This randomized clinical trial investigates if eptinezumab is efficacious and well tolerated for the treatment of episodic cluster headache.
Key Points
Question
Is eptinezumab efficacious and well tolerated for the treatment of episodic cluster headache?
Findings
In this double-blind randomized clinical trial of 231 adults with episodic cluster headache, eptinezumab was generally well tolerated but did not reduce the mean number of weekly cluster headache attacks over weeks 1 to 2 compared with placebo.
Meaning
Results demonstrate that eptinezumab did not separate from placebo on the primary end point for this trial, suggesting that consideration for different primary end points is important for future trials in cluster headache.
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
Introduction
Cluster headache (CH) is a primary headache disorder characterized by attacks of very severe unilateral pain lasting 15 to 180 minutes occurring in bouts. In its most typical form (episodic CH [ECH]), bouts last weeks or months with attack frequency varying from once every other day to 8 times per day. Pain during attacks is excruciating, with nearly three-fourths of people rating the intensity 10 on a 0- to 10-point scale. CH affects approximately 0.1% of the population, causes substantial negative impacts on all areas of life, and is associated with disability, reduced self-rated health and quality of life (QOL), worsened family and social relations, decreased work productivity, and psychological health decline.
Due to this high disease burden, a preventive therapy capable of rapidly reducing the severity and frequency of CH attacks and inducing improvements in QOL is highly needed. However, none of the recommended preventive medications (eg, verapamil, lithium, topiramate) were developed specifically for CH, and data supporting their efficacy and safety for CH are limited. These agents are often used in higher doses than those recommended in approved indications, and their use is associated with adverse events (AEs) that may require burdensome clinical management, including laboratory and instrumental testing.
Clinical trials with monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP)—a neuromodulatory and vasodilatory peptide involved in pathophysiology of headache disorders—have provided conflicting results in CH. A galcanezumab trial in ECH was positive, whereas another in chronic CH (CCH) was negative; fremanezumab trials in ECH and CCH were negative and terminated early. Ultimately, galcanezumab was approved for ECH prevention in the US but not in Europe.
Eptinezumab is a high-affinity, humanized anti-CGRP mAb approved for the preventive treatment of migraine. Administered intravenously, eptinezumab provides 100% bioavailability by the end of the infusion and allows rapid binding to CGRP, inhibiting its action. In migraine, eptinezumab was effective during a migraine attack and, therefore, may provide a similar fast onset of benefit in CH. The current trial, Eptinezumab in Participants With Episodic Cluster Headache (ALLEVIATE), was designed to evaluate efficacy and safety of eptinezumab in adults with ECH; we present results of the placebo-controlled period (weeks 1-4).
Methods
The ALLEVIATE double-blind, parallel-group, placebo-controlled, delayed-start randomized clinical trial was conducted in 64 sites across 18 countries (Belgium, Czech Republic, Denmark, Finland, France, Georgia, Germany, Greece, Italy, Japan, Netherlands, Norway, Portugal, Russia, Spain, Sweden, UK, and US) from December 23, 2020, to October 5, 2023. The trial was conducted in accordance with Good Clinical Practice, Declaration of Helsinki, US Food and Drug Administration and European Medicines Agency guidelines, and International Headache Society guidelines for controlled trials of drugs in CH. The appropriate ethics committees and institutional review boards approved the trial for each site before any recruitment initiated. Participants provided written informed consent before any trial-related procedures. The trial protocol and statistical analysis plan are provided in Supplement 1 and Supplement 2, respectively. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Trial Design and Treatment
The trial consisted of an initial 52-week screening period (SP1; with possibility of extension), then a second 7-day screening period (SP2; with possibility of extension), with participants entering SP2 no later than 1 week after occurrence of the first typical CH attack (eFigure 1 in Supplement 3). At the end of SP2, eligible participants were randomized in a 1:1 ratio to receive initial treatment with eptinezumab or placebo at the baseline visit (day 0). At the end of the 4-week placebo-controlled period, participants entered a delayed-start period, wherein those previously exposed to placebo received eptinezumab and vice versa for an additional 4 weeks (active treatment). During the delayed-start period, participants were observed for 12 weeks after active treatment, followed by an 8-week safety follow-up period (eFigure 1 in Supplement 3).
Eptinezumab, 400 mg, and placebo were administered intravenously over 45 (+15) minutes. Although a migraine trial administering eptinezumab, 1000 mg, supports the safety of eptinezumab in higher doses than that approved for migraine prevention, there has been no substantial efficacy advantage shown beyond 300 mg. However, evidence at the time suggested patients with CH have higher CGRP levels than patients with migraine; thus, with higher doses assumed necessary together with the high frequency of attacks, eptinezumab, 400 mg, was used in this trial.
Participant Recruitment
Eligible participants aged 18 to 75 years (inclusive) at screening visit 1 must have been diagnosed with ECH (The International Classification of Headache Disorders, third edition, criteria), have adequately documented diagnosis of ECH of 12 months or longer before screening visit 1, have a medical history of first CH symptoms before or at age 60 years, and have adequately documented records, or reliable history of, previous acute and preventive medication for ECH for 12 months or longer before screening visit 1. Participants had to report 7 to 56 total CH attacks during SP2. Full details of inclusion and exclusion criteria, including disallowed/allowed treatments, are shown in eTable 1 in Supplement 3. Detailed information about race and ethnicity was not collected at all sites, as some participating countries did not allow this information to be collected. Thus, neither race nor ethnicity was reported; however, the geographic region of participants was reported along with other baseline characteristics.
Assessments
Participants completed a daily CH electronic diary (eDiary) from screening visit 2 until the completion visit (end of week 16) or until the withdrawal visit, inputting information on each CH attack, including attack number, pain severity, and use of abortive medication. Monitoring was performed to ensure compliance with the eDiary. Several electronic patient-reported outcomes (PROs) were captured at various time points throughout the trial to assess the impact on outcomes important from participants’ perspectives. The Patient Global Impression of Change (PGIC) assesses disease status change in relation to activity limitations, symptoms, emotions, and overall QOL. The Sleep Impact Scale (SIS) assesses QOL resulting from insomnia. The EQ-5D-5L assesses participant well-being, focusing on mobility, self-care, usual activities, pain/discomfort, and depression/anxiety, with a visual analog scale (VAS) quantifying overall health state. The Work Productivity and Activity Impairment: General Health, version 2.0 (WPAI:GH2.0) questionnaire assesses self-rated productivity.
Safety was assessed through AEs, laboratory test values, vital signs, weight, electrocardiograms, development of antidrug antibodies, and the Columbia–Suicide Severity Rating Scale score.
Efficacy End Points
The primary end point was change from baseline in number of weekly attacks (weeks 1-2). Key secondary end points were 50% or greater reduction from baseline in number of weekly attacks (weeks 1-2), change from baseline in number of weekly times abortive medications were used (weeks 1-2), change from baseline in number of daily attacks (days 1-3), change from baseline in number of weekly days with fewer than 3 attacks per day (weeks 1-2), time from first infusion to resolution of CH bout (within the first 4 weeks), and number of attacks starting 24 hours or less after the start of first infusion. Other efficacy end points included other response definitions (≥30%, ≥75%; weeks 1 through 4), change from baseline in average attack-related daily pain (weeks 1 through 4), PGIC score (weeks 1, 2, and 4), changes from baseline in SIS and EQ-5D-5L VAS scores (weeks 2 and 4) and WPAI:GH2.0 subscores (week 4).
Statistical Analysis
For sample size assumptions, in a galcanezumab trial, the average of the mean differences from placebo at weeks 1 and 2 in the change from baseline in weekly attack frequency was estimated at −3.0. Assuming a mean (SD) difference of eptinezumab vs placebo of −3.0 (9.0) attacks, 144 participants per treatment were estimated to provide 80% power for seeing an effect using a 2-sided 5.0% significance level. Because the estimated treatment difference may have been slightly decreased due to use of a placebo-based multiple imputation method, an additional 5% of participants were added to yield a total of 152 participants/treatment.
Demographics, baseline characteristics, and safety analyses were based on the all-participants-treated set, which included all randomized participants who received eptinezumab. Efficacy analyses were based on the all-participants-randomized set. An interim futility analysis was performed after approximately two-thirds of participants had completed the week 4 visit with the contemplation of ending the trial if the treatment effect for the primary end point was less than one-third the expected effect size.
The primary analysis used placebo-based multiple imputation, simulating 200 complete datasets, which were analyzed by mixed-model repeated measures (MMRM). The MMRM analysis included week, country, and treatment as factors and baseline score as continuous covariate, treatment-by-week interaction, and baseline score-by-week interaction. An unstructured covariance structure was used to model the within-participant errors. The mean difference between eptinezumab and placebo in the change from baseline in the number of weekly attacks (weeks 1-2) was estimated based on least-squares means from the MMRM for the treatment-by-week interaction, using weights (1/2, 1/2, 0, 0) for the eptinezumab-by-week estimates and weights (−1.2, −1.2, 0, 0) for the placebo-by-week estimates. Full details of the statistical methodology are available in eTable 2 in Supplement 3.
A post hoc sensitivity analysis of predicted residual error sum of squares (PRESS) residuals was used to identify participants with the highest influence of observations on the results. Change from baseline in the number of weekly attacks and 50% or greater responder rates were then analyzed excluding the participants with very high or high influence on the modeled results (PRESS values) to assess the 2 end points toward a limited set of very influential observations. Data were analyzed using SAS software, version 9.4 (SAS Institute).
Results
Participants
Recruitment was stopped for futility after the results of the preplanned interim analysis were available. Of 628 total participants screened, 320 entered the second screening period, and 231 met eligibility criteria. Of the 231 participants who met eligibility criteria, 118 were randomized to placebo, 113 were randomized to eptinezumab, and all were included in the primary analysis (Figure 1). One participant in each group was randomized but not treated. Of those treated, 10 participants in the placebo group and 4 in the eptinezumab group withdrew during the placebo-controlled period (Figure 1).
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.
The participant mean (SD) age was 44 (11) years, 51 of 229 were female (22.3%), and 178 of 229 were male (78%). Baseline demographics and disease characteristics were generally similar between eptinezumab and placebo (Table 1), except the eptinezumab group had a slightly longer time since CH diagnosis (mean [SD], 10.5 [8.6] years vs 9.5 [8.5] years) and since first CH symptoms (mean [SD], 17.5 [10.5] years vs 15.3 [10.9] years). The mean (SD) number of weekly CH attacks at baseline was 15.2 (8.1) in the eptinezumab group and 15.7 (8.3) in the placebo group. At screening visit 1, most participants described that the usual pain intensity at its worst was excruciating (eptinezumab: 64 of 112 [57.1%] and placebo: 71 of 117 [60.7%]).
Table 1. Baseline Demographics and Disease Characteristics.
| Characteristic | Placebo | Eptinezumab | Total |
|---|---|---|---|
| Demographics, No. | 117 | 112 | 229 |
| Sex, No. (%) | |||
| Female | 24 (20.5) | 27 (24.1) | 51 (22.3) |
| Male | 93 (79.5) | 85 (75.9) | 178 (77.7) |
| Age, mean (SD), y | 43.9 (11.0) | 44.2 (11.1) | 44.1 (11.0) |
| Geographic region, No. (%) | |||
| Europe | 107 (91.5) | 103 (92.0) | 210 (91.7) |
| North America | 7 (6.0) | 7 (6.3) | 14 (6.1) |
| Asia | 3 (2.6) | 2 (1.8) | 5 (2.2) |
| Disease characteristics per participant recall, No.a | 117 | 112 | 229 |
| Time since CH diagnosis, mean (SD), y | 9.5 (8.5) | 10.5 (8.6) | 10.0 (8.5) |
| Time since 1st symptoms of CH, mean (SD), y | 15.3 (10.9) | 17.5 (10.5) | 16.4 (10.7) |
| No. of CH attacks/d, mean (SD) | 2.6 (1.3) | 2.8 (1.6) | 2.7 (1.4) |
| Duration of CH attacks, mean (SD), min | 58.8 (38.7) | 64.9 (42.5) | 61.8 (40.6) |
| Usual pain intensity at its worst, No. (%) | |||
| Excruciating | 71 (60.7) | 64 (57.1) | 135 (59.0) |
| Severe | 43 (36.8) | 44 (39.3) | 87 (38.0) |
| Moderate | 3 (2.6) | 4 (3.6) | 7 (3.1) |
| No. taking preventive medication, No. (%)b | 54 (46.2) | 55 (49.1) | 109 (47.6) |
| No. of previous preventive CH treatments that were ineffective, No. (%)c | |||
| 0 | 78 (66.7) | 82 (73.2) | 160 (69.9) |
| 1 | 28 (23.9) | 21 (18.8) | 49 (21.4) |
| 2 | 7 (6.0) | 8 (7.1) | 15 (6.6) |
| ≥3 | 4 (3.4) | 1 (0.9) | 5 (2.2) |
| Type of preventive treatment failure, No. (%) | |||
| Lack of efficacy | 36 (30.8) | 24 (21.4) | 60 (26.2) |
| Safety and tolerability | 5 (4.3) | 8 (7.1) | 13 (5.7) |
| Disease characteristics per eDiary report, No.d | 118 | 113 | 231 |
| No. of CH attacks/d, mean (SD) | 2.2 (1.2) | 2.2 (1.2) | 2.2 (1.2) |
| No. of CH attacks/wk, mean (SD) | 15.7 (8.3) | 15.2 (8.1) | 15.4 (8.2) |
| Average pain per d, mean (SD) | 2.4 (0.8) | 2.3 (0.7) | 2.4 (0.7) |
| Weekly use of abortive medication, mean (SD) | 12.1 (10.8) | 11.9 (9.7) | 12.0 (10.3) |
| Baseline attack group, No. (%) | |||
| ≤14 Baseline attacks | 73 (61.9) | 63 (55.8) | 136 (58.9) |
| >14 Baseline attacks | 45 (38.1) | 50 (44.2) | 95 (41.1) |
Abbreviations: CH, cluster headache; eDiary, electronic diary.
