MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART)
Secondary Progressive Multiple Sclerosis
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Multi-arm Phase IIB Randomised, Double Blind Placebo-controlled Clinical Trial Comparing the Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis.|
- MRI-derived Percentage Brain Volume Change (PBVC). [ Time Frame: 2 years ]To establish whether a drug, from a panel of 3 leading candidate neuroprotective drugs, slows the rate of brain volume loss in SPMS over 96 weeks using MRI-derived percentage brain volume change (PBVC).
- Multi-arm trial strategy assessment [ Time Frame: 2 years ]To establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS and can become the template for future work.
- Count of new and enlarging T2 lesions [ Time Frame: 2 years ]To explore any anti-inflammatory drug activity using the count of new and enlarging T2 lesions.
- Pseudo-atrophy [ Time Frame: 6 months ]Examining for evidence of pseudo-atrophy (to ensure reliability of the primary outcome measure).
- Clinical measure of neuroprotection [ Time Frame: 2 years ]To examine the clinical effect of neuroprotection as measured by clinician - EDSS, MSFC, SDMT, SLCVA, relapse rate and patient reported outcome measures - MSIS29 v2, MSWS v2, Pain - NPRS and BPI and Fatigue - NFI.
- Health economics [ Time Frame: 2 years ]To collect basic health economic data (EQ-5D) to inform future phase III trials.
- New T1 hypotense lesion count [ Time Frame: 2 years ]Persistent new T1 hypointense lesion count to assess neuroprotection in new lesions.
- Grey matter volume change [ Time Frame: 2 years ]Grey matter volume change to assess cortical neuroprotection.
- MR spectroscopy measured N-acetyl aspartate, myoinositol and glutamate [ Time Frame: 2 years ]MR spectroscopy (MRS) to measure N-acetyl aspartate (reversal of neuronal mitochondrial dysfunction), myoinositol (prevention of glial cell inflammation) and glutamate (prevention of excitotoxicity).
- Myelination [ Time Frame: 2 years ]Magnetic Transfer Ratio (MTR) to evaluate myelination.
- Cervical cord imaging [ Time Frame: 2 years ]Cervical cord imaging to assess cord neuroprotection.
- Composite MRI/disability scores [ Time Frame: 2 years ]Composite MRI/disability scores to increase sensitivity and study interaction of treatment mechanisms.
- Cerebrospinal fluid (CSF) neurofilament levels [ Time Frame: 2 years ]Quantification of Cerebrospinal fluid (CSF) neurofilament levels to measure neuroprotection.
- Optical Coherence Tomography (OCT) measured Retinal Nerve Fibre Layer (RNFL) thickness [ Time Frame: 2 years ]Optical Coherence Tomography (OCT) measured Retinal Nerve Fibre Layer (RNFL) thickness as a measure of neuroprotection.
|Study Start Date:||December 2014|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2018 (Final data collection date for primary outcome measure)|
Amiloride 5 mg twice per day (5 mg once per day for first 4 weeks) for 96 weeks
Comparison with placebo
Riluzole 50 mg twice per day (50 mg once per day for first 4 weeks) for 96 weeks
Comparison with placebo
Fluoxetine 20 mg twice per day (20 mg once per day for first 4 weeks) for 96 weeks
Comparison with placebo
Placebo Comparator: Placebo
Matched placebo 1 capsule twice per day (1 capsule a day for first 4 weeks) for 96 weeks
MS-SMART will test the efficacy and mechanism of action of three repurposed drugs (fluoxetine, riluzole and amiloride). All three drugs are in human use and have a good safety record. Critically for the purpose of MS-SMART they all have shown promise in early phase human MS clinical trials and target one or more of the pivotal neurodegenerative causing pathways implicated in SPMS. This is a Type B trial, as the IMPs are all in human use, have a good safety profile but are not currently used for this patient population.
The major need for patients with established and progressive MS is neuroprotective or disease modifying treatments that will slow or even stop disease progression. This study will evaluate three highly promising putative neuroprotective drugs as well as comprehensively address several of the current knowledge gaps related to the understanding of neuroprotection and neurodegeneration in SPMS through MRI and CSF examination.
MS-SMART is a multicentre, multi-arm, double blind, placebo-controlled phase IIb randomised controlled trial. A total of 440 patients with SPMS, with an entry criteria of an EDSS score of 4.0-6.5 will be equally randomised to receive placebo or one of the three active agents (fluoxetine 20mgbd, amiloride 5mg bd or riluzole 50mg bd). Patients will be followed up for 96 weeks with outcome-data collected after 0, 24, 48 and 96 weeks. That is, the duration of the trial for a trial participant is 96 weeks (a telephone assessment at week 100, 4 weeks post completion will be conducted). This is standard practice for phase II trials in SPMS.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01910259
|Anne Rowling Regenerative Neurology Clinic, Royal Infirmary of Edinburgh|
|Edinburgh, United Kingdom, EH16 4SA|
|Gartnavel Royal Hospital, 1055 Great Western Road|
|Glasgow, United Kingdom, G12 OXH|
|Brighton and Sussex University Hospitals|
|Haywards Heath, United Kingdom, RH16 4EX|
|St James's University Hospital|
|Leeds, United Kingdom, LS9 7TF|
|The Walton Centre|
|Liverpool, United Kingdom, L9 7LJ|
|The National hospital for Neurology and Neurosurgery, University College London|
|London, United Kingdom, WC1N 3BG|
|The Royal Victoria Infirmary|
|Newcastle, United Kingdom, NE1 4LP|
|Queens Medical Centre|
|Nottingham, United Kingdom, NG7 2UH|
|John Radcliffe Hospital, Oxford University Hospitals NHS Trust|
|Oxford, United Kingdom, OX3 9DU|
|Plymouth, United Kingdom, PL6 8DH|
|Royal Hallamshire Hospital|
|Sheffield, United Kingdom, S10 2JF|
|University Hospital of North Staffordshire|
|Stoke-on-Trent, United Kingdom, ST4 7LN|
|Royal Cornwall Hospital|
|Truro, United Kingdom, TR1 3LJ|
|Principal Investigator:||Jeremy Chataway||University College, London|
|Principal Investigator:||Siddharthan Chandran||University of Edinburgh|