PDF: HALO EM
(2018)Objective
To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with monthly dosing or single higher dose regimens
Study Summary
• Fremanezumab significantly reduced monthly migraine days: -1.5 days (monthly dosing) and -1.3 days (single higher dose) vs placebo, both p<0.001
• ≥50% responder rates were 47.7% (monthly) and 44.4% (single higher dose) vs 27.9% (placebo), both p<0.001
• Treatment effects observed as early as week 4 and maintained throughout 12-week period
• ≥50% responder rates were 47.7% (monthly) and 44.4% (single higher dose) vs 27.9% (placebo), both p<0.001
• Treatment effects observed as early as week 4 and maintained throughout 12-week period
Intervention
Subcutaneous fremanezumab monthly dosing (225 mg at baseline, weeks 4, 8), single higher dose (675 mg at baseline, placebo at weeks 4, 8), or placebo over 12 weeks
Inclusion Criteria
Adults 18-70 years with episodic migraine (6-14 headache days with ≥4 migraine days during 28-day baseline) per ICHD-3 beta, migraine history ≥12 months, onset before age 50
Study Design
Arms: 3 arms (1:1:1): Fremanezumab monthly (n=290), Fremanezumab single higher dose/quarterly (n=291), Placebo (n=294)
Patients per Arm: 290 (monthly), 291 (single higher dose), 294 (placebo)
Outcome
• Primary: Significant reduction in monthly migraine days with both doses vs placebo (monthly: LSM -3.7 days, difference -1.5, p<0.001; single higher dose: LSM -3.4 days, difference -1.3, p<0.001)
• Secondary: Higher ≥50% responder rates, reduced acute medication use, improved MIDAS scores (all p≤0.002)
• Safety: Injection-site reactions most common (pain 26-30%), low discontinuation rates (1.7% all groups), generally well-tolerated
• Secondary: Higher ≥50% responder rates, reduced acute medication use, improved MIDAS scores (all p≤0.002)
• Safety: Injection-site reactions most common (pain 26-30%), low discontinuation rates (1.7% all groups), generally well-tolerated
Bottom Line
Among 875 patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab resulted in statistically significant reductions in monthly migraine days compared to placebo: -1.5 days with monthly dosing (225 mg) and -1.3 days with single higher dose (675 mg quarterly) over 12 weeks (both p<0.001). Both regimens also significantly improved ≥50% responder rates (47.7% and 44.4% vs 27.9%, p<0.001), reduced acute medication use, and improved disability scores. Treatment was generally well-tolerated with injection-site reactions as the most common adverse event. This trial established fremanezumab as an effective preventive treatment for episodic migraine targeting the CGRP pathway with flexible dosing options
Major Points
- Phase 3, multicenter (123 sites in 9 countries), randomized (1:1:1), double-blind, placebo-controlled, parallel-group trial conducted March 2016 to April 2017
- 875 patients randomized: 290 to fremanezumab monthly, 291 to fremanezumab single higher dose, 294 to placebo; 791 (90.4%) completed trial
- Baseline characteristics balanced: mean age 41.8 years, 85% female, mean 8.9-9.3 migraine days per month, severe disability (MIDAS 37.3-41.7)
- Fremanezumab is fully humanized IgG2a monoclonal antibody that selectively binds both α and β isoforms of CGRP ligand, administered subcutaneously
- Monthly dosing: 225 mg at baseline, weeks 4 and 8 (loading dose 675 mg at baseline via three 225 mg injections, then 225 mg monthly)
- Single higher dose (quarterly): 675 mg at baseline (three 225 mg injections), placebo at weeks 4 and 8, intended to support quarterly dosing regimen
- Primary endpoint: Mean change from baseline in monthly migraine days during 12 weeks (migraine day defined as ≥2 consecutive hours meeting ICHD-3 beta criteria OR use of triptans/ergots)
- Primary outcome POSITIVE: Monthly dosing LSM -3.7±0.3 days (from 8.9 to 4.9 days), single higher dose LSM -3.4±0.3 days (from 9.2 to 5.3 days) vs placebo LSM -2.2±0.3 days (from 9.1 to 6.5 days)
- Placebo-adjusted differences: monthly dosing -1.5 days (95% CI -2.01 to -0.93, p<0.001), single higher dose -1.3 days (95% CI -1.79 to -0.72, p<0.001)
- ≥50% responder rate significantly higher with fremanezumab: monthly 47.7% (137/287), single higher dose 44.4% (128/288) vs placebo 27.9% (81/290), both p<0.001
- Acute headache medication use significantly reduced: monthly LSM -3.0±0.3 days, single higher dose LSM -2.9±0.3 days vs placebo LSM -1.6±0.3 days (differences -1.4 and -1.3 days, both p<0.001)
- Early treatment effect at week 4: monthly LSM -3.5±0.3 days, single higher dose LSM -3.3±0.3 days vs placebo LSM -1.7±0.3 days (differences -1.8 and -1.6 days, both p<0.001)
- Effect consistent in patients not receiving concomitant preventive medications (79% of participants): monthly LSM -3.7 days, single higher dose LSM -3.5 days vs placebo LSM -2.4 days (both p<0.001)
- MIDAS scores (disability) significantly improved: monthly LSM -24.6 points (p<0.001), single higher dose LSM -23.0 points (p=0.002) vs placebo LSM -17.5 points
- Safety profile favorable: any AE 66.2% (monthly), 66.3% (single higher dose) vs 58.4% (placebo); treatment-related AEs 47.6%, 47.1% vs 37.2%
- Most common AEs were injection-site reactions: pain 30.0% (monthly), 29.6% (single higher dose) vs 25.9% (placebo); induration 24.5%, 19.6% vs 15.4%; erythema 17.9%, 18.9% vs 14.0%
