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

Materials and Methods

Study Design

This was a prospective, randomized, double-blind, placebo-controlled, multicentre phase 3 study in patients with migraine with and without aura (Headache Classification Committee of the International Headache Society, 2013) from 125 headache centres in the USA, UK and Germany (NCT02605174). Patients were stratified for use of concomitant preventive medications that reduced frequency of their migraine attacks. The study consisted of three treatment phases: screening visit to confirm eligibility, treatment period (up to 8 weeks), and end of study visit (within 1 week of treating attack) for a total study duration of up to 11 weeks. Patients were to treat a single migraine attack of moderate-to-severe intensity with study drug within 8 weeks of enrolment on an outpatient basis. A second dose was permitted between 2 and 24 h after initial dosing, if needed, for rescue or recurrence of migraine. Patients who did not experience and/or treat a migraine attack during the study period were excluded from all safety and efficacy analyses.

The primary efficacy objectives were to evaluate the efficacy of each dose of lasmiditan (200 mg, 100 mg, 50 mg) at 2 h compared to placebo on the proportion of patients achieving headache pain freedom and freedom from the most bothersome symptom (MBS), as identified by the patient, from the associated symptoms of nausea, phonophobia and photophobia. Secondary efficacy objectives were to explore the effect of headache pain relief and time course of lasmiditan on pain freedom and freedom from MBS, pain relief, number of patients who experience sustained pain freedom and freedom from individual symptoms associated with migraine, pain relief, disability, and patient global impression of change. The safety objective was to assess the safety and tolerability of lasmiditan in terms of adverse events, physical examinations, vital signs, laboratory tests and ECGs.

Patients

Patients were recruited from clinical research centres in three countries.

Inclusion criteria. Males or females (≥18 years) who had at least a 1-year history of disabling migraine with or without aura (International Headache Society diagnostic criteria 1.1 and 1.2.1) (Headache Classification Committee of the International Headache Society, 2013), a Migraine Disability Assessment (MIDAS) score ≥11 (Lipton et al., 2001), onset before the age of 50 years, and three to eight migraine attacks per month were eligible for enrolment.

Exclusion criteria. Included history of chronic migraine or other forms of primary or secondary headache disorder such as hemicranias continua, or medication overuse headache, where headache frequency is ≥15 headache days per month within the past 12 months; haemorrhagic stroke, epilepsy, or any other condition placing the patient at increased risk of seizures; recurrent dizziness and/or vertigo including benign paroxysmal positional vertigo, Meniere's disease, vestibular migraine, and other vestibular disorders; diabetes mellitus with complications (diabetic retinopathy, nephropathy or neuropathy); orthostatic hypotension with syncope; significant renal or hepatic impairment; current evidence of abuse of any drug, prescription or illicit, or alcohol within the previous 3 years; and patients who were at imminent risk of suicide by the Columbia Suicide Severity Rating Scale (C-SSRS) or had a suicide attempt within 6 months prior to the screening visit. In addition, patients who used more than three doses per month of either opioids or barbiturates or had initiation of or a change in concomitant medication to reduce the frequency of migraine attacks within 3 months prior to the screening visit were considered ineligible for study entry.

Patients with cardiovascular risk factors were identified using the American College of Cardiology/American Heart Association guidelines (Goff et al., 2014), which identified factors with greatest predictive potential for a first cardiovascular event. They include age, total and high-density lipoprotein cholesterol, systolic blood pressure (including treated or untreated), diabetes, and current smoking status. In contrast to the first phase 3 trial (Kuca et al., 2018), this trial did not exclude individuals with known coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension.

The study was approved by the authorities and independent ethics committees. This study was conducted in accordance with the Declaration of Helsinki and internationally accepted standards of Good Clinical Practice. All patients gave written informed consent before enrolment.

