Amarin Corp Plc (AMRN)

[AVII77]

This is not about egos. This is about a difference of opinions on how events within the trial are tabulated and which ones are counted, and which ones are not counted. This is very important, because it could potentially decrease the the number of events in the "primary objective in both arms of the trial. This would not only play havoc with our estimations, prolonging the time to interim and the ensuing final count.. -JL

I'm glad you agree it is important and worth discussing. And yes, it is not about egos. I have a lot of respect for your views and have appreciated your contributions (I've lurked off and on for many years). When considered minds disagree it is often worthwhile exploring further.

While it may cause havoc in your estimations it will not cause any havoc in the trial; the trial is powered to account for this "first occurrence" issue. As for "your estimations", you simply need to take this issue into account as well.

I've been scratching my head on how best to convince you that you are in error on this point. I could make a mathematical argument but the vast majority of people (and physicians) don't appreciate the math involved with KM analysis or the Log Rank Test (while they may fully appreciate the output of the calculations). But the math issue there is that the "at risk" population is an important part of the calculations and if a patient is allowed to experience multiple events he is continually "at risk" and the KM curves and the Logrank test would be meaningless if used to analyze the results (and the Log Rank test is the test used here in REDUCE-IT to test the null hypothesis).

I am hoping a more convincing argument would be to demonstrate by way of example how this "first MACE occurrence" is expressed in other trials.

To that end, below is from a recent FDA review of a trial where the primary endpoint was First Occurrence of MACE. They also show all the events (not just the first occurrence of them) and pay special attention to the footnote.




The difference is even more pronounced in their secondary endpoint since that includes softer components that may precede the harder components. And again, only the first occurrence counts for the endpoint.



So yes, all events will be examined. But only the first occurrence of a MACE event will be included in the primary analysis. We need 967 first MACE occurrences for the interim.

An tertiary endpoint in this trial is:
"The second, third, fourth, and fifth major CV event of the primary composite endpoint. The type of (nonfatal) events may occur in any order."

"For the tertiary endpoints that count a single event, the first occurrence of this type of event will be counted in each patient. For tertiary endpoints that are composites of two or more types of events, the first occurrence of any of the event types included in the composite will be counted in each patient (except when stated otherwise, for the second, third, fourth, and fifth major CV event)."

So yes, patients will be followed for all MACE events and they will be adjudicated but only the first occurrence will be counted in the primary analysis.

From an earlier post you said:

For example a patient has an MI and is hospitalized, in the hospital he develops a arrhythmia and dies. This would be considered a fatal MI (the proximal cause). Even though the MI was complicated by VFib..and both events are secondary events, only the MI would be counted, because the Vfib resulted from the MI. -JL

It's a bit more complex than that. The adjudication process will determine exactly what counts as a first MACE occurrence. For example, the CEC Charter below (not from REDUCE-IT) says that it would only count as a cardiac death if it occurs within 14 days of the AMI.




I hope this helps (and I truly say that without implied smugness)