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Proposal 1335

Title of the Proposed Research

Investigation into the natural course of epilepsy and the implications on clinical trials

Lead Researcher

Daniel Goldenholz

Affiliation

NINDS, National Institutes of Health

Funding Source

This research is funded by the National Institute of Neurological Disorders and Stroke (NINDS) NIH Division of Intramural Research

Potential Conflicts of Interest

None

Data Sharing Agreement Date

6 December 2016

Lay Summary

BACKGROUND Epilepsy affects at least 2.2 million Americans, costs $9.5-$12.5 billion annually, and has a 10-fold increased risk of sudden death compared to the general public. Medicines currently do not help 1 out of 3 patients with this disease, and surgery either is ineffective or unavailable to many of these patients. When new medicines are tested in clinical studies, they are compared to placebo. If the medicine is stronger than placebo, then it is considered effective.

Clinical studies of epilepsy report a “placebo effect” of 4-19%. Studies in the natural course of epilepsy have found 30-60% of patients that become seizure-free from their disease temporarily or permanently. Recently a simulation using at the largest database of seizures found effects identical to the “placebo effect” without any placebo being given. Taken together, it seems possible that the “placebo effect” of clinical studies might actually be the natural course of epilepsy, not the placebo effect. Also, it is possible that if we understand this problem better, we may be able to better tell the difference between a “powerful” medicine, and a non-helpful one.

HOW THIS WILL HELP PATIENTS
If the studies can tell the difference between “natural” changes in seizure versus changes from “placebo effects” or medicines, then better medicines can be found faster and for less money.

HYPOTHESIS:
Review of clinical trials placebo arm patients will show evidence of natural seizure fluctuations rather than true placebo effects.

SPECIFIC AIMS:
1. To analyze clinical trial data from patients in reverse time. Instead of comparing baseline to treatment and looking for response, the comparison will be reversed. The expectation is placebo arm patients will continue to show “response” and active treatment arm patients will demonstrate “worsening”.
2. To pool clinical trial data from placebo arm patients in multiple placebo controlled epilepsy trials, and to clinically validate the findings in the recent simulation study.
3. To study the possibility of decreasing the “placebo effect” by retrospective review of the clinical data in a fashion analogous to that used in the recent simulation study.

PUBLICATION PLAN
The outcome of these investigations will be submitted for publication in a peer reviewed journal.

Study Data Provided

GSK-LAM100036: An open-label study in healthy male and female volunteers to evaluate the repeat dose pharmacokinetics and dose strength equivalence of lamotrigine enteric coated modified release tablets over the dose range 25-200 mg.
GSK-LAM100034: A Multicenter, Double-Blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-release Adjunctive Therapy in Subjects with Partial Seizures
GSK-LAM40097: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Evaluation of Lamotrigine Adjunctive Therapy in Subjects wtih Primary Generalized Tonic-Clonic Seizures
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
UCB-SP754: SPM 927 (400mg/Day and 600mg/Day) as Adjunctive Therapy in Subjects With Partial Seizures With or Without Secondary Generalization
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
UCB-N01057: Study to Evaluate the Safety and Efficacy of Levetiracetam in Patients Suffering From Idiopathic Generalized Epilepsy With Primary Generalized Tonic-clonic Seizures
GSK-VRX-RET-E22-301: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Phase 3 Study to Determine the Efficacy and Safety of Retigabine (1200mg/day) Used as Adjunctive Therapy in Refractory Epilepsy Patients with Partial-Onset Seizures
GSK-VRX-RET-E22-302: Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
GSK-3065A1-205: Open-label Study of Levetiracetam Intravenous Infusion in Children (1 Month-4 Years Old) With Epilepsy

Statistical Analysis Plan

Publication Citation

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

Summary Results

Results summary or link will be posted when available.