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

DOI: https://doi.org/10.1186/s10194-021-01343-2

Abstract-Summary Detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION).

Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1).

The incidences of treatment-emergent serious adverse events (SAEs) were - pla- cebo, n  =  2 (0.4 %); LTN100, n  =  1 (0.2 %); LTN200, n  =  2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient.

The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity.

The incidences of these TEAEs were highest during the first attack and decreased

during subsequent attacks.

For patients who experienced a common TEAE with the first attack, less than

45 % experienced the same event in subsequent attacks.

4.1 Acute Treatment

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It was shortest for paresthesia (<2 h for all attacks); it ranged from 1.8 to 5.5 h

for other common TEAEs and was generally similar across attacks.

In this blinded, controlled, multiple-attack study, LTN was associated with gen-

erally mild or moderate CNS- related TEAEs of short duration.

Extended: Patients were randomized in a blinded fashion in a 1:1:1 ratio to one of 3 treatment groups (1) lasmiditan 200 mg for 4 attacks; (2) lasmiditan 100 mg for 4 attacks; or (3) a control group that received placebo for 3 attacks and lasmiditan 50 mg for 1 attack.

The most common TEAEs with lasmiditan were dizziness, nausea, paresthesia,

fatigue, somnolence and vertigo.

The most common TEAEs were similar to those previously reported for Phase 3 single-dose lasmiditan studies; the incidences of TEAEs were somewhat higher than previously reported but decreased over the 4 attacks.

For patients who treated all 4 attacks, ≤ 1 % reported severe dizziness with las-

miditan in any attack.

It was shortest for paresthesia (less than 2 h for all attacks) and ranged from 1.8

to 5.5 h for other common TEAEs.

Introduction The value of an acute treatment for migraine depends not only on its ability to rap- idly and consistently relieve symptoms, but also on acceptable drug safety and tolerability.

In Phase 3 studies, lasmiditan was effective in the treatment of a migraine attack, as measured by pain freedom, pain relief, most bothersome symptom (MBS) free- dom at 2  h, [122, 125, 126] and demonstrated a consistent response across attacks [126].

We report the detailed safety findings from the CENTURION study, a large Phase 3 placebo-controlled study designed to assess the efficacy, consistency, and safety of lasmiditan in acute treatment of 4 migraine attacks with or without aura.

Methods Adverse events and symptoms between migraine attacks as well as any unusual symptoms within 48 h after dosing were to be recorded by patients in a paper journal.

Tolerability and safety evaluation included the assessment of TEAEs, defined as

new or worsening adverse events during the 48 h after a dose of study drug.

Summaries of adverse events were performed using all patients who treated at least one attack as well as using only patients who treated four attacks during the double-blind period.

For summaries of common TEAEs by severity, if the patient experienced the same event multiple times during the same attack, the severity for that event was defined as that of worst severity.

In the situation where multiple cases of the same event occurred with a given treated attack, the time to onset was defined as the time to dosing until the start of the first case.

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4 Treatment

Results Over the course of the study, patients treated ≤4 attacks with lasmiditan 100 mg, ≤4 attacks with lasmiditan 200 mg or ≤3 attacks with placebo and ≤1 with lasmidi- tan 50 mg.

For patients who treated all four attacks, ≤1 % reported severe dizziness with

lasmiditan in any attack.

Shortly after taking study drug (lasmiditan 200 mg) to treat a migraine attack, the patient experienced CNS symptoms and findings (including myoclonus, ataxia and increased muscle reflexes) along with sweating and increased temperature.

Of the 8 injury-related cases with lasmiditan, three patients also reported a cen- tral nervous system (CNS) TEAE during the same attack - joint dislocation occurred a few hours after the resolution of formication and vertigo; rib fracture occurred more than a day after the resolution of paresthesia; one case of limb injury occurred approximately one hour after the resolution of dizziness.

Discussion The incidences of common TEAEs during the first attack in CENTURION were higher than in previous single-attack Phase 3 studies.

In a pooled analysis of data from SAMURAI and SPARTAN (single attack stud- ies), the incidence of any TEAE was 14% with placebo, 36% with lasmiditan 100  mg and 41% with lasmiditan 200  mg compared with 22%, 53% and 61%, respectively in CENTURION (first attack data).

The decreases in TEAEs across attacks treated with lasmiditan in the CENTURION study were similar to decreases observed in the GLADIATOR study [123].

The most common TEAEs were similar to those previously reported for Phase 3 single-dose lasmiditan studies; the incidences of TEAEs were somewhat higher than previously reported but decreased over the four attacks.

Acknowledgement A machine generated summary based on the work of Tassorelli, C; Bragg, S; Krege, JH; Doty, EG; Ardayfio, PA; Ruff, D; Dowsett, SA; Schwedt, T. 2021 in The Journal of Headache and Pain.

Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine