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Randomized Controlled Trial
. 2025 Jun 2;8(6):e2516318.
doi: 10.1001/jamanetworkopen.2025.16318.

Erenumab for Chronic Cluster Headache: A Randomized Clinical Trial

Jasper Mecklenburg  1 , Charly Gaul  2 , Mira Fitzek  1   3 , Lucas H Overeem  1 , Axel Heinze  4 , Robert Fleischmann  5 , Andreas Boeger  6 , Dagny Holle-Lee  7 , Andreas Straube  8 , Astrid Gendolla  9 , Heike Israel-Willner  10 , Mario Lorenz  1 , Gudrun Gossrau  11 , Steffen Naegel  12 , Florian Rimmele  13 , Simrit Rattan  3   14 , Bianca Materne  14 , Daniel Schulze  14 , Bianca Raffaelli  1   3 , Uwe Reuter  1   15 ; CHERUB01 Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Erenumab for Chronic Cluster Headache: A Randomized Clinical Trial

Jasper Mecklenburg et al. JAMA Netw Open. .

Abstract

Importance: Calcitonin gene-related peptide (CGRP) is involved in the pathophysiology of cluster headache (CH). Prophylactic pharmacologic treatment options for chronic CH (CCH) are limited. The potential effects of erenumab, a CGRP receptor antagonist monoclonal antibody, in treating CCH have not been assessed.

Objective: To evaluate the superiority of erenumab compared with placebo in the prophylaxis of CCH.

Design, setting, and participants: A 12-week, double-blind, placebo-controlled randomized clinical trial (CHERUB01) was conducted at 11 sites in Germany from December 2, 2021, to September 27, 2023. Participants (aged 18-65 years) had a diagnosis of CCH, had no previous sufficient response to standard CCH prophylactic medications approved in Germany, and had experienced at least 9 attacks during screening.

Intervention: Loading dose of erenumab (280 mg subcutaneously) or matching placebo in a 1:1 randomization, followed by another dose of erenumab (140 mg subcutaneously) or placebo 4 weeks later.

Main outcomes and measures: The primary end point was the reduction of mean weekly CH attacks from baseline over weeks 5 and 6. Key secondary end points were 50% responder rates and changes in Patient Global Impression of Improvement (PGI-I) scores. Safety and tolerability were also assessed. A bayesian analysis scheme was used for statistical analysis.

Results: This study randomized 81 participants (mean [SD] age, 48.9 [10.4] years; 60 men [74.1%]) with CCH (mean [SD], 21.5 [9.7] attacks per week) to erenumab (n = 41) or placebo (n = 40). Recruitment was stopped prematurely due to insufficient patient numbers meeting the inclusion criteria within the planned recruitment period. The primary end point was not met over weeks 5 and 6 of the double-blind phase because the mean (SD) reduction of weekly CH attacks was -7.3 (8.6) per week for erenumab and -5.9 (10.5) per week for placebo (group difference, -1.5 [95% credible interval [CrI], -5.7 to 2.8]). At weeks 5 and 6, the percentage of participants with a 50% or greater reduction in CH attacks was not significantly different between the erenumab (13 [31.7%]) and placebo (18 [45.0%]) groups (odds ratio, 0.5 [95% CrI, 0.2-1.5]). PGI-I scores were also not different between groups. More participants reported adverse events with erenumab than placebo (27 [65.9%] vs 17 [42.5%]), which were mostly of mild or moderate intensity.

Conclusions and relevance: In this clinical trial of patients with CCH, blockade of the CGRP receptor with erenumab was not successful in the prophylaxis of attacks. Future studies should revisit the role of CGRP in CCH.

Trial registration: ClinicalTrials.gov Identifier: NCT04970355; EudraCT Number: 2020-004399-16.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gaul reported receiving speaking fees and honoraria from Novartis during the conduct of the study. In addition, Dr Gaul reported receiving grants from the German Research Foundation and personal fees from Novartis, Lilly, Hormosan, Teva, Vectura Pharma, AbbVie, Lundbeck, Reckitt Benckiser, Sanofi Aventis, Perfood, and Chordate outside the submitted work. Dr Fitzek reported receiving personal fees from Novartis and Teva outside the submitted work. Dr Heinze reported receiving grants from Charité Universitätsmedizin Berlin during the conduct of the study. In addition, Dr Heinze reported receiving speaking fees from and serving on advisory boards for Novartis, Lilly, Teva, Lundbeck, and AbbVie outside the submitted work. Dr Fleischmann reported receiving personal fees from Teva, Lundbeck, AbbVie, Novartis, and Lilly outside the submitted work. Prof Holle-Lee reported receiving personal fees from Novartis, Lundbeck, AbbVie, Teva, and Lilly during the conduct of the study. Dr Israel-Willner reported receiving personal fees from Charité University during the conduct of the study. Dr Gossrau reported receiving personal fees for patient recruitment and investigation from Charité Universitätsmedizin Berlin during the conduct of the study. In addition, Dr Gossrau reported receiving grants from Kosing Stiftung and personal fees from Novartis, Teva, Lundbeck, Sanofi, Reckitt Benckiser, and Lilly outside the submitted work. Dr Naegel reported receiving compensation from Charité Universitätsmedizin Berlin during the conduct of the study. Dr Rimmele reported receiving grants from Charité Universitätsmedizin Berlin during the conduct of the study. In addition, Dr Rimmele reported receiving royalties from Elsevier and serving on advisory boards for Allergan/AbbVie, Novartis, Teva, Ipsen, Lundbeck, Lilly, and Hormosan outside the submitted work. Dr Raffaelli reported receiving grants from Novartis and Lundbeck as well as personal fees from Novartis, Lundbeck, Teva, Organon, Perfood, and AbbVie outside the submitted work. Dr Reuter reported receiving grants from Novartis (to Charité Universitätsmedizin Berlin) during the conduct of the study. In addition, Dr Reuter reported that Universitätsmedizin Greifswald received compensation from AbbVie, Lilly, Lundbeck, Novartis, Pfizer, and Teva for Dr Reuter’s participation in advisory boards, consultations, or scientific presentations. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Flow Diagram
ITT indicates intention to treat.
Figure 2.
Figure 2.. Study Design
Figure 3.
Figure 3.. Primary End Point Analysis Using Bayesian Posterior Distribution of the Estimated Difference in the Reduction of Weekly Cluster Headache Attacks With Erenumab vs Placebo
CrI indicates credible interval.
See this image and copyright information in PMC

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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
    1. Petersen AS, Lund N, Goadsby PJ, et al. Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache. Lancet Neurol. 2024;23(7):712-724. doi: 10.1016/S1474-4422(24)00143-1 - DOI - PubMed
    1. 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 - PubMed
    1. 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
    1. Brandt RB, Wilbrink LA, de Coo IF, et al. ; ICON study group . A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache. EBioMedicine. 2023;98:104895. doi: 10.1016/j.ebiom.2023.104895 - DOI - PMC - PubMed

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