [0246] Subjects will be randomized to one of the study arms (treatment or placebo). [0247] Documentation of Medical history and medication consumption (present and past) [0248] BP, Heart Rate, Blood testing (chemistry, blood count). [0249] Fibromyalgia Tender Points counts. [0250] BMI calculation [0251] Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD).
[0252] Based on the urine testing and questionnaires, eligibility confirmation will be performed and the patient will be asked to swallow a tablet. 1 hour and 2 hours after tablet intake Blood tests for CBD and THC will be performed.
[0253] Patients are instructed to start home use of a single tablet at night time with a possible bidaily increment up to a maximum dosage of 10 tablets. The increments are done at night time and when needed the other half dose is taken every morning.
[0254] On the follow-up visits (including final visit) the following is performed: [0255] Documentation medication consumption. [0256] Urine testing for pregnancy and Cannabinoids. [0257] BP, Heart Rate, Blood testing (chemistry, blood count). [0258] Subjects will be asked to fill the following questionnaires: Brief pain inventory, Sleep history questionnaire (PSQI), SF-36 Quality of life assessment, Fibromyalgia impact questionnaire (FIQ), Mini International Neuropsychiatric Interview, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HRSD).
[0259] At the final visit, the un-used tablets are collected.
[0260] In case of an Adverse Event, patients will be asked to contact the clinic immediately. Rescue therapy will be provided by paracetamol and/or dypirone drops in an unblinded manner.
8.1 Unscheduled Visits
[0261] An unscheduled visit is a visit unrelated to the study visits. It should be distinguished from an "Out of Window" visit that was performed outside the .+-.2 day visit window allowed per protocol, but was planned. In case of an "Out of Window" visit, the data collected at the visit is recorded in the closest scheduled visit CRF pages.
9. Treatment Principles
9.1 Method of Subject Identification
[0262] Subjects signing the informed consent are assigned a unique screening identifying number (3 digits number) and additional unique randomization number.
9.2 Removal of Subjects from Therapy or Assessment
[0263] All subjects are free to withdraw from participation in the study at any time, for any reason, without prejudice. The investigator may terminate a subject from the study at any time for lack of therapeutic effect that is intolerable to the subject or otherwise considered unacceptable, for intolerable or unacceptable AE's, inter-current illness, noncompliance with study procedures, or in the investigator's opinion to protect the subject's best interest.
[0264] All subjects prematurely discontinuing the study must be seen for a final evaluation unless the subject withdrew consent. If a subject is withdrawn before completing the study, the date and reason for withdrawal are entered on the appropriate page of the case report form (CRF). If study withdrawal was due to an AE, the subject should be followed until resolution or until the principal investigator deems it to be no longer medically indicated.
[0265] The primary reason for a premature withdrawal will be selected from the following standard categories of early termination: Adverse Event (AEs): Clinical or laboratory events which occurred that in the medical judgment of the investigator for the best interest of the subject are grounds for discontinuation. This includes serious and non-serious AEs regardless of relation to the study product. [0266] 1. Death of the subject. [0267] 2. Withdrawal due to Pregnancy. [0268] 3. Withdrawal of Consent: The subject desired to withdraw from further participation in the study in the absence of a medical need to withdraw as determined by the investigator. If the subject gave a reason for this desire, this should be recorded in the CRF. [0269] 4. Protocol Violation: The subject's findings or conduct failed to meet the protocol entry criteria or failed to adhere to the protocol requirements (e.g. treatment noncompliance, failure to return for defined number of visits). The violation necessitated premature termination from the study. [0270] 5. Lost to Follow-Up: The subject stopped coming for visits and study personnel were unable to contact the patient. 6. Other: The subject was terminated for a reason other than those listed above (e.g., termination of study by Principal Investigator). The actual reason should be entered into the CRF.
9.3 Concomitant Therapy
[0271] Medications, not allowed prior to the start of the study, are listed in the exclusion criteria.
[0272] In case of new medications or changes in dosing of existing medications, the drug, reason for use, dose and dosage regimen must be recorded in the Case Report Form.
[0273] Females must continue the use of contraceptives. These must be recorded in the Case Report Form.
[0274] For any concomitant therapy given as a treatment for a new condition or a worsening of an existing condition, the condition must be documented on the Adverse Event Form of the CRF.
9.4 Laboratory Tests
[0275] Blood samples for biochemistry, serology and haematology including and a urine sample for urinalysis and drugs screen are taken as defined in the protocol and as per PI decision.