Randomization and Masking

Patients were centrally randomized via the Interactive Response Technology system to one of seven treatment sequences to receive lasmiditan (200 mg, 100 mg, 50 mg) or placebo for the first dose (in a 1:1:1:1 ratio) and the second dose of lasmiditan or placebo (in a 2:1 ratio), if needed for rescue or recurrence of migraine. All patients who were randomized to placebo for the first dose were given placebo for the second dose. Masking of treatment was achieved using a modified-dummy technique. All patients and investigators, and sponsor staff were masked to treatment allocation.

Procedures

At screening, medical and migraine history were taken, and vital signs, physical examination, ECG, clinical laboratory tests, and MIDAS and C-SSRS questionnaires were completed for all patients. Medical history and adverse events were classified based on Medical Dictionary for Drug Regulatory Activities (MedDRA) version 21.0. Patients were asked about any medication use for migraine or pain during the 90 days before enrolment and other drugs used during the 30 days before enrolment, family history of cardiovascular disease, and occurrence of any cardiovascular events in the last 6 months. Patients were provided with an electronic diary and trained to record information about their migraine, their use of study medication, and to complete post-dose assessments. Patients were randomized and provided with a dosing card (four tablets for initial and second doses). Within 7 days of the screening visit, the patients were contacted by phone to confirm eligibility.

Study Conduct

Eligible patients were instructed to treat their next migraine attack within 4 h of onset, provided that their headache was moderate or severe and not improving. Triptans, ergots, opioids and barbiturates were disallowed within 24 h of study drug administration. Prior to taking their first dose of study drug, the patient identified in the electronic diary the time of onset, the severity of the pain, presence or absence of nausea, phonophobia, and photophobia and which was most bothersome, and presence or absence of vomiting. Patients recorded their response to the first dose in an electronic diary for 48 h after intake of study drug and up to 72 h if a second dose was taken.

After dosing, headache severity was assessed by the patient and recorded in the electronic diary at specified times: 0.5, 1, 1.5, 2, 3, 4, 24 and 48 h post-dose using a headache severity rating scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain). Patients documented the presence or absence of any associated symptoms at the same time points. Patient disability was assessed with a 4-point item regarding the degree of interference in normal activities due to migraine (none, mild, moderate, requires bed rest). Global impression at 2 h after study drug intake was recorded by the patient on a 7-point scale (very much better, much better, a little better, no change, a little worse, much worse, and very much worse). The date and exact time when the patient became headache pain-free and experienced meaningful headache pain relief was also recorded. Patients also recorded any unusual symptom (possible adverse event) within the treatment period following initial or second doses of the study drug. Severity of adverse events (mild, moderate, severe), and causal relation to study drug, were assigned by the investigator. The 48-h evaluation period for identification of treatment emergent adverse events (TEAEs) was considered adequate in light of the 5.7-h terminal elimination half-life of lasmiditan (data on file, Eli Lilly and Company).

A second dose of the study drug was permitted up to 24 h after the first dose if the migraine did not respond at 2 h and no other rescue medication had been used or if the migraine responded within 2 h (headache becomes pain-free) but then recurred after 2 h. Patients recorded their response to the second dose in an electronic diary for 48 h after intake of the study drug.

At follow-up within 7 days after treatment, patients returned their study drug pack and compliance was assessed via the electronic diary. A physical examination, vital signs, 12-lead ECG, and laboratory assessments were done, and adverse events, concomitant drugs, and rescue drugs reported since screening were reviewed.

Efficacy Outcomes/End-points

The primary efficacy objective was the comparison between each dose of lasmiditan and placebo on the proportion of patients who were headache pain-free and MBS-free at 2 h after the first dose. While patients were directed to take the study drug only when their pain was moderate to severe, a small number of patients (n = 33) took the study drug when their pain was mild. These patients were distributed across all four treatment groups [50 mg n = 12 (2.2%), 100 mg n = 9 (1.7%), 200 mg n = 7 (1.3%), and placebo n = 5 (0.9%)]. Thus, headache pain-free response was defined as a reduction of headache severity from mild, moderate or severe pain to none. If a second dose, or any rescue medication, was taken before 2 h, the patient was considered to be a non-responder to the first dose.

