Evidence map›Paper›PMID 37085329›Full record

ArticleNeurology2023

Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.

Jordi W J van Unnik, Stavros Nikolakopoulos, Marinus J C Eijkemans, Jésus Gonzalez-Bermejo, Gaelle Bruneteau, Capucine Morelot-Panzini, Leonard H van den Berg, Merit E Cudkowicz, Christopher J McDermott, Thomas Similowski and 2 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed, 1 pooled it
1.0field-weighted citation impact, top 24% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 1 synthesis or guideline pooled it, 3 citations in OpenAlex.

  1. Pooled it
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 1 institution in 4 countries.

Jordi W J van UnnikFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Stavros NikolakopoulosFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Marinus J C EijkemansFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Jésus Gonzalez-BermejoFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Gaelle BruneteauFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Capucine Morelot-PanziniFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Leonard H van den BergFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Merit E CudkowiczFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Christopher J McDermottFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Thomas SimilowskiFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom.
Ruben P A van EijkFrom the Department of Neurology (J.W.J.v.U., L.H.v.d.B., R.P.A.v.E.), UMC Utrecht Brain Center, and Biostatistics & Research Support (S.N., M.J.C.E., R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; Sorbonne Université (J.G.-B., C.M.-P., T.S.), INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, Département R3S; APHP (G.B.), Groupe Hospitalier Paris 6, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre Référent SLA, France; Department of Neurology (M.E.C.), Massachusetts General Hospital, Boston; and Sheffield Institute for Translational Neuroscience (C.J.M.), University of Sheffield, United Kingdom. r.p.a.vaneijk-2@umcutrecht.nl.ORCID 0000-0002-7132-5967
DiPALS, RespiStimALS and Ceftriaxone Study Group
Inserm · FR

Funding

Clinical Trial of Ceftriaxone in Subjects with ALSU01NS049640 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI CUDKOWICZ, MERIT E · 2006 to 2012
$37.7M
NINDS NIH HHS U01 NS049640
6 · The paper itself

Abstract

BACKGROUND AND

objectivesLate-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs.

methodsA simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to 3 clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared with conventional interim designs.

resultsWe evaluated 183-1,351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2-19.4 months earlier (reduction of 4.6%-57.7% in trial duration), and could have reduced the number of randomized patients by 1.7%-58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios. DISCUSSION: Our algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments and result in significant ethical and efficiency gains.

Indexed as

Amyotrophic Lateral SclerosisComputer SimulationHumansMedical FutilityResearch DesignRetrospective StudiesUncertainty

Identifiers

PMID37085329
PMCPMC10256133
OpenAlexW4366605600

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.