PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.
Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.
Examining Ibudilast in a Phase II Trial
Robert Fox, MD, a neurologist at Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.
Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.
The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.
Researchers Observed Gastrointestinal Side Effects
The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.
In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.
Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.
There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.
Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.
Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.
Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.