Efficacy and Tolerability of Lasmiditan, an Oral 5-HT1F Receptor Agonist, for the Acute Treatment of Migraine: A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study

Background: Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in phase 2 studies. We aimed to replicate these findings in a population that includes patients with migraine and cardiovascular risks. Methods: This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom (MBS)-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Findings: Patients (n=3005) were assigned and treated (n=2583, safety population): 1938 lasmiditan (200 mg n=528, 100 mg n=532, and 50 mg n=556 included in primary analysis) and 645 placebo (540 included in primary analysis) Most patients (79·2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38·8%, OR 2·3, 95% CI 1·8-3·1, p<0·001; 100 mg: 31·4%, OR 1·7, 1·3-2·2, p<0·001; 50 mg: 28·6%, OR 1·5, 1·1-1·9, p=0·003 versus placebo 21·3%) and freedom from MBS at 2 h (lasmiditan 200 mg: 48·7%, OR 1·9, 95% CI 1·4-2·4, p<0·001; 100 mg: 44·2%, OR 1·6, 1·2-2·0, p<0·001; 50 mg: 40·8%, OR 1·4, 1·1-1·8, p=0·009 versus placebo 33·5%). Treatment-emergent adverse events were reported in 253 of 649 (39·0%), 229 of 635 (36·1%), and 166 of 654 (25·4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11·6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence, and paresthesia. Interpretation: Lasmiditan was effective at 2-h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety was consistent with another phase 3 study. Clinical Trial Number: This study is registered with ClinicalTrials.gov, number NCT02605174. Funding Statement: CoLucid Pharmaceuticals and Eli Lilly and Company. Declaration of Interests: PJG reports grants and personal fees from Amgen and Eli-Lilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Dr Reddy's Laboratories, Electrocore LLC, eNeura, Novartis, Scion, Teva Pharmaceuticals, and Trigemina Inc., and personal fees from MedicoLegal work, Up-to-Date, Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer; and a patent Magnetic stimulation for headache assigned to eNeura without fee. AW, ED, MGC, and SKA are full time employees and minor stockholders for Eli Lilly and Company. BK was a full-time employee and minor stockholder for CoLucid Pharmaceuticals when the study was designed and conducted. CG has received honoraria for consulting and lectures within the past three years from Allergan Pharma, Ratiopharm, Boehringer Ingelheim Pharma, Lilly Germany, Novartis Pharma, Desitin Arzneimittel, Cerbotec, Bayer vital, Hormosan Pharma, electroCore, Grunenthal, Reckitt Benckiser, and TEVA. He does not hold any stocks of pharmaceutical companies or medical device companies. Ethics Approval Statement: The study was approved by the authorities and independent ethics committees. This study was conducted in accordance with the Declaration of Helsinki and internationally accepted standards of Good Clinical Practice. All patients gave written informed consent before enrollment. Protocol Number COL MIG-302.