[0276] Female subjects will provide a urine sample for a pregnancy test during the screening visit.
[0277] The Medical Center local laboratory test results will be transferred to the CRF. The lab report must be interpreted, signed and dated by the principal investigator or his/her designee; any clinically significant changes occurring during the study must be recorded on the AE Form of the CRF.
9.4.1 Chemistry:
[0278] Glucose, Urea, Creatinine, Sodium, Potassium, Chloride, Calcium, Phosphorus, Uric Acid, AST (SGOT), ALT (SGPT), Gamma GT, LDH, Alkaline Phosphatase, Total Bilirubin, Direct Bilirubin, Total Protein, Albumin, Total Cholesterol, HDL, LDL, Trig
9.4.2 Hematology:
[0279] Haemoglobin, Haematocrit, RBC, MCV, WBC, White differential blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), Platelets count, MPV.
9.4.3 Urinalysis
[0280] A 20 ml midstream urine sample must be provided for urinalysis for Cannabinoids.
9.5 Vital Signs
[0281] Blood pressure and heart rate measurements are assessed either manually by a sphygmomanometer or by an automated blood pressure device.
[0282] Heart rate and blood pressure are obtained at specified time points after subject has been in a supine position for 5 minutes.
10. Investigational Product (MGC, Ointment)
[0283] The principal investigator must maintain an adequate record of the receipt, distribution and return or destruction of all MGC tubes using an appropriate accountability forms provided for the study by the Sponsor. These forms must be available for inspection at any time.
10.1 Packing and Labelling
[0284] All tablets are packed and labeled in compliance with the EUROPEAN COMMISSION, Good Manufacturing Practice, Annex 13 (Brussels, 3 Feb. 2010) and according to the Israeli Guidelines for Clinical Trials in Human Subjects, 2006 (section 11 from December 2008).
11. Statistical Methods
11.1 Sample Size Justification
[0285] A sustained response is defined as a 30% reduction from baseline to endpoint in the BPI with a 30% reduction from baseline at least 2 weeks prior to the last, and with at least a 20% reduction from baseline at every week in between. The primary outcome variable is the reduction in BPI from baseline to endpoint.
12. Adverse Events
12.1 Definitions
12.1.1 Adverse Event (AE):
[0286] Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device.
12.1.2 Serious Adverse Event (SAE):
[0287] Adverse event that [0288] a) Led to death, [0289] b) Led to serious deterioration in the health of the subject, that either resulted in [0290] 1) A life-threatening illness or injury, or [0291] 2) A permanent impairment of a body structure or a body function, or [0292] 3) In-patient or prolonged hospitalization, or [0293] 4) Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, [0294] c) Led to fetal distress, fetal death or a congenital abnormality or birth defect Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration in health, is not considered a serious adverse event.
12.1.3 Unexpected Adverse Event
[0295] An adverse event of which the nature or severity of which is not consistent with the applicable product information.
12.1.4 Life-Threatening
[0296] Any event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
12.1.5 Adverse Event Severity
[0297] The investigator rates the severity of an adverse event as follows: [0298] Grade 1--Mild AE [0299] Grade 2--Moderate AE [0300] Grade 3--Severe AE [0301] Grade 4--Life threatening or disabling AE [0302] Grade 5--Death related to AE
12.1.6 Adverse Event Attribution
[0303] Attribution definitions are in accordance with the NCI-CTEP guidelines for adverse events reporting.
[0304] An adverse event is considered associated with the use of the MGC ointment if the attribution is possible, probable or definite.
[0305] Adverse event attribution categories:
[0306] Unrelated--The AE is clearly not related to the use of the MGC ointment.
[0307] Unlikely--The AE is doubtfully related to the use of the MGC ointment.
[0308] Possible--The AE may be related to the use of the MGC ointment.
[0309] Probable--The AE is likely related to the use of the MGC ointment.
[0310] Definite--The AE is clearly related to the use of the MGC ointment.
12.1.7 Adverse Event Reporting
[0311] Adverse events or baseline signs and symptoms that occur during the screening period, between signing of the Informed Consent and actual MGC ointment treatment will be documented as part of the applicable medical history page(s) and adverse events pages of the CRF which will allow for designation of the event/symptom as a baseline event/symptom.
[0312] Adverse events occurring after the MGC ointment treatment will be reported on the adverse events CRF page and followed to satisfactory resolution. New adverse events will be recorded 1 week post end of MGC ointment active treatment visit.
