Long-term safety, tolerability, and efficacy of eptinezumab in chronic cluster headache (CHRONICLE): an open-label safety trial

Background: Chronic cluster headache is an uncommon but highly debilitating primary headache disorder characterised by excruciating head pain recurring in daily attacks and without remission periods longer than 3 months. Treatment is challenging due to the few strategies available. Eptinezumab, approved for migraine prevention, is a humanised monoclonal antibody that targets calcitonin gene-related peptide, which has been implicated in the pathophysiology of cluster headaches. The CHRONICLE trial evaluated the long-term safety and efficacy of eptinezumab for the treatment of chronic cluster headache. Methods: CHRONICLE was a 60-week, open-label, fixed-dose trial conducted in 28 specialist headache centres in nine countries (Denmark, Finland, France, Germany, Italy, Netherlands, Spain, the UK, and the USA). Participants were aged 18–75 years with a diagnosis of chronic cluster headache according to the International Classification of Headache Disorders, 3rd edition. Eptinezumab 400 mg was administered intravenously every 12 weeks. The primary objective was to evaluate the long-term safety and tolerability of eptinezumab by assessing treatment-emergent adverse events. The efficacy of eptinezumab was assessed by attack frequency, pain severity, and patient-reported outcomes. CHRONICLE is registered on ClinicalTrials.gov (NCT05064397) and EudraCT (2020–001968–28) and is completed. Findings: From Sept 17, 2021, to June 29, 2023, 131 participants were enrolled and treated, of whom 108 (82%) completed the trial. The participants were primarily male (n=84 [64%]), with a mean age of 45·2 years (SD 10·8), and a mean time since diagnosis of 7·3 years (5·8). Treatment-emergent adverse events were reported in 106 participants (81%), with few leading to treatment withdrawal (four participants) or infusion interruption (one participant). The three most common treatment-emergent adverse events were COVID-19 (n=29; 22%), nasopharyngitis (n=24; 18%), and fatigue (n=23; 18%, most commonly on the first day of infusion). There were no treatment-related serious adverse events and no deaths during the trial. Consistent improvements in attack frequency, pain severity, and patient-reported outcomes were observed. Interpretation: Eptinezumab was generally well tolerated in participants with chronic cluster headache, with a similar safety profile as previously seen in participants with migraine. Although clinical efficacy over 12 months was observed, randomised controlled trials (when feasible) or trials with an innovative design are needed to confirm the clinical relevance of these observations. Funding: H Lundbeck A/S.