MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART)

A Multi-arm Phase IIB Randomised, Double Blind Placebo-controlled Clinical Trial Comparing the Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a disabling and progressive neurological disease that affects approximately 100,000 people in the UK. Many patients with MS experience two phases of disease; early MS (also called relapsing remitting MS, RRMS) and late MS (also called secondary progressive MS (SPMS). Early MS is due to inflammation of the nerves and the insulation (called myelin) that surrounds the nerves. Early MS is often characterised by periods of "attacks" interspersed with periods of "remission" with no or low disease symptoms. Late or progressive MS, which affects the majority of patients and typically emerges after 10-15 years of disease, results from actual nerve death (also called neurodegeneration). The progressive stage of disease results not in individual attacks but slow, cumulative and irreversible disability affecting walking, balance, vision, cognition, pain control, bladder and bowel function. Critically, and unlike early disease, there is no proven treatment for the late stage of MS. This is therefore an urgent and major unmet health need. MS-SMART directly addresses this need and will evaluate in this clinical trial three drugs (fluoxetine, riluzole or amiloride), all of which have shown some promise in MS, and in particular in SPMS. The trial is randomised and blinded. Randomisation means patients can get any one of the three active drugs or the inactive placebo/dummy; blinded means that neither patients nor the doctors will know which drug or placebo patients are receiving. Randomisation and blinding are standard approaches in clinical trials to ensure unbiased testing of drugs. All patients in MS-SMART will have periodic MRI (magnetic resonance imaging) brain scans and after 96 weeks these will be analysed. We will then compare the scans of each drug to the placebo or dummy to see if any of the drugs slow the rate of brain shrinkage that normally occurs in SPMS. This measured change in brain size is the primary (major) outcome of MS-SMART.

Study Overview

• Status: Completed
• Conditions: Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Amiloride; Drug: Riluzole; Drug: Fluoxetine

Detailed Description

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
• Enrollment (Actual): 445
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Anne Rowling Regenerative Neurology Clinic, Royal Infirmary of Edinburgh
  • Glasgow, United Kingdom, G12 OXH
    • Gartnavel Royal Hospital, 1055 Great Western Road
  • Haywards Heath, United Kingdom, RH16 4EX
    • Brighton and Sussex University Hospitals
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Liverpool, United Kingdom, L9 7LJ
    • The Walton Centre
  • London, United Kingdom, WC1N 3BG
    • The National hospital for Neurology and Neurosurgery, University College London
  • Newcastle, United Kingdom, NE1 4LP
    • The Royal Victoria Infirmary
  • Nottingham, United Kingdom, NG7 2UH
    • Queens Medical Centre
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital, Oxford University Hospitals NHS Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
  • Stoke-on-Trent, United Kingdom, ST4 7LN
    • University Hospital of North Staffordshire
  • Truro, United Kingdom, TR1 3LJ
    • Royal Cornwall Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 23 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• Epilepsy/seizures
• Glaucoma
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amiloride; Amiloride 5 mg twice per day (5 mg once per day for first 4 weeks) for 96 weeks	Drug: Amiloride; Comparison with placebo
Experimental: Riluzole; Riluzole 50 mg twice per day (50 mg once per day for first 4 weeks) for 96 weeks	Drug: Riluzole; Comparison with placebo
Experimental: Fluoxetine; Fluoxetine 20 mg twice per day (20 mg once per day for first 4 weeks) for 96 weeks	Drug: Fluoxetine; Comparison with placebo
Placebo Comparator: Placebo; Matched placebo 1 capsule twice per day (1 capsule a day for first 4 weeks) for 96 weeks	Drug: Placebo; Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI-derived Percentage Brain Volume Change (PBVC).	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).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multi-arm trial strategy assessment	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.	2 years
Count of new and enlarging T2 lesions	To explore any anti-inflammatory drug activity using the count of new and enlarging T2 lesions.	2 years
Pseudo-atrophy	Examining for evidence of pseudo-atrophy (to ensure reliability of the primary outcome measure).	6 months
Clinical measure of neuroprotection	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.	2 years
Health economics	To collect basic health economic data (EQ-5D) to inform future phase III trials.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
New T1 hypotense lesion count	Persistent new T1 hypointense lesion count to assess neuroprotection in new lesions.	2 years
Grey matter volume change	Grey matter volume change to assess cortical neuroprotection.	2 years
MR spectroscopy measured N-acetyl aspartate, myoinositol and glutamate	MR spectroscopy (MRS) to measure N-acetyl aspartate (reversal of neuronal mitochondrial dysfunction), myoinositol (prevention of glial cell inflammation) and glutamate (prevention of excitotoxicity).	2 years
Myelination	Magnetic Transfer Ratio (MTR) to evaluate myelination.	2 years
Cervical cord imaging	Cervical cord imaging to assess cord neuroprotection.	2 years
Composite MRI/disability scores	Composite MRI/disability scores to increase sensitivity and study interaction of treatment mechanisms.	2 years
Cerebrospinal fluid (CSF) neurofilament levels	Quantification of Cerebrospinal fluid (CSF) neurofilament levels to measure neuroprotection.	2 years
Optical Coherence Tomography (OCT) measured Retinal Nerve Fibre Layer (RNFL) thickness	Optical Coherence Tomography (OCT) measured Retinal Nerve Fibre Layer (RNFL) thickness as a measure of neuroprotection.	2 years