[0313] SAEs should be reported by the investigator to the sponsor within 24 hours of their occurrence by telephone, facsimile (fax) or e-mail. The principal investigator must provide the minimal information: i.e. study number, subject's initials and date of birth, investigational product code number, period of administration, nature of the adverse event and the principal investigator's opinion of the attribution of a MGC to the SAE. This report of an SAE by telephone must always be confirmed by a written, more detailed report on the provided SAE reporting forms.
[0314] The Investigator shall report immediately, within 48 hours of actual knowledge of the event, to the chairman of the Institutional Ethics Committee, the following events: [0315] death; [0316] unexpected SAE when a connection between the event and use of the investigational product cannot be excluded; [0317] any malfunction in an investigational product that can compromise the safety and efficacy of the investigational product.
[0318] The Investigator shall issue the report on the provided SAE reporting form.
[0319] New SAEs will be reported up to 2 weeks following the end of active treatment visit.
[0320] Follow up of ongoing adverse events will continue until resolution or until the principal investigator deems them to be no longer medically indicated.
[0321] Mortality will be reported as an SAE. The date of death, cause of death of the subject in a clinical study, whether the event is expected or associated with the investigational agent and autopsy findings if applicable will be recorded in the CRF.
[0322] Pregnancies occurring during clinical study must be reported to Sponsor/EC within 24 hours using the provided reporting form. The outcome of the pregnancy must also be reported to Sponsor/EC.
[0323] Appropriate reporting of adverse events to the regulatory authorities will be performed. All serious adverse events that are unexpected and associated with the use of MGC to the principal investigator(s) will be reported.
[0324] Unexpected Serious Adverse Effect that somehow related to treatment with the investigational product occurring in sites in Israel, shall be report to the Ministry of Health, the Investigators and all the parties involved in the trial, according to the following timetable: [0325] A. Cases of death or life-threatening events shall be reported within 7 days of the Sponsor's actual knowledge of the event. [0326] B. All other events shall be reported within 15 days of the Sponsor's actual knowledge of the event.
[0327] It is the principal investigator's responsibility to report such adverse events to the Local Ethics Committee (EC) which has approved the protocol unless otherwise required and documented by the EC.
[0328] Each subject will be provided with a "study card" indicating the name of the MGC ointment and indication, the study number, the principal investigator's name, the site's name and a 24-hour emergency contact number.
13. Study Closure Considerations
[0329] Reasons for closure of the investigational site(s) or termination of the study by the sponsor may include: [0330] 1. Successful completion of the study at the center; [0331] 2. The required number of subjects for the study has been recruited; [0332] 3. Failure of the principal investigator to comply with the protocol or GCP guidelines; [0333] 4. Safety concerns; [0334] 5. Sufficient data suggesting lack of efficacy; [0335] 6. Inadequate recruitment of subjects by the principal investigator(s)
14. Ethics and Regulations
[0336] This study is conducted in accordance with the following guidelines and regulations: [0337] Declaration of Helsinki 2008: Sixth revision, 59th Meeting, Seoul, [0338] Public Health Regulations: Clinical Trials in Human Subjects, Israel Ministry of Health, 1980 [0339] Guidelines for Clinical Trials in Human Subjects, Israel Ministry of Health, 2014.
[0340] These standard and guidelines addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety or efficacy for regulatory purposes.
[0341] Compliance with this standard provides public assurance that the rights, safety and well-being of study subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical study data are credible.
15. Study Materials And Documentation
[0342] The principal investigator acknowledges that the study medications is an investigational and as such must be handled strictly in accordance with the protocol and the container label. Study medication must be verified upon receipt and retained in a safe, secure location and stored under the appropriate conditions as specified on delivery. Study medication should be dispensed under the supervision of the principal investigator's designee such as the medical center pharmacist (if applicable). All dispensing must be performed by the site recorded on the Investigator's Statement.
15.1 Subject Information and Informed Consent
[0343] The informed consent process will be conducted in accordance with "Good clinical practice". Prior to entry in the study, the principal investigator or his/her designee must explain to potential subjects the study and the implications of participation. Subjects will be informed that their participation is voluntary and that they may withdraw consent to participate at any time. They will be informed that choosing not to participate will not impact on the care that the subject will receive for the treatment of his/her disease. Subjects will be told that alternative treatments are available if they refuse to take part and that such refusal will not prejudice future treatment. Finally, they will be told that their records may be accessed by competent authorities and CRO without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) and/or regulations. By signing the Informed Consent Form (ICF) the subject is authorizing such access.
