Re: fully adjudicated?
in response toby
Top-Line Results for Phase 3 BETonMACE Cardio Outcomes Trial were Announced September 30, 2019
"Would it be fair to say since we achieved around 220 events or there abouts 3 months ago that all those events have now been fully adjudicated? Say even 200 of them?"
Resverlogix has not publicly disclosed the breakdown between adjudicated MACE events vs unadjudicated events. But IR has previously stated that adjudication is ongoing as events occur. So theoretically, most of the events that have occurred thus far have been fully adjudicated. However, Resverlogix has stated consistently that adjudication of all 250+ MACE events is expected to take 2 to 3 months post trial completion, which I believe is defined as reaching 250 MACE events and ending of dosing. This final adjudication period allows for adjudication of the lagging "unconfirmed" events that had not yet been adjudicated at the time of reaching 250. This is why they may end up with 250+ in the final adjudicated count. It is also possible that during this 2-3 month period another independent group does a second adjudication process on all events...kind of like two separate adjudication processes.
"If yes - who gets to see that blinded information first & how quickly? (trials annouced as over & we have hit our 250+)? Would it then be safe to say several/many/inside people would now have a pretty good idea how this trial went looking at 4/5th's of the trials population fully adjudicated profile or at least a very significant portion of it? If any of the above rings true we could see action one way or another a lot quicker that what we might have thought?"
As stated in the most recent DSMB report "Resverlogix, the clinical steering committee, and all investigators remain blinded to the trial data." After 250 events are reached and dosing ends, there will be a 2-3 month period for final adjudication. Safety follow ups may occur simultaneously. At some point after (or during?) this period, the database will be locked. ONLY after this database lock will the data become unblinded for analysis. Until this database lock happens, then no peeking!
"Maybe they keep all the info blinded until the very last patient is fully adjudicated?"
Bingo. After adjudication of all events is complete, the database is locked. Only at this point will the data become unblinded.
Below, I have copied and pasted from this post a reminder of the possible order of events.
A good time for a reminder of "possible" order of events.
1) BETonMACE reaches 250 "unofficial" 3-point MACE events. IR recently clarified that "We have not publicly disclosed the breakdown between adjudicated MACE events vs unadjudicated." Therefore, those updates communicated right now at the corporate updates are very likely a combination of adjudicated and unadjudicated. Although most are likely already adjudicated, an unknown number of the current total are likely still undergoing the adjudication process. So when 250 "unofficial" 3-point MACE events are reached, keep in mind that not all of these are necessarily adjudicated yet.
2) BETonMACE reaches 250 adjudicated 3-point MACE events. Enough of the unadjudicated from #1 above have now moved into the adjudicated category to cross the 250 adjudicated threshhold. IR recently replied to Growacet "Reaching 250 adjudicated MACE events would be material and thus would require/prompt a public announcement." Also, management has conveyed that they will continue dosing until reaching 250 events. So very likely at this point, dosing of all patients will end and a news release will be issued. This is what I think the company is defining as trial completion.
3) Next comes the trial wrap up. According to IR, "Adjudication and safety follow-up can occur simultaneously" and "adjudication of all 250+ MACE events is expected to take 2 to 3 months post trial completion." At this point, any unadjudicated events that had occurred prior to ending of dosing will complete the adjudication process. So the trial may end of with greater than 250 adjudicated 3-point MACE events for analysis. As Tada has pointed out, management has expressed an option to pay for expedited adjudication. So maybe this adjudication process can be sped up. BETonMACE trial design slides have indicated that the safety follow up period is 4 to 16 weeks. That is a big range. Even if adjudication is expedited, is the rate-limiting step for trial wrap up the safety follow up visits? Is adjudication, safety follow up, or both the determining factor for wrapping up this step #3?
4) Adjudication is complete. Now the fun part. The database is locked and the data is analyzed. How long will this step take before top-line is announced? There is not normally a new release for completion of adjudication; however, it is common for a news release to be issued when last patient study visit has occurred, which could indicate that safety follow up visits are done. This last patient study visit announcement could possibly be around the same time as database lock, after which all the study investigators finally get to see the unblinded data and do all of their number crunching!
5) Top line data is announced. It may just be a simple statement of meeting or not meeting the primary endpoint with no numerical value given at the time for % relative risk reduction. Often, top-line data announcements are kind of like teasers that make you wait for the full data presentation to find out the %RRR. Not always. Amarin bucked the trend recently by announcing the %RRR for REDUCE-IT in the top-line. In most recent CVOTs no %RRR is offered at top-line announcement.
6) Full data on primary outcome presented at major scientific meeting, publication in major peer-reviewed scientific journal. This is probably where one will see some of the pre-specified analyses (i.e. rosuvastatin vs. atorvastatin) if not offered in the top-line. How long after top-line before full data presentation? It depends on the timing. There are only so many meetings each year. So if the top-line comes out in a lull period of not meetings in the near future, there may be a wait. Could be a month. Could be 3 months. Could be more. Could be less.
7) Sub-studies like the CKD and dementia sub-studies presented as major scientific meetings.