Data were collected at screening visit 1 and analyzed in the all-participants-treated set. Participants must have adequately documented records or reliable history of episodic CH history and previous treatment for episodic CH within the 12 months before screening visit 1.
The preventive medications included those with a start date before or at the date for screening visit 2.
The treatment failures where the reason for stopping a preventive medication was either lack of efficacy or safety/tolerability and that the end date of the medication was before or at the date for screening visit 2.
Data were collected prospectively via an eDiary during screening period 2 and analyzed in the all-participants-randomized set.
Primary and Key Secondary End Points
The primary end point of the change from baseline in mean number of weekly attacks over weeks 1 to 2 did not show a statistically significant difference between the eptinezumab (mean [SD], −4.0 [0.93]) and placebo groups (mean [SD], −4.6 [0.89]), with a mean difference of 0.7 (95% CI, −1.3 to 2.6; P = .50) (Figure 2A). Given the primary end point was not met, all other P values were not controlled for multiplicity and are considered descriptive.
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.
None of the key secondary end points showed an advantage of eptinezumab vs placebo at the P < .05 level (eTable 3 in Supplement 3).
Sensitivity Analysis of the Primary End Point
A numerically greater proportion of participants achieved a 50% or greater reduction in the number of weekly attacks in weeks 1 through 4 with eptinezumab vs placebo (prespecified secondary end points) (Figure 2B). The percentage of 50% or greater responders with eptinezumab vs placebo over week 1 was 33.0% (36 of 109) vs 24.1% (28 of 116; odds ratio [OR], 1.56 95% CI, 0.87-2.82; P =.14), over week 2 was 50.9% (54 of 106) vs 37.3% (41 of 110; OR, 1.77; 95% CI, 1.03-3.07; P =.04), over week 3 was 62.5% (65 of 104) vs 43.8% (49 of 112; OR, 2.26; 95% CI, 1.30-3.97; P =.004), and over week 4 was 66.7% (68 of 102) vs 50.5% (54 of 107; OR, 2.14; 95% CI, 1.21-3.83; P =.009). The discrepancy in conclusions stemming from the primary end point and 50% or greater responder rates motivated post hoc sensitivity analyses based on PRESS residuals and participant influence (eFigure 2 in Supplement 3). This analysis found 6 participants (5 eptinezumab, 1 placebo) with PRESS residual values greater than 2000, indicating a very high influence on results (eFigure 2A in Supplement 3). These participants had a high variability in the number of CH attacks reported during the placebo-controlled period (eFigure 2B in Supplement 3). After removing these 6 participants (2.6%), the result for change from baseline in number of attacks across weeks 1 to 4 changed, with an advantage favoring eptinezumab vs placebo (eFigure 2C in Supplement 3). A separate analysis of change from baseline removing 29 (12.6%) participants with PRESS residual values greater than 500 showed an advantage for eptinezumab for each week (eFigure 2C in Supplement 3). In the PRESS analysis for 50% or greater responder rates, the values were almost unchanged by removal of participants with PRESS residuals greater than 500 or participants with PRESS residuals greater than 2000 (eFigure 2D in Supplement 3).
Other Secondary and Exploratory Efficacy End Points
The 30% or greater and 75% or greater responder rates were higher for eptinezumab vs placebo at all time points (eFigure 3 in Supplement 3 and Figure 2C, respectively). The percentage of 30% or greater responders with eptinezumab vs placebo over week 1 was 44.0% (48 of 109) vs 43.1% (50 of 116; OR, 1.04; 95% CI, 0.61-1.76; P =.88), over week 2 was 62.3% (66 of 106) vs 60.0% (66 of 110; OR, 1.12; 95% CI, 0.64-1.94; P =.70), over week 3 was 68.3% (71 of 104) vs 54.5% (61 of 112; OR, 1.92; 95% CI, 1.10-3.41; P =.02), and over week 4 was 73.5% (75 of 102) vs 64.5% (69 of 107; OR, 1.64; 95% CI, 0.90-3.02; P =.11). The percentage of 75% or greater responders with eptinezumab vs placebo over week 1 was 14.7% (16 of 109) vs 11.2% (13 of 116; OR, 1.34; 95% CI, 0.61-3.01; P =.47), over week 2 was 34.0% (36 of 106) vs 21.8% (24 of 110; OR, 1.84; 95% CI, 1.01-3.42; P =.05), over week 3 was 45.2% (47 of 104) vs 28.6% (32 of 112; OR, 2.07; 95% CI, 1.18-3.68; P =.01), and over week 4 was 52.0% (53 of 102) vs 35.5% (38 of 107; OR, 1.98; 95% CI, 1.14-3.50; P =.02).
