MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART)
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|ClinicalTrials.gov Identifier: NCT01910259|
Recruitment Status : Completed
First Posted : July 29, 2013
Last Update Posted : March 26, 2020
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|Condition or disease||Intervention/treatment||Phase|
|Secondary Progressive Multiple Sclerosis||Drug: Amiloride Drug: Riluzole Drug: Fluoxetine Drug: Placebo||Phase 2|
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 20mg bd, 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||445 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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.|
|Actual Study Start Date :||December 18, 2014|
|Actual Primary Completion Date :||June 14, 2018|
|Actual Study Completion Date :||July 4, 2018|
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
- 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||25 Years to 65 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Confirmed diagnosis of SPMS. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Evidence of progression, either an increase of at least one point in EDSS or clinical documentation of increasing disability in patient notes
- Expanded Disability Status Scale (EDSS) 4.0-6.5
- Aged 25 to 65 inclusive
- Women and men with partners of childbearing potential must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent, to 6 weeks after treatment inclusive
- Women must have a negative pregnancy test within 7 days prior to the baseline visit unless not of child bearing potential (e.g. have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are postmenopausal)
- Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fulfils the requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids), ability to understand and complete questionnaires
- Written informed consent provided
- Pregnancy or breast feeding patients
- Baseline MRI scan not of adequate quality for analysis (e.g. too much movement artefact)
- Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure)
- Relapse within 3 months of baseline visit
- Patients who have been treated with iv or oral steroids for an MS relapse/progression within 3 months of baseline visit (these patients can undergo future screening visits once the 3 month window has expired), patients on steroids for another medical condition may enter as long as the steroid prescription is not for multiple sclerosis (relapse/ progression).
- Use of Simvastatin at 80mg dose within 3 months of baseline visit (lower doses of Simvastatin and other statins are permissible)
- Commencement of fampridine within 6 months of baseline visit
- Use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine) or disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
- Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research of an investigational medicinal product) within 12 months of baseline visit
- Use of mitoxantrone/ natalizumab/ alemtuzumab/ daclizumab if treated within 12 months of baseline visit
- Primary progressive MS
- Relapsing-remitting MS
- Known hypersensitivity to the active substances and their excipients to any of the active drugs for this trial
- Use of: lithium, chlorpropamide, triamterene and spironolactone within 6 months of the baseline visit
- Current use of potassium supplements
- Current use of tamoxifen
- Current use of herbal treatments containing St. John's Wort
- Significant signs of depression
- Use of an SSRI within 6 months of the baseline visit
- Use of monoamine oxidase inhibitors, phenytoin, L-tryptophan) and/or neuroleptic drugs within 6 months of the baseline visit
- A Beck Depression Index score of 19 or higher
- Bipolar disorder
- Receiving or previously received Electro-Convulsive Therapy
- Patients with a history of bleeding disorders or currently on anticoagulants Routine screening blood values (LFT) >/ 3 x upper limit of normal (ULN) of site reference ranges (ALT/AST, bilirubin,ˠGT) Potassium <2.8mmol/l or >5.5mmol/l
- Sodium <125mmol/l
- Creatinine >130μmol/l
- WBCs <3 x 109/l
- Lymphocytes <0.8 x 109/l
- Neutrophil count <1.0 x 109 /l
- Platelet count <90 x 109 /l
- Haemoglobin <80g/l
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||University College, London|
|Other Study ID Numbers:||
|First Posted:||July 29, 2013 Key Record Dates|
|Last Update Posted:||March 26, 2020|
|Last Verified:||March 2020|
Secondary Progressive Multiple Sclerosis
Percentage Brain Volume Change
Magnetic Resonance Imaging
Optical Coherence Tomography
Multiple Sclerosis, Chronic Progressive
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Immune System Diseases
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors