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Proposal 1062/1130

Title of the Proposed Research

Factors that determine placebo response in epilepsy trials

Lead Researcher

Emilia Bagiella

Affiliation

Icahn School of Medicine at Mount Sinai

Funding Source

Epilepsy Foundation of America

Potential Conflicts of Interest

Potential conflicts of interest will be disclosed when the research is presented and published.

Data Sharing Agreement Date

1062 - 13 May 2015
1130 - 17 June 2015

Lay Summary

Clinical trials constitute the gold standard of research that informs treatment of epilepsy as well as the drug approval process. Improper trial design or a design based on incorrect assumptions could lead to the wrong conclusions and, potentially, to a misuse of the drug.

Clinical trials in patients with drug resistant epilepsy are becoming increasingly challenging due to the difficulty to enroll eligible patients. There is a need to design trials that are efficient and yield robust and reliable results. Important assumptions in the design phase of a clinical trial involve estimates of baseline response rates and effect size as they directly affect the size of the trial. Wrong assumptions lead to studies that are either over-powered or under-powered. In the former case, a high number of patients may be unnecessary exposed to placebo or a potentially ineffective therapy. In the latter case, a type II error may lead to reject a potentially effective drug. Therefore, it is imperative that trials be designed based on reliable and robust estimates. Other factors that profoundly influence the success of a trial include the choice and characteristics of the target population, a rigorous definition of the outcome, the study conduct and monitoring and the careful recording of adverse events.

A recent meta-analysis of adjunctive Anti-Epileptic Drugs (AEDs) in placebo-controlled randomized clinical trials (RCT) showed that responder rates increased over time with higher responder rates in more recent studies than in older trials (Rheims et al, 2010). The meta-analysis also showed a corresponding decrease of the effect size comparing active drugs against placebo. In addition, a couple of recent large studies in patients with drug resistant epilepsy have failed to show superiority of new drugs against placebo (REF).

In order to design successful trials for the treatment of refractory epilepsy it is essential to understand the factors that influence the increasing trend in the placebo response as well the decreased size of the treatment effect. The goal of this project is to determine factors associated with response in patients randomised to placebo in adjunctive randomized clinical trials of AEDs in adults and children with focal epilepsy. To this end, the International League Against Epilepsy has partnered with several pharmaceutical companies who are willing to share information about their trials. The context in which clinical trials in epilepsy are conducted has changed over time. In order to design the most efficient and most successful trials it is essential to understand what factors need to be taken into consideration during the design phase and the conduct of the trial. The proposed study will help understand these factors and will inform the design of new studies in patients with drug resistant epilepsy.

Study Data Provided

Study LEP111102: A pivotal single-dose, randomised, parallel-group, open-label study to demonstrate bioequivalence of 250mg lamotrigine XR relative to 200mg + 50mg lamotrigine XR and to demonstrate lack of food effect on 250mg lamotrigine XR in healthy male and female volunteers
Study SCAA4001: A Double-blind, Double-dummy, Parallel-group Comparison of Lamotrigine and Divalproex Sodium Initial Monotherapy in Patients with Epilepsy
Study LAM105377: A randomised, open-label, parallel-group design study to evaluate the pharmacokinetic characteristics, safety and tolerability of single oral doses of three prototype 300mg enteric coated - modified release formulations of Lamotrigine in healthy subjects.
Study LAM100036: A Multicenter, Double-blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-Release Adjunctive Therapy in Patients with Primary Generalized Tonic-Clonic Seizures
Study LAM100034: A Multicenter, Double-Blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-release Adjunctive Therapy in Subjects with Partial Seizures
Study LAM40091: Lamictal in Combination with Newer and Older Antiepileptic Drugs and as Monotherapy: A Practical Clinical Assessment of Tolerability and Clinical Effectiveness (The TARGET Study: Trial to Assess and Refine Global Epilepsy Treatment)
Study LAM30055: A Multicenter, Double-Blind, Randomized Conversion to Monotherapy Comparison of Two Doses of Lamotrigine for the Treatment of Partial Seizures
Study LAM40097: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Evaluation of Lamotrigine Adjunctive Therapy in Subjects wtih Primary Generalized Tonic-Clonic Seizures
Study LAM20006: A Double-Blind, Placebo-Controlled, Add-On Clinical Trial of the Safety, Pharmacokinetics and Efficacy of Lamictal in Pediatric Age Subjects (1-24 months)
Study LAM40112: Double-blind Randomized Trial of Cognitive Effects of LAMICTAL (lamotrigine) versus Topiramate in Epilepsy
Study LAM40013: A Multicenter, Open-Label Conversion of Valproate Monotherapy to Lamotrigine Monotherapy in Patients with Epilepsy
Study UCB-SP667: A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Trial to Investigate the Efficacy and Safety of SPM 927 (200mg/day, 400mg/day, 600mg/day) as Adjunctive Therapy in Subjects with Partial Seizures with or without Secondary Generalization Medicine: Lacosamide , Condition: Epilepsy, Phase: 2, Clinical Study ID: SP667, Sponsor: UCB
Study UCB-SP754: SPM 927 (400mg/Day and 600mg/Day) as Adjunctive Therapy in Subjects With Partial Seizures With or Without Secondary Generalization Medicine: Lacosamide , Condition: Epilepsy, Phase: 3, Clinical Study ID: SP754, Sponsor: UCB
Study UCB-SP755: A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Trial to Investigate the Efficacy and Safety of SPM 927 (200mg/Day and 400mg/Day) as Adjunctive Therapy in Subjects With Partial Seizures With or Without Secondary Generalization Medicine: Lacosamide , Condition: Epilepsy, Phase: 3, Clinical Study ID: SP755, Sponsor: UCB

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.