- Low discontinuation rates due to AEs: 1.7% in all three groups. Serious AEs rare: 1.0% (both fremanezumab groups) vs 2.4% (placebo)
- One death in single higher dose group 109 days post-dose (diphenhydramine overdose/suicide, deemed unrelated). Four patients in monthly group developed antidrug antibodies without significant AEs
- Mixed-effects repeated-measures and multiple imputation sensitivity analyses confirmed primary results. Treatment effects sustained throughout 12-week period across all monthly assessments
- Study conducted in parallel with chronic migraine trial (HALO CM, NCT02621931), with patients screened for both and enrolled in appropriate trial based on eligibility
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, investigators, sponsor, and designated personnel blinded to treatment assignments. Randomization via electronic interactive-response technology, stratified by sex, country, and baseline preventive medication use. Block size fixed at 3 within each stratum. Fremanezumab and placebo packaged identically
- Sample Size
- 875
- Follow-up
- Screening visit, 28-day pretreatment baseline period, 12-week double-blind treatment period (reported here), final evaluation at week 12. Ongoing extension evaluating long-term safety and efficacy via blinded assessment over additional 12 months (results pending)
- Centers
- 123
- Countries
- United States, Canada, Argentina, Czech Republic, Germany, Israel, Italy, Mexico, Netherlands
Primary Outcome
Definition: Mean change from baseline (28-day pretreatment period) in mean number of monthly migraine days during 12-week period after first injection. Migraine day defined as calendar day with ≥2 consecutive hours headache meeting ICHD-3 beta criteria for migraine (with or without aura) or probable migraine (only 1 criterion absent), OR day when acute migraine-specific medication (triptans or ergots) used to treat headache of any duration
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| LSM -2.2 ± 0.3 days; baseline 9.1 days → 6.5 days during 12 weeks | Monthly: LSM -3.7 ± 0.3 days, baseline 8.9 days → 4.9 days; Single higher dose: LSM -3.4 ± 0.3 days, baseline 9.2 days → 5.3 days | - (Monthly vs placebo: LSM difference -1.5 days (95% CI -2.01 to -0.93); Single higher dose vs placebo: LSM difference -1.3 days (95% CI -1.79 to -0.72)) | Both p<0.001 vs placebo |
Limitations & Criticisms
- Short 12-week double-blind treatment period insufficient for long-term safety assessment; ongoing extension evaluating additional 12 months (results pending)
- Study powered to detect 1.6-day difference, but observed effect sizes were 1.3-1.5 days. However, no minimal clinically important difference established for episodic migraine
- Included patients with long disease history (20 years) and those on/failed prior preventives, but excluded treatment-refractory patients with >2 failed preventive drug clusters or continuous headache
- Trial less restrictive than others and allowed current preventive medications (21%), but may limit generalizability to more refractory populations
- Limited to short-term follow-up of 3 months after randomization; long-term durability and safety require further study
- No head-to-head comparison with other active preventive treatments or other CGRP antibodies, though active comparators usually not included in pivotal migraine trials
- Did not assess response of post-randomization attacks to acute treatment, though acute medication consumption significantly decreased
- Effect of fremanezumab on migraine aura frequency not evaluated
- Did not include certain populations: pregnant, acute coronary syndrome/ischemic stroke, compromised blood-brain barrier; further studies needed in these groups
- Systematic assessment of injection sites immediately and 1 hour post-dose may have inflated injection-site reaction rates vs real-world use
- Relatively homogeneous population (85% female, predominantly white from 9 countries), limiting generalizability to more diverse populations
- Low percentage with prior topiramate use (17.5-22.1%) highlights limited use of preventive medications for episodic migraine in general population
- Electronic diary compliance required (≥10 days postbaseline for efficacy analysis, ~85% adherence during baseline), may have excluded patients with poor compliance
- Primary endpoint definition included both duration/severity criteria AND use of acute migraine-specific medication, which could potentially inflate migraine day counts
- One death occurred (suicide by diphenhydramine overdose in single higher dose group), though investigator deemed unrelated. Highlights need for psychiatric screening
- No assessment of cost-effectiveness compared to other preventive treatments
- Study conducted in parallel with chronic migraine trial (HALO CM), with patients signing consent for both and enrolled based on eligibility; may have influenced enrollment patterns
- Concurrent use of 1 preventive medication allowed (≤30% of patients), introducing some heterogeneity though subgroup analysis without preventives showed consistent results
Citation
JAMA. 2018;319(19):1999-2008