That's exactly what happened to patients in the RESET study.
Here's another, more important chart taken from the RESET poster. This tracks time to relapse in a Kaplan-Meier Curve.
The dotted line represents non-24 patients treated with tasimelteon. Each step down is a patient who relapses, defined as a 45-minute decrease in daily average nighttime sleep over a period of a week. [Vanda created this definition of relapse.]
Four of the 10 tasimelteon treated patients relapsed before Day 50. A 40 percent relapse rate despite a 90 percent maintenance of entrainment through Day 60, according to Vanda.Now, look where the dotted line turns horizontal. See those circles? There are six of them (two overlap), each representing a patient censored from the analysis. Censored means Vanda has no data on sleep-time relapse for these patients. In other words, of the 10 patients treated with tasimelteon, Vanda is missing data on six patients, or 60 percent. The tasimelteon curve is misleading with all that missing patient data. Vanda claims that median time to relapse for tasimelteon patients was not reached but that's only because 60 percent of the data are missing! In reality, time to relapse for tasimelteon patients might actually look entirely like the time to relapse for placebo patients, depicted in the chart with the solid line. The p-value calculated for the time to relapse analysis is omitted from the Kaplan-Meier Curve but it's listed elsewhere on the RESET study poster. It's 0.0907, meaning tasimelteon failed to reduce time to sleep relapse compared to placebo, even with all that missing data. I believe FDA will be much more interested in the failure of tasimelteon to prevent sleep-time relapse in the RESET study than successful maintenance of entrainment at an arbitrarily defined two-month time point. Vanda has already admitted that FDA will not approve any sleep drug based solely on an entrainment endpoint. Now, about the 20 patients who made it all the way through the RESET study. The study started with 57 patients screened and entered into the run-in stage, so Vanda was left with just 35 percent of patients to analyze for the primary endpoint (maintenance of entrainment.) The RESET study lost patients left and right. Here's a rundown from the poster:
-- 58 patients screened, 57 patient eligible for the run-in phase.
-- 48 patients actually entered the run-in phase (9 patients thrown out immediately for missing data)
-- Of the 48 patients treated with tasimelteon for the three months of the run-in stage, 24 patients, or 50 percent, achieved entrainment.
-- If you add back the 9 patients entering the run-in stage but thrown out before treatment began, the tasimelteon entrainment rate was actually 42 percent.
-- The entrainment failure rate was 68 percent.
-- 24 patients exited the three month run-in stage but four patients did not enter the randomized withdrawal stage of the study for a variety of reasons, including adverse events and data quality issues. (Another red flag?)
-- That left 20 patients evaluable for the study's primary endpoint, maintenance of entrainment. RESET, like the previously discussed SET, are poorly conducted studies which raise lots of troubling questions about tasimelteon. Vanda's chance of gaining FDA approval are slim. -- Reported by Adam Feuerstein in Boston. Follow @AdamFeuerstein
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