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REGAIN MO

Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine

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Year of Publication: 2021

Authors: Virginia L Stauffer, Jakub Jedynak, Yan Dong, Eric M Pearlman

Journal: Cephalalgia

Citation: Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Cephalalgia. 2021.

Link: https://doi.org/10.1177/0333102420966658

Clinical Question

Is galcanezumab effective for migraine prevention in patients with episodic or chronic migraine who overuse acute headache medications?

Bottom Line

Galcanezumab 120 mg and 240 mg monthly are effective for preventive treatment of both episodic and chronic migraine in patients with baseline acute medication overuse, significantly reducing monthly migraine headache days and rates of medication overuse compared with placebo.

        Major Points
        Subgroup analysis of three phase 3 RCTs: EVOLVE-1 and EVOLVE-2 (episodic migraine; pooled, post hoc) and REGAIN (chronic migraine; a priori stratified).
Baseline medication overuse prevalence was 17.3–19.4% across EVOLVE arms and 63.4–64.3% across REGAIN arms.
In EVOLVE pooled patients with MO, overall LS mean change in monthly migraine headache days was −2.7 (placebo), −6.3 (galcanezumab 120 mg), and −5.8 (galcanezumab 240 mg); both doses p < 0.001 vs placebo.
In EVOLVE patients without MO, LS mean changes were −2.5 (placebo), −4.1 (120 mg), −4.0 (240 mg); both doses p < 0.001 vs placebo.
Treatment-by-subgroup interaction (MO yes vs no) was significant in EVOLVE (p < 0.001 for 120 mg; p = 0.001 for 240 mg), suggesting larger absolute benefit in patients with medication overuse.
In both episodic and chronic migraine populations with baseline MO, galcanezumab 120 mg and 240 mg significantly reduced average monthly medication overuse rates vs placebo (p < 0.001).
Galcanezumab appears effective for preventive treatment of migraine in patients who overuse acute medications, even without a structured withdrawal program.

      

Design

Study Type: Subgroup analysis of three phase 3, double-blind, randomized, placebo-controlled trials (EVOLVE-1, EVOLVE-2, REGAIN)

Randomization: 1

Blinding: Double-blind

Allocation: 2:1:1 to placebo : galcanezumab 120 mg : galcanezumab 240 mg

Follow-up Duration: 6 months (EVOLVE-1/-2); 3 months (REGAIN)

Centers: 0

Countries: North America, Europe, Other

Sample Size: 1042

Analyzed: 1042

Analysis: Linear mixed model with repeated measures for continuous endpoints (change in monthly migraine headache days, change in monthly migraine headache days with acute medication use). Generalized linear mixed model with logit link for binary endpoints (≥50% reduction in MMHD; medication overuse after randomization). Treatment-by-subgroup interaction terms used for cross-subgroup comparison. Two-sided alpha = 0.05.

Registration: ClinicalTrials.gov NCT02614183, NCT02614196, NCT02614261

Inclusion Criteria

Adults meeting EVOLVE-1/-2 criteria: episodic migraine with 4–14 monthly migraine headache days
Adults meeting REGAIN criteria: chronic migraine with ≥15 monthly headache days, ≥8 of which had migraine features, for >3 months
Provided written informed consent
Subgroup-of-interest: met IHS-based definition of baseline medication overuse during the 30-day prospective baseline (e.g., triptans ≥10 days/month, NSAIDs/aspirin ≥15 days/month, acetaminophen ≥15 days/month, ergots ≥10 days/month, combination drugs ≥10 days/month, or ≥10 total days from ≥2 categories)

Exclusion Criteria

Patients with a diagnosis of medication overuse headache in the 3 months preceding screening were excluded from EVOLVE-1 and EVOLVE-2 (but not from REGAIN)
Use of opioids for acute treatment of headache more than 3 days per month during the original studies