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: University of Leeds; University of Sheffield; Medical Research Council; Queen Mary University of London; University of Edinburgh; University of Warwick; National Institute for Health Research, United Kingdom; National Multiple Sclerosis Society; Keele University
• Investigators: Principal Investigator: Jeremy Chataway, University College, London; Principal Investigator: Siddharthan Chandran, University of Edinburgh

Publications and helpful links

General Publications

• Williams T, Alexander S, Blackstone J, De Angelis F, John N, Doshi A, Beveridge J, Braisher M, Gray E, Chataway J; MS-SMART and MS-STAT2 Investigators. Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials. Trials. 2022 Aug 9;23(1):644. doi: 10.1186/s13063-022-06588-z.
• Chataway J, De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, John N, Stutters J, MacManus D, Prados Carrasco F, Barkhof F, Ourselin S, Braisher M, Ross M, Cranswick G, Pavitt SH, Giovannoni G, Gandini Wheeler-Kingshott CA, Hawkins C, Sharrack B, Bastow R, Weir CJ, Stallard N, Chandran S; MS-SMART Investigators. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol. 2020 Mar;19(3):214-225. doi: 10.1016/S1474-4422(19)30485-5. Epub 2020 Jan 22.
• Connick P, De Angelis F, Parker RA, Plantone D, Doshi A, John N, Stutters J, MacManus D, Prados Carrasco F, Barkhof F, Ourselin S, Braisher M, Ross M, Cranswick G, Pavitt SH, Giovannoni G, Gandini Wheeler-Kingshott CA, Hawkins C, Sharrack B, Bastow R, Weir CJ, Stallard N, Chandran S, Chataway J; UK Multiple Sclerosis Society Clinical Trials Network. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open. 2018 Aug 30;8(8):e021944. doi: 10.1136/bmjopen-2018-021944.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2014
• Primary Completion (Actual): June 14, 2018
• Study Completion (Actual): July 4, 2018

Study Registration Dates

• First Submitted: July 19, 2013
• First Submitted That Met QC Criteria: July 24, 2013
• First Posted (Estimate): July 29, 2013

Study Record Updates

• Last Update Posted (Actual): March 26, 2020
• Last Update Submitted That Met QC Criteria: March 25, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Optical Coherence Tomography; Cerebrospinal fluid; Placebo; Riluzole; Fluoxetine; Neuroprotective; Secondary Progressive Multiple Sclerosis; Amiloride; Double blind; Repurposed drugs; Brain atrophy; Percentage Brain Volume Change
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Neoplastic Processes; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Neoplasm Metastasis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neuroprotective Agents; Protective Agents; Natriuretic Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Diuretics; Cytochrome P-450 Enzyme Inhibitors; Anticonvulsants; Antidepressive Agents, Second-Generation; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Diuretics, Potassium Sparing; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Fluoxetine; Riluzole; Amiloride
• Other Study ID Numbers: 12/0219