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(2017)Objective
To compare two dose regimens of fremanezumab (quarterly and monthly) with placebo for the preventive treatment of chronic migraine
Study Summary
• Fremanezumab significantly reduced headache days per month: -4.3 (quarterly) and -4.6 (monthly) vs -2.5 (placebo), difference approximately -2 days, both p<0.001
• ≥50% responder rate was 38% (quarterly) and 41% (monthly) vs 18% (placebo), both p<0.001
• Treatment effects observed within 4 weeks and maintained throughout 12-week period
• ≥50% responder rate was 38% (quarterly) and 41% (monthly) vs 18% (placebo), both p<0.001
• Treatment effects observed within 4 weeks and maintained throughout 12-week period
Intervention
Subcutaneous fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at weeks 4 and 8), or placebo over 12 weeks
Inclusion Criteria
Adults 18-70 years with chronic migraine per ICHD-3 beta (≥15 headache days/month with ≥8 migraine days) for ≥12 months, prospectively confirmed during 28-day baseline period
Study Design
Arms: 3 arms (1:1:1 ratio): Fremanezumab quarterly (n=376), Fremanezumab monthly (n=379), Placebo (n=375)
Patients per Arm: 376 (quarterly), 379 (monthly), 375 (placebo)
Outcome
• Primary: Significant reduction in headache days with both fremanezumab doses vs placebo (LSM difference -1.8 quarterly, -2.1 monthly, both p<0.001)
• Secondary: Reduced migraine days, higher ≥50% responder rates, decreased acute medication use, improved HIT-6 scores (all p<0.001)
• Safety: Injection-site reactions common but generally well-tolerated, low discontinuation rates
• Secondary: Reduced migraine days, higher ≥50% responder rates, decreased acute medication use, improved HIT-6 scores (all p<0.001)
• Safety: Injection-site reactions common but generally well-tolerated, low discontinuation rates
Bottom Line
In this Phase 3 trial of 1130 patients with chronic migraine, both fremanezumab dosing regimens (quarterly and monthly) demonstrated significant efficacy over placebo in reducing the average number of headache days per month by approximately 2 days (quarterly: -4.3 days, monthly: -4.6 days vs placebo: -2.5 days, both p<0.001). Both regimens also significantly reduced migraine days, increased ≥50% responder rates (38-41% vs 18%), decreased acute medication use, and improved headache-related disability. Treatment effects were apparent within 4 weeks. Injection-site reactions were common but generally well-tolerated, with low discontinuation rates. This trial established fremanezumab as an effective preventive treatment for chronic migraine targeting the migraine-specific CGRP pathway
Major Points
- Phase 3, multicenter (132 sites in 9 countries), randomized (1:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week active treatment phase
- 1130 patients randomized: 376 to fremanezumab quarterly, 379 to fremanezumab monthly, 375 to placebo; 1034 (92%) completed trial
- Baseline characteristics similar across groups: mean age 41-42 years, 87-88% female, mean 19.7-20.1 years since migraine diagnosis, mean 12.8-13.3 headache days per month
- Fremanezumab is humanized IgG2a monoclonal antibody that selectively targets both α and β isoforms of CGRP ligand, administered by subcutaneous injection
- Quarterly regimen: 675 mg at baseline (three 225 mg injections), placebo at weeks 4 and 8. Monthly regimen: 675 mg at baseline, 225 mg at weeks 4 and 8
- Primary endpoint: Mean change from baseline in average number of headache days per month (≥4 consecutive hours at ≥moderate severity OR use of acute migraine-specific medication)
- Primary outcome positive: LSM reduction -4.3±0.3 (quarterly) and -4.6±0.3 (monthly) vs -2.5±0.3 (placebo), both p<0.001; difference vs placebo approximately -2 days
- During 12-week period, patients had average of 8.5±6.3 headache days (quarterly), 8.0±6.3 (monthly) vs 10.4±6.4 (placebo)
- Migraine days significantly reduced: LSM -4.9±0.4 (quarterly) and -5.0±0.4 (monthly) vs -3.2±0.4 (placebo), difference -1.7 to -1.8 days, both p<0.001
- ≥50% responder rate for headache days: 38% (141/375 quarterly) and 41% (153/375 monthly) vs 18% (67/371 placebo), both p<0.001
- Acute headache medication use significantly reduced: LSM -3.7±0.3 days (quarterly) and -4.2±0.3 days (monthly) vs -1.9±0.3 days (placebo), both p<0.001
- Treatment effects observed early: significant reductions in headache days during 4-week period after first dose (-4.4 and -4.5 vs -2.1 days, p<0.001)
- HIT-6 scores (headache-related disability) significantly improved: LSM -6.4±0.5 (quarterly) and -6.8±0.4 (monthly) vs -4.5±0.5 (placebo), both p<0.001
- Efficacy maintained in subgroup not receiving concomitant preventive medications (79% of patients): LSM -4.6 (quarterly) and -4.8 (monthly) vs -2.6 (placebo), p<0.001
- Safety profile favorable: Any AE 70% (quarterly), 71% (monthly) vs 64% (placebo); 95-96% were mild to moderate severity
