A phase 4, randomized, double-blind, placebo-controlled trial evaluating the efficacy and tolerability of rimegepant for the prevention of episodic migraine in adults with a history of inadequate response to traditional oral preventive medications

Aim This study aimed to evaluate the efficacy and tolerability of rimegepant for the prevention of episodic migraine in participants with a documented history of inadequate response to 2–4 categories of traditional oral preventive medication (OPM). Methods This multinational phase 4 trial consisted of an untreated 28-day observational phase (OP) and a 12-week double-blind treatment (DBT) phase. Participants with 4–14 monthly migraine days (MMDs), <15 monthly headache days (<7 non-migraine) and documented previous inadequate response to 2–4 traditional OPM categories were enrolled. Participants were randomized to rimegepant 75 mg orally disintegrating tablet (ODT) or placebo every other day (EOD). The primary endpoint was mean change from the OP in MMDs through the 12-week DBT phase. Key secondary endpoints were tested hierarchically to control type I errors. Tolerance and safety were assessed throughout the DBT phase. Results In total, 328 participants received rimegepant and 324 received placebo. The most common OPM categories with prior inadequate response were anticonvulsants (61%), beta-blockers (56%) and amitriptyline (51%). The mean ± SD number of MMDs in the OP was 8.4 ± 2.4 and 8.3 ± 2.3, respectively, in the rimegepant (n = 324) and placebo (n = 319) groups. Across the DBT phase, participants who received rimegepant had a significantly larger mean change from the OP in MMDs than those who received placebo (−2.1 vs. −0.5 days; difference = −1.6 days; 95% confidence interval (CI) = −2.1 to −1.2; p < 0.0001). All key secondary endpoints favored rimegepant: (i) percentage of participants with ≥50% reduction from the OP in MMDs with moderate or severe pain intensity across the DBT phase (difference: 20.1%; 95% CI = 13.7 to 26.5; p < 0.0001); (ii) mean change from the OP in MMDs in the first month of the DBT phase (difference: −1.7 days; 95% CI = −2.3 to −1.2; p < 0.0001); (iii) mean change from the OP in MMDs in the last month of the DBT phase (difference: −1.4 days; 95% CI = −2.1 to −0.8; p < 0.0001); (iv) mean change from baseline in Migraine-Specific Quality-of-Life Questionnaire v2.1 Restrictive Role Function domain score at week 12 of the DBT phase (difference: 6.6 points; 95% CI = 3.6 to 9.5; p < 0.0001); and (v) mean change from baseline in Migraine Interictal Burden Scale score at week 12 of the DBT phase (difference: −0.9 points; 95% CI = −1.4 to −0.4; p = 0.0006). Rimegepant was well tolerated with a safety profile not notably different from placebo. Conclusions Rimegepant 75 mg ODT EOD is efficacious and well tolerated for the prevention of episodic migraine in participants with a documented history of inadequate response to 2–4 categories of traditional OPM. Trial Registration ClinicalTrials.gov, NCT05518123 ( https://clinicaltrials.gov/study/NCT05518123 ).