Title: A multi-arm phase IIb randomised, double blind clinical trial comparing the efficacy of 3 neuroprotective drugs compared to placebo in secondary progressive multiple sclerosis.
Funder: Department of Health and Social Care

Abstract: HYPOTHESIS:Neuroprotective drugs will slow disability progression in SPMS. AIM:To test efficacy of 3 neuroprotective drugs of different mechanistic classes against placebo in SPMS over 2 years. DESIGN: The cohort is randomised to placebo or one of the 3 treatments. At 24 months the primary MRI outcome is measured (change in brain volume). POPULATION: Patients with established SPMS, demonstrating progression over the previous 2 years, age 25-65 inclusive, ambulatory with an EDSS 4.0-6.5, no relapses for at least 3 months, not on current immuno-suppressive/modulating treatment or SSRIs. INTERVENTIONS: Fluoxetine (20mg twice per day) or Amiloride (5mg twice per day) or Riluzole (50mg twice per day). PRIMARY OUTCOME: Percentage Brain Volume Change (PBVC) from M0 to M24. SECONDARY OUTCOMES [clinical]: 1)EDSS, 2)Timed 25 Foot Walk, 3) 9 Hole Peg Test, 4) Paced Auditory Serial Addition Test, 5) 2-4, combined as MSFC, 6)SDMT, 7) Sloan Low Contrast Visual Acuity, 8)Relapse rate, 9) MSIS, 10) MSWS. HEALTH ECONOMICS /QoL: 11) EuroQoL EQ-5D, 12)Fatigue, 13) Pain. SECONDARY OUTCOMES [MRI]: 14) New and enlarging T2 lesions, 15) Pseudoatrophy assessment. TOXICITY & SAFETY: 16) SAEs/SUSARs. EXPLORATORY OUTCOMES AND FURTHER MECHANISTIC EVALUATION:1) Proportion of new T2 lesions at 6 months being persistently T1 hypointense at 24 months, 2) Change in grey matter volume, 3) Proton (1H) MR spectroscopy, 4) Magnetisation transfer ratio, 5) Identification of composite MRI and disability parameters, 6) Cerebrospinal fluid neurofilament analysis, 7) OCT. ASSESSMENT AND FOLLOW UP: Screening will occur at M-1. Core MRI will occur at M0, 6, 24, with advanced (mechanistic) MRI at M0&24; OCT (n=270) M0,12&24; CSF NF (n=120) M0,6,12. All secondary outcomes will be measured at M0, 6, 12, 24. Toxicity and safety monitoring will be carried out monthly M1, 2, 3, then 3 monthly M6, 9, 12, then 6 monthly M18, 24. SAMPLE SIZE: 440 with 110 patients/arm - 90% power to detect a 40% reduction in atrophy on any active arm compared to the placebo, or 80% power to detect a 35% reduction, with an overall two-sided 5% significance level after Bonferroni adjustment (1.67% two-sided tests) to allow for the multiple comparisons. For a more exploratory analysis without adjusting for multiple comparisons, this sample size will give 90% power to detect a 35% reduction in atrophy. The study is not powered to detect differences between the three active treatment arms. STATISTICAL ANALYSIS: A normal linear modelling approach will be used to compare the groups adjusting for baseline normalised brain volume (NBV) and other baseline prognostic and demographic factors. PROJECT TIMETABLES INCLUDING RECRUITMENT RATE: Trial duration 51M Start Date 03/2013; Set-up 9M; Recruitment 12M 440 SPMS patients over 10 centres (recruitment rate: 148 M1-6 and 296 M6-12 as greater efficiency when all sites have R&D approvals and open); Follow-up:24M and Analysis 6M. TEAM EXPERTISE: Chataway & Chandran will lead a multidisciplinary team, with expertise in clinical trials, MRI, statistics and PPI. It has been working for the past 5 years through the MS-CTN to develop MS-SMART.

Lay abstract: Multiple sclerosis (MS) is the commonest disabling neurological disease affecting young adults in temperate latitudes. It is a progressive disorder of the brain and spinal cord that affects approximately 100,000 people in the UK. Most patients with MS experience two phases of disease: (i) early MS relapsing remitting MS, RRMS) due to bouts of largely reversible inflammation that results in nerve damage and (ii) late MS, secondary progressive MS (SPMS), which affects the majority of patients emerges after 10-15 years and results from nerve death (neurodegeneration) that causes accumulating and irreversible disability as well as a range of devastating problems affecting walking, balance, vision, cognition, pain control, bladder and bowel function. Unlike RRMS, where there are an increasing number of advanced medications, there is no proven treatment for SPMS - it is therefore a major unmet health need for the NHS. These patients require nerve protection (neuroprotection) treatments that will slow, stop and ultimately reverse progressive disease. In response to this,the UK MS Society set up the MS Clinical Trials Network (CTN) involving people with MS(PwMS), clinicians and researchers to explore new approaches to clinical trials for SPMS patients. This process included a systematic search of all relevant pre-clinical and clinical data globally and a review by an international MS expert workshop,which has led to the identification of three leading drugs (Fluoxetine, Riluzole or Amiloride) suitable to trial in SPMS. The MS-SMART trial will test these drugs in 440 SPMS patients using a simultaneous multi-arm trial design, an approach used with great success in cancer drug trials each compared against a dummy drug (placebo). Patients and treating trial clinician will not know which drug they are receiving to enable an unbiased testing of the drugs. All patients will have MRI (magnetic resonance imaging) brain scans and after 24 months these will be analysed to determine which drugs are the most promising. The main (primary) outcome is change in MRI, to see if any of the drugs can slow the rate of brain shrinkage that we would normally see in SPMS,compared to being on the dummy drug. This trial is a world-first in MS, with great economies of Scale. The MRI scans are expensive but are the gold standard means of detecting improvement of the brain and advance our understanding of how the drugs are providing neuroprotection in SPMS patients.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL