Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial

Abstract

Importance: Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown.

Objective: To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache.

Design, setting, and participants: A randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse.

Interventions: Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on 2 study days.

Main outcomes and measures: Difference in incidence of cluster headache-like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups.

Results: Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide-induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99).

Conclusions and relevance: Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management.

Trial registration: ClinicalTrials.gov (NCT02466334).

Conflict of interest statement

Conflict of Interest Disclosures: Dr Snoer has received honoraria from AstraZeneca for lecturing. Dr Ashina is a consultant, speaker, or scientific advisor for Allergan, Amgen Inc, Alder BioPharmaceuticals, ATI Pharmacology, Eli Lilly and Company, Novartis, and Teva Pharmaceutical Industries and is primary investigator for Amgen 20120178 (phase 2), 20120295 (phase 2), 20130255 (OLE), 20120297 (phase 3), Alder ALD403-CLIN-001 (phase 3), Amgen PAC1 20150308 (phase 2a), and GM-11 gamma-Core-R trials. Dr Hoffmann has consulted for and/or serves on an advisory board for Allergan, Autonomic Technologies Inc (ATI), Chordate Medical AB, Novartis, and Teva Pharmaceutical Industries and received honoraria for speaking from Allergan, Novartis, and Teva Pharmaceutical Industries. Dr Jensen has given lectures for Pfizer, Berlin-Chemie, Norspan, Merck & Co, and Autonomic Technologies (ATI); has been a member of the advisory boards of ATI, Medotech, and ElectroCore; and a principal investigator on clinical trials sponsored by Eli Lilly and Company. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Participant Recruitment of Patients With Episodic and Chronic Cluster Headache

Figure 2.. Onset of Clusterlike Attack, Cephalic Autonomic Symptoms, Restlessness, and Intake of Rescue Medication

Medians, interquartiles, and ranges from 0 to 90 minutes after 20-minute intravenous infusion of calcitonin gene-related peptide (1.5 μg/min) are reported. The blue arrow indicates the duration of infusion. CCH indicates chronic cluster headache, ECHA, episodic cluster headache in active phase.

Figure 3.. Numerical and Verbal Rating Scores of Patients

The median is indicated by orange lines, and individuals are indicated by blue lines. Headache intensity was rated on an 11-point numerical scale from 0 to 10 for 9 patients with episodic cluster headache in active phase, 14 patients with chronic cluster headache, and 9 patients with episodic cluster headache in remission from 0 to 90 minutes after 20-minute intravenous infusion of calcitonin gene-related peptide (CGRP) (1.5 μg/min) and placebo. In episodic active phase, the area under the curve (AUC) 0 to 90 minutes of headache intensity after CGRP was larger than placebo (P = .04), the median peak attack pain intensity after CGRP was 3.5 (range, 1-10), mean of AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes of placebo was 0.343 (95% CI, 0-0.867). In chronic cluster headache, the AUC from 0 to 90 minutes of headache intensity after CGRP was larger than placebo (P = .01), the mean of AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and mean AUC from 0 to 90 minutes of placebo was 0.036 (95% CI, 0-0.114). In episodic remission phase there was no difference in the AUC from 0 to 90 minutes of headache intensity between CGRP and placebo (P > .99, mean of AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and mean AUC from 0 to 90 minutes of placebo was 0.019 (95% CI, 0-0.062).

Figure 4.. Number of Patients With Chronic Cluster Headache (CCH) Taking Preventive Treatment and Experiencing Usual Attacks

Usual attacks happened 24 hours after completing study days 1 and 2. Data are reported 0 to 90 minutes after 20-minute intravenous infusion of calcitonin gene-related peptide (CGRP) (1.5 μg/min) and placebo.