Connick, P, De Angelis, F, Parker, RA, Plantone, D, Doshi, A, John, N, Stutters, J, MacManus, D, Prados Carrasco, F, Barkhof, F, Ourselin, S, Braisher, M, Ross, M, Cranswick, G, Pavitt, SH, Giovannoni, G, Gandini Wheeler-Kingshott, CA, Hawkins, C, Sharrack, B, Bastow, R, Weir, CJ, Stallard, N, Chandran, S and Chataway, J (2018) Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open, 8 (8). ISSN 2044-6055

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Abstract

Introduction
The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).

Methods and analysis
Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.

Ethics and dissemination
MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.

Trial registration numbers NCT01910259; 2012-005394-31; ISRCTN28440672.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via BMJ Publishing Group at https://doi.org/10.1136/bmjopen-2018-021944 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: progressive multiple sclerosis, neuroprotection, clinical trial, drug repurposing, mechanistic evaluation
Subjects: R Medicine > RC Internal medicine > RC346 Neurology. Diseases of the nervous system, including speech disorders
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 25 Oct 2018 09:45
Last Modified: 25 Oct 2018 15:41
URI: http://eprints.keele.ac.uk/id/eprint/5459

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