The Multiple Sclerosis-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART) is the first multiarm trial designed specifically to address the unmet need for further identification of neuroprotective drugs in secondary progressive multiple sclerosis.
The Multiple Sclerosis-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART) is the first multiarm trial designed specifically to address the unmet need for further identification of neuroprotective drugs in secondary progressive multiple sclerosis (SPMS). In a recent publication, Connick et al describe the layout of the trial and the outcomes they will evaluate and release when the trial results are publicized.1
SPMS is a debilitating phase of multiple sclerosis (MS) associated with neurodegeneration and irreversible disability. Despite many drugs that are used to treat MS in the relapsing-remitting phase, there is a need for improvement in treating SPMS. MS-SMART assessed 3 drugs with potential therapeutic benefits in neuroprotection—fluoxetine, riluzole, and amiloride—using magnetic resonance brain atrophy measurements.
The phase 2B multiarm, double-blind, randomized, placebo-controlled MS-SMART trial is designed to verify whether fluoxetine, riluzole, or amiloride can slow down the rate of brain volume loss in SPMS over 96 weeks compared with placebo. A total of 440 patients were randomized in a 1:1:1:1 ratio to fluoxetine, riluzole, amiloride, or placebo. Magnetic resonance imaging (MRI) baseline scan was done at the start of the trial, with another MRI scan at week 24, and a final scan at week 96.
For this trial, the investigators purposely selected fluoxetine, riluzole, and amiloride as the test drugs based on previous clinical trials. A potassium-sparing diuretic, amiloride has been shown to exhibit neuroprotective effects. In an open label single-arm trial, 14 patients with primary progressive MS had significant reductions in whole-brain atrophy rates.2
Fluoxetine, a serotonin selective reuptake inhibitor for depression, also has potential neuroprotective effects. A trial in progressive multiple sclerosis patients showed slower progression of disability measured by the 25-foot walk test and the 9-hole peg test.3 Riluzole, a glutamate antagonist, also showed beneficial changes associated with reduced lesion accumulation and brain atrophy.
In the current trial, dosing regimens were patient dependent. Patients started off on either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo once a day. After 4 weeks, patients received their respective drugs twice a day. Patients experiencing adverse events (AEs) were down-titrated to once a day and rechallenged 2 to 4 weeks later. Patients who still could not tolerate the drugs remained on a once a day regimen or stopped the medication all together. Evaluation of adherence was done through a pill count and patient diaries where the patient records the number of capsules taken.
AEs will be recorded in medical records by the patient. Progressive changes caused by disease progression will not be listed in the adverse reactions report. Potassium, sodium, and other electrolyte abnormalities will require suspension of drug until the electrolyte is normalized. If normalized, treatment can continue.
Creatinine, liver function tests, and hematology values will also be analyzed. Any irregularities that are not resolved or occur after rechallenge will lead to the study drug being discontinued. All patients will have an emergency card, indicating that they are enrolled in the trial, and what type of care they are receiving. Unblinding will occur if needed.
The MS-SMART started in December 2014 and is expected to have results towards the end of 2018 (NCT01910259). If any of the 3 drugs shows significant signs of neuroprotection benefits, a follow-up phase 3 trial will be conducted for definitive disability outcomes.