Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications
Abstract
Background and Objectives
Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials.
Methods
A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial.
Results
The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%–113% and 65%–110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor.
Discussion
These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
References
1.
Kerr WT, Auvin S, Van der Geyten S, et al. Time-to-event clinical trial designs: existing evidence and remaining concerns. Epilepsia. 2023;64(7):1699-1708.
2.
French JA, Temkin NR, Shneker BF, Hammer AE, Caldwell PT, Messenheimer JA. Lamotrigine XR conversion to monotherapy: first study using a historical control group. Neurotherapeutics. 2012;9(1):176-184.
3.
Kerr WT, Chen H, Figuera Losada M, Cheng C, Liu T, French J. Reasons for ineligibility for clinical trials of patients with medication resistant epilepsy. Epilepsia. 2023;64(5):e56-e60.
4.
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010;51(10):1936-1943.
5.
French JA, Gil-Nagel A, Malerba S, Kramer L, Kumar D, Bagiella E. Time to prerandomization monthly seizure count in perampanel trials: a novel epilepsy endpoint. Neurology. 2015;84(20):2014-2020.
6.
Rheims S, Perucca E, Cucherat M, Ryvlin P. Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis. Epilepsia. 2011;52(2):219-233.
7.
Fureman BE, Friedman D, Baulac M, et al. Reducing placebo exposure in trials: considerations from the Research Roundtable in Epilepsy. Neurology. 2017;89(14):1507-1515.
8.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 2011;10(11):961-968.
9.
Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1375-1386.
10.
Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1363-1374.
11.
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1016-1026.
12.
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000-1015.
13.
Vossler DG, Knake S, O'Brien TJ, et al. Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2020;91(10):1067-1075.
14.
Auvin S, Williams B, McMurray R, Kumar D, Perdomo C, Malhotra M. Novel seizure outcomes in patients with Lennox-Gastaut syndrome: post hoc analysis of seizure-free days in rufinamide Study 303. Epilepsia Open. 2019;4(2):275-280.
15.
Oliveira A, Romero JM, Goldenholz DM. Comparing the efficacy, exposure, and cost of clinical trial analysis methods. Epilepsia. 2019;60(12):e128-e132.
16.
Kerr WT, Brandt C, Ngo LY, et al. Time to exceed pre-randomization monthly seizure count for perampanel in participants with primary generalized tonic-clonic seizures: a potential clinical end point. Epilepsia. 2022;63(11):2994-3004.
17.
Johnson ME, McClung C, Bozorg AM. Analyses of seizure responses supportive of a novel trial design to assess efficacy of antiepileptic drugs in infants and young children with epilepsy: post hoc analyses of pediatric levetiracetam and lacosamide trials. Epilepsia Open. 2021;6(2):359-368.
18.
Sullivan J, Specchio N, Devinsky O, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130-138.
19.
Aboumatar S, Krishnaiengar SR, Cantu D, Zhang Y, Grinnell T. Time to baseline seizure count in patients with focal seizures receiving adjunctive eslicarbazepine acetate in a phase IV clinical trial. Clin Neurol Neurosurg. 2023;225:107552.
20.
Halasz P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50(3):443-453.
21.
Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51(6):958-967.
22.
Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U; Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69(18):1751-1760.
23.
Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia. 2014;55(1):57-66.
24.
Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;55(1):47-56.
25.
Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia. 2014;55(1):38-46.
26.
Klein P, Schiemann J, Sperling MR, et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia. 2015;56(12):1890-1898.
27.
Naritoku DK, Warnock CR, Messenheimer JA, et al. Lamotrigine extended-release as adjunctive therapy for partial seizures. Neurology. 2007;69(16):1610-1618.
28.
Biton V, Di Memmo J, Shukla R, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy Behav. 2010;19(3):352-358.
29.
Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS, Messenheimer JA. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology. 2005;65(11):1737-1743.
30.
Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology. 1999;52(7):1330-1337.
31.
Yu Z, Guindani M, Grieco SF, Chen L, Holmes TC, Xu X. Beyond t test and ANOVA: applications of mixed-effects models for more rigorous statistical analysis in neuroscience research. Neuron. 2022;110(1):21-35.
32.
Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1-48.
33.
Stram DO. Meta-analysis of published data using a linear mixed-effects model. Biometrics. 1996;52(2):536-544.
34.
Horvath L, Fekete K, Márton S, Fekete I. Correlation between prescribed daily dose, seizure freedom and defined daily dose in antiepileptic drug treatment. Int J Clin Pharm. 2017;39(2):459-467.
