Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

Introduction Acute medication overuse is prevalent in patients with migraine. Methods In three phase 3, double-blind, randomized, placebo-controlled studies, patients with episodic migraine (EVOLVE-1 and EVOLVE-2) or chronic migraine (REGAIN) were randomized 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg for 3 or 6 months. This subgroup analysis evaluated mean changes in the number of monthly migraine headache days in each treatment among patients with versus without baseline acute medication overuse via mixing modelling with repeated measures. Results The percentages of patients with baseline medication overuse in placebo, galcanezumab 120-mg and 240-mg groups, respectively, were 19.4%, 17.3%, and 19.3% for EVOLVE-1/-2 (pooled; post hoc), and 63.4%, 64.3%, and 64.1% for REGAIN ( a priori). Both galcanezumab doses demonstrated significant improvement compared with placebo for overall least squares mean change in monthly migraine headache days in patients with baseline medication overuse in both the episodic and chronic migraine studies ( p ≤ 0.001). Furthermore, both galcanezumab doses reduced average monthly medication overuse rates compared to placebo ( p < 0.001) in both patient populations with medication overuse at baseline. Conclusions Galcanezumab appears to be effective for the preventive treatment of episodic and chronic migraine in patients who overuse acute medications. Trial registration: ClinicalTrials.gov Identifiers: NCT02614183, NCT02614196, and NCT02614261

BackgroundIn addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs.MethodsSAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects.ResultsIn this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations.ConclusionsWhen analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety.Trial registrationClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.Electronic supplementary materialThe online version of this article (10.1186/s10194-019-1044-6) contains supplementary material, which is available to authorized users.

Background We assessed the safety profile of lasmiditan, a selective 5-HT1F receptor agonist without vasoconstrictive activity being developed as an acute therapy for migraine. Methods SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses. Results The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events. Conclusions As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting. Trial registration at clinicaltrials.gov SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

Objective To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine‐associated symptoms. Background Lasmiditan is a novel selective 5‐hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose. Methods Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine‐related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed. Results Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100‐ and 200‐mg lasmiditan‐treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100‐ and 200‐mg lasmiditan‐treated groups. A significantly higher percentage of patients in the 200‐mg lasmiditan‐treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200‐mg lasmiditan‐treated group achieved freedom from migraine‐related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001). Conclusions Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first asse...