PGIC scores showed a more marked improvement with eptinezumab than with placebo at weeks 1 and 2 (Figure 3A), and EQ-5D-5L VAS scores had a 7.8-point mean difference from placebo in change from baseline at week 4 favoring eptinezumab (95% CI, 1.49-14.03; P = .02) (eTable 3 in Supplement 3). On all 7 domains of the SIS, week 4 comparisons favored eptinezumab vs placebo, with week 2 comparisons for daily activity, emotional well-being, energy/fatigue, emotional impact, and social well-being domains also favoring eptinezumab (eTable 4 in Supplement 3). All WPAI:GH2.0 subscores at week 4 showed a numerical advantage for eptinezumab vs placebo (eTable 4 in Supplement 3).
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.
Mean reductions in average attack-related daily pain were numerically greater for eptinezumab at all time points vs placebo (Figure 3B).
Safety
Trial treatment was generally well tolerated, with overall incidence of treatment-emergent adverse events (TEAEs) across the placebo-controlled period similar between eptinezumab (28 of 112 [25.0%]) and placebo (31 of 117 [26.5%]) (Table 2). The most commonly reported AEs (≥2% of participants in either treatment group) were constipation, fatigue, nasopharyngitis, and COVID-19 infection (Table 2). There were 3 serious AEs in 2 participants (1.8%) treated with eptinezumab at baseline. One participant experienced 2 same-day allergic reactions (a moderate, and then mild reaction with probable causality to eptinezumab) and was withdrawn from the trial. Another participant had cystocele and urinary incontinence (both moderate events with no related causality to eptinezumab) and remained in the trial with no change to trial drug. Both participants recovered from all serious AEs.
Table 2. Overview of Treatment-Emergent Adverse Events (TEAEs) for the 4-Week Placebo-Controlled Period (APTS).
| TEAE history | Placebo (n = 117) | Eptinezumab (n = 112) |
|---|---|---|
| Participants with TEAEs, No. (%) [total event No.] | 31 (26.5) [43] | 28 (25.0) [52] |
| Participants with SAEs, No. (%) [total event No.] | 0 | 2 (1.8) [3] |
| Participants with TEAEs leading to withdrawal, No. (%) [total event No.] | 0 | 1 (0.9) [1] |
| Participants with TEAEs leading to infusion interruption, No. (%) | 0 | 0 |
| Most common TEAEs (≥2% of either arm), No. (%) | ||
| Constipation | 2 (1.7) | 4 (3.6) |
| Fatigue | 1 (0.9) | 4 (3.6) |
| Nasopharyngitis | 3 (2.6) | 2 (1.8) |
| COVID-19 | 3 (2.6) | 1 (0.9) |
Abbreviations: APTS, all-participants-treated set; SAE, serious adverse event.
Discussion
The ALLEVIATE trial is the largest, to our knowledge, randomized clinical trial that has been conducted in ECH. Although eptinezumab did not separate from placebo on the primary end point of attack frequency during weeks 1 to 2 or key secondary end points, eptinezumab treatment was associated with numerically greater improvements at numerous time points for several other secondary end points, including higher 50% or greater responder rates, greater reduction in average attack-related daily pain, and larger improvements in multiple PROs. PGIC scores reflected a numerically greater global impact (considering various components of improvement) of eptinezumab compared with placebo, with improvements in EQ-5D-5L, SIS domains, and WPAI:GH 2.0 domains with eptinezumab indicative of functional benefits related to QOL, sleep, and work productivity. The PRO data support that the higher responder rates observed with eptinezumab vs placebo may represent valuable and clinically meaningful improvements for patients with CH. As most participants had indicated that the usual pain intensity at its worst during CH attacks was excruciating, the observed reductions in average attack-related daily pain with eptinezumab during weeks 3 and 4 may represent an important clinical benefit.
The primary efficacy end point for randomized clinical trials in CH has consistently been the number of CH attacks (as derived from International Headache Society guidelines), for which nonsignificant results have been observed for 3 anti-CGRP mAbs: galcanezumab for CCH prevention, fremanezumab for ECH and CCH prevention, and eptinezumab for ECH prevention in this trial. Despite evidence that CGRP is linked to CH attack genesis, the pathophysiology of CH may be more complex, with CGRP being just 1 factor. A recent prospective case-control study using blood samples from 297 participants showed plasma CGRP levels were significantly lower in participants with CH compared with healthy controls while also showing higher CGRP levels in participants with ECH in a bout vs in remission; however, as noted by the authors, studies comparing CGRP levels in patients with CH vs controls have methodological differences in timing of data capture and assays used, thus the results do not rule out the importance of targeting CGRP in CH. Other neuropeptides, such as pituitary adenylate cyclase–activating polypeptide, may also trigger CH attacks and may be potential therapeutic targets.
