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How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients
OBJECTIVES: Epileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473786/ https://www.ncbi.nlm.nih.gov/pubmed/37662339 http://dx.doi.org/10.1101/2023.08.21.23294339 |
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author | Parikh, Harsh Sun, Haoqi Amerineni, Rajesh Rosenthal, Eric S. Volfovsky, Alexander Rudin, Cynthia Westover, M. Brandon Zafar, Sahar F. |
author_facet | Parikh, Harsh Sun, Haoqi Amerineni, Rajesh Rosenthal, Eric S. Volfovsky, Alexander Rudin, Cynthia Westover, M. Brandon Zafar, Sahar F. |
author_sort | Parikh, Harsh |
collection | PubMed |
description | OBJECTIVES: Epileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine feasibility of RCTs evaluating EA treatment. METHODS: In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. RESULTS: Sample sizes ranged from 500 for levetiracetam 7 mg/kg vs placebo, to >4000 for levetiracetam 15 vs. 7 mg/kg to achieve 80% power (5% type I error). For propofol 1mg/kg/hr vs. placebo 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. INTERPRETATION: Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and assess feasibility of future trials of EA treatment. |
format | Online Article Text |
id | pubmed-10473786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104737862023-09-02 How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients Parikh, Harsh Sun, Haoqi Amerineni, Rajesh Rosenthal, Eric S. Volfovsky, Alexander Rudin, Cynthia Westover, M. Brandon Zafar, Sahar F. medRxiv Article OBJECTIVES: Epileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine feasibility of RCTs evaluating EA treatment. METHODS: In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. RESULTS: Sample sizes ranged from 500 for levetiracetam 7 mg/kg vs placebo, to >4000 for levetiracetam 15 vs. 7 mg/kg to achieve 80% power (5% type I error). For propofol 1mg/kg/hr vs. placebo 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. INTERPRETATION: Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and assess feasibility of future trials of EA treatment. Cold Spring Harbor Laboratory 2023-08-22 /pmc/articles/PMC10473786/ /pubmed/37662339 http://dx.doi.org/10.1101/2023.08.21.23294339 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Parikh, Harsh Sun, Haoqi Amerineni, Rajesh Rosenthal, Eric S. Volfovsky, Alexander Rudin, Cynthia Westover, M. Brandon Zafar, Sahar F. How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title | How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title_full | How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title_fullStr | How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title_full_unstemmed | How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title_short | How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients |
title_sort | how many patients do you need? investigating trial designs for anti-seizure treatment in acute brain injury patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473786/ https://www.ncbi.nlm.nih.gov/pubmed/37662339 http://dx.doi.org/10.1101/2023.08.21.23294339 |
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