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Galcanezumab Cluster

Trial of Galcanezumab in Prevention of Episodic Cluster Headache

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Year of Publication: 2019

Authors: Goadsby PJ, Dodick DW, Leone M, ..., Martinez JM

Journal: New England Journal of Medicine

Citation: N Engl J Med 2019;381(2):132-141

Link: https://doi.org/10.1056/NEJMoa1813440

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1813440

Clinical Question

Does galcanezumab reduce cluster headache attack frequency in patients with episodic cluster headache?

Bottom Line

In episodic cluster headache, galcanezumab 300 mg monthly reduced the weekly frequency of attacks by 3.5 attacks more than placebo across weeks 1–3 (p=0.04), with 71% vs 53% achieving ≥50% reduction at week 3. This was the first CGRP pathway antibody to show significant efficacy in cluster headache and led to FDA approval for episodic cluster prevention.

        Major Points
        Phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 35 sites in North America, Europe, and Israel
106 adults (49 galcanezumab, 57 placebo) with episodic cluster headache (ICHD-3) enrolled during an active cluster period
Galcanezumab 300 mg or placebo given subcutaneously at baseline and at 1 month (two doses total)
Primary endpoint: mean change from baseline in weekly cluster headache attacks across weeks 1–3
Secondary endpoints: ≥50% reduction at week 3 and safety
Baseline mean attacks per week: 17.8±10.1 (galcanezumab) and 17.3±10.1 (placebo) — severely affected population
Primary result: mean reduction −8.7 (galcanezumab) vs −5.2 (placebo); difference 3.5 attacks/wk (95% CI 0.2–6.7; p=0.04)
Key secondary: 71% (galcanezumab) vs 53% (placebo) achieved ≥50% reduction at week 3
Onset of benefit observed at week 1 and sustained through week 3
Safety: injection-site reactions more frequent with galcanezumab; no significant hepatotoxicity, anaphylaxis, or cardiovascular events during the short trial
Led to FDA approval in 2019 for prevention of episodic cluster headache in adults — the first CGRP pathway mAb approved in cluster

      

Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind (patients, investigators, sponsor)

Enrollment Period: 2016-2017

Follow-up Duration: 8-week double-blind period + 8-week follow-up

Centers: 35

Countries: USA, Canada, Europe, Israel

Sample Size: 106

Analyzed: 106

Analysis: Modified intention-to-treat; mixed model repeated measures

Inclusion Criteria

Age 18-65
Episodic cluster headache (ICHD-3 diagnosis)
In active cluster period at baseline
≥1 attack every other day and ≥4 total attacks during prospective baseline
≤8 attacks per day
History of cluster periods lasting ≥6 weeks

Exclusion Criteria

Chronic cluster headache
Other primary headache disorder
Medication overuse
Recent use of CGRP-pathway antibodies
Pregnancy

Arms

Field	Control	Galcanezumab 300 mg
N	57	49
Intervention	Matching placebo subcutaneously at baseline and month 1	Galcanezumab 300 mg subcutaneously at baseline and month 1
Duration	8 weeks	8 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Mean change from baseline in weekly frequency of cluster headache attacks averaged across weeks 1 through 3 after the first dose	Primary	-5.2 attacks/week	-8.7 attacks/week	p=0.04
≥50% reduction from baseline in weekly attack frequency at week 3 (key secondary)	Secondary	53% (placebo)	71% (galcanezumab)	Statistically significant
Baseline mean weekly attack frequency	Secondary	17.3±10.1 attacks/week	17.8±10.1 attacks/week	Balanced between arms
Onset of treatment effect	Secondary	Gradual improvement	Benefit apparent from week 1	Early separation of curves
Attack-free status at week 3 (exploratory)	Secondary	Uncommon	Numerically higher with galcanezumab	Not formally tested
Any adverse event	Adverse	~80%	~82%	Similar across arms
Injection-site reactions (pain, erythema, pruritus)	Adverse	~3%	~8%	More frequent with galcanezumab
Nasopharyngitis	Adverse	~7%	~8%	Similar
Upper respiratory tract infection	Adverse	~5%	~6%	Similar
Serious adverse events	Adverse	Rare	Rare	No attributable SAEs
Hepatotoxicity	Adverse	None observed	None observed	Not applicable
Cardiovascular events	Adverse	None observed	None observed during short trial	Not applicable
Discontinuation due to AE	Adverse	Uncommon	Uncommon	Similar low rates

Subgroup Analysis

Effect of galcanezumab was consistent across prespecified subgroups by age, sex, baseline attack frequency, and prior preventive use. The companion chronic cluster headache trial (Dodick 2020) was NEGATIVE — galcanezumab's efficacy in episodic cluster does NOT extend to chronic cluster, highlighting a meaningful biological difference between these two cluster phenotypes.