- Injection-site reactions most common: 47% with both fremanezumab regimens vs 40% placebo; pain (26-30%), induration (20-24%), erythema (20-21%)
- Low discontinuation rates due to AEs: 1% (quarterly), 2% (monthly), 2% (placebo). Serious AEs rare: <1% (quarterly), 1% (monthly), 2% (placebo)
- Hepatic abnormalities (ALT/AST ≥3× ULN or bilirubin ≥2× ULN) occurred in 5 patients each fremanezumab group (1%) and 3 placebo (<1%), not statistically significant
- One death in quarterly group (COPD, determined unrelated to treatment). No anaphylaxis or severe hypersensitivity reactions. Antidrug antibodies developed in only 2 patients
- Results consistent with Phase 2b trial and provide strong evidence for CGRP pathway inhibition as effective therapeutic strategy for chronic migraine prevention
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, investigators, sponsor, and trial staff unaware of treatment assignments. Fremanezumab and placebo packaged identically. Randomization stratified by sex, country, and baseline preventive medication use using electronic interactive-response technology
- Sample Size
- 1130
- Follow-up
- Screening visit, 28-day preintervention period, 12-week double-blind intervention period (reported here), with final evaluation at week 12. Ongoing extension phase and safety follow-up not reported
- Centers
- 132
- Countries
- United States, Canada, Argentina, Czech Republic, Germany, Israel, Italy, Mexico, Netherlands, Russia, Spain, Taiwan, United Kingdom
Primary Outcome
Definition: Mean change from baseline (28-day preintervention period) in average number of headache days per month during 12-week period after first dose. Headache day defined as calendar day with headache pain lasting ≥4 consecutive hours with peak severity ≥moderate level, OR day when acute migraine-specific medication (triptans or ergots) used to treat headache of any severity or duration
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| LSM -2.5 ± 0.3 days; mean value during 12 weeks: 10.4 ± 6.4 days | Quarterly: LSM -4.3 ± 0.3 days, mean 8.5 ± 6.3 days; Monthly: LSM -4.6 ± 0.3 days, mean 8.0 ± 6.3 days | - (Quarterly vs placebo: LSM difference -1.8 ± 0.3; Monthly vs placebo: LSM difference -2.1 ± 0.3) | Both p<0.001 vs placebo |
Limitations & Criticisms
- Short 12-week double-blind treatment period insufficient to assess long-term durability and safety; ongoing extension and safety follow-up results not yet available
- Conducted in parallel with episodic migraine trial, allowing ineligible patients to enroll in other trial, which may have influenced enrollment patterns
- Included patients with long disease history and those previously on or not responding to preventive medications, but excluded more refractory patients (those failing ≥2 of 4 preventive clusters or with continuous headache)
- Eligibility restricted to relatively healthy patients per clinical trial requirements; further studies needed in patients with migraine and coexistent diseases
- No head-to-head comparison with other approved chronic migraine preventives (onabotulinumtoxinA, topiramate, other CGRP antibodies)
- No direct comparison between quarterly and monthly dosing regimens (only vs placebo comparisons)
- Protocol allowed up to 30% to continue stable preventive medication, which may have introduced heterogeneity (though subgroup analysis in those without concomitant preventive showed consistent results)
- Systematic assessment of injection sites for 1 hour after dosing may have inflated rates of injection-site reactions compared to real-world use
- Relatively homogeneous population (87-88% female, predominantly white patients from 9 countries), limiting generalizability to more diverse populations
- Electronic diary compliance required (≥10 days postbaseline data for efficacy analysis), which may have excluded some patients with poor compliance
- Primary endpoint definition included both duration/severity criteria AND use of acute migraine-specific medication, which could inflate headache day counts in patients using medications liberally
- Phase 2b trial suggested 1.7-day difference for sample size calculation, but observed effect was larger (2.1 days), suggesting trial may have been overpowered
- Hepatic enzyme elevations occurred in some patients using concomitant NSAIDs, acetaminophen, or antidepressants, making attribution difficult
- One death (COPD) and one serious psychiatric AE (suicidal ideation) occurred in fremanezumab groups, though both determined unrelated to treatment
- No assessment of medication overuse headache specifically, though patients using opioids/barbiturates >4 days excluded
- Limited assessment of cardiovascular safety despite theoretical CGRP vasodilation concerns (though no hemodynamic changes observed)
- Missing data handled by prorating to 28-day equivalent, which assumes constant headache patterns throughout measurement period
Citation
N Engl J Med 2017;377:2113-22