Phase 3 Randomized, Placebo-controlled, Double-blind Study of Lasmiditan for Acute Treatment of Migraine

Peter J. Goadsby; Linda A. Wietecha; Ellen B. Dennehy; Bernice Kuca; Michael G. Case; Sheena K. Aurora; Charly Gaul

Disclosures

Brain. 2019;142(7):1894-1904. 

In This Article

Results

Between 19 May 2016 and 29 Jun 2017, 3005 patients were randomized, of whom 2869 (95.5%) had confirmed eligibility (Figure 1). Subsequently, 2583 (86.0%) patients received at least one dose of the study medication (safety population). Of these, 2310 patients provided any post-dose headache severity or symptom assessment data (ITT), and 2156 of these patients treated the migraine within 4 h (full analysis set).

Figure 1.

Study trial flow (first dose). ITT = intent-to-treat. aPatients who were randomized but then deemed ineligible at the telephone confirmation. bOriginally referred to as the modified intent-to-treat population.

Of the 373 (12.4%) patients who discontinued (81 treated, 292 untreated), discontinuation rates were similar between treatment groups. The most common reasons for discontinuation were lost to follow-up and randomization failure (i.e. deemed ineligible at the telephone confirmation). The full analysis set included 2156 patients (71.7%) who treated a qualifying migraine within 4 h of onset.

Demographics

Table 1 shows patient demographics and clinical characteristics of previously treated migraine attacks. The majority of patients in the safety population were female (84.2%), white (80.2%), and the mean [standard deviation (SD)] age was 42.7 (12.8) years.

Baseline Characteristics

At baseline, headache characteristics were similar across groups for the safety population. Patients reported having migraine for an average of 18.3 years with a mean (SD) of 5.3 (2.1) migraine attacks per month in the past 3 months. Most patients experienced moderate disability associated with their migraine attacks with a mean (SD) MIDAS total score of 32.2 (23.2). Overall, 95.3% of patients reported at least one prior medication for migraine, which most frequently included ibuprofen (37.6%), sumatriptan (32.2%), caffeine/paracetamol/acetylsalicylic acid (30.8%), paracetamol (18.2%), topiramate (12.1%), and rizatriptan benzoate (8.3%).

Characteristics of the treated migraine attacks in this study were similar between treatment groups (Table 1). The majority of patients reported moderate-to-severe headache, with ~90% reporting the presence of nausea, phonophobia, or photophobia; photophobia was the most commonly reported MBS across the treatment groups. The mean (SD) time to first dose from the start of the migraine attack (of any severity) was similar in the 200 mg, 100 mg, 50 mg and placebo treatment groups: 1.2 (±1.1) h, 1.2 (±1.1) h, 1.1 (±1.0) h, and 1.2 (±1.1) h, respectively.

Efficacy

The study met its primary efficacy objectives after a single dose; in each lasmiditan dose group a significantly higher proportion of patients were headache pain-free at 2 h and MBS-free at 2 h compared with placebo (Table 2). The proportion of patients who were pain-free at 2 h was significantly higher for the lasmiditan 200 mg group compared with placebo [38.8% versus 21.3%; OR = 2.3 (95% CI 1.8, 3.1); P < 0.001]. Significance for the proportion of patients who were pain-free at 2 h was also observed for the 100 mg and 50 mg lasmiditan dose groups compared with placebo. The proportion of patients who were MBS-free at 2 h was significantly higher for the 200 mg lasmiditan group compared with placebo [48.7% versus 33.5%; OR = 1.9 (95% CI 1.4, 2.4); P < 0.001]. Significance for the proportion of patients who were MBS-free at 2 h was also observed for the 100 mg and 50 mg lasmiditan dose groups compared with placebo. The time course for the proportion of patients pain-free (Figure 2) and MBS-free (Figure 3) show that higher doses of lasmiditan separated from placebo as early as 1 h for proportions reporting pain-free (200 mg and 100 mg; P < 0.05) and 0.5 h for proportions reporting MBS-free (200 mg; P < 0.01).

Figure 2.

Headache pain-free after first dose. Full analysis set (originally referred to as the modified intent-to-treat population). P < 0.001, **P < 0.01, *P < 0.05 versus placebo.

Figure 3.

Most bothersome symptom-free after first dose. Full analysis set (originally referred to as the modified intent-to-treat population). P < 0.001, **P < 0.01 versus placebo.

Considering the other secondary efficacy analyses, headache pain relief at 2 h post-dose was significantly higher for each lasmiditan treatment group versus placebo (P< 0.001) and a significant dose-related response for sustained pain freedom at 24 h was observed with lasmiditan (all doses) versus placebo (Table 2 and Figure 4). Lasmiditan also showed benefits over placebo at 2 h in terms of the proportion of patients free from the migraine symptoms of phonophobia or photophobia (P ≤ 0.005) (Table 2), and in global impression of change ratings and disability level ratings (each P < 0.001) (Table 3). Notably, there were significant dose-related improvements for patients who reported a global impression of 'very much better' and 'much better' across the lasmiditan treatment groups (42.5% 200 mg, 41.2% 100 mg, 36.6% 50 mg) versus placebo (28.0%).

Figure 4.

Headache pain-relief after first dose (intent-to-treat population). P < 0.001, **P < 0.01, *P < 0.05 versus placebo.

Patients who received lasmiditan were less likely to use a second dose of study drug versus patients who received placebo: 21.2% (159/750) of the 200 mg lasmiditan group, 26.3% (198/754) of the 100 mg lasmiditan group, 34.4% (258/750) of the 50 mg lasmiditan group, and 39.5% (297/751) of the placebo group took a second dose between 2 and 24 h after the first dose. Of these second doses, 868 were taken as rescue medication, and 44 for recurrence of headache pain after initially achieving pain freedom.

Tolerability and Safety

The proportion of patients who reported at least one TEAE after the first dose was higher in the lasmiditan treatment groups than in the placebo group and was dose-related [253/649 (39.0%), 230/635 (36.2%), 167/654 (25.5%) for 200, 100 and 50 mg lasmiditan, respectively versus 75/645 (11.6%) for placebo]. Of the 725 TEAEs reported, the majority [676 (93.2%)] were considered to be treatment-related by the investigator. The majority of TEAEs were mild or moderate in severity. The most frequently reported TEAEs (i.e. reported by at least 2% of the lasmiditan safety population and which were also greater than reported by the placebo group) were associated with the CNS (e.g. dizziness, somnolence and paraesthesia) (Table 4). A total of five serious adverse events were reported, of which two were considered treatment-related (dystonic reaction 100 mg; presyncope 200 mg); both resolved with sequelae (positive Romberg test and fatigue, respectively). One treatment discontinuation was attributed to adverse events following 200 mg lasmiditan (fatigue and dizziness); however, the patient completed all required study assessments.

The incidence of cardiovascular-related TEAEs after the first dose was low [12 (0.5%)] (Table 4). All cardiovascular TEAEs (seven palpitations, five tachycardia) were considered reasonably or possibly related to the study drug.

Laboratory Tests

Patients completed laboratory assessments at the end of study visit, usually conducted within 7 days of dosing. There were no clinically meaningful differences in haematology, blood chemistry, urinalysis, vital signs, physical examination, or ECGs across the treatment groups, or with regards to changes from baseline.

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