Trial Population

Eligible participants were 18 to 65 years of age, had a history of episodic cluster headache as defined according to the International Classification of Headache Disorders, 3rd edition (beta version),27 and were able to distinguish cluster headache attacks from other headache disorders, such as migraine. To be eligible for randomization, patients were required to have a cluster headache attack frequency of at least one attack every other day, at least four total attacks, and no more than eight attacks per day during 7 consecutive days of the prospective baseline period. To minimize the possibility of early spontaneous remission owing to the natural course of the disease, patients were also required to have had a cluster headache period that had lasted at least 6 weeks.28

Key exclusion criteria were recent participation in a clinical trial of an investigational drug or device, current or any previous use of any CGRP antibody, antibody to the CGRP receptor or antibody to nerve growth factor, concurrent use of other therapeutic monoclonal antibodies, and status of having another distinct trigeminal autonomic cephalalgia (suspected on the basis of clinical history and examination)27 or a history of migraine variants that could have been due to cerebral ischemia. Additional inclusion and exclusion criteria are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Patients were allowed to use only the following medications to treat their cluster headache attacks: subcutaneous, intranasal, or oral triptans; high-flow oxygen; acetaminophen (paracetamol); and nonsteroidal antiinflammatory drugs. No concomitant preventive medications for cluster headache were permitted.

Trial Oversight

The protocol (available at NEJM.org) was approved by the ethics review board for each investigative site. All the patients provided written informed consent in accordance with the principles of the Declaration of Helsinki. Eli Lilly funded this trial, provided galcanezumab, and conducted the analyses. The initial draft of the manuscript was written by two of the authors, one of whom was an employee of the sponsor. There was no commercial writing support. Confidentiality agreements were in place between the authors and the sponsor. All the authors vouch for the accuracy and completeness of the data, for the adherence of the trial to the protocol, and for the reporting of adverse events.

Trial Design

This international, randomized, blinded trial was conducted at 35 sites in Europe and North America. The trial compared galcanezumab (at a dose of 300 mg) with placebo, both of which were administered subcutaneously at baseline and at 1 month. The trial comprised a screening period, a prospective baseline period, and an 8-week double-blind, placebo-controlled period. Patients were also observed in a subsequent 4-month washout period, the data from which have not yet been analyzed. Patients who met the initial screening criteria were given an electronic diary in which to record their daily information regarding cluster headache attacks during the prospective baseline and double-blind periods.

Patients could enter the screening phase either during an active cluster headache period or while they were in remission. Patients who entered the screening phase during an active cluster headache period could directly enter the prospective baseline period after any necessary washout period for excluded medications, and those who entered screening during remission transitioned into the prospective baseline period when they entered an active cluster headache period and began to record information about the cluster headache attacks in their electronic diary. Patients who entered the screening phase while they were in remission were withdrawn from the trial after 12 months if they had not entered a cluster headache period or had a cluster headache attack; they could be rescreened and reenter the trial once. The prospective baseline period lasted 10 to 15 days, of which 7 consecutive days were used to determine eligibility. Eligible participants were then enrolled in the 8-week double-blind, placebo-controlled period.

Patients who met all the eligibility criteria were randomly assigned in a 1:1 ratio to receive galcanezumab or placebo in a double-blind manner. Randomization was performed by means of a computer-generated random sequence and an interactive Web-response system. Assignments were balanced according to the mean daily frequency of cluster headache attacks (≤4 or >4 attacks per day), sex, and trial site on the basis of a minimization algorithm.29 Galcanezumab or placebo was administered subcutaneously by trained staff at the start of the double-blind period (month 0) and at month 1. Galcanezumab was supplied as a lyophilized formulation in glass vials and reconstituted by designated personnel who were aware of the trial-group assignments but did not have contact with patients and were not involved in any clinical aspects of the study, including administration of galcanezumab or placebo, clinical evaluations, and assessments of adverse events.

Patients entered the following information in their electronic diaries daily during the prospective baseline and double-blind periods: the number of cluster headache attacks regardless of attack duration, the average attack severity and duration over a 24-hour period, and the use of treatments for attacks. The data regarding the frequency of cluster headache attacks were converted into nine intervals of approximately 7 calendar days each: the baseline 7-day interval, week 1 (starting from the day of the first injection and lasting 7 days), week 2 (7 days), week 3 (7 days), week 4 (from the end of week 3 to the day before the second injection), week 5 (starting from the day of the second injection and lasting 7 days), week 6 (7 days), week 7 (7 days), and week 8 (from the end of week 7 to the end of the double-blind period). Weeks 4 and 8 could have been shorter or longer than a calendar week, and if a patient was withdrawn early, the last week of the patient’s trial participation may not have been a full 7 days. The total number of cluster headache attacks for each interval was calculated; subsequently, the weekly totals were adjusted to a 7-day cluster headache attack frequency, and changes from baseline to each of the weeks 1 through 8 were calculated.