Arms

Field	Control	Galcanezumab 120 mg (EVOLVE-1/-2, MO subgroup)	Galcanezumab 240 mg (EVOLVE-1/-2, MO subgroup)	Control	Galcanezumab 120 mg (REGAIN, MO subgroup)	Galcanezumab 240 mg (REGAIN, MO subgroup)
N	173	77	84	353	178	177
Intervention	Monthly subcutaneous placebo for 6 months	Monthly subcutaneous galcanezumab 120 mg	Monthly subcutaneous galcanezumab 240 mg	Monthly subcutaneous placebo for 3 months	Monthly subcutaneous galcanezumab 120 mg	Monthly subcutaneous galcanezumab 240 mg
Duration	6 months	6 months	6 months	3 months	3 months	3 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Overall least squares mean change from baseline in the number of monthly migraine headache days in patients with baseline medication overuse	Primary	EVOLVE pooled placebo (MO subgroup): −2.7 (SE 0.5)	EVOLVE pooled galcanezumab 120 mg (MO): −6.3 (SE 0.6); galcanezumab 240 mg (MO): −5.8 (SE 0.6)	p < 0.001 for both galcanezumab 120 mg and 240 mg vs placebo (in both MO and non-MO subgroups, EVOLVE pooled); p ≤ 0.001 for both doses vs placebo in REGAIN MO subgroup
	Secondary	Placebo −2.5 (SE 0.2)	Galcanezumab 120 mg −4.1 (SE 0.2); galcanezumab 240 mg −4.0 (SE 0.2)	p < 0.001 for both doses vs placebo
	Secondary			p < 0.001 for galcanezumab 120 mg; p = 0.001 for galcanezumab 240 mg
	Secondary		Both galcanezumab doses reduced monthly medication overuse rates vs placebo in both episodic and chronic migraine populations	p < 0.001 for each dose vs placebo
	Secondary		Analyzed via generalized linear mixed model with logit link; results presented as odds ratios with 95% CIs (specific values not provided in the source excerpt)

Subgroup Analysis

Pre-specified stratification by acute headache medication overuse (yes/no) was a priori in REGAIN; subgroup analysis in EVOLVE-1/-2 was post hoc with pooled data. Treatment-by-subgroup interactions were significant in EVOLVE (p < 0.001 for 120 mg; p = 0.001 for 240 mg), suggesting larger absolute reductions in MMHD among medication-overusing patients. Status change from baseline medication overuse to non-overuse was descriptively summarized by acute medication category (NSAIDs/aspirin, triptans, multiple drugs).

Criticisms

Subgroup analysis in EVOLVE-1/-2 was post hoc; only REGAIN had a priori stratification by medication overuse.
Patients with formal diagnosis of medication overuse headache in the 3 months before screening were excluded from EVOLVE, limiting generalizability of episodic-migraine findings to confirmed MOH patients.
Short follow-up (3 months in REGAIN; 6 months in EVOLVE) limits assessment of durability and impact on long-term medication overuse behavior.
Different durations and pooling approaches between episodic (EVOLVE) and chronic (REGAIN) cohorts complicate cross-population comparisons.
Small sample sizes in EVOLVE galcanezumab arms with medication overuse (n=77 and n=84) reduce precision of subgroup estimates.

Based on: REGAIN MO (Cephalalgia, 2021)

Authors: Virginia L Stauffer, Jakub Jedynak, Yan Dong, Eric M Pearlman

Citation: Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Cephalalgia. 2021.

Content summarized and formatted by NeuroTrials.ai.

REGAIN MO

(2021)

Objective

To evaluate whether galcanezumab is effective for preventive treatment of episodic and chronic migraine in patients with baseline acute medication overuse, via subgroup analysis of three phase 3 placebo-controlled trials (EVOLVE-1, EVOLVE-2, REGAIN).

Study Summary

• Both galcanezumab doses (120 mg and 240 mg) significantly reduced monthly migraine headache days vs placebo in patients with baseline medication overuse (p ≤ 0.001)
• EVOLVE-1/-2 (episodic migraine) overall LS mean change in MMHD: placebo −2.7, galcanezumab 120 mg −6.3, galcanezumab 240 mg −5.8
• Treatment-by-subgroup interaction (medication overuse yes vs no) was significant in EVOLVE pooled analysis (p < 0.001 for 120 mg; p = 0.001 for 240 mg)
• Both galcanezumab doses reduced average monthly medication overuse rates vs placebo (p < 0.001) in both episodic and chronic migraine populations
• Baseline medication overuse prevalence: ~17–19% in EVOLVE-1/-2, ~63–64% in REGAIN

Intervention

Monthly subcutaneous galcanezumab 120 mg or 240 mg vs placebo for 6 months (EVOLVE-1/-2) or 3 months (REGAIN).

Inclusion Criteria

Adults with episodic migraine (4–14 monthly migraine headache days; EVOLVE-1/-2) or chronic migraine (≥15 monthly headache days with ≥8 migraine features for >3 months; REGAIN). Subgroup defined by baseline acute medication overuse per IHS criteria.

