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CHRONICLE

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

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Year of Publication: 2025

Authors: Tassorelli C, Jensen RH, Goadsby PJ, ..., Boneva N

Journal: Lancet Neurology

Citation: Lancet Neurol. 2025;24:429-440

Link: https://doi.org/10.1016/S1474-4422(25)00065-1

Clinical Question

Is eptinezumab 400 mg IV every 12 weeks safe, tolerable, and effective for long-term prevention of chronic cluster headache?

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.

      

Design

Study Type: Multicenter, single-arm, open-label, fixed-dose safety trial

Randomization:

Blinding: None (open-label)

Allocation: Single arm

Enrollment Period: September 17, 2021 – June 29, 2023

Follow-up Duration: 60 weeks total (4-week screening + 48-week treatment + 8-week safety follow-up)

Centers: 28

Countries: Denmark, Finland, France, Germany, Italy, Netherlands, Spain, UK, USA

Sample Size: 131

Analyzed: 131

Analysis: Mixed model for repeated measures (MMRM); summary statistics for safety

Power Calculation: Sample size chosen to provide 100 participants exposed for 1 year per ICH E1 guidelines for long-term safety database

Registration: NCT05064397; EudraCT 2020-001968-28

Inclusion Criteria

Age 18-75 years
Chronic cluster headache per ICHD-3 criteria
Onset of cluster headache at or before age 50
History of chronic cluster headache for at least 12 months before screening
Adequate documentation of previous abortive, transitional, and preventive medications for cluster headache for 12 months or more before screening
Prospective documentation of 14 or more cluster headache attacks during the 4-week screening period
Diary compliance: entering data for 24 or more days out of 28 during the screening period
Ability to distinguish cluster attacks from other headache types

Exclusion Criteria

Confounding pain syndromes (fibromyalgia, complex regional pain syndrome)
History of chronic paroxysmal hemicrania, chronic tension-type headache, hemicrania continua, or NDPH
Neurological disorder or systemic disease likely to affect CNS function
Clinically significant cardiovascular disease, uncontrolled hypertension, vascular ischaemia, or thromboembolic events
Prior anti-CGRP therapy within 5 half-lives (monoclonal antibodies) or 1 month (gepants)
Participation in a clinical trial within 30 days or having taken any investigational products within five half-lives (whichever was longer) before screening

Baseline Characteristics

Eptinezumab (N=131):

Male, %: 64%
Female, %: 36%
Age, mean (SD), years: 45.2 (10.8)
Age range, years: 20-70
Region Europe, %: 97%
Region USA, %: 3%
Time since cluster headache diagnosis, mean (SD), years: 7.3 (5.8)
Time since first cluster headache symptoms, mean (SD), years: 13.5 (9.6)
Always chronic, %: 52%
Transition from episodic to chronic, %: 45%
Duration of cluster headache attack, mean (SD), min: 71.2 (51.7)
Pain at worst -- Excruciating, %: 60%
Pain at worst -- Severe, %: 36%
Pain at worst -- Moderate, %: 5%
Prior verapamil, %: 47%
Prior topiramate, %: 30%
Prior lithium, %: 25%
Prior valproate, %: 11%
Attacks per week at baseline, mean (SD): 17.9 (16.7)
Abortive medication use per week, mean (SD): 14.5 (18.8)
Oxygen use per week, mean (SD): 7.2 (14.8)
Pain per attack, mean (SD): 2.6 (0.67)
Average daily pain, mean (SD): 2.3 (0.78)
Prior preventive treatment failure -- 0, %: 38%
Prior preventive treatment failure -- 1, %: 16%
Prior preventive treatment failure -- 2+, %: 46%

