Time-to-event clinical trial designs: Existing evidence and remaining concerns

Abstract

Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.

Keywords: pre-randomization seizure count; recruitment; research roundtable for epilepsy (RRE); seizure cycling; sudden unexpected death in epilepsy (SUDEP).

Figure 1:

Typical timeline of a double-blind placebo-controlled parallel trial for a treatment of epilepsy. Abbreviations: antiseizure medications (ASMs), weeks (wks).

Figure 2:

A hypothetical illustration of how the estimate of seizure frequency (seizure freq) stabilizes over the course of the typical 12-week randomized controlled trial (RCT) for a simulated participant randomized to placebo who had 6 seizures (Sz) in a 4-week baseline. The simulation was using the methods of Goldenholz and colleagues (Ann Clin Trans Neurol 2017). The time-to-event endpoint of time-to-prerandomization monthly seizure count (T-PSC) is illustrated at 48 days, with an interim seizure frequency reduction of 44%, compared to a 56% reduction when treatment was continued through 12-weeks. Comparison to other historical escape criteria is illustrated by highlighting seizure clusters.

Figure 3:

Time to pre-randomization monthly seizure count for participants with Dravet Syndrome enrolled in the fenfluramine (FFA) trial. Reproduced from Sullivan et al. Epilepsia 2021.

Figure 4:

The expected time to pre-randomization monthly seizure count (PSC) for participants with simulated seizure frequency (SF) response to an antiseizure medication. The 100% curve reflects no change; 200% reflects doubling of SF; and 50% reflects halving of SF. Simulations based on Goldenholz et al. Ann Clin Trans Neurol 2017.

Figure 5:

Individual seizure diaries from blinded adult participants in an ongoing time-to-event clinical trial for focal-onset seizures. (A) Periodicity in seizures with brief periods of seizures and semi-regular seizure free intervals. (B) Variability in the seizure frequency in the first versus second baseline period.