Koo wrote "Bear...The bigger question is why did they choose to go with an 18-month trial and let say, for the sake of argument, not a 12-month trial?"

Together with the BETonMACE Clinical Steering Committee and with guidance from the EMA and FDA, Resverlogix designed BETonMACE an event driven trial. The trial will go until 250 3-point MACE events are reached. The length of the BETonMACE trial (time to achieve 250 3-point MACE events) was estimated in part based upon the 3-point MACE event rate in the EXAMINE trial. The EXAMINE trial used a similar patient population as in BETonMACE (diabetes and a recent acute coronary syndrome event). Based upon observing an ~11% event rate at 18-months in EXAMINE, the team estimated that they would need to achieve 3600 patient years (2400 patients with average treatment for 18 months) to achieve 250 3-point MACE events. In BETonMACE, patients get treated for up to 24 months and last patients enrolled get treated for 12 months, giving an 18 month average treatment period. If the average event rate ends up being much greater than 11%, then the average treatment period will likely be shorter and the trial won't take as long to get to 250 events. And conversely if the average event rate is much lower than 11% then the average treatment period will likely be longer and it will take longer to get to 250 events. The additional risk factor in BETonMACE patients of low-HDL may increase the overall event rate; however, the treatment with RVX-208 in half of the patients should counteract this. I discussed this in a previous post. 

To get to 250 events any faster, you either need to enroll more patients/increase the enrollment rate or you need to find a population with an even greater risk for cardiovascular disease. However, the higher risk group you demand, the harder it will be to find the patients. So a balance between patient risk and practical enrollment rate/total enrollment must be taken into account. Furthermore, BETonMACE is on the shorter end of the spectrum with respect to trial length in a cardiovascular outcomes trial (CVOT). Most CVOTs are longer (for example 3-5 years). This is partly due to the event rate in the patient population.

One must also consider that another benefit of a longer trial (18 months average treatment in BETonMACE), as opposed to the shorter trial period you suggested, is that a longer trial affords the opportunity to further prove safety. RVX-208 is a first in class molecule; only bromodomain selective BET inhibitor in trials and only BET inhibitor of any kind in Phase 3 trial. No BET inhibitor has been approved by the FDA or EMA for sale or marketing. BET inhibitors still need to prove that they are safe long term, and a longer Phase 3 BETonMACE allows for a longer safety track record to be established.

BearDownAZ