MS-SMART was a multi-arm two year placebo (dummy tablet) controlled study looking at three putative neuroprotectants in secondary progressive MS (SPMS). The agents studied were amiloride, fluoxetine and riluzole, selected from previous successes at a smaller Phase II level.
The scientific rationale is as follows:
“Amiloride, widely used as a potassium-sparing diuretic, is an acid-sensing ion channel blocker. ASIC1 opens in response to inflammation-induced acidosis, causing sodium and calcium influxes. This action is associated with axonal injury in post-mortem studies of patients with acute multiple sclerosis, and blockade of ASIC1 with amiloride reduces axonal damage and improves clinical outcomes in rodent models. A pilot study in individuals with progressive multiple sclerosis showed a significant reduction in whole-brain atrophy.”
“Fluoxetine, a selective serotonin reuptake inhibitor used for depression, has pleiotropic neuroprotective effects stimulating glycogenolysis and improving mitochondrial energy metabolism. In an underpowered negative trial, fluoxetine showed non-significant benefits in some markers of clinical progression.“
“Riluzole, licenced for motor neuron disease, reduces glutamate release and antagonises voltage-dependent sodium channels. Glutamate excitotoxicity results in neuronal injury and its blockade in EAE reduces clinical impairment and axonal damage. In a pilot study of riluzole in people with progressive multiple sclerosis, a reduction in the rate of cervical cord atrophy and the number of new brain T1 hypointense lesions was recorded, although findings of another study in individuals with early relapsing-remitting multiple sclerosis or clinical isolated syndrome did not show a reduction in the rate of atrophy.“
Unfortunately many of you may have already heard, the study outcomes based on the rate of brain volume loss was negative with no evidence of slowing compared to placebo (see Figure below).
Although we use brain atrophy in RRMS as an outcome measure, some of us do not believe it is a good outcome measure in progressive MS.
If you look at EDSS (Expanded Disability Status Scale, ranging from 0-10 of increasing disability) there were large fluctuations in each of the treatment groups (see figure below).
Around 11% of the subjects reported a relapse during the course of the study, raising the question of whether neuroprotection is possible when there is ongoing background inflammatory activity? This is not a criticism of the original study design, but a point for future studies of this ilk that a combination of an anti-inflammatory agent with a neuroprotectant should be considered. Particularly, when we now have two anti-inflammatory agents currently licensed for progressive MS (ocrelizumab, siponimod).
CoI – I was an involved in this study from a biomarker perspective.
Lancet Neurol. 2020 Jan 22. pii: S1474-4422(19)30485-5. doi: 10.1016/S1474-4422(19)30485-5. [Epub ahead of print]
Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial.
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.
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.
We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.
Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.
The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.