The next quarter should provide much clarity on the issues of number of US patients and their expected length in the trial, and any changes to current BETonMACE protocol that may affect number of patients enrolled, target # of MACE events, and estimated timeline for top-line data. If indeed US patients start enrolling Q1 2018, then I expect any FDA recommended/required changes to BETonMACE protocol will be disclosed.

More importantly though, the sample size re-estimation analysis will be key, and in my opinion this will come by end of Q1 2018 or shortly thereafter (see below for my justification). The MD&A posted yesterday stated "a sample size reestimation analysis is planned after 75% of the primary MACE events have been adjudicated." This confirms what some on this board relayed to us from the AGM Q&A. 75% of the 250 planned events is ~188. Assuming that 1) a futility analysis will still occur at the same time as the sample size re-estimation analysis, and 2) BETonMACE passes the futility analysis, then this sample size re-estimation analysis might significantly increase the number of patients and number of target MACE events. As I posted earlier, I recall around the start of BETonMACE hearing (I think from Michael Sweeney's presentation) that this analysis could result in increasing the number of patients from 2400 to 3600 and the number of target MACE events from 250 to 375. If this does happen, then my concern of US patients being dosed for less than a year is no longer a concern because this trial will go on for much longer.

When will we hit 188 events? For those of you familiar with this this thread, you know I like to base estimates off of the EXAMINE trial that also looked at high-risk diabetic patients and that I accept many assumptions. For more details, look at previous posts in this thread. Based on those events rates in EXAMINE and the BETonMACE enrollment numbers reported to us over the past couple of years, one can estimate how long "waves" of patients have been in the trial and then match them up with the respective event rates observed in EXAMINE. If I do this and project out to end of Q1 2018, I have a conservative estimate of 170 MACE events and a less conservative estimate of 196 MACE events. Just to remind you, this assumes 30% RRR in the apabetalone treated patients, assumes no difference between statin type, and assumes that any increased MACE frequency in the entire BETonMACE population due to the additional low-HDL requirement (not a requirement in EXAMINE) is counterbalanced by the 30% apabetalone RRR.

So assuming that the trial is not stopped for futility, then I see a few possibilities:

1) No changes to 2400 patient enrollment, no changes to 250 target MACE events. Even though US patients may be dosed for less than a year, BETonMACE stops at 250 MACE events with no prolonging of the US portion. Top-line reads out and if primary outcome is acheived, MAA and NDA filings with EMA and FDA, respectively, proceed. No amendments to BETonMACE.

2) No changes to 2400 patient enrollment, no changes to 250 target MACE events. BETonMACE partially stops at 250 MACE events to allow for top-line readout. If primary outcome is achieved, the trial is amended to allow for an unblinded open-label extension or blinded safety analysis in both US and non-US sites. One variation could be that US patients continue to be followed for MACE during trial extension period. MAA can be filed with EMA and NDA can be filed with FDA around the same time (i.e. amended trial for open-label extension or long-term safety doesn't delay MAA or NDA filing).

3) No changes to 2400 patient enrollment, no changes to 250 target MACE events. BETonMACE partially stops at 250 MACE events to allow for top-line readout. If primary outcome is achieved, the European and other non-US/non-FDA portions of the trial end. MAA can be filed with EMA. However, FDA requires US patients to stay in trial longer before considering an NDA application. This scenario may also include a BETonMACE amendment to allow for some kind of open-label extension or long-term safety analysis.

4) Enrollment increases to up to 3600 patients and 375 target MACE events. We wait.