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

Secondary Progressive Multiple Sclerosis Clinical Trial

— MS-SMART  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01910259
• Other study ID #: 12/0219
• Status: Completed
• Phase: Phase 2
• Start date: December 18, 2014
• Est. completion date: July 4, 2018

Study information

• Verified date: March 2020
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 445
• Est. completion date: July 4, 2018
• Est. primary completion date: June 14, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 65 Years

Eligibility

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 (ß-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,?GT) 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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Neoplasm Metastasis
• Sclerosis
• Secondary Progressive Multiple Sclerosis

Intervention

Drug:
• Amiloride
Comparison with placebo
• Riluzole
Comparison with placebo
• Fluoxetine
Comparison with placebo
• Placebo
Placebo comparator

Locations

Country	Name	City	State
United Kingdom	Anne Rowling Regenerative Neurology Clinic, Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Gartnavel Royal Hospital, 1055 Great Western Road	Glasgow
United Kingdom	Brighton and Sussex University Hospitals	Haywards Heath
United Kingdom	St James's University Hospital	Leeds
United Kingdom	The Walton Centre	Liverpool
United Kingdom	The National hospital for Neurology and Neurosurgery, University College London	London
United Kingdom	The Royal Victoria Infirmary	Newcastle
United Kingdom	Queens Medical Centre	Nottingham
United Kingdom	John Radcliffe Hospital, Oxford University Hospitals NHS Trust	Oxford
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Royal Hallamshire Hospital	Sheffield
United Kingdom	University Hospital of North Staffordshire	Stoke-on-Trent
United Kingdom	Royal Cornwall Hospital	Truro

Sponsors (10)

Lead Sponsor	Collaborator
University College, London	Keele University, Medical Research Council, MS Society, National Institute for Health Research, United Kingdom, Queen Mary University of London, University of Edinburgh, University of Leeds, University of Sheffield, University of Warwick

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	New T1 hypotense lesion count	Persistent new T1 hypointense lesion count to assess neuroprotection in new lesions.	2 years
Other	Grey matter volume change	Grey matter volume change to assess cortical neuroprotection.	2 years
Other	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
Other	Myelination	Magnetic Transfer Ratio (MTR) to evaluate myelination.	2 years
Other	Cervical cord imaging	Cervical cord imaging to assess cord neuroprotection.	2 years
Other	Composite MRI/disability scores	Composite MRI/disability scores to increase sensitivity and study interaction of treatment mechanisms.	2 years
Other	Cerebrospinal fluid (CSF) neurofilament levels	Quantification of Cerebrospinal fluid (CSF) neurofilament levels to measure neuroprotection.	2 years
Other	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
Primary	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	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
Secondary	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
Secondary	Pseudo-atrophy	Examining for evidence of pseudo-atrophy (to ensure reliability of the primary outcome measure).	6 months
Secondary	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
Secondary	Health economics	To collect basic health economic data (EQ-5D) to inform future phase III trials.	2 years

External Links

•   Trial website