The findings from the ALLEVIATE trial merit consideration for an alternative primary end point in pivotal CH trials given the mixed results with other anti-CGRP mAbs. Two observations from the ALLEVIATE trial indicate that attack frequency should be reconsidered as a primary end point: (1) there was a discrepancy between results for change from baseline in weekly attacks and 50% or greater and 75% or greater responder rates, and (2) removing the limited set of participants with high PRESS values had a disproportionate influence on the primary end point analysis (in favor of eptinezumab, while there was no impact on the responder analysis). Change from baseline in weekly attacks may disproportionately reflect higher baseline values or extreme fluctuations, given the wide variability to the number of attacks that can be reported in a day, which affects the weekly assessments. In contrast, the 50% or greater responder rate similarly weights all participants, reducing the risk for a few participants to have a large influence, indicating that weekly responder rate may be a more relevant primary end point in CH. Discussion within scientific societies and across regulators to identify and approve more reliable end points, and consideration for active comparison trials should be undertaken.
Positive outcomes outside weeks 1 to 2 suggest that this may not be the most adequate primary time point, despite the early onset of efficacy expected with eptinezumab as observed in migraine trials. However, although galcanezumab had success in ECH using a 3-week observation period, it is unlikely that an extended primary time point would have altered the outcome of this trial; a major deficit of the primary outcome is its vulnerability to fluctuations due to baseline and postbaseline variability in attack frequency, which is inherent to the nature of CH.
Eptinezumab was well tolerated at a dose higher than currently prescribed for migraine prevention, with no new safety signals relative to its established profile in migraine prevention. This corroborates findings from a pooled analysis of 5 migraine trials showing similar TEAE incidence across eptinezumab doses between 10 to 1000 mg.
Limitations
This trial might have limited generalizability to the general CH population, given that the ALLEVIATE population was mainly male and located in Europe. As recruitment was stopped for futility, fewer participants were enrolled than planned, limiting sample size and potentially power; however, the enrolled sample was considered sufficient to analyze the primary and key secondary end points. The 4-week duration of the placebo-controlled period provided a limited time frame to determine if the effect of eptinezumab builds over a longer interval, such as the 12-week duration of the regimens approved for migraine prevention.
Conclusions
In the ALLEVIATE randomized clinical trial, eptinezumab did not meet the primary end point of attack frequency during weeks 1 to 2 in ECH, however, treatment led to numerically higher weekly responder rates, reduced pain severity of attacks, and improved multiple PROs. The results from this trial indicate that future trials should consider different primary and secondary end points not reflecting the influence of high variability attack frequency in this population.
Trial Protocol.
Statistical Analysis Plan.
eTable 1. Full Inclusion and Exclusion Criteria, and Allowed and Disallowed Treatments
eTable 2. Statistical Analysis for Primary, Secondary, and Exploratory End Points
eTable 3. Key Secondary End Points
eTable 4. Changes From Baseline in Other Patient-Reported Outcomes
eFigure 1. Trial Design
eFigure 2. Sensitivity Analysis Identifying and Excluding Participants With the Highest Influence Using PRESS Residuals
eFigure 3. Responder Rates: Percentage of Participants With ≥30% Reduction in the Number of Weekly Attacks
Data Sharing Statement.
