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. Issue 8 (30th August 2018)

• Record Type: Journal Article
• Authors: Connick, Peter; De Angelis, Floriana; Parker, Richard A; Plantone, Domenico; Doshi, Anisha; John, Nevin; Stutters, Jonathan; MacManus, David; Prados Carrasco, Ferran; Barkhof, Frederik; Ourselin, Sebastien; Braisher, Marie; Ross, Moira; Cranswick, Gina; Pavitt, Sue H; Giovannoni, Gavin; Gandini Wheeler-Kingshott, Claudia Angela; Hawkins, Clive; Sharrack, Basil; Bastow, Roger; Weir, Christopher J; Stallard, Nigel; Chandran, Siddharthan; Chataway, Jeremy
• Other Names: author non-byline.; Chataway Jeremy author non-byline.; Wheeler-kingshott Claudia Gandini author non-byline.; Angelis Floriana De author non-byline.; Plantone Domenico author non-byline.; Doshi Anisha author non-byline.; John Nevin author non-byline.; Williams Thomas author non-byline.; Chandran Siddharthan author non-byline.; Connick Peter author non-byline.; Cameron James author non-byline.; Mollison Daisy author non-byline.; Dhillon Baljean author non-byline.; Weir Christopher J author non-byline.; Parker Richard author non-byline.; Giovannoni Gavin author non-byline.; Gnanapavan Sharmilee author non-byline.; Nicholas Richard author non-byline.; Rashid Waqar author non-byline.; Aram Julia author non-byline.; Ford Helen author non-byline.; Overell James author non-byline.; Young Carolyn author non-byline.; Duddy Martin author non-byline.; Guadagno Joe author non-byline.; Evangelou Nikolaos author non-byline.; Craner Matthew author non-byline.; Palace Jacqueline author non-byline.; Hobart Jeremy author non-byline.; Sharrack Basil author non-byline.; Paling David author non-byline.; Hawkins Clive author non-byline.; Kalra Seema author non-byline.; Mclean Brendan author non-byline.;
• Is Part Of: BMJ open. Volume 8:Issue 8(2018)
• Publication Date: 2018-08-30
• Subjects: progressive multiple sclerosis -- neuroprotection -- clinical trial -- drug repurposing -- mechanistic evaluation; Medicine -- Research -- Periodicals; 610.72
• DOI: 10.1136/bmjopen-2018-021944
• Languages: English
• ISSNs: 2044-6055

Abstract

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 .