Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study

DOI: https://doi.org/10.1186/s10194-020-01088-4

Abstract-Summary Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine.

We analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study.

Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmidi- tan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity.

Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups

were 29.4 and 28.9, respectively, indicating severe migraine-related disability.

Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and

12 months for both dose groups.

At 12 months, changes in MIDAS scores were −12.5 and −12.2 for lasmiditan 100  mg and 200  mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score.

Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1  year.

Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/ no) during initial attacks.

Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism.

Extended: Baseline mean MIDAS values differed somewhat (approximate means 27.1 and 31.7, respectively) between patients with pain-free response in at least 2 of 3 attacks vs those who did not.

4.1 Acute Treatment

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Responses were generally similar in the two dose groups across the different

cutoffs.

Background Two completed placebo-controlled Phase 3 studies assessed lasmiditan for the acute treatment of migraine: SAMURAI (N = 1856, ClinicalTrials.gov identifier: NCT02439320) and SPARTAN (N = 2583; NCT02605174) [48, 122].

The studies were similarly designed, double-blind, and placebo-controlled, with participants randomized to treat a single migraine attack with oral lasmiditan (50 mg [SPARTAN only], 100 mg, or 200 mg) or placebo.

The GLADIATOR study is a prospective, randomized, open-label, Phase 3 study designed to assess the long-term safety of lasmiditan with inclusion of efficacy mea- sures, including migraine disability.

Data assessing the interim efficacy and safety and tolerability of lasmiditan in GLADIATOR have been reported previously, including overall data for MIDAS total score and headache days [123].

Mean MIDAS total scores and number of days with headache decreased signifi-

cantly from baseline at all timepoints for both lasmiditan treatment arms.

Methods Patients were instructed to use lasmiditan as the first treatment for each new migraine attack within 4 h of pain onset, provided that pain was moderate or severe and not improving.

Other assessments included change from baseline in MIDAS total score, number of days with headache over the past 3 months, and average headache pain intensity over the last 3 months at 1, 3, 6, 9, and 12 months.

For the purposes of these analyses, clinically meaningful change in MIDAS total score was defined as a 5-point decrease, per previous findings [124], and the propor- tion of patients with a 50% or greater reduction in MIDAS score was also assessed. All analyses were performed on the MIDAS population, which included all patients with any MIDAS assessment post- baseline; the exception was the analysis of “interference with normal activities” during the course of each attack, which included all patients who took study medication and reported interference values at each time point.

Results Of 2116 patients randomized, 1978 patients received at least 1 dose of lasmiditan (safety population), and 19,058 total migraine attacks were treated.

Findings were similar in a sensitivity analysis analyzing the subgroup of patients with total lost productive days at baseline > 0 (lasmiditan 100 mg, n = 783, lasmidi- tan 200 mg, n = 893), with improvements of up to 42% following 1 year of lasmidi- tan treatment.

The proportions of patients with 50% and 100% improvements from baseline in

migraine-related total lost workplace productivity were assessed.

In order to examine whether the frequency of migraine attacks at baseline affected MIDAS reductions, we assessed response for patients with baseline fre- quency of attacks of ≤5 or >5 per month.

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4 Treatment

For the lasmiditan 100-mg and 200-mg treatment groups, 31.7% (292/920) and 34.3% (332/969) of patients, respectively, achieved pain-free response on their first treated attack in GLADIATOR.

Discussion A clinically meaningful response of at least a 5-point decrease from baseline in MIDAS total score [124] was seen in a steadily increasing proportion of patients over time, reaching ≥70% across the 2 lasmiditan dose groups at 12 months.

While mean migraine-related disability and headache days decreased for patients receiving lasmiditan in the present study, treatment with triptans results in variable effects on migraine disability and a relatively stable number of migraine headache days at a population level.

Headache days decreased significantly and progressively during treatment for up to a year; the mean number of migraine attacks treated with lasmiditan per patient per quarter decreased over time from 6.0 to 3.7 for lasmiditan 100 mg and 6.0 to 3.4 for lasmiditan 200 mg dose [123].

Acknowledgement A machine generated summary based on the work of Lipton, Richard B.; Lombard, Louise; Ruff, Dustin D.; Krege, John H.; Loo, Li Shen; Buchanan, Andrew; Melby, Thomas E.; Buse, Dawn C. 2020 in The Journal of Headache and Pain.

Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine