Natural Variability in Seizure Frequency: Implications for Trials and Placebo

Overview

Journal Epilepsy Res

Specialty Neurology

Date 2020 Mar 16

PMID 32172145

Citations 14

Authors

Juan Romero

Phil Larimer

Bernard Chang

Shira R Goldenholz

Daniel M Goldenholz

Affiliations

Soon will be listed here.

Abstract

Background: Changes in patient-reported seizure frequencies are the gold standard used to test efficacy of new treatments in randomized controlled trials (RCTs). Recent analyses of patient seizure diary data suggest that the placebo response may be attributable to natural fluctuations in seizure frequency, though the evidence is incomplete. Here we develop a data-driven statistical model and assess the impact of the model on interpretation of placebo response.

Methods: A synthetic seizure diary generator matching statistical properties seen across multiple epilepsy diary datasets was constructed. The model was used to simulate the placebo arm of 5000 RCTs. A meta-analysis of 23 historical RCTs was compared to the simulations.

Results: The placebo 50 %-responder rate (RR50) was 27.3 ± 3.6 % (simulated) and 21.1 ± 10.0 % (historical). The placebo median percent change (MPC) was 22.0 ± 6.0 % (simulated) and 16.7 ± 10.3 % (historical).

Conclusions: A statistical model of daily seizure count generation which incorporates quantities related to the natural fluctuations of seizure count data produces a placebo response comparable to those seen in historical RCTs. This model may be useful in better understanding the seizure count fluctuations seen in patients in other clinical settings.

Citing Articles

Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy.

Kerr W, Suprun M, Kok N, Reddy A, McFarlane K, Kwan P Epilepsia. 2024; 66(2):407-416.

PMID: 39707877 PMC: 11827720. DOI: 10.1111/epi.18197.

The present and future of seizure detection, prediction, and forecasting with machine learning, including the future impact on clinical trials.

Kerr W, McFarlane K, Pucci G Front Neurol. 2024; 15:1425490.

PMID: 39055320 PMC: 11269262. DOI: 10.3389/fneur.2024.1425490.

Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

Kerr W, Kok N, Reddy A, McFarlane K, Stern J, Pennell P Neurology. 2024; 103(4):e209713.

PMID: 39052963 PMC: 11271390. DOI: 10.1212/WNL.0000000000209713.

Minimum clinical utility standards for wearable seizure detectors: A simulation study.

Goldenholz D, Karoly P, Viana P, Nurse E, Loddenkemper T, Schulze-Bonhage A Epilepsia. 2024; 65(4):1017-1028.

PMID: 38366862 PMC: 11018505. DOI: 10.1111/epi.17917.

Increasing challenges to trial recruitment and conduct over time.

Kerr W, Reddy A, Seo S, Kok N, Stacey W, Stern J Epilepsia. 2023; 64(10):2625-2634.

PMID: 37440282 PMC: 10592378. DOI: 10.1111/epi.17716.

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