Evaluation of Time to Event endpoints in randomized controlled trials of multiple antiseizure medications for uncontrolled epilepsy

Lead Investigator: Wesley Kerr, University of Pittsburgh
Title of Proposal Research: Evaluation of Time to Event endpoints in randomized controlled trials of multiple antiseizure medications for uncontrolled epilepsy
Vivli Data Request: 8944
Funding Source: This work is being funded through the American Academy of Neurology, American Brain Foundation, Epilepsy Foundation, and American Epilepsy Society as part of a Susan S. Spencer Clinical Research Training Scholarship in Epilepsy and Epilepsy Study Consortium Mini-Grant.
Potential Conflicts of Interest: Dr. Kerr has paid consulting agreements with SK Lifesciences, Biohaven Pharmaceuticals, and Radius Health. He has other research agreements with Eisai and Janssen. He is the statistician for another approved Vivli & YODA request including data from UCB, GSK, and Janssen. Dr. Kerr will not share non-public information with any of these companies.

Summary of the Proposed Research:

Epilepsy is the third most common cause of neurological disability and death globally, but a third of patients are failed by antiseizure medications (ASMs). Randomized placebo-Control Trials (RCTs) for epilepsy have been the mainstay of trials for regulatory approval of new ASMs for decades. In a placebo-controlled RCT, participants were randomly assigned to receive either placebo, which is an inactive substance, or active treatment, which aims to improve their seizure frequency. In traditionally designed RCTs, patients with high seizure burden may remain on placebo or ineffective treatment for at least 5 months, even if seizures are frequent. While death was rare within RCTs at 6 per 1000 participant-years, participants randomized to placebo had a 5.8-fold increased risk of death, therefore it is critical to reduce participants’ exposure to ineffective treatments. These risks of participating in RCTs also contributes to trial recruitment issues.
The fundamental clinical research question this work addresses is if a Time-to-Event design can shorten participants’ exposure to placebo or ineffective treatment while also achieving the dual goals of evaluating treatment efficacy and safety. In a Time-to-Event design, participants receive treatment until they reach specific efficacy or safety endpoints. This proposal is important and original because it directly addresses concerns that have been barriers to adoption of the most promising Time-to-Event design, known as time to pre-randomization seizure count (T-PSC). In T-PSC, participants receive treatment until their post-randomization seizure count exceeds the average monthly PSC experienced during baseline. The expected societal impact is to have sufficient ad hoc evidence that T-PSC is a safe and effective method that could be applied in prospective RCTs. The expected impact of this research on patient care and human health is to reduce trial participants risk of death, trial cost, and improve participant recruitment. The rationale of this project is that by making RCTs safer, cheaper, and more efficient, we enable further development of novel treatments for epilepsy to reduce the impact of seizures and adverse effects of treatment on quality of life and mortality through all causes including Sudden Unexpected Death in Epilepsy (SUDEP). Both prior to and after this work, RCTs maintain the highest ethical standards to protect participants from adverse effects based on the data available at the time. If this re-analysis demonstrates that efficacy can be measured equivalently and safety can be improved with the T-PSC design, then our results may provide new data that could change RCT protocols directly.
We will perform this analysis by re-calculating the effectiveness and safety outcomes of as many RCTs for uncontrolled epilepsy as are available with the T-PSC and other Time to Event designs. We can do this by re-producing each trial’s original analysis with truncating data, where data after the Time to Event endpoint is not included. By demonstrating the effectiveness of T-PSC on as many historical RCTs as possible, we will build strong evidence that T-PSC could be applied prospectively.

