ArticleNeurology2021
Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.
Abstract read
In one paragraph
Article in Neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed, 1 pooled it
–field-weighted citation impact
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.
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.
Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Herbal medicine for amyotrophic lateral sclerosis: A systematic review and meta-analysis.Frontiers in pharmacology · 2022Pooled it
- Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.JAMA neurology · 2026Trial
- An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.Brain communications · 2025Trial
- Small RNA sequencing identifies serum tDR-1:34-Gly-GCC tiRNA levels as a biomarker for survival in amyotrophic lateral sclerosis.iScience · 2026Article
- Survival of Intravenous Edaravone-Treated Patients With ALS: Evidence From Administrative Claims Analyses.Muscle & nerve · 2026Article
- Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.Journal of neurology · 2026Article
- Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.Drug design, development and therapy · 2026Review
- Application of the ENCALS predictive survival model in assessing the effect of the 24/44 inclusion criteria in FORTITUDE-ALS.Journal of neuromuscular diseases · 2025Article
- Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.Journal of racial and ethnic health disparities · 2025Article
- Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.Life (Basel, Switzerland) · 2025Review
- Rethinking phase 2 trials in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2025Article
- ALS Motor Observational Telemedicine Objective Rasch-Built Assessment: A Quantitative Scale for the Era of Teleneurology.Neurology. Clinical practice · 2025Article
- Population-Based Versus Hospital-Based Data in Amyotrophic Lateral Sclerosis-A Factor to Consider?European journal of neurology · 2025Article
- Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.European journal of neurology · 2024Article
- Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.Amyotrophic lateral sclerosis & frontotemporal degeneration · 2024Article
- Predicting clinical progression trajectories of early Alzheimer's disease patients.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- [Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].Revista medica del Instituto Mexicano del Seguro Social · 2024Review
- At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.Nature communications · 2023Article
- Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.Neurology · 2023Article
- Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.EClinicalMedicine · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
17 authors.
Ruben P A van EijkFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK. r.p.a.vaneijk-2@umcutrecht.nl.
Stavros NikolakopoulosFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Kit C B RoesFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Lindsay KendallFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.ORCID 0000-0003-2812-0154
Steve S HanFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Arseniy LavrovFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Noam EpsteinFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Tessa KliestFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Adriaan D de JonghFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Henk-Jan WestenengFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Ammar Al-ChalabiFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.ORCID 0000-0002-4924-7712
Philip Van DammeFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.ORCID 0000-0002-4010-2357
Orla HardimanFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Pamela J ShawFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Christopher J McDermottFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Marinus J C EijkemansFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Leonard H van den BergFrom the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.
Funding
Medical Research Council MR/L501529/1Medical Research Council MR/R024804/1
Abstract
Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.
Indexed as
Research DesignAmyotrophic Lateral SclerosisClinical Trials as TopicDisease ProgressionHumansPatient SelectionRisk Factors
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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.