Rimegepant for acute treatment of migraine in triptan-unsuitable adults: A randomized, double-blind, placebo-controlled phase 4 trial

Background A subset of individuals with migraine are unsuitable for triptans due to intolerance, lack of efficacy, or contraindications. This phase 4 study assessed the efficacy and tolerability of a single 75-mg dose of rimegepant orally disintegrating tablet (ODT) for acute treatment of migraine in adults with documented triptan unsuitability. Methods Participants (aged ≥18 years with 4–14 migraine days per month) with documented history of (A) intolerance and/or lack of efficacy to ≥2 triptans or (B) contraindication to triptans were randomized (1:1) to rimegepant 75 mg ODT or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomization was stratified by history of clinically relevant cardiovascular disease. The primary endpoint was the percentage of participants with migraine pain relief (no or mild pain) at 2 h post dose. Key secondary endpoints, tested using a hierarchal approach to control type 1 error, included the percentage of participants with migraine pain freedom at 2 h, rescue medication use within 24 h, return to normal function at 2 h, sustained return to normal function from 2–24 h and from 2–48 h, sustained migraine pain relief from 2–24 h and from 2–48 h, sustained migraine pain freedom from 2–24 h and from 2–48 h, and most bothersome symptom freedom at 2 h. Safety was assessed via adverse events (AEs) and laboratory tests. Results Overall, 585 participants (89.1% were female, mean age was 42.9 years) received study medication (rimegepant, n = 295; placebo, n = 290). Participants analyzed for efficacy (rimegepant, n = 286; placebo, n = 284) had documented failure to ≥2 triptans with ≥1 reason due to prior intolerance (30.5%) and/or ≥1 reason due to lack of efficacy (84.9%); 9.1% had a contraindication. Rimegepant demonstrated superiority over placebo for the primary endpoint of migraine pain relief at 2 h (55.9% vs 32.7%; difference [95% CI]: 23.2% [15.3–31.1%]; p < 0.0001) and all 10 alpha-protected key secondary endpoints including pain freedom at 2 h (all p ≤ 0.0005). AE rates were similar across treatments (12.5% vs 12.1%), with no severe AEs, serious AEs, or clinically significant laboratory test abnormalities reported in the rimegepant group. Conclusions A single 75-mg dose of rimegepant ODT was efficacious and well tolerated for acute treatment of migraine in adults unsuitable for triptans. This first prospective trial of a gepant in this population supports calcitonin gene-related peptide antagonism as a valuable option when triptans are unsuitable. Trial Registration Clinicaltrials.gov NCT05509400.