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Review
. 2023 Jul;64(7):1699-1708.
doi: 10.1111/epi.17621. Epub 2023 May 2.

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

Wesley T Kerr  1 , Stéphane Auvin  2   3   4 , Serge Van der Geyten  5 , Christopher Kenney  6 , Gerald Novak  5 , Nathan B Fountain  7 , Caitlin Grzeskowiak  8 , Jacqueline A French  9
Affiliations
Review

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

Wesley T Kerr et al. Epilepsia. 2023 Jul.

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).

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Conflict of interest statement

Conflict of Interest Disclosures & Ethical Publication:

Dr. Kerr writes review articles for Medlink Neurology and has consulting agreements with SK Life Science, Janssen, Biohaven Pharmaceutical, and Radius Health. Dr. French receives salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Angelini Pharma S.p.A, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Camp4 Therapeutics Corporation, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Eisai, Eliem Therapeutics, Encoded Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc., Equilibre BioPharmaceuticals, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Phamaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Marck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuroelectives USA Corporation, Neuronetics Inc., Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Paladin Labs, Passage Bio, Pfizer, Praxis, Pure Tech LTY Inc., Rafa Laboratories Ltd, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Inc., Ventus Therapeutics, Xenon, Xeris, Zogenix, Zynerba. Dr. French also has received research support from the Epilepsy Study Consortium (Funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, Vogelstein Foundation), the Epilepsy Study Consortium/Epilepsy Foundation (Funded by UCB), GW/FACES, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is Chief Medical/Innovation Officer of the Epilepsy Foundation. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Angelini Pharma S.p.A., Clinical Education Alliance, NeuCyte, Inc., Neurocrine, Praxis, and Xenon. Stéphane Auvin is Deputy Editor for Epilepsia. He has served as consultant or gave lectures for Angelini, Biocodex, Eisai, Encoded, Grintherapeutics, Jazz Pharmaceuticals, Neuraxpharm, Orion, Nutricia, Proveca, UCB Pharma, Vitaflo, Xenon, Zogenix. He has been investigator for clinical trials for Eisai, Marinus, Proveca, Takeda, UCB Pharma and Zogenix. Dr. Van der Geyten is an employee of Janssen Research & Development, a division of Janssen Phamaceutica, Belgium, and holds stock in Johnson & Johnson companies. Dr. Kenney is employed full-time at Xenon Pharmaceuticals as Chief Medical Officer. Dr. Novak is a full-time employee of Janssen Research and Development. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Dr. Fountain has received clinical trial grants to the University of Virginia from UCB, SK Lifesciences, Xenon, Neurelis, Medtronic, and InSightec and is an independent director and holds stock at Acumen Pharmaceuticals and Hexokine Therapeutics, and consults and receives stock options at Shackleton Pharma. Dr. Grzeskowiak was an employee of the Epilepsy Foundation. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1:
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:
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:
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:
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:
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.
See this image and copyright information in PMC

References

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