Phase 3 Randomized, Placebo-controlled, Double-blind Study of Lasmiditan for Acute Treatment of Migraine

Peter J. Goadsby; Linda A. Wietecha; Ellen B. Dennehy; Bernice Kuca; Michael G. Case; Sheena K. Aurora; Charly Gaul

Disclosures

Brain. 2019;142(7):1894-1904. 

In This Article

Abstract and Introduction

Abstract

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. 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-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). 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%, odds ratio 2.3, 95% confidence interval 1.8–3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3–2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1–1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4–2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2–2.0, P < 0.001; 50 mg: 40.8%, odds ratio 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 paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Introduction

Migraine is a common neurological disease that was ranked by the WHO as the second highest cause of disability worldwide as measured in years of life lost to disability (GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). The American Migraine Prevalence and Prevention concluded that >40% of patients with episodic migraine have significant unmet needs including relatively high rates of moderate/severe headache-related disability (47%) and dissatisfaction with current acute medication regimen (37.4%) (Lipton et al., 2013).

Triptans are considered the gold standard for acute treatment of migraine, with strong evidence in support of their efficacy (Ferrari et al., 2001; Marmura et al., 2015) and representing 28–36% of prescribed acute migraine medications (Mafi et al., 2015; Molina et al., 2018). However, triptans are not efficacious in all patients (Ferrari et al., 2001; Cameron et al., 2015) and are contraindicated in patients with coronary artery disease, peripheral vascular disease, or uncontrolled hypertension (Dodick et al., 2004) and in patients with risk factors for undiagnosed coronary artery disease (Buse et al., 2017; Lipton et al., 2017).

Understanding of the pathophysiology of migraine has recently evolved away from vasodilation (vascular hypothesis) to a brain disorder involving pain and other sensory processing (Goadsby et al., 2017). Migraine involves activation and sensitization, or the perception thereof, of trigeminal nociceptors in the dura mater, with neuropeptide release such as calcitonin gene-related peptide (CGRP). 5-HT1Freceptor agonists are a potential treatment alternative to triptans (Raffaelli et al., 2017). Lasmiditan, a centrally-penetrant, highly selective and potent 5-HT1Freceptor agonist without vasoconstrictive activity (Rubio-Beltrán et al., 2018; Vila-Pueyo, 2018), is a novel acute therapy for migraine. As current treatment approaches do not meet the needs of all patients with migraine in terms of both efficacy and tolerability (Viana et al., 2013), lasmiditan may provide an alternative acute treatment option for patients with migraine.

Lasmiditan was effective in previous studies, with adverse events primarily related to its CNS activity (Ferrari et al., 2010; Färkkilä et al., 2012; Kuca et al., 2018). We undertook a second pivotal phase 3 study to confirm the efficacy and safety of three doses of oral lasmiditan (200 mg, 100 mg and 50 mg) versus placebo for the acute treatment of a single migraine attack in patients with migraine (with and without aura).

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