[0344] After this explanation and before entry to the study, written, dated and signed informed consent should be obtained from the subject or legally acceptable representative.
[0345] The subject will be given sufficient time to read the Informed Consent Form and to ask questions. After this explanation and before entry to the study, consent should be appropriately recorded by means of both the subject's dated signature and the principal investigator's designee who conducted the informed consent discussion. After having obtained the consent, a copy of the Informed Consent must be given to the subject.
[0346] The informed consent form will contain contact details for the subject in case of pertinent questions about subject rights and in case of research related injury.
[0347] In case the subject is unable to read, an impartial witness must attest the informed consent. Subjects who are unable to comprehend the information provided are unable to be enrolled.
15.2 Source Data & Source Documents
[0348] If data are inadvertently recorded directly into the CRF, there should be, at a minimum, an entry in the medical record that each of the assessments was done, by whom, and the date it was done.
[0349] The nature and location of all source documents will be identified to ensure that all sources of original data required to complete the CRF are known to the company and investigational staff and are accessible for verification by the monitor. If electronic records are maintained, the method of verification must be discussed between the investigational staff and the monitor.
[0350] Source documents should include the following information for each subject: [0351] subject identification (name, date of birth, gender) [0352] documentation that subject meets eligibility criteria, i.e., history, physical examination, and confirmation of diagnosis (to support inclusion and exclusion criteria) [0353] participation in the study (including study number) [0354] study discussed and informed consent forms [0355] dates of visits [0356] documentation that protocol specific procedures were performed [0357] results of efficacy parameters, as required by the protocol [0358] Investigational product start and end date [0359] record of all adverse events and other safety parameters [0360] concomitant medication [0361] date of study completion and reason for early discontinuation, if applicable
[0362] Each laboratory test will be reviewed for clinical significance, signed and dated by the Principal Investigator's designees/Co-PI.
15.3 Case Report Form
[0363] All data relating to the study must be recorded on CRFs. These CRFs are to be completed in a timely fashion, with the exception of results of tests performed outside the investigator's office, so that they always reflect the latest observations on the subjects participating in the study.
[0364] The CRF will be compared with the source documents to ensure that there are no discrepancies between data. All entries, corrections and alterations are to be made by the principal investigator's designees.
15.4 Subject Identification Log
[0365] In order to permit easy identification of the individual subject during and after the study, the principal investigator is responsible for keeping an updated Subject Identification Log. The Subject Identification Log records the personal identification of all subjects that have signed the informed consent form. This document will be reviewed by the monitor for completeness. However, in order to ensure subject confidentiality, no copy will be made.
15.5 Archiving
[0366] The principal investigator shall maintain the study documents. Study document include those listed in "Good clinical practice" and any additional documents required by the applicable regulatory requirement(s). The principal investigator should take measures to prevent accidental or premature destruction of these documents.
[0367] Essential documents should be retained until at least 2 years after the last approval of a marketing application and until there are no pending or contemplated marketing applications, or at least until 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements.
[0368] If it becomes necessary for the appropriate Regulatory Authority to review any documentation relating to this study, the principal investigator must permit access to such reports.
15.6 Protocol Modification
[0369] Any protocol modification must be documented in writing. Any change in the research activity, except that necessary to remove an apparent immediate hazard to the patient, must be reviewed and approved by the local ethics committee before implementation and submitted to the regulatory authorities.
15.7 Privacy of Personal Data
[0370] The processing of personal data in pursuit of this study will be limited to those data that are reasonably necessary to investigate the efficacy, safety, quality and utility of the investigational product(s) used in this study.
[0371] These data will be processed with adequate precautions to ensure confidentiality.
[0372] It is ensured that the personal data are: [0373] 1. Collected for a specified and legitimate purpose [0374] 2. Processed fairly and lawfully [0375] 3. Accurate and up to date
[0376] Explicit consent for the processing of personal data will be obtained from the participating subject (or his/her legally acceptable representative) prior to any processing of personal data.
[0377] This confidentiality will be maintained throughout the complete data processing.
* * * * *
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20180116998.PGNR.&OS=DN/20180116998&RS=DN/20180116998
$OWCP
LOL.. looks like shorts are freaking out....
..."Whatever you gotta post, just get the new investors scared so they'll sell their shares tomorrow."
I'm Long and Strong!!!
$OWCP is looking good