SAMURAI and SPARTAN6,7 were randomized, double-blind, placebo-controlled Phase 3 trials designed to study the effects of lasmiditan in the acute treatment of migraine; both studies were conducted in the United States, and, SPARTAN also included study sites in the United Kingdom and Germany. The studies were almost identical in design. Key inclusion criteria were as follows: Migraine Disability Assessment score of at least 11 indicating moderate or severe migraine-associated disability; history of migraine of at least 1 year; 3-8 migraine attacks per month with less than 15 headache days per month; and migraine onset before 50 years of age.
For first dose of study drug, patients were randomized equally to lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo, to be taken on an outpatient basis. Patients were instructed to take study drug within 4 hours of onset of a migraine attack with a headache of at least moderate severity and not improving. A second dose was taken 2 to 24 hours after first dose if needed for rescue or recurrence. Patients taking lasmiditan as a first dose were randomized in a 2:1 ratio to the same dose of lasmiditan or placebo, and patients taking placebo as a first dose received a second dose of placebo; randomization to the second dose occurred at the same time as randomization to first dose. The rescue population referred to patients who did not achieve headache pain-free status at 2 hours, completed the 2-hour assessments, and took a second dose of study drug between 2 and 24 hours post-first dose. The recurrence population referred to patients who achieved headache pain-free status at 2 hours but then experienced recurrence of mild, moderate, or severe migraine pain and took a second dose of study drug up to 24 hours from the first dose.
The primary and key secondary endpoints in SAMURAI and SPARTAN were the proportion of patients who were headache pain-free and the proportion who were MBS free at 2 hours post-first dose.
This paper adheres to CONSORT guidelines.
Patients were asked to record in the electronic diary their headache pain severity as none, mild, moderate, or severe and whether they were experiencing nausea, phonophobia, photophobia, or vomiting at baseline, at half hour intervals up to 2 hours and at 3, 4, 24, and 48 hours after dosing. Patients identified at baseline their most bothersome migraine associated symptom out of nausea, phonophobia and photophobia. Patients were also asked the following questions: 1) “How much is your migraine interfering with your usual activities?” (asked at all time points, responses reported using a 4-point numeric rating scale); and 2) the Patient Global Impression of Change (PGIC) question,8 “How do you feel after taking study medication” (asked at 2 hours post dose, responses recorded using a seven-point Likert scale from “very much better” to “very much worse”).
Adverse Event Collection
At 0.5, 1, 1.5, 2, 3, 4, 24, and 48 hours after the first dose and again at the same intervals after a second dose of study drug, , if taken, an electronic diary was employed to ask “Do you feel anything unusual since taking the study medication that you have not felt with a migraine before?” If the patient answered “yes”, they were to receive a call from the site to determine if an adverse event (AE) had been experienced. Those AEs that occurred or worsened within 48 hours of dosing were considered treatment-emergent.
Efficacy hypotheses were that, after a first dose of lasmiditan, a second dose of lasmiditan would be superior to a second dose of placebo when taken for rescue or when taken for recurrence. Since the number of patients choosing to take a second dose of study medication could not be determined prior to the conduct of the study, no formal power analyses were conducted.
Efficacy analyses were performed in the intention-to-treat (ITT) second dose population, which was defined as patients who used a second dose of study drug to treat a migraine and had any post-second dose headache severity or symptom assessments. This population was further classified as ITT second dose rescue population (not pain-free at 2 hours and took a second dose of study medication) and ITT second dose recurrence population (pain-free at 2 hours and took a second dose of study medication). Safety analyses utilized the second dose safety population, which was defined as all patients who used 2 doses of study drug, regardless of whether they completed any study assessments.
Mantel-Haenszel odds ratios (ORs) for efficacy outcomes were computed and compared between lasmiditan and placebo, with study as a covariate. For treatment comparisons, an estimate of the OR of achieving a response, as well as the corresponding confidence interval (CI) and p-value using Wald’s test, was computed. Time to second dose graphics were created using Kaplan-Meier analyses. Continuous variables were summarized using descriptive statistics; categorical variables were summarized using counts and percentages. All efficacy endpoints were tested at a 2-sided significance level of 0.05.
To enable some level of comparison of pain recurrence findings for lasmiditan with those for triptans, we performed a post hoc sensitivity analysis using data from SAMURAI and SPARTAN and an alternate definition of recurrence to be consistent with prior studies.4
Analyses were performed using SAS software, version 9.4/EG 7.1 (SAS Institute, Cary, NC).