CHRONICLE
(2025)Objective
To evaluate the long-term safety, tolerability, and efficacy of eptinezumab 400 mg IV every 12 weeks over 60 weeks in adults with chronic cluster headache.
Study Summary
• Monthly cluster headache attacks decreased from a baseline of ~71.6/month by a mean of -16.6 in month 1 and -22.7 over months 1-12, sustained throughout the 48-week treatment period.
• 50% or more responder rate increased from 29% at month 1 to 52% at month 12; 30% or more responder rate went from 41% to 63%.
• 55% of participants rated themselves as 'much improved' or 'very much improved' on global impression of change at week 48; improvements in QoL, sleep, and work productivity were also sustained.
Intervention
Eptinezumab 400 mg IV every 12 weeks x 4 infusions (weeks 0, 12, 24, 36) with 8-week safety follow-up
Inclusion Criteria
Adults 18-75 years with chronic cluster headache per ICHD-3, onset at or before age 50, history of chronic cluster headache for at least 12 months, prospective documentation of 14 or more attacks per week during screening
Study Design
Arms: Eptinezumab 400 mg IV every 12 weeks (n=131) -- single-arm open-label trial (no placebo comparator)
Patients per Arm: 131 (single arm); 108 (82%) completed 60-week trial
Outcome
• Efficacy (secondary): Mean monthly attacks reduced by -16.6 at month 1 and sustained at -22.7 over months 1-12 (baseline ~71.6/month).
• Responder rates (>=50% reduction): 29% at month 1 rising to 52% at month 12; open-label design without comparator limits interpretation.
Bottom Line
Eptinezumab 400 mg IV every 12 weeks was well tolerated over 60 weeks in chronic cluster headache, with no treatment-related serious adverse events, low discontinuation rates, and sustained reductions in attack frequency and improvements in patient-reported outcomes. However, the open-label single-arm design without a control group limits conclusions about clinical efficacy, and randomized controlled trials are needed.
Major Points
- Eptinezumab 400 mg IV every 12 weeks was well tolerated over 1 year: 81% had at least one TEAE but only 3% withdrew and there were no treatment-related serious adverse events.
- Most TEAEs were mild-to-moderate; most common were COVID-19 (22%), nasopharyngitis (18%), and fatigue (18%) -- largely consistent with the expected infection-related background.
- Monthly cluster headache attacks decreased from ~71.6 at baseline by a mean of -16.6 in month 1, sustained at -22.7 over the full 12 months.
- 50% or more responder rate improved from 29% at month 1 to 52% at month 12, and 30% or more responders went from 41% to 63%.
- 55% of participants felt 'much' or 'very much improved' at week 48; improvements sustained in sleep, QoL, work productivity, and abortive medication use.
- 7/131 (5%) converted from chronic to episodic cluster headache during the trial.
- This is the largest prospective long-term dataset in chronic cluster headache; however, the absence of a control arm means efficacy results cannot be definitively attributed to drug effect -- placebo response in cluster headache trials can be substantial.
- Randomized controlled trials (when feasible) or innovative trial designs are needed to confirm clinical relevance of these findings.
Study Design
- Study Type
- Multicenter, single-arm, open-label, fixed-dose safety trial
- Randomization
- No
- Blinding
- None (open-label)
- Sample Size
- 131
- Follow-up
- 60 weeks total (48-week treatment + 8-week safety follow-up)
- Centers
- 28
- Countries
- Denmark, Finland, France, Germany, Italy, Netherlands, Spain, UK, USA
Primary Outcome
Definition: Long-term safety and tolerability: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory tests, vital signs, weight, BMI, ECG, Columbia-Suicide Severity Rating Scale
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| N/A (single arm) | 106/131 (81%) had TEAEs; 11 (8%) had SAEs; 4 (3%) withdrew due to TEAEs; 0 deaths; no treatment-related SAEs | - | N/A (descriptive) |
Limitations & Criticisms
- Single-arm open-label design without a placebo comparator -- cannot attribute efficacy to drug vs. natural history or placebo effect
- Placebo response in cluster headache trials can be substantial, as acknowledged by the authors
- 62% of participants had prior preventive treatment failures, which may reduce placebo susceptibility but also reduce generalizability
- Participants withdrew primarily for lack of efficacy (12/23) -- those who continued may represent a selected responder population, biasing month 12 efficacy estimates upward
- Relatively small population (n=131) for a rare disease; single assessor bias cannot be excluded in patient-reported outcomes
- 97% of participants were European, limiting generalizability to other populations
- Adherence to ICH E1 safety guidelines was the primary driver of sample size, not statistical power for efficacy
Citation
Lancet Neurol. 2025;24:429-440