- In the SPRINT-MS multicenter, randomized, double-blind phase 2 trial of ibudilast in patients with progressive multiple sclerosis, progression of brain atrophy over 96 weeks was 48% less with the drug than with placebo
- Further trials are needed to assess the longer term safety and effect of ibudilast on neurological disability
- The drug was well-tolerated, but gastrointestinal complaints, headache and depression were more common with ibudilast than with placebo
In patients with progressive multiple sclerosis, cerebrospinal fluid shows increased levels of macrophage migration inhibitory factor and toll-like receptor 4, which can cause inflammation in the central nervous system. These proteins are inhibited by ibudilast, a small-molecule drug available in Asia for the treatment of asthma and poststroke vertigo.
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The Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), sponsored by the National Institutes of Health, completed the phase 2 SPRINT-MS trial of ibudilast as a potential treatment for multiple sclerosis. In this trial, reported in The New England Journal of Medicine, it was found that ibudilast was significantly and substantially more efficacious than placebo in slowing brain atrophy.
A team comprising of Eric C. Klawiter, MD, director of the Multiple Sclerosis and Neuromyelitis Optica Unit at Massachusetts General Hospital, Merit E. Cudkowicz, MD, the principal investigator of the Clinical Coordination Center for NeuroNEXT, chief of the Neurology Service and director of the Sean M. Healey and AMG Center for ALS, and colleagues studied 244 patients at 28 U.S. sites. The key eligibility criteria for patients were age of 21 to 65 years, a diagnosis of primary or secondary progressive multiple sclerosis, typical multiple sclerosis lesions on magnetic resonance imaging, a score of 3.0 to 6.5 on the Expanded Disability Status Scale and documented progression of disability in the previous two years.
The patients were randomly assigned 1:1 in double-blind fashion to receive ibudilast or matching placebo. After an initial two-week period of ibudilast 60 mg or placebo, the ibudilast dosage was increased to 100 mg/day. Dose adjustment for side effects was allowed up to week 8, after which time patients maintained their then-current regimen in two or three divided doses for 96 weeks.
The primary endpoint of the study was the rate of brain atrophy. MRI was performed every 24 weeks to quantify the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain, including the CSF). As atrophy progresses, CSF replaces brain tissue and the brain parenchymal fraction decreases.
The estimated rate of change in the brain parenchymal fraction was −0.0010 per year with ibudilast and −0.0019 per year with placebo. The absolute difference was 0.0009 per year (95% CI, 0.00004 to 0.0017; P = .04), or approximately 48% less brain-tissue loss with ibudilast than with placebo over 96 weeks. The relative difference was 48%.
The results of all prespecified sensitivity analyses were consistent with the primary analysis for the difference between the two groups.
Adverse events that were more common in the ibudilast group than in the placebo group (P ≤ .10) were gastrointestinal symptoms (abdominal pain, diarrhea and nausea), headache and depression. There were no reports of suicidality or suicide.
In total, 71 patients discontinued the trial regimen or withdrew from the trial, of whom 38 attributed their decision to one or more adverse events (18% in the ibudilast group and 12% in the placebo group, P = NS).
The researchers comment that the 48% difference in atrophy progression favoring ibudilast compares well with trials of ocrelizumab and trials of two agents that are investigational for multiple sclerosis, siponimod and simvastatin. Brain atrophy is thought to be an imaging surrogate for disability progression in multiple sclerosis. Improving imaging outcomes in progressive MS clinical trials was an additional aim of the SPRINT-MS trial.
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