Arms

Field	Eptinezumab
N	131
Intervention	Eptinezumab 400 mg (four vials of 100 mg/mL) in 100 mL of 0.9% saline administered intravenously over 45 min (60 min if needed) at weeks 0, 12, 24, and 36
Duration	48 weeks (4 infusions every 12 weeks) plus 8-week safety follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
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	Primary	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	N/A (descriptive)
Change from baseline in number of monthly cluster headache attacks -- month 1	Secondary	N/A	-16.6 (SE 3.2)
Change from baseline in number of monthly cluster headache attacks -- month 12	Secondary	N/A	-19.2 (SE 4.9)
Change from baseline in number of monthly cluster headache attacks -- months 1-12 (overall)	Secondary	N/A	-22.7 (SE 4.4)
>=30% reduction in monthly attacks (responder rate) -- month 1	Secondary	N/A	51/125 (41%)
>=30% reduction in monthly attacks (responder rate) -- month 12	Secondary	N/A	53/84 (63%)
>=50% reduction in monthly attacks (responder rate) -- month 1	Secondary	N/A	36/125 (29%)
>=50% reduction in monthly attacks (responder rate) -- month 12	Secondary	N/A	44/84 (52%)
>=75% reduction in monthly attacks -- month 12	Secondary	N/A	27/84 (32%)
PGIC 'much improved' or 'very much improved'	Secondary	N/A	41% (week 4); 55% (week 48)
Conversion from chronic to episodic cluster headache	Secondary	N/A	7/131 (5%)
Abortive therapy use (times per month) -- month 12	Secondary	N/A	-18.5 (SE 3.3) change from baseline
EQ-5D-5L visual analogue scale -- week 48	Secondary	N/A	+6.9 (SE 2.3) change from baseline
Any treatment-emergent adverse event	Safety	N/A	106/131 (81%)
Serious adverse event	Safety	N/A	11/131 (8%); none considered possibly or probably related to treatment
Withdrawal due to TEAE	Safety	N/A	4/131 (3%)
Death	Safety	N/A	0
Treatment-related serious adverse event	Safety	N/A	0
Suicidal ideation or behavior after baseline (Columbia-SSRS)	Safety	N/A	13 participants (including 4 who reported it as an adverse event); of whom 9 had suicidal ideation or behaviour at screening or baseline
COVID-19	Adverse	N/A	29 (22%)
Nasopharyngitis	Adverse	N/A	24 (18%)
Fatigue	Adverse	N/A	23 (18%)
Back pain	Adverse	N/A	10 (8%)
Influenza	Adverse	N/A	10 (8%)
Pruritus	Adverse	N/A	9 (7%)
Insomnia	Adverse	N/A	8 (6%)
Nausea	Adverse	N/A	8 (6%)
Weight increase	Adverse	N/A	8 (6%)
Dizziness	Adverse	N/A	7 (5%)
Vomiting	Adverse	N/A	7 (5%)

Subgroup Analysis

No formal subgroup analyses reported. Efficacy outcomes were consistent across the 48-week treatment period with responder rates increasing from month 1 through month 2 then plateauing. Subgroup data by sex showed some differences in specific AE types (female participants reported fatigue, influenza, nausea, weight gain, dizziness, and vomiting more than twice as often as males; males reported back pain and rhinitis more than twice as often).

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

Funding

H Lundbeck A/S (sponsor and partial funder of medical writing)

Based on: CHRONICLE (Lancet Neurology, 2025)

Authors: Tassorelli C, Jensen RH, Goadsby PJ, ..., Boneva N

Citation: Lancet Neurol. 2025;24:429-440

Content summarized and formatted by NeuroTrials.ai.

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

• Eptinezumab was well tolerated: 81% had at least one TEAE (mostly mild/moderate), only 3% withdrew due to TEAEs, and there were no treatment-related serious adverse events and no deaths.
• 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 before screening, adequate documentation of previous abortive, transitional, and preventive medications for 12 months or more, prospective documentation of 14 or more cluster headache attacks during the 4-week screening period with diary compliance of 24 or more days out of 28

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

• Safety (primary): 81% had TEAEs; 8% had SAEs; no treatment-related SAEs; 3% withdrew due to TEAEs; 0 deaths -- well tolerated safety profile over 1 year.
• 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

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 (4-week screening + 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

View Original Publication →

CHRONICLE

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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