Dosage Topic
Think about this for a minute. Start as a logic proposition.
If a company wishes to be able to dose patients at certain distinct levels and also to be able to vary and titrate those levels in an OLE, but can most economically produce a supply of inventory in the levels of compound which allow for maximum variability to get to n+10mg using the same number of tablets so as to remain blinded from patients even in the OLE, the solution is produce 10 and 20 mg tablets only for your entire inventory.
During the trial (blinded) dispense 3 tablets (identical) to all participants. The placebo patients take 3 pills all firing blanks. The 30mg group takes 3 10mg tablets at one time. The 50mg group takes 2 20’s and a 10 - all identical.
So, they all take exactly 3 pills and cannot derive any meaning from this.
Cut to the OLE. Use same inventory. Start the placebo group with 2 placebos and a 10. Then titrate to 1 placebo and 2 10’s. Then go to 3 10’s. After that 2 tens and a twenty will get to 40 and two twenty’s and a 10 gets to 50.
For those on 30mg dose from the trial, in the OLE, give 2 twenty’s and a placebo to titrate to 40.
Etc in this manner all can be titrated to dose of n+10 without manufacturing pills in each dose strength from 10 to 50 and it’s the fewest dose levels necessary.
So, when the trial said they wanted to keep the doses restricted and reported 10 and 20, they may have been technically adhering to the reporting of the actual doses of compound in the pills available being used but not how many each participant was getting. If we now know that “high” is 50 and “low” is 30, that still allows for blinded titration in the OLE which a rigorous trial designer would want in order to eliminate any knowledge to create a bias, i.e., no OLE patient can assume first jump to 30mg, could be just 10mg and the titration is known only to the trial coordinator and each patient can be stopped in orders of 10mg to reach MTD or max efficacy to reach the necessary blood concentration without going over.
As for the EMA registration:
This: from F1ash’s post is possible. A technicality, but, nonetheless:
“Could it be possible that the 10 and 20 mg concentrations listed on the EU site were simply two separate pill forms that Anavex had manufactured and each had to be registered separately? “
That made sense to me.
A legit logic exercise as a food for thought post.
Good weekend, all
Bio
