Efficacy and tolerability of lasmiditan, an oral 5-HT_1F receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study

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• 作者：Prof Markus Fä ; rkkilä ; MD^a ; Prof Hans-Christoph Diener ; MD^b ; Prof Gilles Gé ; raud ; MD^c ; Prof Miguel Lá ; inez ; MD^d ; Prof Jean Schoenen ; MD^e ; Nadja Harner ; MSc^f ; Alison Pilgrim ; BM^g ; Dr Uwe Reuter ; MD^h ; ^{uwe.reuter@charite.de} ; for the COL MIG-202 study group^&Dagger ;
• 刊名：Lancet Neurology
• 出版年：2012
• 期刊代码：300_14744422
• 类别：med
• 出版时间：May, 2012
• 卷：11
• 期：5
• 页码：405-413
• 文件大小：241 K

摘要

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Summary

Background

Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT_1F receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine.

Methods

In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with , number .

Findings

Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p<0路0001). Every lasmiditan treatment dose significantly improved headache response at 2 h compared with placebo (lasmiditan 50 mg: difference 17路9%, 95%CI 3路9-32路1, p=0路022; 100 mg: 38路2%, 24路1-52路4, p<0路0001; 200 mg: 28路8%, 9路6-39路9, p=0路0018; 400 mg: 38路7%, 23路9-53路6, p<0路0001). The proportion of patients with treatment-emergent adverse events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%], and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence.

Interpretation

Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy.

Funding

CoLucid Pharmaceuticals.