RT Journal Article
SR Electronic
T1 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
JF BMJ Open
JO BMJ Open
FD British Medical Journal Publishing Group
SP e021944
DO 10.1136/bmjopen-2018-021944
VO 8
IS 8
A1 Peter Connick
A1 Floriana De Angelis
A1 Richard A Parker
A1 Domenico Plantone
A1 Anisha Doshi
A1 Nevin John
A1 Jonathan Stutters
A1 David MacManus
A1 Ferran Prados Carrasco
A1 Frederik Barkhof
A1 Sebastien Ourselin
A1 Marie Braisher
A1 Moira Ross
A1 Gina Cranswick
A1 Sue H Pavitt
A1 Gavin Giovannoni
A1 Claudia Angela Gandini Wheeler-Kingshott
A1 Clive Hawkins
A1 Basil Sharrack
A1 Roger Bastow
A1 Christopher J Weir
A1 Nigel Stallard
A1 Siddharthan Chandran
A1 Jeremy Chataway
A1 ,
YR 2018
UL http://bmjopen.bmj.com/content/8/8/e021944.abstract
AB 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.