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.
A clinical trial is testing three cheap, already-licensed drugs—fluoxetine, amiloride, and riluzole—against a placebo in 440 people with secondary progressive multiple sclerosis (SPMS) to see if any can slow the relentless loss of brain volume that drives disability. SPMS is the phase of MS where disability steadily worsens even without relapses, and no drug has yet been proven to slow that progression. Existing treatments mostly target inflammation, not the underlying neurodegeneration. This trial directly tests whether repurposed neuroprotective agents can fill that gap. If any of the three drugs shows a 35–40% reduction in brain shrinkage over two years, it would provide the first evidence that a safe, inexpensive, oral therapy can slow disability in SPMS. That could change clinical practice immediately, since these drugs are already available and off-patent. For patients, it might mean preserving mobility and independence for longer. For the NHS, it could offer a low-cost option where none currently exists. The trial also collects advanced MRI and spinal fluid samples to understand *how* the drugs work, which could guide future drug development.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know