Criticisms

Small sample size (N=106), particularly in the galcanezumab arm (49)
Short 8-week double-blind period does not assess prevention across an entire cluster bout
Placebo response was substantial (-5.2 attacks/week), reducing absolute effect size
Did not compare against active preventive therapy (verapamil)
Follow-up CHRONIC cluster trial (Dodick 2020) was NEGATIVE, highlighting differential biology between episodic and chronic forms

Funding

Eli Lilly (manufacturer of galcanezumab)

Based on: Galcanezumab Cluster (New England Journal of Medicine, 2019)

Authors: Goadsby PJ, Dodick DW, Leone M, ..., Martinez JM

Citation: N Engl J Med 2019;381(2):132-141

Content summarized and formatted by NeuroTrials.ai.

Galcanezumab Cluster

(2019)

Objective

Galcanezumab 300 mg monthly SC — to evaluate efficacy and safety of a CGRP-pathway monoclonal antibody for the prevention of episodic cluster headache.

Study Summary

• Galcanezumab 300 mg monthly cut cluster attack frequency by 3.5 more attacks per week than placebo across weeks 1–3 (mean −8.7 vs −5.2; 95% CI 0.2–6.7; p=0.04) in patients with episodic cluster headache.
• At week 3, 71% of galcanezumab patients achieved ≥50% attack reduction vs 53% on placebo — a clinically meaningful near-doubling of rapid response.
• This was the first CGRP-pathway monoclonal antibody to show positive Class I evidence in cluster headache and set the stage for galcanezumab's FDA approval for episodic cluster prevention.

Intervention

Galcanezumab 300 mg subcutaneously at baseline and month 1 (two doses total) versus matching placebo.

Inclusion Criteria

Adults 18–65 years with episodic cluster headache (ICHD-3), at least one attack every other day, ≥4 total attacks, ≤8 attacks per day during baseline, cluster periods lasting ≥6 weeks.

Study Design

Arms: Galcanezumab 300 mg monthly vs Placebo

Patients per Arm: Galcanezumab 49; Placebo 57

Outcome

• Primary: Mean change in weekly cluster attacks across weeks 1–3: −8.7 (galcanezumab) vs −5.2 (placebo); difference 3.5 attacks/wk (95% CI 0.2–6.7; p=0.04)
• Key secondary: ≥50% reduction at week 3: 71% (galcanezumab) vs 53% (placebo)
• Safety: injection-site reactions more common with galcanezumab; no significant hepatotoxicity or cardiovascular events
• Baseline mean attacks/week ~17 in both arms (severe cluster population)

Clinical Question

Does galcanezumab, a humanized monoclonal antibody against CGRP, reduce cluster headache attack frequency in patients with episodic cluster headache?

Bottom Line

Major Points

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 35 sites in North America, Europe, and Israel
106 adults (49 galcanezumab, 57 placebo) with episodic cluster headache (ICHD-3) enrolled during an active cluster period
Galcanezumab 300 mg or placebo given subcutaneously at baseline and at 1 month (two doses total)
Primary endpoint: mean change from baseline in weekly cluster headache attacks across weeks 1–3
Secondary endpoints: ≥50% reduction at week 3 and safety
Baseline mean attacks per week: 17.8±10.1 (galcanezumab) and 17.3±10.1 (placebo) — severely affected population
Primary result: mean reduction −8.7 (galcanezumab) vs −5.2 (placebo); difference 3.5 attacks/wk (95% CI 0.2–6.7; p=0.04)
Key secondary: 71% (galcanezumab) vs 53% (placebo) achieved ≥50% reduction at week 3
Onset of benefit observed at week 1 and sustained through week 3
Safety: injection-site reactions more frequent with galcanezumab; no significant hepatotoxicity, anaphylaxis, or cardiovascular events during the short trial
Led to FDA approval in 2019 for prevention of episodic cluster headache in adults — the first CGRP pathway mAb approved in cluster

Study Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind (patients, investigators, sponsor)
Sample Size: 106
Follow-up: 8-week double-blind period + 8-week follow-up
Centers: 35
Countries: USA, Canada, Europe, Israel

Primary Outcome

Definition: Mean change from baseline in weekly frequency of cluster headache attacks averaged across weeks 1 through 3 after the first dose

Control	Intervention	HR/OR	P-value
-5.2 attacks/week	-8.7 attacks/week	- (Difference 3.5 attacks/week (95% CI 0.2 to 6.7))	p=0.04

Limitations & Criticisms

Small sample size (N=106), particularly in the galcanezumab arm (49)
Short 8-week double-blind period does not assess prevention across an entire cluster bout
Placebo response was substantial (-5.2 attacks/week), reducing absolute effect size
Did not compare against active preventive therapy (verapamil)
Follow-up CHRONIC cluster trial (Dodick 2020) was NEGATIVE, highlighting differential biology between episodic and chronic forms

Citation

N Engl J Med 2019;381(2):132-141

View Original Publication →

Galcanezumab Cluster

Trial of Galcanezumab in Prevention of Episodic Cluster Headache

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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