Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    MS-SMART
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01910259
Recruitment Status : Completed
First Posted : July 29, 2013
Last Update Posted : March 26, 2020
Sponsor:
Collaborators:
Medical Research Council
National Institute for Health Research, United Kingdom
MS Society
University of Edinburgh
Queen Mary University of London
Keele University
University of Sheffield
University of Leeds
University of Warwick
Information provided by (Responsible Party):
University College, London

Tracking Information
First Submitted Date  ICMJE July 19, 2013
First Posted Date  ICMJE July 29, 2013
Last Update Posted Date March 26, 2020
Actual Study Start Date  ICMJE December 18, 2014
Actual Primary Completion Date June 14, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2013)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2013)
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 24, 2013)
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial
Official Title  ICMJE A Multi-arm Phase IIB Randomised, Double Blind Placebo-controlled Clinical Trial Comparing the Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis.
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Secondary Progressive Multiple Sclerosis
Intervention  ICMJE
  • Drug: Amiloride
    Comparison with placebo
  • Drug: Riluzole
    Comparison with placebo
  • Drug: Fluoxetine
    Comparison with placebo
  • Drug: Placebo
    Placebo comparator
Study Arms  ICMJE
  • Experimental: Amiloride
    Amiloride 5 mg twice per day (5 mg once per day for first 4 weeks) for 96 weeks
    Intervention: Drug: Amiloride
  • Experimental: Riluzole
    Riluzole 50 mg twice per day (50 mg once per day for first 4 weeks) for 96 weeks
    Intervention: Drug: Riluzole
  • Experimental: Fluoxetine
    Fluoxetine 20 mg twice per day (20 mg once per day for first 4 weeks) for 96 weeks
    Intervention: Drug: Fluoxetine
  • Placebo Comparator: Placebo
    Matched placebo 1 capsule twice per day (1 capsule a day for first 4 weeks) for 96 weeks
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 12, 2016)
445
Original Estimated Enrollment  ICMJE
 (submitted: July 24, 2013)
440
Actual Study Completion Date  ICMJE July 4, 2018
Actual Primary Completion Date June 14, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01910259
Other Study ID Numbers  ICMJE 12/0219
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University College, London
Study Sponsor  ICMJE University College, London
Collaborators  ICMJE
  • Medical Research Council
  • National Institute for Health Research, United Kingdom
  • MS Society
  • University of Edinburgh
  • Queen Mary University of London
  • Keele University
  • University of Sheffield
  • University of Leeds
  • University of Warwick
Investigators  ICMJE
Principal Investigator: Jeremy Chataway University College, London
Principal Investigator: Siddharthan Chandran University of Edinburgh
PRS Account University College, London
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP