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]

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.