Requested Studies:

A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study to Determine the Efficacy and Safety of 2 Doses of Retigabine Immediate Release (900 mg/Day and 600 mg/Day) Used as Adjunctive Therapy in Adult Asian Subjects With Drug-resistant Partial-onset Seizures.
Data Contributor: GlaxoSmithKline
Study ID: NCT01648101
Sponsor ID: RTG114855

An Open-Label, Uncontrolled, Long-Term Study to Assess the Safety of LAMICTAL in Pediatric Subjects Previously Enrolled in Protocol LAM20006 and In LAMICTAL-naive Subjects (1-24 Months of Age)
Data Contributor: GlaxoSmithKline
Study ID: NCT00044278
Sponsor ID: LAM20007

Double-blind Randomized Trial of Cognitive Effects of LAMICTAL (lamotrigine) versus Topiramate in Epilepsy
Data Contributor: GlaxoSmithKline
Study ID: LAM40112
Sponsor ID: LAM40112

Double-Blind Parallel Comparison of Three Doses of Topiramate and Placebo in Refractory Partial Epilepsy
Data Contributor: Johnson & Johnson
Study ID: NCT00236730
Sponsor ID: CR005458

A Multicenter, Open-Label, Long-Term, Safety, Tolerability and Efficacy Study of Retigabine in Adult Epilepsy Patients With Partial-Onset Seizures (Extension of Study VRX-RET-E22-302)
Data Contributor: GlaxoSmithKline
Study ID: NCT00310388
Sponsor ID: VRX-RET-E22-304

A Multicenter, Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Investigate the Efficacy and Safety of Lacosamide as Adjunctive Therapy in Subjects With Epilepsy ≥4 Years to <17 Years of Age With Partial Onset Seizures
Data Contributor: UCB
Study ID: NCT01921205
Sponsor ID: SP0969

An International, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible Dose Study: Evaluation of the Safety and Efficacy of Brivaracetam in Subjects (≥ 16 to 70 Years Old) Suffering From Localization-related or Generalized Epilepsy.
Data Contributor: UCB
Study ID: NCT00504881
Sponsor ID: N01254

A Multicenter, Placebo-Controlled Parallel-Design, Phase III Evaluation of the Safety of Lamotrigine (LAMICTAL) as Add-On Therapy in Outpatients with Partial Seizures
Data Contributor: GlaxoSmithKline
Study ID: P42-16
Sponsor ID: P42-16

A Multicenter, Placebo-Controlled, Parallel-Design, Dose-Response Evaluation of the Safety and Efficacy of Lamotrigine as Add-On Therapy in Epileptic Outpatients with Partial Seizures
Data Contributor: GlaxoSmithKline
Study ID: P42-05
Sponsor ID: P42-05

Double-Blind Parallel Comparison of Topiramate 200 mg Twice Daily to Placebo in Patients With Refractory Partial Epilepsy
Data Contributor: Johnson & Johnson
Study ID: NCT00236873
Sponsor ID: CR005563

Double-Blind, Parallel Comparison of Topiramate 300 mg Twice Daily to Placebo in Patients With Refractory Partial Epilepsy
Data Contributor: Johnson & Johnson
Study ID: NCT00236847
Sponsor ID: CR005566

Double-Blind Parallel Comparison of Topiramate 400 mg Twice Daily to Placebo in Patients With Refractory Partial Epilepsy
Data Contributor: Johnson & Johnson
Study ID: NCT00236860
Sponsor ID: CR005569

A Multicenter, Double-blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-Release Adjunctive Therapy in Patients With Primary Generalized Tonic-Clonic Seizures
Data Contributor: GlaxoSmithKline
Study ID: NCT00104416
Sponsor ID: LAM100036

A Multicenter, Double-Blind, Placebo-Controlled, Add-On, Crossover Study of Lamotrigine in Epileptic Outpatients with Partial Seizures
Data Contributor: GlaxoSmithKline
Study ID: P42-06
Sponsor ID: P42-06

A Randomized, Double-Blind, Parallel-Group, Monotherapy Study to Compare the Safety and Efficacy of Two Doses of Topiramate in the Treatment of Newly Diagnosed or Recurrent Epilepsy
Data Contributor: Johnson & Johnson
Study ID: NCT00231556
Sponsor ID: CR003259

A Multicenter, Open-label, Long-term, Safety, Tolerability and Efficacy Study of Retigabine in Adult Epilepsy Patients With Partial-onset Seizures (Extension of Study VRX-RET-E22-301)
Data Contributor: GlaxoSmithKline
Study ID: NCT00310375
Sponsor ID: VRX-RET-E22-303

