"Dewophile (or somebody else) can you please help me understand why in the UF PhII trial(see slide 10) it appears that the 12.5mg dose improved hemoglobin levels the best (better than the 25mg dose) yet the p-value is significantly worse for the 12.5mg vs. placebo than it is for the 25 mg vs. placebo???"
its not clear to me the 12.5 mg arm is more effective in month 1. the explanation, i would guess, lies in the pts themselves - both groups started out at the same low hgb, but i would guess the 12.5 mg group was skewed with having more baseline bleeding - this is suggested by the PBAC, which shows a higher bleeding score for the 12.5 mg arm at baseline. bear in mind, same baseline hgb does not equate to same amount of menorrhagia - the lowest hgbs i've seen at baseline were actualy pts who had relatively modest menorrhagia and adapted chronically to the low hgb - they are the ones that can walk in your door with hbg of 10, whereas if someone bleeds down to 10 quickly you can bet they would present wiht severe sxs of anemia. so my guess is the 12.5mg arm was skewed to ahve worse bleeding at baseline (and so would have greater improvement initially on a drug that suppressed bleeding) despite having the same baseline hgb - veyr easy to happen in a small trial with a mixed bag of chronic and mroe actue anemic pts. the only other way i can reconcile the data is to theorize that proellex sometimes has a negative effect initially and then kicks in, much like lupron in fact which has a flare - which could then putatively explain owrse efficacy initialy despite a more effective overall dose (as suggested in months 2 and 3), but this does not jive with what we know about time to onset of effect and all other drugs in this class
why add the 50? well this is the one opportunity to really evaluat ethe entire uterus on pathology. the 50mg arm is associated with a thinner endometrium (remember hte negative dose-response on teh lining from the endo trial). so my guess is teh curiosity to get to examine the lining at 50mg, the fact its a thinner endometrium to report, and that there may still be added efficacy between 25 and 50
"This particularly so given that the 50mg dose in the Endo trial was the one that had the episodes of significant post-treatment bleeding. Something is not adding up"
i know you don't need me pointing out the obvious, but post-treatment bleeding is not a concern in the anemia trial since the day after the last dose these pts will have their uteri removed - no tenough time to withdraw and hemmorrhage. but its curious that the endo trial had these cases requiring D&C, and 2/3 weer at the 50 mg dose - no denying that. does anyone know if we can assume there were no D&Cs int he fibroid trial? it wouldn't be all that much of a surprise despite the fact it was a larger trial because bleeding is a part of these pts lives - pts won;t recognize that a withdrawal is heavier than normal becaus they already have heavy periods, and docs won't rush in with a curette to evaluate one episode of withdrawal menses in a pt with an explanation for that bleeding - the fibroid. remember, sometimes a D&C is performed not jsut therapeutically, but for diagnostic reasons as abnormal bleeding can signfify pathology (polyps, hyperplasia, CA) - so these docs may have jumped to intervene quickly when all they probably needed to do was ride out the bleed - simply to get histology. (particularly in a case with exposure to a new drug with theoretical hyperplasia risks). I'm making this point simply because there will be a tendency to take this data out of context to the chronic fibroid trial, where i highly doubt docs will be so quick to do D&Cs to temporize a bleed that should be self-limiting - particularly knowing the pts starting hgb is now higher than before tx, and they will ge ttheri pathology specimens the following month when a luteal phase biopsy is built into the off drug cycle. need for too many "invasive procedures" killed asoprisnil (supposedly), so this whether or not a D&C is performed to tx a bleed is relevant. the reason the 12.5 mg is dropped is partly because too many DIAGNOSTIC procedures would be required (biopsies, D&Cs, etc.)because of the thicker lining
bob - the high dropout on placebo highlights the efficacy of the drug, since these pts continue to bleed all over themselvves, but from a statistical perspective i agree its a concern. will this trial be able to handle a placebo group where only 10, or say even 5 made it through month 3? i guess that depends in part on the endpoint - i would like to think a dropout that then needed a transfusion or rushed to surgery because anemia continued to worsen would somehow not be lost in the statistical analysis. you can bet % that needed transfusion will be a secondary endpoint, but perhaps the primary will be comparison of hemoglobin between arms at the time intervention is performed - either surgery or transfusion, or a % that achieved what FDA may believe is a clinically meaningful improvement in hgb of > 1, where dropouts who required intervention before month 3 are included in the analysis since they clearly didn't achieve an increase? again i defer to the stats people here, but i woudl think either such endpoint would not hurt the power on an ITT analysis
regarding the endpoint - io - it can't be resolution of anemia, because this would not take into account the vast majority of anemic pts who recover most of the way but still remain mildly anemic pre-op (i can tell you in the real world this is how it works, because i wouldn't hesitate to operate on a mildly anemic pt, and if yo uwait preoperatively until their anemia has completely resolved you probably could have done the surgeyr 1-2 months prior already).
corp - it's possible for the anemia indication to get approval and then fail on the chronic indication, but less so simply because FDA has said they want to see somes afety from the chronic indication before approving anemia - my guess is they want to see a decent # of pts who had an off drug menses just to make sure they don't run into trouble if pre-op pts decide to stop drug, cancel surgery, etc. once the drug is used in real world setting. i highly doubt that if one cycle of drug results in acceptable safety subsequent cycles will show a cumulative drug effect - I've posted on this before that i think if luteal biopsies show normal histology in month 1 off drug, there is no reason to think it won't be normal in subsequent cycles off drug
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