Other secondary efficacy end-points included the proportion of patients with headache pain relief [defined as a reduction in headache severity from moderate (2) or severe (3) at baseline, to mild (1) or none (0), or a reduction in headache severity from mild (1) at baseline, to none (0)]; proportions of patients who had sustained pain freedom at 24 h and 48 h after the first dose (defined as being headache pain-free at 2 h after the first dose, and at the indicated assessment time, having not used any medications after the first dose) compared to placebo; comparisons between lasmiditan 200 mg/100 mg/50 mg and placebo of the proportion of patients who were headache pain-free; MBS-free and headache pain relief at other time points; proportion of patients who were free from migraine symptoms (phonophobia, photophobia, nausea, vomiting); patient global impression of change; level of disability; and proportion of patients who used a second dose of study drug for rescue or recurrence.

Statistical Analysis

The sample size was estimated based on the 2 h headache pain-free and associated symptoms (nausea, phonophobia or photophobia) free response rates observed from the previous phase 2 study (Färkkilä et al., 2012). Using a one-sided, two-sample comparison at the 2.5% level of significance, a sample size of 570 patients per treatment group (as defined by the first dose) provided >90% power to detect a difference in the proportion of patients who were headache pain-free at 2 h for assumed true rates of 7.4% and 18.8% (placebo and 200 mg), 7.4% and 13.6% (placebo and 100 mg), 7.4% and 13.9% (placebo and 50 mg) and >90% power for MBS for both the 50 mg dose arm and the 100 mg dose arm and very near or >80% power for MBS in the 200 mg dose arm.

Primary efficacy analyses were performed in the full analysis set [originally referred to as the modified intent-to-treat (ITT) population], which was defined a priori in the protocol/statistical analysis plan as patients who used at least one dose of study drug to treat a qualifying attack within 4 h of onset and had any post-dose headache severity or symptom assessments. Secondary efficacy analyses were carried out in the intent-to-treat population, which was defined as all patients in the safety population (see below) who recorded any post-dose headache severity or symptom assessments in the electronic diary. Safety/tolerability analyses used the safety population, which was defined as all randomized patients who used at least one dose of the study drug, regardless of whether they completed any study assessments. Any event that first occurred or worsened in severity within 48 h after treatment with the study drug was considered a TEAE.

All primary and secondary efficacy analyses were made using a logistic regression model with treatment group and background use of migraine preventive medication as covariates. For treatment comparisons, an estimate of the odds ratio (OR) of achieving a response, as well as the corresponding confidence interval (CI) and P-value using Wald's test, were computed. Exceptions to this were global impression of change and level of disability, which used a Cochran–Mantel–Haenszel test controlling for background use of migraine preventive medication. Primary efficacy analyses on headache pain-free and MBS-free at 2 h were tested at a one-sided significance level of 0.025. A testing hierarchy was used to prevent type I error inflation for multiple comparisons: the primary efficacy end-point (pain free for the 200 mg group) was tested first and, if it was statistically significant, the MBS-free end-point was tested for the 200 mg group, followed by pain-free and MBS-free end-points for the 100 mg and then for the 50 mg groups, similarly. Continuous variables were summarized using descriptive statistics; categorical variables were summarized using counts and percentages. Other secondary efficacy end-points were tested at a two-sided significance level of 0.05.

Because each patient received up to two doses of lasmiditan within a range that had been well tolerated in prior studies, there was no data safety monitoring board for this study. This study is registered with ClinicalTrials.gov, number NCT02605174.

Data Availability

Data are available to request 6 months after the indication studied has been approved in the US and EU. For details on submitting a request, please see the instructions provided at http://www.clinicalstudydatarequest.com.

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