Efficacy End Points

The primary end point was the overall mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after the receipt of the first dose of galcanezumab. The key secondary end point was the percentage of patients with a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. The primary and key secondary end points were evaluated after the initial dose, and the trial included secondary end-point assessments of efficacy and safety after the second dose. The other secondary end points were the following: the mean change in the weekly frequency of cluster headache attacks from baseline to each weekly interval through week 8; the percentage of patients with reduction of at least 50% in the weekly frequency of cluster headache attacks from baseline at each weekly interval through week 8; the percentage of patients with reduction of at least 30% in the weekly frequency of cluster headache attacks through week 8; and the percentage of patients reporting that their condition was “very much better” or “much better” on the Patient Global Impression of Improvement scale (patients’ responses were rated on a scale from 1 [very much better] to 7 [very much worse]) at weeks 4 and 8.

Safety

The safety evaluation included the assessment of spontaneously reported adverse events (adverse events that first occurred or worsened during the postbaseline period and serious adverse events), vital signs, electrocardiograms, and laboratory measures. Suicidal ideation and behaviors were assessed with the use of the Columbia–Suicide Severity Rating Scale (C-SSRS).30 The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The scale includes suggested questions to solicit the type of information needed to determine whether a suicide-related thought or behavior occurred.

Immunogenicity of the antibody was assessed by a validated assay that was designed to detect antidrug antibodies to galcanezumab. During the double-blind period, a patient was classified as having a positive result for antidrug antibody if antibodies were present at baseline and at least one postbaseline antibody titer during the double-blind period was at least 4 times as high as the baseline measurement or if antibodies were not present at baseline and at least one postbaseline result of antibody titer during the double-blind period was at least 1:20.

Statistical Analysis

We planned for the trial to include a minimum of 162 participants and allowed for the opportunity to increase the maximum sample size to 222 at an interim analysis on the basis of a prespecified sample-size reestimation process to mitigate the uncertainty with the expected effect size. The sample-size reestimation approach provided the trial with 73 to 89% power for assumed effect sizes of 0.4 to 0.5 to detect a significant difference between the galcanezumab and placebo groups at a one-sided alpha level of 0.025, assuming that 10% of the participants discontinued and with a futility assessment at an interim analysis. We planned to conduct the interim analysis when approximately 114 participants (70% of the planned minimum sample size) had completed the first 3 weeks of the double-blind period. However, no interim analysis was performed because enrollment was halted before reaching 114 participants.

All efficacy and safety analyses were conducted in the modified intention-to-treat population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of galcanezumab or placebo.31 The primary end point of the change from baseline in the weekly frequency of cluster headache attacks was analyzed with the use of a mixed-effects–model, repeated-measures analysis that used data from week 1 through week 3. The model included the fixed, categorical effects of trial-group assignment, sex, pooled investigative site, week, and trial group–by–week interaction, as well as the continuous, fixed covariate of baseline value of weekly frequency of cluster headache attacks.

For the key secondary efficacy end point, the between-group difference in the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3 was determined with the use of Koch’s nonparametric randomization-based analysis of covariance method.32 Adjustments were made for pooled investigative site by including it as a stratification variable and for the continuous baseline value of weekly frequency of cluster headache attacks and sex as covariates. A SAS/IML software macro (NParCov3)33 was used for the calculation. A post hoc mixed-effects–model analysis that was conducted for the percentage change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 used a model similar to that used for the primary end point.

To maintain the overall type I error rate at a two-sided alpha level of 0.05 for the primary and key secondary end points, a gatekeeping strategy was used in which significance of the key secondary end point would be evaluated only if a significant treatment effect in the primary efficacy end point was achieved. There was no adjustment for multiple comparisons for other secondary end points, and only point estimates with 95% confidence intervals, unadjusted for multiple comparisons, are presented. These analyses should be considered to be exploratory.

Missing data were handled as follows: For the primary and secondary efficacy end points, for which data were captured with the use of the electronic diary, if there were 4 or more days with nonmissing diary data and the adherence to using the diary was more than 50% in the weekly interval, the mean number of cluster headache attacks across the nonmissing days was used to impute the missing days. Otherwise, the data for the weekly interval were considered to be missing and were not imputed in the analyses. For the key secondary efficacy end point, patients with missing data at week 3 were considered not to have had a response. Sensitivity analyses were conducted under a missing-not-at-random assumption to assess the robustness of the primary analysis.