35.
Therneau T. Mixed effects cox models. 2022. Accessed September 7, 2023. cran.r-project.org/web/packages/coxme/vignettes/coxme.pdf.
36.
Kassambara A. survminer R package: survival data analysis and visualization. 2016. Accessed September 7, 2023. sthda.com/english/wiki/survminer-r-package-survival-data-analysis-and-visualization.
37.
Kerr WT, Reddy AS, Seo SH, et al. Increasing challenges to trial recruitment and conduct over time. Epilepsia. 2023;64(10):2625-2634.
38.
Goldenholz DM, Westover MB. Flexible realistic simulation of seizure occurrence recapitulating statistical properties of seizure diaries. Epilepsia. 2023;64(2):396-405.
39.
Romero J, Larimer P, Chang B, Goldenholz SR, Goldenholz DM. Natural variability in seizure frequency: implications for trials and placebo. Epilepsy Res. 2020;162:106306.
40.
Chiang S, Haut SR, Ferastraoaru V, et al. Individualizing the definition of seizure clusters based on temporal clustering analysis. Epilepsy Res. 2020;163:106330.
41.
Goldenholz DM, Goldenholz SR. Placebo in epilepsy. Int Rev Neurobiol. 2020;153:231-266.
42.
Karoly PJ, Romero J, Cook MJ, Freestone DR, Goldenholz DM. When can we trust responders? Serious concerns when using 50% response rate to assess clinical trials. Epilepsia. 2019;60(9):e99-e103.
43.
Ferastraoaru V, Goldenholz DM, Chiang S, Moss R, Theodore WH, Haut SR. Characteristics of large patient-reported outcomes: where can one million seizures get us? Epilepsia Open. 2018;3(3):364-373.
44.
Goldenholz DM, Goldenholz SR, Moss R, et al. Is seizure frequency variance a predictable quantity? Ann Clin Transl Neurol. 2018;5(2):201-207.
45.
Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018;17(11):977-985.
46.
Goldenholz DM, Goldenholz SR, Moss R, et al. Does accounting for seizure frequency variability increase clinical trial power? Epilepsy Res. 2017;137:145-151.
47.
Goldenholz DM, Tharayil J, Moss R, Myers E, Theodore WH. Monte Carlo simulations of randomized clinical trials in epilepsy. Ann Clin Transl Neurol. 2017;4(8):544-552.
48.
Auvin S, French J, Dlugos D, et al. Novel study design to assess the efficacy and tolerability of antiseizure medications for focal-onset seizures in infants and young children: a consensus document from the regulatory task force and the pediatric commission of the International League against Epilepsy (ILAE), in collaboration with the Pediatric Epilepsy Research Consortium (PERC). Epilepsia Open. 2019;4(4):537-543.
49.
Baulac M, Cascino GD. Antiepileptic drug trials: less placebo exposure for safer studies? Neurology. 2015;84(20):2010-2011.
Information & Authors
Information
Published In
Copyright
© 2024 American Academy of Neurology.
Publication History
Received: October 30, 2023
Accepted: May 24, 2024
Published online: July 25, 2024
Published in issue: August 27, 2024
Disclosure
W.T. Kerr writes review articles for Medlink Neurology, is a paid consultant for SK Life Sciences and Biohaven Pharmaceuticals, and has collaborative or data use agreements with Eisai, Janssen, Radius Health, UCB, GSK, and Jazz Pharmaceuticals. J.M. Stern has consulting agreements with SK Life Sciences, Jazz Pharmaceuticals, UCB Pharma, Neurelis, Eisai, LivaNova, and Sunovion. J. 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, and Zynerba, 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 the National Institute of Neurological Disorders and Stroke, is on the editorial board of Lancet Neurology and Neurology Today, is Chief Medical/Innovation Officer of the Epilepsy Foundation, and 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. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
This work was supported by the US National Institute for Neurological Disorders and Stroke (NIH R25NS089450, NIH U24NS107158), the American Epilepsy Society, the Epilepsy Foundation, the American Academy of Neurology, the American Brain Foundation, the Epilepsy Study Consortium, and the Christina Louise George Trust.
Authors
Metrics & Citations
Metrics
Citation information is sourced from Crossref Cited-by service.
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials, Epilepsia, 66, 4, (1014-1023), (2025).https://doi.org/10.1111/epi.18265
- Epilepsy research highlights in 2024: avenues for discovery, The Lancet Neurology, 24, 1, (13-15), (2025).https://doi.org/10.1016/S1474-4422(24)00481-2
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.