References
- 1.Headache Classification Committee of the International Headache Society (IHS) the International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. doi: 10.1177/0333102417738202 [DOI] [PubMed] [Google Scholar]
- 2.Freeman E, Adair M, Beeler D, et al. Patient-identified burden and unmet needs in patients with cluster headache: An evidence-based qualitative literature review. Cephalalgia Rep. 2022;5:1-17. doi: 10.1177/25158163221096866 [DOI] [Google Scholar]
- 3.Burish MJ, Pearson SM, Shapiro RE, Zhang W, Schor LI. Cluster headache is one of the most intensely painful human conditions: results from the International Cluster Headache Questionnaire. Headache. 2021;61(1):117-124. doi: 10.1111/head.14021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wei DY, Khalil M, Goadsby PJ. Managing cluster headache. Pract Neurol. 2019;19(6):521-528. doi: 10.1136/practneurol-2018-002124 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia. 2008;28(6):614-618. doi: 10.1111/j.1468-2982.2008.01592.x [DOI] [PubMed] [Google Scholar]
- 6.Grinberg AS, Best RD, Min KM, et al. Cluster headache: clinical characteristics and opportunities to enhance quality of life. Curr Pain Headache Rep. 2021;25(10):65. doi: 10.1007/s11916-021-00979-8 [DOI] [PubMed] [Google Scholar]
- 7.Kim SA, Choi SY, Youn MS, Pozo-Rosich P, Lee MJ. Epidemiology, burden and clinical spectrum of cluster headache: a global update. Cephalalgia. 2023;43(9):1-17. doi: 10.1177/03331024231201577 [DOI] [PubMed] [Google Scholar]
- 8.Petersen AS, Lund N, Snoer A, Jensen RH, Barloese M. The economic and personal burden of cluster headache: a controlled cross-sectional study. J Headache Pain. 2022;23(1):58. doi: 10.1186/s10194-022-01427-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kingston WS, Dodick DW. Treatment of cluster headache. Ann Indian Acad Neurol. 2018;21(suppl 1):S9-S15. doi: 10.4103/aian.AIAN_17_18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.May A, Evers S, Goadsby PJ, et al. ; European Academy of Neurology Task Force . European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol. 2023;30(10):2955-2979. doi: 10.1111/ene.15956 [DOI] [PubMed] [Google Scholar]
- 11.Lund NLT, Petersen AS, Fronczek R, et al. Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments—a consensus article. J Headache Pain. 2023;24(1):121. doi: 10.1186/s10194-023-01660-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Dodick DW, Goadsby PJ, Ashina M, et al. Challenges and complexities in designing cluster headache prevention clinical trials: a narrative review. Headache. 2022;62(4):453-472. doi: 10.1111/head.14292 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007;69(7):668-675. doi: 10.1212/01.wnl.0000267319.18123.d3 [DOI] [PubMed] [Google Scholar]
- 14.Lanteri-Minet M, Silhol F, Piano V, Donnet A. Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day). J Headache Pain. 2011;12(2):173-176. doi: 10.1007/s10194-010-0289-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183-187. doi: 10.1002/ana.410280213 [DOI] [PubMed] [Google Scholar]
- 16.Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117(Pt 3):427-434. doi: 10.1093/brain/117.3.427 [DOI] [PubMed] [Google Scholar]
- 17.Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141. doi: 10.1056/NEJMoa1813440 [DOI] [PubMed] [Google Scholar]
- 18.Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia. 2020;40(9):935-948. doi: 10.1177/0333102420905321 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.EU Clinical Trials Register . A multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study comparing the efficacy and safety of 2 dose regimens (intravenous/subcutaneous and subcutaneous) of TEV-48125 vs placebo for the prevention of chronic cluster headache. Version 1.3, August 2019. Accessed September 6, 2024. https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003278-42/results
- 20.EU Clinical Trials Register . A multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study comparing the efficacy and safety of 2 dose regimens (intravenous/subcutaneous and subcutaneous) of TEV-48125 vs placebo for the prevention of episodic cluster headache. Version 1, May 2020. Accessed September 16, 2024. https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003278-42/results
- 21.Eli Lilly and Company . EMGALITY [package insert]. Accessed October 31, 2024. https://emgality.lilly.com/
- 22.Garcia-Martinez LF, Raport CJ, Ojala EW, et al. Pharmacologic characterization of ALD403, a potent neutralizing humanized monoclonal antibody against the calcitonin gene-related peptide. J Pharmacol Exp Ther. 2020;374(1):93-103. doi: 10.1124/jpet.119.264671 [DOI] [PubMed] [Google Scholar]
- 23.Lundbeck Seattle BioPharmaceuticals Inc . VYEPTI [package insert]. Accessed October 31, 2024. https://www.vyeptihcp.com/
- 24.Baker B, Schaeffler B, Beliveau M, et al. Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine. Pharmacol Res Perspect. 2020;8(2):e00567. doi: 10.1002/prp2.567 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Winner PK, McAllister P, Chakhava G, et al. Effects of intravenous eptinezumab vs placebo on headache pain and most bothersome symptom when initiated during a migraine attack: a randomized clinical trial. JAMA. 2021;325(23):2348-2356. doi: 10.1001/jama.2021.7665 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Schoenen J, Snoer AH, Brandt RB, et al. ; IHS Standing Committee for Clinical Trials; IHS cluster headache trial guideline subcommittee . Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache. Cephalalgia. 2022;42(14):1450-1466. doi: 10.1177/03331024221120266 [DOI] [PubMed] [Google Scholar]
