MS-SMART Trial: a multi-arm phase 2b randomised, double blind, parallel group, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis [NCT01910259]
ECTRIMS Online Library. Chataway J. Oct 12, 2018; 232077; 324
Jeremy Chataway
Jeremy Chataway

Abstract: 324

Type: Scientific Session

Abstract Category: N/A

Background: Reducing the disability gradient in progressive multiple sclerosis is a fundamental aim. A strong therapeutic pipeline at phase 2 is a key part of this work.
Objectives: We aimed to carry out a multi-arm phase 2 trial in secondary progressive multiple sclerosis (SPMS) which would determine if drugs targeting different candidate pathways in the pathobiology of progression, which had early phase 2a success, could reduce whole brain atrophy. The drugs chosen with postulated mechanisms were: amiloride (acid-sensing ion channel-1 antagonist - reducing calcium and sodium influx), fluoxetine (increased production of brain-derived neurotrophic factor; enhanced astrocyte glycogenolysis) and riluzole (reduction in glutamate release; antagonism of voltage gated sodium channels).
Methods: 445 patients with SPMS were randomised 1:1:1:1 to 96 weeks of treatment with amiloride (5mg bd), fluoxetine (20mg bd), riluzole (5mg bd) or matched placebo. The study took place at 13 neuroscience centres around the UK. The major entry criteria were SPMS progressing over at least the previous 2 years, age 25-65 years, EDSS 4.0-6.5, not taking disease modifying treatment, no recent relapse activity or significant depression. Patients, healthcare professionals and those assessing outcomes were blinded to treatment assignment. The primary outcome was the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalization, of Atrophy (SIENA) method. Major Secondary outcomes were: (i) to establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS. (ii) evaluate anti-inflammatory drug activity using the count of new and enlarging T2 lesions. (iii) examine for evidence of pseudo-atrophy by MRI. (iv) examine for clinical efficacy as measured by clinician and patient reported outcomes.
Results: 557 patients were screened and 445 randomised. The median EDSS was 6.0 (IQR 6.0 to 6.5). Other baseline characteristics were [mean (SD)] age 54 yrs (7), 67% female, MS duration 22 yrs (10), SPMS duration 8 yrs (6), Paced Auditory Serial Addition Test 38.5 (14.8), and Symbol Digit Modalities Test 44.2 (12.4). The 96 week primary and major secondary outcomes will be presented.
Conclusions: A multi-arm strategy is viable, can significantly speed up phase 2 activity and interrogate the biology of progression in vivo.
Disclosure: Funding
MS-SMART is an investigator led project sponsored by University College London (UCL). This independent research is awarded by the Efficacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC), the UK Multiple Sclerosis Society and the National Multiple Sclerosis Society (USA NMSS) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. Additional support comes from the University of Edinburgh; the National Institute for Health Research University College London Hospitals (NIHR-UCLH) Biomedical Research Centre (BRC) and University College London; NIHR Leeds CRF (DenTCRU). CJW and RP were supported in this work by NHS Lothian via the Edinburgh Clinical Trials Unit.

Competing interests

PC, FDA, DP, AD, NJ, JS, SHP, CH, CJW, RP, NS, SC, GC, RB, DMCM, MR declare no conflict of interests with respect to this work.
MB has received funding from the UK Multiple Sclerosis Society and NIHR Local Clinical Research Network.
FP receives a Guarantors of Brain fellowship.
FB serves on the editorial boards of Brain, European Radiology, Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis, and Neuroradiology, and serves as consultant for Bayer Shering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA Pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research, and Lundbeck.
CGKW receives research grants (PI and co-applicant) from Spinal Research, Craig H. Neilsen Foundation, EPSRC, Wings for Life, UK MS Society, Horizon2020, NIHR/MRC.
JC has received support from the Efficacy and Mechanism Evaluation Programme and Health Technology Assessment Programme (NIHR); UK Multiple Sclerosis Society and National Multiple Sclerosis Society. In the last three years, he has been a local principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Roche and Biogen Idec, and has received an investigator grant from Novartis outside this work. He has taken part in Advisory Boards/consultancy for Roche, Merck, MedDay, Biogen and Apitope.
BS has received funding from NIHR and the UK MS Society, has been a principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Biogen, Merck, Genzyme, Roche and Teva.
GG is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen-Idec, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva, and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck-Serono, Genzyme-Sanofi, and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians' summit and several medical education meetings. He is also the co-chief editor of Multiple Sclerosis and Related Disorders (Elsevier).

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