Trial Oversight

The protocol, available with the full text of this article at NEJM.org, was approved by relevant ethics committees and institutional review boards. The authors vouch for the conduct of the trial, adherence to the protocol, and the accuracy and completeness of the data and analyses and the reporting of adverse events. The trial complied with the International Conference on Harmonisation Guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki, and relevant national and local regulations. At the time of screening, participants signed consent forms for both this trial and a concurrent trial of fremanezumab for episodic migraine (ClinicalTrials.gov number, NCT02629861). The trial sponsor, Teva Pharmaceuticals, provided the trial medication, performed the data analysis, and funded the trial. Assistance with manuscript preparation was provided by a medical writer funded by the sponsor.

Trial Participants

Patients were recruited at 132 sites in nine countries from March 2016 through January 2017. These sites were clinics caring for persons with headaches, and potential participants were identified from their databases. Key inclusion criteria were an age of 18 to 70 years, a history of migraine (according to the criteria of the International Classification of Headache Disorders, 3rd edition [beta version], or ICHD-3 beta) for at least 12 months, and the fulfillment of the criteria for chronic migraine during the 28-day preintervention period (headache of any duration or severity on ≥15 days and headache meeting ICHD-3 beta criteria for migraine on ≥8 days). The protocol allowed inclusion of up to 30% of patients using a stable dose of one migraine-preventive medication (hereafter referred to as preventive medication) for at least 2 months before the beginning of the preintervention period to continue these medications.

Key exclusion criteria were the use of onabotulinumtoxinA during the 4 months before screening; the use of interventions or devices for migraine, such as nerve blocks and transcranial magnetic stimulation, during the 2 months before screening; the use of opioid or barbiturate medications on more than 4 days during the preintervention period; and a lack of efficacy, after an adequate therapeutic trial, of at least two of four clusters of preventive medications, the details of which are provided in the protocol.

Trial Design

This randomized, double-blind, placebo-controlled, parallel-group trial consisted of a screening visit, a 28-day preintervention period, and a 12-week intervention period, with a final evaluation at week 12. On the basis of the screening visit and information collected in a daily diary during the preintervention period, patients were enrolled in the appropriate trial or were excluded if they were not eligible for either trial.

Eligible patients were randomly assigned in a 1:1:1 ratio to receive fremanezumab quarterly, fremanezumab monthly, or placebo. All the patients received three abdominal subcutaneous injections at baseline and one injection at weeks 4 and 8. In the fremanezumab-quarterly group, patients received a single dose of 675 mg of fremanezumab at baseline (three injections of 225 mg per 1.5 ml), followed at weeks 4 and 8 by placebo (one 1.5-ml injection). In the fremanezumab-monthly group, patients received 675 mg of fremanezumab at baseline (as above) and 225 mg of fremanezumab at weeks 4 and 8 (one injection of 225 mg per 1.5 ml). In the placebo group, placebo was administered as three 1.5-ml injections at baseline and one 1.5-ml injection at weeks 4 and 8. Randomization was performed by means of electronic interactive-response technology, with stratification according to sex, country, and baseline use of preventive medication (yes or no). Patients, investigators, the sponsor, and trial staff were unaware of the trial-group assignments.

Patients were seen at five scheduled visits for protocol-specified evaluations: at screening, baseline, weeks 4 and 8, and week 12, or at the time of early withdrawal from the trial. Patients who withdrew prematurely had final protocol-specified evaluations performed as soon as possible after withdrawal. Headache data (e.g., occurrence, duration, and pain severity; occurrence of photophobia, phonophobia, nausea, or vomiting; and any use of migraine medication) were captured daily through an electronic headache-diary device (ERT DIARYpro platform on the Bluebird Pidion BM-170 device).

Trial End Points

The primary end point was the mean change in the average number of headache days (days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month, comparing the baseline 28-day preintervention period with the 12-week period after the first dose of the trial regimen.

Secondary end points were the mean change from baseline in the average number of migraine days per month, the percentage of patients with a reduction of at least 50% in the average number of headache days per month, and the mean change from baseline in the average number of days per month in which acute headache medication was used during the 12-week period after the first dose. A migraine day was defined as a calendar day in which headache pain lasted at least 4 consecutive hours and met criteria for migraine (with or without aura) or probable migraine (subtype in which only one migraine criterion is absent), or a day in which acute migraine–specific medication (triptans or ergots) was used to treat a headache of any duration. Other secondary end points included the mean change from baseline in the number of headache days during the 4-week period after the first dose in all the patients and during the 12-week period after the first dose in patients not receiving concomitant preventive medication, as well as the mean change in the score on the six-item Headache Impact Test (HIT-6; scores range from 36 to 78, with higher scores indicating a greater degree of headache-related disability)15 from baseline (day 0) to 4 weeks after administration of the last dose of the trial regimen.

Safety and side-effect profiles were evaluated according to reported adverse events, vital signs (systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate), physical examination, 12-lead electrocardiography, clinical laboratory tests (serum chemical, hematologic, coagulation, and urinalysis tests), systematic assessments of local injection-site reactions (erythema, induration, ecchymosis, and pain, all evaluated both immediately and 1 hour after dose administration), concomitant medication use, and suicidal ideation and behavior as assessed by means of scores on the electronic Columbia–Suicide Severity Rating Scale. Serum levels of antidrug antibodies were assessed with the use of a validated method.

Statistical Analysis

Estimations based on the phase 2b trial of fremanezumab in chronic migraine14 predicted that a sample of 867 patients who had completed the trial and could be evaluated would provide 90% power to detect a mean (±SD) difference of 1.7±6.3 in the average number of headache days per month between the fremanezumab-monthly group and the placebo group at a two-sided alpha level of 0.05. With an anticipated rate of discontinuation of 15%, 1020 participants were planned for randomization in this trial. Efficacy analyses were conducted in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of a trial regimen and had at least 10 days of postbaseline efficacy assessments regarding the primary end point. Safety analyses included all randomly assigned patients who received at least one dose of a trial regimen.

The primary end point was analyzed with the use of an analysis of covariance. Trial regimen, sex, country, and baseline use of preventive medication (yes or no) were used as fixed effects, and the baseline number of migraine days and of years since the onset of migraines were covariates. We calculated 95% confidence intervals for the least-squares mean differences between each fremanezumab group and the placebo group. The Wilcoxon rank-sum test was performed as the primary analysis if there was deviation from the normality assumption as assessed by means of the Shapiro–Wilk test. For management of missing data in the primary analysis, the average number of headache days per month during the 12-week period was prorated to a 28-day equivalent with the use of all postbaseline observations. The same analyses were used for relevant secondary end points. For the percentage of patients with a reduction of at least 50% in the average number of headache days per month, the Cochran–Mantel–Haenszel test was used, with baseline use of preventive medication (yes or no) as a stratification variable.

To control the type I statistical error rate at 0.05, a hierarchical testing procedure was applied, with a prespecified sequence of comparisons beginning with the primary end point and proceeding to secondary end points in the order given in the protocol. Each comparison was performed only if the preceding comparison had a two-sided P value of 0.05 or less. Results are presented in the sequence in which end points were evaluated.