1Eli Lilly and Company, Indianapolis, USA. 2Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Copenhagen, Denmark. 3University of Copenhagen, Copenhagen, Denmark. 4StudyMetrix Research, St Peters, USA. 5Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
Purpose Lasmiditan is a novel, selective 5-HT1F receptor agonist, approved by the FDA for the acute treatment of migraine, with or without aura, in adults. We present findings from the multicenter, placebo-controlled, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy, including consistency of response, and safety of lasmiditan in the acute treatment of migraine across 4 attacks. Methods Patients were randomized 1:1:1 to one of 3 treatment groups 1) lasmiditan 200 mg; 2) lasmiditan 100 mg; or 3) a control group which received placebo for 3 attacks and lasmiditan 50 mg for either the third or fourth attack (1:1). The primary endpoints were pain freedom at 2h (first attack) and pain freedom at 2h in at least 2 out of 3 attacks. Statistical testing used a logistic regression model and graphical multiplicity methodology to preserve overall type I error at 1-sided alpha level of 0.025. Results 1613 patients were randomized, and 1471 patients (mean age 41 years; 84% female; 76% Europe, 12% N. America, 12% Asia; MIDAS mean score 31.9) treated ≥1 migraine attack with study drug (control, n=500; lasmiditan 100 mg, n=485, lasmiditan 200 mg, n=486). All primary and gated secondary endpoints were met (p<0.001 in all cases).Here we present efficacy findings for the first attack; consistency findings across multiple attacks will be reported elsewhere. Pain freedom rates at 2h (primary endpoint) were for placebo, 8.4%; lasmiditan 100 mg, 25.8% (Odds ratio vs placebo,3.8 [2.6, 5.7], with a therapeutic gain of ~17%); lasmiditan 200 mg, 29.3% (OR 4.6 [3.1, 6.8]; therapeutic gain ~21%). Both doses of lasmiditan were significantly better than placebo for pain freedom at 1h, and for pain relief at 2h with significant separation from placebo beginning at 30 minutes in the 200 mg group and 1 hour in the 100 mg group. Additional statistically significant differences between lasmiditan and placebo included migraine-related disability freedom at 2h, much/very much better on the Patient Global Impression of Change at 2h, most bothersome symptom freedom at 2h, need for rescue medication, and sustained pain freedom at 24 and 48h. In a predefined subset of patients who were triptan insufficient responders, lasmiditan was significantly superior to placebo for pain freedom at 2h. Across the study, the incidence of treatment emergent serious adverse events was similar across treatment groups - control, n=2 (0.4%) (both after treatment with placebo); lasmiditan 100mg, n=1 (0.2%), lasmiditan 200mg, n=2 (0.4%); there were no major cardiovascular events consistent with ischemia. The most frequent treatment emergent adverse events with lasmiditan (≥2% in either dose group in the first attack) were dizziness, paresthesia, fatigue, nausea, vertigo, somnolence, hypoesthesia, muscle weakness, asthenia, and feeling abnormal. Conclusions The CENTURION study had a modified parallel design enabling a comparison of the consistency of effect of two doses of lasmiditan to placebo. Lasmiditan was superior to placebo for all gated endpoints and its overall safety and tolerability was generally consistent with that observed in previous Phase 3 lasmiditan studies. During the first attack, lasmiditan was significantly superior to placebo for pain freedom and pain relief beginning at 1h, and for sustained pain freedom at 24 and 48h. Lasmiditan was also efficacious in triptan insufficient responders. These results confirm the early and sustained efficacy of lasmiditan.