PDF: EVOLVE-1
(2018)Objective
Galcanezumab - to evaluate the efficacy and safety of galcanezumab compared with placebo for the prevention of episodic migraine.
Study Summary
• Over 60% of treated patients achieved ≥50% response.
• Functional outcomes and migraine-related disability significantly improved.
• Low discontinuation rates and favorable tolerability profile.
Intervention
Phase 3, double-blind, randomized controlled trial across 90 North American centers. Adults with episodic migraine (4–14 migraine days/month) were randomized 2:1:1 to monthly placebo, galcanezumab 120 mg, or galcanezumab 240 mg subcutaneously for 6 months. No concurrent preventive treatments were allowed. Outcome measures included monthly migraine headache days (MHDs), acute medication use, and patient-reported outcomes (MSQ, MIDAS, PGI-S).
Inclusion Criteria
Adults (18–65 years) with ≥1 year of migraine history, 4–14 migraine headache days per month, and at least 2 migraine attacks/month. Diagnosed before age 50 and not currently on preventive therapy.
Study Design
Arms: Placebo, Galcanezumab 120 mg, Galcanezumab 240 mg
Patients per Arm: Placebo: 433, 120 mg: 213, 240 mg: 212
Outcome
• ≥50% response: 38.6% (placebo) vs. 62.3% (120 mg) and 60.9% (240 mg); OR ~2.6; P<0.001
• ≥75% response: 19.3% vs. 38.8% and 38.5%; OR ~2.7; P<0.001
• 100% response: 6.2% vs. 15.6% and 14.6%; P<0.001
• MSQ role-function-restrictive scores improved significantly: +7.7 (120 mg) and +7.4 (240 mg) vs. placebo
• MIDAS score improvement: –21.2 (120 mg) and –20.1 (240 mg) vs. –14.9 (placebo)
• Adverse events were mild to moderate; most common: injection site pain, erythema, pruritus
• Discontinuation due to AEs: <5% across all groups
Bottom Line
Among 858 patients with episodic migraine (4-14 MHD/month), monthly galcanezumab 120 mg and 240 mg both significantly reduced monthly migraine headache days compared to placebo (-4.7 and -4.6 days vs -2.8 days; differences of -1.9 and -1.8 days, both p<0.001) over 6 months of treatment. Response rates (≥50% reduction) were 62.3% and 60.9% vs 38.6% for placebo. Both doses also significantly improved quality of life, disability scores, and disease severity ratings. Galcanezumab demonstrated a favorable tolerability profile with 81.9% completion rate, low discontinuation due to AEs (<5%), and predominantly mild-to-moderate injection-site reactions. No clinically meaningful differences were observed between the two galcanezumab doses. The 6-month treatment benefit translates to approximately 8 additional migraine-free weeks per year
Major Points
- Phase 3, multicenter (90 sites in North America), randomized (2:1:1), double-blind, placebo-controlled trial conducted January 2016 to March 2017
- 1671 patients screened, 862 randomized, 858 received ≥1 dose and included in intent-to-treat population; 703 (81.9%) completed 6-month treatment period
- Galcanezumab is a humanized monoclonal antibody (IgG2a) that binds CGRP and prevents its biological activity without blocking the CGRP receptor
- 120 mg dose group received 240 mg loading dose at baseline (two 120 mg SC injections), then 120 mg monthly; 240 mg group received 240 mg monthly throughout
- Baseline characteristics balanced: mean age 40.7 years, 83.7% female, 80.4% white, mean 9.1 MHD/month, 5.7 migraine attacks/month, 60.6 headache hours/month
- Mean duration of migraine 20.1 years; 60% had prior preventive treatment, 18.5% failed ≥1 prior preventive due to lack of efficacy
- Baseline MIDAS score 33.2 indicating severe disability; mean MSQ RF-R 51.0, PGI-S 4.4 (moderately ill)
- Primary endpoint achieved: LSM change in MHD from baseline to month 1-6 was -4.7 days (120 mg), -4.6 days (240 mg), -2.8 days (placebo); both p<0.001 vs placebo
- Rapid onset of effect: significant improvement observed at month 1 and maintained through month 6 for both doses
- ≥50% responder rates significantly higher: 62.3% (120 mg), 60.9% (240 mg) vs 38.6% (placebo); OR 2.6 and 2.5, both p<0.001
- ≥75% responder rates: 38.8% (120 mg), 38.5% (240 mg) vs 19.3% (placebo); OR 2.7 and 2.6, both p<0.001
- 100% responder rates (migraine-free): 15.6% (120 mg), 14.6% (240 mg) vs 6.2% (placebo); OR 2.8 and 2.6, both p<0.001
- Sustained ≥50% response for all 6 months: 20.5% (120 mg, p<0.001), 19.2% (240 mg, p<0.001) vs 8.9% (placebo)
- MHD with acute medication use reduced: -4.0 days (120 mg), -3.8 days (240 mg) vs -2.2 days (placebo); differences -1.8 and -1.6 days, both p<0.001
- Monthly headache hours reduced: -29.7 hours (120 mg), -29.3 hours (240 mg) vs -15.7 hours (placebo), both p<0.001
- MSQ RF-R improved by 32.4 points (120 mg) and 32.1 points (240 mg) vs 24.7 points (placebo); differences 7.7 and 7.4 points, both p<0.001
