Effect of Montelukast on GI Tolerability in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Delayed-Release Dimethyl Fumarate: Mitigate Study Results

Background: A small single-arm pilot study previously suggested that montelukast, a leukotriene receptor antagonist, may be effective for the treatment of gastrointestinal (GI) symptoms associated with delayed-release dimethyl fumarate (DMF) treatment in patients with relapsing-remitting MS (RRMS).

Objectives: MITIGATE (NCT02410278) evaluated whether montelukast reduced the severity of DMF-related GI events in patients with RRMS.

Methods: MITIGATE was a randomized, multicenter, placebo-controlled Phase 4 study in patients with RRMS treated with DMF at 50 sites in the United States. Eligible patients (≥18 years; diagnosed with RRMS; no significant background GI symptoms) initiated DMF (120mg twice-daily [BID] for 7 days, 240mg bid thereafter), and recorded GI symptoms in an e-diary daily using the Gastrointestinal Symptom Rating Scale (GSRS), consisting of 15 items to assess GI symptoms, for up to 4 weeks. Patients reaching a specific threshold GSRS score were randomized and blinded to symptomatic treatment (montelukast 10mg once-daily or placebo; 1:1 randomization) taken with DMF for 8 weeks. Enrollment into MITIGATE was closed before reaching the target sample size goal of 118 patients randomized to treatment due to slow recruitment. The primary endpoint was change from Day 0 (treatment with DMF) to Day 10 in GSRS rating. Secondary endpoints evaluated discontinuations due to GI events, number of patients taking symptomatic therapies for GI events, and incidence of flushing.

Results: Of 148 patients screened, 102 met the criteria for e-diary compliance and absence of background GI symptoms, and were initiated on DMF. Of these, 64 (63%) patients developed GI symptoms that met the predefined study threshold and received montelukast or placebo treatment. Overall, 49 patients completed the study; discontinuations were primarily due to adverse events (AEs). Efficacy endpoints were assessed in a modified intention-to-treat population (n=63). There was no statistically significant difference between the proportion of patients with worsening of GI symptoms in the two groups (placebo: 5/30 patients, 17%; montelukast: 11/33 patients, 33%; odds ratio [OR]=3.931, P=0.0617). Secondary endpoints were also not met. Incidence of AEs were similar between treatment groups.

Conclusions: These results suggest that montelukast may not reduce the severity of DMF-related GI events. No new safety or tolerability concerns for DMF were identified.