NCT01910259

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
445

participants targeted

Target at P75+ for phase_2

Timeline
Completed

Started Dec 2014

Typical duration for phase_2

Geographic Reach
1 country

13 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

July 19, 2013

Completed
10 days until next milestone

First Posted

Study publicly available on registry

July 29, 2013

Completed
1.4 years until next milestone

Study Start

First participant enrolled

December 18, 2014

Completed
3.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 14, 2018

Completed
20 days until next milestone

Study Completion

Last participant's last visit for all outcomes

July 4, 2018

Completed
Last Updated

March 26, 2020

Status Verified

March 1, 2020

Enrollment Period

3.5 years

First QC Date

July 19, 2013

Last Update Submit

March 25, 2020

Conditions

Secondary Progressive Multiple Sclerosis

Keywords

Secondary Progressive Multiple SclerosisNeuroprotectiveRepurposed drugsBrain atrophyPercentage Brain Volume ChangeMagnetic Resonance ImagingOptical Coherence TomographyCerebrospinal fluidAmilorideRiluzoleDouble blindPlaceboFluoxetine

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (5)

  • Multi-arm trial strategy assessment

    2 years

  • Count of new and enlarging T2 lesions

    2 years

  • Pseudo-atrophy

    6 months

  • Clinical measure of neuroprotection

    2 years

  • Health economics

    2 years

Other Outcomes (8)

  • New T1 hypotense lesion count

    2 years

  • Grey matter volume change

    2 years

  • MR spectroscopy measured N-acetyl aspartate, myoinositol and glutamate

    2 years

  • +5 more other outcomes

Study Arms (4)

Amiloride

EXPERIMENTAL

Amiloride 5 mg twice per day (5 mg once per day for first 4 weeks) for 96 weeks

Drug: Amiloride

Riluzole

EXPERIMENTAL

Riluzole 50 mg twice per day (50 mg once per day for first 4 weeks) for 96 weeks

Drug: Riluzole

Fluoxetine

EXPERIMENTAL

Fluoxetine 20 mg twice per day (20 mg once per day for first 4 weeks) for 96 weeks

Drug: Fluoxetine

Placebo

PLACEBO COMPARATOR

Matched placebo 1 capsule twice per day (1 capsule a day for first 4 weeks) for 96 weeks

Drug: Placebo

Interventions

AmilorideDRUG

Comparison with placebo

Amiloride
RiluzoleDRUG

Comparison with placebo

Riluzole
FluoxetineDRUG

Comparison with placebo

Fluoxetine
PlaceboDRUG

Placebo comparator

Placebo

Eligibility Criteria

Age25 Years - 65 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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
  • +18 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (13)

Anne Rowling Regenerative Neurology Clinic, Royal Infirmary of Edinburgh

Edinburgh, EH16 4SA, United Kingdom

Location

Gartnavel Royal Hospital, 1055 Great Western Road

Glasgow, G12 OXH, United Kingdom

Location

Brighton and Sussex University Hospitals

Haywards Heath, RH16 4EX, United Kingdom

Location

St James's University Hospital

Leeds, LS9 7TF, United Kingdom

Location

The Walton Centre

Liverpool, L9 7LJ, United Kingdom

Location

The National hospital for Neurology and Neurosurgery, University College London

London, WC1N 3BG, United Kingdom

Location

The Royal Victoria Infirmary

Newcastle, NE1 4LP, United Kingdom

Location

Queens Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

John Radcliffe Hospital, Oxford University Hospitals NHS Trust

Oxford, OX3 9DU, United Kingdom

Location

Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

Royal Hallamshire Hospital

Sheffield, S10 2JF, United Kingdom

Location

University Hospital of North Staffordshire

Stoke-on-Trent, ST4 7LN, United Kingdom

Location

Royal Cornwall Hospital

Truro, TR1 3LJ, United Kingdom

Location

Related Publications (4)

  • John N, Li Y, De Angelis F, Stutters J, Prados Carrasco F, Eshaghi A, Doshi A, Calvi A, Williams T, Plantone D, Phan T, Barkhof F, Chataway J; MS-SMART Investigators; Ourselin S, Braisher M, Beyene T, Bassan V, Zapata A, Chandran S, Connick P, Lyle D, Cameron J, Mollison D, Colville S, Dhillon B, Ross M, Cranswick G, Walker A, Smith L, Giovannoni G, Gnanapavan S, Nicholas R, Rashid W, Aram J, Ford H, Pavitt SH, Overell J, Young C, Arndt H, Duddy M, Guadagno J, Evangelou N, Craner M, Palace J, Hobart J, Sharrack B, Paling D, Hawkins C, Kalra S, McLean B, Stallard N, Bastow R. Brain reserve and physical disability in secondary progressive multiple sclerosis. BMJ Neurol Open. 2024 Sep 7;6(2):e000670. doi: 10.1136/bmjno-2024-000670. eCollection 2024.

    PMID: 39262426DERIVED

  • 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.

    PMID: 35945550DERIVED

  • 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.

    PMID: 31981516DERIVED

  • 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.

    PMID: 30166303DERIVED

Related Links

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Interventions

AmilorideRiluzoleFluoxetine

Condition Hierarchy (Ancestors)

Multiple SclerosisDemyelinating Autoimmune Diseases, CNSAutoimmune Diseases of the Nervous SystemNervous System DiseasesDemyelinating DiseasesAutoimmune DiseasesImmune System DiseasesChronic DiseaseDisease AttributesPathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

PyrazinesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsThiazolesSulfur CompoundsOrganic ChemicalsBenzothiazolesAzolesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingPropylaminesAmines

Study Officials

  • Jeremy Chataway

    University College, London

    PRINCIPAL INVESTIGATOR

  • Siddharthan Chandran

    University of Edinburgh

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

July 19, 2013

First Posted

July 29, 2013

Study Start

December 18, 2014

Primary Completion

June 14, 2018

Study Completion

July 4, 2018

Last Updated

March 26, 2020

Record last verified: 2020-03

Locations

GB(13)