"Question: Is the primary endpoint of our trial to achieve 30% RRR or is it just to be better than the existing standard of care.... ie would 10%-15% RRR qualify as making the primary endpoint,..?"

The trial was originally designed/statistically powered assuming that apbetalone (ABL) would elicit a 30% relative risk reduction (RRR). More recently in the AHA poster from November 2018, it stated "With an assumed primary event rate of 7 per 100 patient years in the placebo group, the study has 80% power to detect a 29% reduction in MACE with ABL (or 50% power to detect a 24% reduction) with 2400 patients and an average exposure of 1.5 years."

It's more about statistical power or statistical significance, and not so much about the magnitude of the %RRR. Although the chances of a given %RRR being statistically significant improve with a higher magnitude %RRR, any %RRR value that achieves statistical significance will be a win. The primary endpoint is to show any statistically significant difference in the time to first occurence of 3-point MACE between the placebo and apabetalone groups. 30% RRR or more would be fantastic. A smaller %RRR would still be a successful trial assuming that it clears the statistical significance threshhold.

Also, keep in mind the difference between statistical success and "real world" medically-relevant success. Of course, a big %RRR value like 30% or more would be considered a home-run in the cardiovascular/diabetes medical field if statistically significant. However, a more modest 10-15% RRR might elicit less excitement from the cardio/diabetes field, even if statistically significant, due to the lower effect size. That being said, the only two trials to attempt to reduced MACE in high-risk diabetics with 3-point MACE have failed (the GLP1-R agonist lixisenatide in ELIXA and the DDP4 inhibitor alogliptin in EXAMINE). So the medical community may see ANY statistically significant %RRR in this population as a huge win. 

http://www.nejm.org/doi/full/10.1056/NEJMoa1305889

http://www.nejm.org/doi/full/10.1056/NEJMoa1509225

Then there are the pre-specified analyses of the primary outcome. It could be that in the total population, there is only a modest, but statistically significant, %RRR observed. However, in one of the pre-specified subgroups (i.e. rosuvastatin vs. atorvastatin), we see that hypothesis that apabetalone is synergizing with rosuvastatin (as observed in post-hoc of plaque reduction) is also occurring with MACE reduction. It could turn out that the %RRR for the rosuvastatin subgroup is substantially higher than that for the total population or the atorvastatin subgroup.

Pre-specified subgroup analyses for the primary endpoint include:

– Rosuvastatin/Atorvastatin

– < 30 days/> 30 days post-acute coronary syndrome

– LDL/HDL/TG’s above and below median

– HbA1c above and below median

– eGFR >60 mL/min and < 60 mL/min

• Also change in eGFR for all patients with eGFR <60 mL/min

BearDownAZ