Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study)

Abstract

Objectives: To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year.

Methods: In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit.

Results: As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time.

Conclusions: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://ichgcp.net/clinical-trials-registry/NCT02565186.

Keywords: 5-HT1F agonist; Episodic migraine; MIDAS; ditan; serotonin.

Figures

Figure 1.

GLADIATOR study design. aLasmiditan 50 mg was included only in the SPARTAN study.

Figure 2.

Flow of study participants. aIn the safety population, common adverse events leading to discontinuation (>1%) in the lasmiditan 100 mg group included dizziness (26 patients) and somnolence (14 patients) and in the 200 mg group included dizziness (44 patients), paresthesia (19 patients), fatigue (17 patients), nausea (13 patients), and somnolence (11 patients).

Figure 3.

Frequently reported treatment-emergent adverse events (a) by percentage of patients and (b) by percentage of attacks (safety population). AE: adverse event; MedDRA: Medical Dictionary for Regulatory Activities. Note: Reported by ≥ 2% of patients in either treatment group. An AE that started or worsened within 48 hours after the last dose (either the first or the second dose) of lasmiditan was considered treatment-emergent. AEs were coded using MedDRA Version 21.0.

Figure 4.

Treatment-emergent adverse events by migraine attack in patients who treated ≥ 5 attacks (safety population). TEAE: treatment-emergent adverse event.

Figure 5.

Treated migraine attacks achieving (a) pain freedom, (b) most bothersome symptom freedom, and (c) pain relief at 2 hours post-dose overall and by quarter. ITT: intent-to-treat; MBS: most bothersome symptom; mITT: modified intent-to-treat; Q1: quarter 1 (months 0–3); Q2: quarter 2 (months 3–6); Q3: quarter 3 (months 6–9); Q4: quarter 4 (months 9–12). Note: Pain freedom is defined as a reduction in pain severity from mild, moderate, or severe at baseline to none at 2 hours post-dose. MBS freedom is defined as the absence of the associated symptom of migraine (nausea, phonophobia, or photophobia) at 2 hours post-dose that was identified pre-dose as the MBS. Pain relief is defined as experiencing moderate or severe pain at baseline that becomes mild or none at 2 hours post-dose or mild pain at baseline that becomes none at 2 hours post-dose for each treated attack. Patients who recorded that no symptoms were present at baseline were excluded from the MBS analysis. Patients were assumed to not have achieved pain freedom at 2 hours if they did not have an associated pain severity rating at the 2-hour time point, took rescue medication within the first 2 hours, or used alternative medication prior to the study drug to treat the migraine attack. The pain relief analysis was conducted on the ITT population; the pain freedom and MBS freedom analyses were conducted on the mITT population. *p < 0.001, 100 mg versus 200 mg (based on a one-sided test from a logistic regression model with treatment group and background use of medication to reduce the frequency of migraines as covariates).

Figure 6.

Patients achieving (a) pain freedom, (b) most bothersome symptom freedom, and (c) pain relief at 2 hours post-dose by migraine attack in patients who treated ≥ 5 attacks (ITT population). ITT: intent-to-treat; MBS: most bothersome symptom. Note: Pain freedom is defined as a reduction in pain severity from mild, moderate, or severe at baseline to none at 2 hours post-dose. MBS freedom is defined as the absence of the associated symptom of migraine (nausea, phonophobia, or photophobia) at 2 hours post-dose that was identified pre-dose as the MBS. Pain relief is defined as experiencing moderate or severe pain at baseline that becomes mild or none at 2 hours post-dose or mild pain at baseline that becomes none at 2 hours post-dose for each treated attack. Patients who recorded that no symptoms were present at baseline were excluded from the MBS analysis. Patients were assumed to not have achieved pain freedom at 2 hours if they did not have an associated pain severity rating at the 2-hour time point, took rescue medication within the first 2 hours, or used alternative medication prior to the study drug to treat the migraine attack.

Figure 7.

Change over time in (a) MIDAS total score and (b) days with headache in the past 3 months (MIDAS population). MIDAS: migraine disability assessment. MIDAS total score was calculated as the sum of the answers to the five questions on the MIDAS questionnaire (0–5 = little or no disability; 6–10 = mild disability; 11–20 = moderate disability; ≥ 21 = severe disability). *p < 0.001 vs. baseline (mixed model for repeated measures); no significant differences were observed between the lasmiditan doses.

Figure 8.

Lasmiditan-treated migraine attacks by quarter in patients with a maximum of two, three, and four quarters of data available (safety population). L100: lasmiditan 100 mg; L200: lasmiditan 200 mg; Q1: quarter 1 (months 0–3); Q2: quarter 2 (months 3–6); Q3: quarter 3 (months 6–9); Q4: quarter 4 (months 9–12). The figure includes data for patients who had two quarters, three quarters, and four quarters of data available.