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

Sponsor

University College, London (Other)

Overall Status

Completed

CT.gov ID

NCT01910259

Collaborator

Medical Research Council (Other), National Institute for Health Research, United Kingdom (Other), MS Society (Other), University of Edinburgh (Other), Queen Mary University of London (Other), Keele University (Other), University of Sheffield (Other), University of Leeds (Other), University of Warwick (Other)

445

Enrollment

Locations

Arms

42.5

Actual Duration (Months)

34.2

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Secondary Progressive Multiple Sclerosis	Drug: Amiloride Drug: Riluzole Drug: Fluoxetine Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

445 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, 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.

Actual Study Start Date :

Dec 18, 2014

Actual Primary Completion Date :

Jun 14, 2018

Actual Study Completion Date :

Jul 4, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

MRI-derived Percentage Brain Volume Change (PBVC). [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).

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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