- MIDAS total score improved by -21.2 points (120 mg, p<0.001) and -20.1 points (240 mg, p<0.002) vs -14.9 points (placebo)
- PGI-S improved from moderately ill (4.0) to mildly ill (3.0), significantly better than placebo (p=0.002 and p=0.008)
- Safety: TEAEs reported in 65.5% (120 mg), 67.7% (240 mg) vs 60.4% (placebo); no statistically significant differences
- Injection-site reactions most common: pain 16-20.5%, erythema 4.1-4.9%, pruritus 4.4-4.6% (p<0.05 vs placebo for pruritus and reaction)
- Low SAE rates: 6/213 (2.8%) in 120 mg group, 0/212 in 240 mg group, 5/433 (1.2%) in placebo group; none related to study drug
- Discontinuation due to AEs: 4.2% (120 mg), 3.3% (240 mg), 2.3% (placebo); not statistically different between groups
- No meaningful differences between 120 mg and 240 mg doses on any efficacy measure
- Treatment-emergent antidrug antibodies: 3.5% (120 mg), 5.2% (240 mg) vs 1.7% (placebo); neutralizing ADA present in most
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, site personnel, and sponsor blinded to treatment assignments. Randomization via computer-generated sequence using interactive web-response system. Stratified by region (eastern US, western US, Puerto Rico, Canada) and baseline migraine frequency (<8 vs ≥8 MHD/month). Block size fixed at 3 within each stratum. Two SC injections administered at each dosing visit to maintain blinding
- Sample Size
- 858
- Follow-up
- 6-month double-blind treatment period plus 4-month post-treatment observation period (total 10 months; ~5 elimination half-lives of galcanezumab)
- Centers
- 90
- Countries
- United States, Canada, Puerto Rico
Primary Outcome
Definition: Overall mean change from baseline in the number of monthly migraine headache days (MHD) during the 6-month double-blind treatment period (months 1-6). A migraine headache was defined as headache with or without aura, lasting ≥30 minutes, with both features A (≥2 of: unilateral, pulsatile, moderate/severe intensity, aggravation by physical activity) and B (≥1 of: nausea/vomiting, photophobia and phonophobia) per ICHD-3β. Probable migraine met either A or B but not both. MHD = calendar day with migraine or probable migraine
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| LSM -2.8 days (SE 0.2); baseline 9.1 days | 120 mg: LSM -4.7 days (SE 0.3), baseline 9.2 days; 240 mg: LSM -4.6 days (SE 0.3), baseline 9.1 days | - (120 mg vs placebo: LSM difference -1.9 days (95% CI -2.5 to -1.4); 240 mg vs placebo: LSM difference -1.8 days (95% CI -2.3 to -1.2)) | Both p<0.001 vs placebo; significant after multiplicity adjustment (adjusted significance level 0.026) |
Limitations & Criticisms
- Patients were not tested to determine whether galcanezumab could be effective as adjunctive treatment concurrent with other preventive medications; concomitant preventives were excluded
- Study conducted primarily in North America (US, Canada, Puerto Rico) with predominantly white population (80%), limiting generalizability to other geographies and ethnic groups
- Patients with acute cardiovascular events and/or serious cardiovascular risk were excluded; caution needed when treating such patients as they have not been studied
- Pregnant women were excluded; insufficient human data to establish safety during pregnancy
- Excluded patients who failed ≥3 classes of preventive treatments (treatment-refractory); efficacy in more refractory populations not established in this trial
- 6-month treatment duration, while longer than Phase 2 studies (3 months), may have contributed to higher discontinuation rates compared to shorter CGRP antibody trials
- No active comparator arm; head-to-head comparison with other preventive medications or other CGRP antibodies not performed
- Loading dose (240 mg) used in 120 mg group but not compared directly to non-loading dose regimen
- 2:1:1 randomization ratio resulted in smaller active treatment groups than placebo, potentially limiting power for subgroup analyses
- Daily electronic diary required 80% compliance, may have excluded some patients and may not reflect real-world adherence patterns
- Limited opioid/barbiturate use to 3 days/month during study, which may not reflect real-world prescribing patterns
- Most preexisting conditions and comorbidities not exclusionary, but specific comorbidity subgroup analyses not reported
- Post-treatment washout period (4 months) provided safety data but durability of effect after treatment cessation not primary focus
- No cost-effectiveness analysis performed
- Baseline imbalances in age (240 mg group younger, p<0.05) and MSQ RF-R/PGI-S (240 mg group worse, p<0.01) though overall groups were comparable
Citation
JAMA Neurol. 2018;75(9):1080-1088