A Multicenter, Double-Blind, Placebo-Controlled, Parallel-Design Evaluation of LAMICTAL for Add-on Treatment of Partial Seizures in Pediatric Patients
Data Contributor: GlaxoSmithKline
Study ID: 105-040
Sponsor ID: 105-040

A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Trial to Investigate the Efficacy and Safety of SPM 927 (400mg/Day and 600mg/Day) as Adjunctive Therapy in Subjects With Partial Seizures With or Without Secondary Generalization
Data Contributor: UCB
Study ID: NCT00136019
Sponsor ID: SP0754

A Randomized, Open-label, Parallel Group, Multi-center, Comparative, Phase IV Trial of Levetiracetam (LEV) Versus Topiramate (TPM) as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
Data Contributor: UCB
Study ID: NCT01229735
Sponsor ID: N01353

A Multicenter, Double-blind, Double-dummy, Randomized, Positive- Controlled Study Comparing the Efficacy and Safety of Lacosamide (200 to 600 mg/Day) to Controlled Release Carbamazepine (400 to 1200 mg/Day), Used as Monotherapy in Subjects (≥ 16 Years) Newly or Recently Diagnosed With Epilepsy and Experiencing Partial-onset or Generalized Tonic-clonic Seizures.
Data Contributor: UCB
Study ID: NCT01243177
Sponsor ID: SP0993

A Double-Blind, Placebo-Controlled, Add-On Clinical Trial of the Safety, Pharmacokinetics and Efficacy of Lamictal in Pediatric Age Subjects (1-24 Months)
Data Contributor: GlaxoSmithKline
Study ID: NCT00043875
Sponsor ID: LAM20006

A Multi-center, Double-blind, Parallel-group, Placebo Controlled, Randomized Study: Evaluation of the Efficacy and Safety of Brivaracetam in Subjects (>= 16 to 70 Years Old) With Partial Onset Seizures.
Data Contributor: UCB
Study ID: NCT00490035
Sponsor ID: N01252

Topiramate Clinical Trial in Primary Generalized Tonic-Clonic Seizures
Data Contributor: Johnson & Johnson
Study ID: NCT00236418
Sponsor ID: CR005830

Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Phase 3 Study – Determine Efficacy and Safety of Two Doses of Retigabine (900 Mg/Day and 600 Mg/Day) Used as Adjunctive Therapy in Refractory Epilepsy Patients With Partial-Onset Seizures
Data Contributor: GlaxoSmithKline
Study ID: NCT00235755
Sponsor ID: VRX-RET-E22-302

A Multicenter, Double-Blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-release Adjunctive Therapy in Subjects With Partial Seizures
Data Contributor: GlaxoSmithKline
Study ID: NCT00113165
Sponsor ID: LAM100034

A Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study to Evaluate the Efficacy and Safety of Brivaracetam in Subjects (≥16 to 80 Years Old) With Partial Onset Seizures
Data Contributor: UCB
Study ID: NCT01261325
Sponsor ID: N01358

A Multicenter, Open-Label Study To Investigate The Safety, Tolerability, And Pharmacokinetics Of Lacosamide (LCM) Oral Solution (Syrup) As Adjunctive Therapy In Children With Partial-Onset Seizures
Data Contributor: UCB
Study ID: NCT00938431
Sponsor ID: SP0847

An International, Double-blind, Parallel-group, Placebo-controlled, Randomized Study: Evaluation of the Efficacy and Safety of Brivaracetam in Subjects (>= 16 to 70 Years Old) With Partial Onset Seizures
Data Contributor: UCB
Study ID: NCT00464269
Sponsor ID: N01253

A Double-blind, Multicenter, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Treatment With 3000 mg/Day (Pediatric Target Dose of 60 mg/kg/Day) Oral Levetiracetam (LEV) (166, 250, and 500mg Tablets), in Adult and Pediatric Subjects (4-65 Years) Suffering From Idiopathic Generalized Epilepsy With Primary Generalized Tonic-clonic (PGTC) Seizures.
Data Contributor: UCB
Study ID: NCT00160550
Sponsor ID: N01057