Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment

Abstract

Objective: To report efficacy and safety of galcanezumab in adults with chronic cluster headache.

Background: Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity.

Methods: This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported.

Results: A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was -4.6 placebo versus -5.4 galcanezumab (p = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema.

Conclusion: Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine.

Trial registration: NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826.

Keywords: CGRP; Galcanezumab; LY2951742; chronic cluster headache; humanized monoclonal antibody.

Conflict of interest statement

Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DWD reports the following conflicts: Personal fees: Amgen, AEON, Association of Translational Medicine, University Health Network, Daniel Edelman Inc., Autonomic Technologies, Axsome, Aural Analytics, Allergan, Alder BioPharmaceuticals, Biohaven, Charleston Laboratories, Clexio, Dr Reddy’s Laboratories/Promius, Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), Theranica, Teva, Vedanta, WL Gore, Nocira, PSL Group Services, University of British Columbia, XoC, Zosano, ZP Opco, Foresite Capital, Oppenheimer; Upjohn (Division of Pfizer), Pieris, Revance, Equinox, Salvia, Amzak Health. CME fees or royalty payments: HealthLogix, Medicom Worldwide, MedLogix Communications, Mednet, Miller Medical, PeerView, WebMD Health/Medscape, Chameleon, Academy for Continued Healthcare Learning, Universal Meeting Management, Haymarket, Global Scientific Communications, Global Life Sciences, Global Access Meetings, UpToDate (Elsevier), Oxford University Press, Cambridge University Press, Wolters Kluwer Health; Stock options: Precon Health, Aural Analytics, Healint, Theranica, Second Opinion/Mobile Health, Epien, GBS/Nocira, Matterhorn/Ontologics, King-Devick Technologies; Consulting without fee: Aural Analytics, Healint, Second Opinion/Mobile Health, Epien; Board of Directors: Epien, Matterhorn/Ontologics, King-Devick Technologies. Patent: 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis without fee; Research funding: American Migraine Foundation, US Department of Defense, PCORI, Henry Jackson Foundation; Professional society fees or reimbursement for travel: American Academy of Neurology, American Brain Foundation, American Headache Society, American Migraine Foundation, International Headache Society, Canadian Headache Society. PJG reports grants and personal fees from Amgen and Eli-Lilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Electrocore LLC, eNeura, Impel Neuropharma, MundiPharma, Novartis, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee. CL reports consulting fee/honoraria for advisory board membership or speaking from Novartis, TEVA, Sanofi, Grunenthal, Eli Lilly and Company, Biogen, and Ethypharm. He served as an investigator on clinical trials for Novartis and Eli Lilly and Company. RJ reports speaker’s fees from Novartis, ATI, and Allergan and institutional payments for clinical trials with Eli Lilly and Company and ATI. JB, JM, CZ, SKA, JYY, RC, and TO are employees and minor stock holders of Eli Lilly and Company.

Figures

Figure 1.

Study diagram. ePRO: electronic patient reported outcome. *injection of blinded investigational drug; X, injection of open-label galcanezumab 300 mg. aePRO diary reporting was completed daily during period 2, period 3, and the first month of period 4.

Figure 2.

Patient disposition during the double-blind period. N: population size; n: number in group. aThe most common reasons for screen failure were not meeting cluster headache attack frequency criteria during the prospective baseline period or having a cardiovascular or a drug- or alcohol-related exclusion criterion. bThree patients who were randomized to placebo did not receive treatment.

Figure 3.

Primary endpoint and key secondary endpoints. a) Least squares mean change from baseline in weekly cluster headache attack frequency. The primary endpoint is overall mean change from baseline in weekly cluster headache attack frequency across weeks 1–12. b) Mean percentage of patients achieving a response of ≥ 50% reduction in weekly cluster headache frequency across weeks 1–12 (first key secondary endpoint). c) Percentage of patients achieving a sustained response through week 12. A sustained response was defined as ≥ 50% reduction in the weekly cluster attack frequency from baseline to weeks 3/4 and maintained at weeks 5/6, 7/8, 9/10, and 11/12 (second key secondary endpoint). CHW adjusted p-values are shown. BL: baseline; CHW: Cui, Hung, and Wang; GMB: galcanezumab; LS: least squares; N: population size; PBO: placebo; SE: standard error.