Study Design

Arms: Placebo (EVOLVE n=173 MO; REGAIN n=353 MO) vs Galcanezumab 120 mg SC monthly (EVOLVE n=77 MO; REGAIN n=178 MO) vs Galcanezumab 240 mg SC monthly (EVOLVE n=84 MO; REGAIN n=177 MO)

Patients per Arm: EVOLVE-1/-2 with MO: PBO 173 / GMB120 77 / GMB240 84; REGAIN with MO: PBO 353 / GMB120 178 / GMB240 177

Outcome

• In EVOLVE pooled MO subgroup, LS mean change in MMHD: placebo −2.7, galcanezumab 120 mg −6.3, galcanezumab 240 mg −5.8 (both p < 0.001 vs placebo)
• In EVOLVE patients without MO: placebo −2.5, galcanezumab 120 mg −4.1, galcanezumab 240 mg −4.0 (both p < 0.001 vs placebo)
• Both galcanezumab doses significantly reduced monthly medication overuse rates vs placebo (p < 0.001) in both episodic and chronic migraine
• Significant treatment-by-MO subgroup interaction in EVOLVE (p < 0.001 for 120 mg, p = 0.001 for 240 mg) suggesting greater benefit in MO subgroup

Bottom Line

Major Points

Subgroup analysis of three phase 3 RCTs: EVOLVE-1 and EVOLVE-2 (episodic migraine; pooled, post hoc) and REGAIN (chronic migraine; a priori stratified).
Baseline medication overuse prevalence was 17.3–19.4% across EVOLVE arms and 63.4–64.3% across REGAIN arms.
In EVOLVE pooled patients with MO, overall LS mean change in monthly migraine headache days was −2.7 (placebo), −6.3 (galcanezumab 120 mg), and −5.8 (galcanezumab 240 mg); both doses p < 0.001 vs placebo.
In EVOLVE patients without MO, LS mean changes were −2.5 (placebo), −4.1 (120 mg), −4.0 (240 mg); both doses p < 0.001 vs placebo.
Treatment-by-subgroup interaction (MO yes vs no) was significant in EVOLVE (p < 0.001 for 120 mg; p = 0.001 for 240 mg), suggesting larger absolute benefit in patients with medication overuse.
In both episodic and chronic migraine populations with baseline MO, galcanezumab 120 mg and 240 mg significantly reduced average monthly medication overuse rates vs placebo (p < 0.001).
Galcanezumab appears effective for preventive treatment of migraine in patients who overuse acute medications, even without a structured withdrawal program.

Study Design

Study Type: Subgroup analysis of three phase 3, double-blind, randomized, placebo-controlled trials (EVOLVE-1, EVOLVE-2, REGAIN)
Randomization: Yes
Blinding: Double-blind
Sample Size: 1042
Follow-up: 6 months (EVOLVE-1/-2); 3 months (REGAIN)
Countries: North America, Europe, Other

Primary Outcome

Definition: Overall least squares mean change from baseline in the number of monthly migraine headache days in patients with baseline medication overuse

Control	Intervention	HR/OR	P-value
EVOLVE pooled placebo (MO subgroup): −2.7 (SE 0.5)	EVOLVE pooled galcanezumab 120 mg (MO): −6.3 (SE 0.6); galcanezumab 240 mg (MO): −5.8 (SE 0.6)	-	p < 0.001 for both galcanezumab 120 mg and 240 mg vs placebo (in both MO and non-MO subgroups, EVOLVE pooled); p ≤ 0.001 for both doses vs placebo in REGAIN MO subgroup

Limitations & Criticisms

Subgroup analysis in EVOLVE-1/-2 was post hoc; only REGAIN had a priori stratification by medication overuse.
Patients with formal diagnosis of medication overuse headache in the 3 months before screening were excluded from EVOLVE, limiting generalizability of episodic-migraine findings to confirmed MOH patients.
Short follow-up (3 months in REGAIN; 6 months in EVOLVE) limits assessment of durability and impact on long-term medication overuse behavior.
Different durations and pooling approaches between episodic (EVOLVE) and chronic (REGAIN) cohorts complicate cross-population comparisons.
Small sample sizes in EVOLVE galcanezumab arms with medication overuse (n=77 and n=84) reduce precision of subgroup estimates.

Citation

Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Cephalalgia. 2021.

View Original Publication →

REGAIN MO

Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Ask about REGAIN MO