MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial
Condition: Secondary Progressive Multiple Sclerosis
MeSH terms: Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Amiloride; Riluzole; Fluoxetine; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Comparison with placebo; Comparison with placebo; Comparison with placebo; Placebo comparator
Intervention MeSH terms: Amiloride; Riluzole; Fluoxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Secondary Progressive Multiple Sclerosis; Neuroprotective; Repurposed drugs; Brain atrophy; Percentage Brain Volume Change; Magnetic Resonance Imaging; Optical Coherence Tomography; Cerebrospinal fluid; Amiloride; Riluzole; Double blind; Placebo; Fluoxetine