Efficacy and Safety of Eptinezumab in Episodic Cluster Headache: A Randomized Clinical Trial

Abstract

Importance: Cluster headache, characterized by bouts of excruciating pain attacks, detrimentally affects health and quality of life. Eptinezumab is an anticalcitonin gene-related peptide monoclonal antibody approved for migraine prevention.

Objective: To evaluate the efficacy and safety of eptinezumab in the preventive treatment of episodic cluster headache.

Design, setting, and participants: This double-blind, placebo-controlled, randomized (1:1) clinical trial (Eptinezumab in Participants With Episodic Cluster Headache [ALLEVIATE]) was conducted between December 2020 and October 2023. Results are from the initial 4-week randomized phase. The study took place at 64 sites across Europe, the US, and Japan. Included were adults (aged 18-75 years) with a history of episodic cluster headache for 1 or more years (with bouts lasting ≥6 weeks when untreated) and previous acute and preventive medication use.

Interventions: Eptinezumab, 400 mg, or placebo (intravenous infusion).

Main outcomes and measures: The primary end point was the change from baseline in the number of weekly attacks in weeks 1 to 2. Safety was assessed using treatment-emergent adverse events.

Results: Of 628 total participants screened, 320 entered the second screening period, and 231 met eligibility criteria. Of the 231 participants randomized (eptinezumab, n = 118; placebo, n = 113), 215 (93%) completed the placebo-controlled period. The participant mean (SD) age was 44 (11) years, and 178 of 229 were male (78%). At baseline, the mean (SD) weekly attacks were 15.2 (8.1) in the eptinezumab group and 15.7 (8.3) in the placebo group. There was no statistically significant difference between eptinezumab and placebo in the change from baseline in the number of weekly attacks over weeks 1 to 2 (least-squares mean [SE], -4.0 [0.93] vs -4.6 [0.89]; between-group difference, 0.7; 95% CI, -1.3 to 2.6; P = .50). More eptinezumab-treated participants achieved 50% or greater response vs placebo over week 2 (50.9% [54 of 106] vs 37.3% [41 of 110]; odds ratio [OR], 1.77; 95% CI, 1.03-3.07; P =.04), week 3 (62.5% [65 of 104] vs 43.8% [49 of 112]; OR, 2.26; 95% CI, 1.30-3.97; P =.004), and week 4 (66.7% [68 of 102] vs 50.5% [54 of 107]; OR, 2.14; 95% CI, 1.21-3.83; P =.009). Eptinezumab showed numerically larger improvements than placebo for 75% or greater response, average daily pain scores, and across other patient-reported outcomes. Treatment-emergent adverse events occurred in 25.0% of patients (28 of 112) receiving eptinezumab and 26.5% of patients (31 of 117) receiving placebo.

Conclusions and relevance: Among adults with episodic cluster headache, eptinezumab did not significantly reduce the number of attacks vs placebo, although it was associated with numerically higher responder rates and improvements in average daily pain and patient-reported outcomes. Eptinezumab was generally well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT04688775.

Figure 1.. Participant Disposition

Screening period 1 (SP1) lasted up to 52 weeks with the possibility of extension, and screening period 2 (SP2) lasted 7 days with the possibility of extension. Participants entered SP2 no later than 1 week after occurrence of the first typical cluster headache (CH) attack; thus, screening failure during SP1 means that the participant did not enter into a CH bout within that time frame. During SP2, 11 participants were classified as screening failures due to the trial stopping for futility. At the end of SP2, eligible participants were randomized (1:1) to receive eptinezumab or placebo.

Figure 2.. Weekly Attack End Points (APRS)

A, Change from baseline (Δbaseline) in number of weekly attacks (weeks 1-2; primary end point). The changes from baseline in the number of weekly attacks was analyzed using placebo-based multiple imputation. Missing values in number of weekly attacks were imputed using a sequential regression-based multiple imputation method, based on the imputation models established from the placebo group, with 200 imputations used. Each of the 200 datasets was analyzed using a mixed model for repeated measures as described in the Methods. The Rubin rule was used to combine estimates and SEs from the 200 model fits. B and C, Responder rates of ≥50% and ≥75%, respectively. The comparisons between treatment groups are based on a logistic regression model including treatment and geographical region as factors and baseline number of weekly attacks as a continuous covariate. APRS indicates all-participants-randomized set; Δplacebo, mean difference from placebo in change from baseline.

Figure 3.. Selected Secondary End Points (APRS)

A, Mean Patient Global Impression of Change (PGIC) score. PGIC was rated on a 7-point scale: 1 = very much improved, 2 = much approved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. B, Mean change from baseline in attack-related daily pain. Attack-related daily pain was the average of the daily pain scores, defined as 0 if no attacks occurred during a day or as the average of the pain intensity for the attacks occurring during the day. Headache pain was rated on a 5-point scale: 0 = no pain/barely any pain, 1 = mild, 2 = moderate, 3 = severe, and 4 = excruciating pain. For both end points, the estimated means and mean differences from placebo are from a mixed model for repeated measures with weeks, treatment, and country as factors, baseline score as a continuous covariate, treatment-by-week interaction, and baseline score-by-week interaction. APRS indicates all-participants-randomized set.