- 27.Dodick DW, Goadsby PJ, Silberstein SD, et al. ; ALD403 study investigators . Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomized, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13(11):1100-1107. doi: 10.1016/S1474-4422(14)70209-1 [DOI] [PubMed] [Google Scholar]
- 28.Snoer A, Vollesen ALH, Beske RP, et al. Calcitonin gene–related peptide and disease activity in cluster headache. Cephalalgia. 2019;39(5):575-584. doi: 10.1177/0333102419837154 [DOI] [PubMed] [Google Scholar]
- 29.Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare; 1976. [Google Scholar]
- 30.Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manipulative Physiol Ther. 2004;27(1):26-35. doi: 10.1016/j.jmpt.2003.11.003 [DOI] [PubMed] [Google Scholar]
- 31.Crawford B, Burgess S, Burrell A, Tellefsen C. Development and validation of the sleep impact scale for insomnia. Value in Health. 2007;10(6). doi: 10.1016/S1098-3015(10)65105-4 [DOI] [Google Scholar]
- 32.Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 5-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736. doi: 10.1007/s11136-011-9903-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Reilly Associates . WPAI:GH V2.0. Accessed September 16, 2024. http://www.reillyassociates.net/WPAI_GH.html
- 34.Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-365. doi: 10.2165/00019053-199304050-00006 [DOI] [PubMed] [Google Scholar]
- 35.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 3 multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Allen DM. Mean square error of prediction as a criterion for selecting variables. Technometrics. 1971;13(3):469-475. doi: 10.1080/00401706.1971.10488811 [DOI] [Google Scholar]
- 37.Andrews JS, Kudrow D, Rettiganti M, et al. Impact of galcanezumab on total pain burden: a post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study in patients with episodic cluster headache. J Pain Res. 2021;14:2059-2070. doi: 10.2147/JPR.S305066 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Tronvik E, Wienecke T, Monstad I, et al. Randomized trial on episodic cluster headache with an angiotensin II receptor blocker. Cephalalgia. 2013;33(12):1026-1034. doi: 10.1177/0333102413484989 [DOI] [PubMed] [Google Scholar]
- 39.de Coo IF, Marin JC, Silberstein SD, et al. Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a meta-analysis. Cephalalgia. 2019;39(8):967-977. doi: 10.1177/0333102419856607 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol. 2002;59(6):990-994. doi: 10.1001/archneur.59.6.990 [DOI] [PubMed] [Google Scholar]
- 41.Chowdhury D, Kordcal SR, Nagane R, Duggal A. ANODYNE study: A double-blind randomized trial of greater occipital nerve block of methylprednisolone and lignocaine versus placebo as a transitional preventive treatment for episodic cluster headache. Cephalalgia. 2024;44(10):1-11. doi: 10.1177/03331024241291597 [DOI] [PubMed] [Google Scholar]
- 42.Lipton RB, Micieli G, Russell D, Solomon S, Tfelt-Hansen P, Waldenlind E. Guidelines for controlled trials of drugs in cluster headache. Cephalalgia. 1995;15(6):452-462. doi: 10.1046/j.1468-29821995.1506452.x [DOI] [PubMed] [Google Scholar]
- 43.Vollesen ALH, Snoer A, Beske RP, et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol. 2018;75(10):1187-1197. doi: 10.1001/jamaneurol.2018.1675 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Petersen AS, Lund N, Meßlinger K, et al. Reduced plasma calcitonin gene-related peptide level identified in cluster headache: a prospective and controlled study. Cephalalgia. 2024;44(3):1-11. doi: 10.1177/03331024231223970 [DOI] [PubMed] [Google Scholar]
- 45.Giani L, Proietti Cecchini A, Leone M. Cluster headache and TACs: state of the art. Neurol Sci. 2020;41(suppl 2):367-375. doi: 10.1007/s10072-020-04639-4 [DOI] [PubMed] [Google Scholar]
- 46.Medrea I, Tepper SJ, Wang D, Mathew PG, Burish M. Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions. J Headache Pain. 2024;25(1):32. doi: 10.1186/s10194-024-01732-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Dodick DW, Gottschalk C, Cady R, Hirman J, Smith J, Snapinn S. Eptinezumab demonstrated efficacy in sustained prevention of episodic and chronic migraine beginning on day 1 after dosing. Headache. 2020;60(10):2220-2231. doi: 10.1111/head.14007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Smith TR, Spierings ELH, Cady R, et al. Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials. J Headache Pain. 2021;22(1):16. doi: 10.1186/s10194-021-01227-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
Statistical Analysis Plan.
eTable 1. Full Inclusion and Exclusion Criteria, and Allowed and Disallowed Treatments
eTable 2. Statistical Analysis for Primary, Secondary, and Exploratory End Points
eTable 3. Key Secondary End Points
eTable 4. Changes From Baseline in Other Patient-Reported Outcomes
eFigure 1. Trial Design
eFigure 2. Sensitivity Analysis Identifying and Excluding Participants With the Highest Influence Using PRESS Residuals
eFigure 3. Responder Rates: Percentage of Participants With ≥30% Reduction in the Number of Weekly Attacks
Data Sharing Statement.