Re: What Jardiance/EMPA-REG Outcome means for RVX-208

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BearDownAZ

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Re: What Jardiance/EMPA-REG Outcome means for RVX-208

in response to

Re: What Jardiance/EMPA-REG Outcome means for RVX-208

Toinv

posted on Sep 18, 2015 01:45PM

Toniv,

You make a great point and one that I hope Resverlogix will clarify at the AGM or upon launch of BETonMACE. It seems ridiculous if they get statistically significant MACE reduction but it misses the arbitrary 30% RRR threshhold by just a small amount.

If one looks at the Clincialtrial.gov page for the EMPA-REG OUTCOME trial, nowhere do I see that they had to meet a particular RRR number. Here are their primary and secondary outcomes:

"Primary Outcome Measures:

Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint: cardiovascular death (including fatal stroke and fatal myocardial infarction(MI)), non-fatal MI (excluding silent MI) and non-fatal stroke. [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The composite of all events adjudicated: cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction, non-fatal stroke (excluding silent MI) and hospitalization for unstable angina pectoris. [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
To determine the incidence of new onset albuminuria [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
To determine the incidence of silent MI [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
To determine the incidence of heart failure requiring hospitalization [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
To determine the incidence of new onset macroalbuminuria [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
Composite microvascular outcome [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]"

However, in this article on EMPA-REG OUTCOME design, they write: "With a minimum of 691 events, the trial will also have at least 80% power to detect a hazard ratio of 0.785 (corresponding to a 21.5% risk reduction in CV outcome events) for the primary outcome." BETonMACE, according to what Resverlogix has publicly discussed so far, will likely be 2400-3600 patient, much less than the ~7000 in EMPA-REG Outcome. And BETonMACE has currently been disclosed to be shooting for a minimum of 250 events.

In my opinion, the success of BETonMACE, as well as EMPA-REG Outcome is more reliant upon the statistical p-value. Is the study powered well enough to detect a statistical change. In other words, do the stats support that the drug intervention is having an effect dependent upon the drug and not just due to chance? EMPA-REG Outcome was powered to detect as 21.5% RRR but the placebo and treatment groups end up diverging less than this for an RRR of 14.2%. They barely had the statistical power to detect this effect size, which I agree is not that impressive.

Why can Resverlogix get away with less patients and less target events than EMPA-REG Outcome? The most obvious and easy to understand explanation is the increased CVD risk of the BETonMACE patient population. Although both EMPA-REG OUTCOME and proposed BETonMACE will be targeting high CVD risk diabetic patients, BETonMACE has a further qualification criteria of demanding patients to have low HDL levels of less than 40 mg/dL. As we all know (or should know), low HDL is a very strong risk factor for CVD. So the CVD event rate in the BETonMACE patient population should be higher than that for the EMPA-REG OUTCOME patient population, allowing a smaller number of patients to reach their total MACE event target.

Also note that the Study/Primary Completion date was listed as April 2015 for EMPA-REG Outcome, but the topline data wasn't released until August and the full data disclosure wasn't until September. So this may help us understand why in the upcoming BETonMACE trial that patients will be dosed up to 2 years (1 to 2 year range with 18 month average per current information) but that Don tells us that trial data won't be released for 2 1/2 years.