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Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis

Li, Vivien; Leurent, Baptiste; Barkhof, Frederik; Braisher, Marie; Cafferty, Fay; Ciccarelli, Olga; Eshaghi, Arman; ... Chataway, Jeremy; + view all (2022) Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis. Neurology 10.1212/WNL.0000000000200604. (In press). Green open access

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Abstract

Progressive multiple sclerosis (PMS) is a significant health problem with few treatments shown to slow disability progression. One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multi-stage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS, focusing on selection of interim and final outcome measures, sample size and statistical considerations.The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design parameters. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate and sample size assumptions. People with MS formed a Patient and Public Involvement group and contributed to the trial design ensuring it would meet the needs of the MS community.The proposed design evaluates three experimental arms compared to a common standard of care arm in two stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to six-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Score, Timed 25-Foot Walk and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit around 1,900 participants and last around 6 years. This is approximately two-thirds the size and half the time of separate two-arm phase II and III trials.The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatment for PMS. The design was also well-received by people with MS. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Type: Article
Title: Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1212/WNL.0000000000200604
Publisher version: https://doi.org/10.1212/WNL.0000000000200604
Language: English
Additional information: This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Statistical Science
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Brain Repair and Rehabilitation
URI: https://discovery.ucl.ac.uk/id/eprint/10145941
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