RESOLUTION
(2026)Objective
To evaluate the efficacy and safety of eptinezumab 100 mg IV combined with a standardized brief educational intervention (BEI) compared with placebo IV with BEI in adults with chronic migraine (CM) and medication-overuse headache (MOH).
Study Summary
• Reduction in MMDs was sustained through weeks 1–12 (−7.4 vs −4.5; difference −2.9; 95% CI −3.9 to −2.0; p < 0.0001)
• More eptinezumab participants no longer fulfilled CM nor MOH criteria at weeks 1–4 (37.8% vs 18.1%; OR 3.3; 95% CI 2.2–4.9; p < 0.0001) and weeks 1–12 (27.2% vs 12.7%; OR 3.1; 95% CI 1.9–4.9; p < 0.0001)
• Monthly days with acute migraine medication use decreased more with eptinezumab at weeks 1–4 (−11.3 vs −7.7; difference −3.6; p < 0.0001) and weeks 1–12 (−11.2 vs −7.8; difference −3.4; p < 0.0001)
• All key secondary endpoints were met with multiplicity control
• TEAEs were similar between groups (41.9% vs 36.9%); no new safety signals identified
Intervention
Eptinezumab 100 mg IV single infusion plus standardized brief educational intervention (BEI) vs placebo IV plus BEI
Inclusion Criteria
Adults 18–75 years with dual diagnosis of chronic migraine and medication-overuse headache per ICHD-3; migraine onset ≤50 years of age; history of migraine ≥12 months; ≥1 preventive treatment failure within past 5 years; ≥15 headache days per 4-week screening (≥8 migraine days); medication overuse per ICHD-3 criteria
Study Design
Arms: Eptinezumab 100 mg IV + BEI (n=303) vs Placebo IV + BEI (n=301)
Patients per Arm: 303 eptinezumab, 301 placebo (604 treated total)
Outcome
• MMDs weeks 1–12: −7.4 vs −4.5 (difference −2.9; 95% CI −3.9 to −2.0; p < 0.0001)
• MHDs weeks 1–4: −6.5 vs −3.4 (difference −3.2; 95% CI −4.1 to −2.2; p < 0.0001)
• No longer fulfilling CM nor MOH criteria weeks 1–4: 37.8% vs 18.1% (OR 3.3; p < 0.0001)
• No longer fulfilling CM nor MOH criteria weeks 1–12: 27.2% vs 12.7% (OR 3.1; p < 0.0001)
• Average daily pain weeks 1–2: difference −0.3 (95% CI −0.4 to −0.2; p < 0.0001)
• Monthly acute medication days weeks 1–4: −11.3 vs −7.7 (difference −3.6; p < 0.0001)
• PGIC week 4: 2.6 vs 3.6 (difference −1.0; p < 0.0001)
• PGIC week 12: 2.6 vs 3.5 (difference −0.9; p < 0.0001)
• PI-MBS week 12: 2.9 vs 3.6 (difference −0.7; p < 0.0001)
• TEAEs: 41.9% eptinezumab vs 36.9% placebo; serious TEAEs 0.7% vs 0.3%
Bottom Line
In adults with chronic migraine and medication-overuse headache, a single IV infusion of eptinezumab 100 mg combined with brief patient education significantly reduced monthly migraine days, headache days, acute medication use, and pain severity compared with placebo plus education, with benefits evident from weeks 1–4 and sustained through 12 weeks. Nearly 38% of eptinezumab patients no longer met criteria for either chronic migraine or MOH within the first month. This supports initiating anti-CGRP preventive therapy concurrently with patient education rather than sequential withdrawal-first approaches.
Major Points
- Primary endpoint met: eptinezumab + BEI reduced MMDs by 6.9 days vs 3.7 days with placebo + BEI over weeks 1–4 (difference −3.2; 95% CI −4.2 to −2.2; p < 0.0001), exceeding the pre-specified assumed effect size of 1.5 days
- All 9 key secondary endpoints were met with full multiplicity control, demonstrating consistent superiority of eptinezumab across MMDs, MHDs, diagnostic status, pain severity, and acute medication use
- 37.8% of eptinezumab vs 18.1% of placebo participants no longer fulfilled criteria for either CM or MOH at weeks 1–4 (OR 3.3), demonstrating a qualitative diagnostic shift
- Monthly days with acute migraine medication use decreased by 11.3 days with eptinezumab vs 7.7 days with placebo (weeks 1–4), suggesting effective medication withdrawal without a formal wean
- Average daily pain was reduced significantly more with eptinezumab as early as weeks 1–2, which is clinically valuable since headache intensity may worsen after acute medication withdrawal
- PGIC and PI-MBS scores consistently favored eptinezumab at weeks 4 and 12, reflecting patient-perceived global improvement
- Safety was comparable between groups (TEAEs 41.9% vs 36.9%); no new safety signals were identified
- The trial could not determine the independent contribution of BEI vs eptinezumab since all participants received BEI for ethical reasons
- Results support the IHS position statement advocating for early preventive intervention to prevent disease progression, rather than sequential withdrawal-first approaches
- 98% completion rate (596/608) indicates high participant retention and data quality
Study Design
- Study Type
- Phase 4, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; placebo participants received 100 mL IV 0.9% saline; centralized interactive response technology used for randomization
- Sample Size
- 608
- Follow-up
- 12 weeks (placebo-controlled period); 36 weeks total including open-label and safety follow-up
- Centers
- 76
- Countries
- Australia, Denmark, France, Georgia, Germany, Italy, Netherlands, Norway, Spain, Sweden, United States
Primary Outcome
Definition: Mean change from baseline in monthly migraine days (MMDs) over weeks 1–4
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −3.7 (SE 0.52) | −6.9 (SE 0.52) | - (−4.2 to −2.2) | <0.0001 |
Limitations & Criticisms
- No arm without BEI was included, so the independent contribution of patient education vs eptinezumab cannot be determined
- The causal relationship between migraine/headache reductions and acute medication use reductions cannot be disentangled since improvements occurred simultaneously
- 97.8% of participants were from Europe, limiting generalizability to other regions and ethnicities
- Race data were unknown/not collected for 48.2% of participants due to local European legislation
- Patients with prior CGRP pathway treatment failure, significant opioid/barbiturate use (>4 days/month), clinically significant psychiatric or cardiovascular disease, or confounding pain syndromes were excluded, limiting generalizability
- Results are specific to CM with MOH and may not apply to MOH with other underlying headache disorders
- Only a single dose of eptinezumab 100 mg was tested; no dose-response assessment with the 300 mg dose
- The 12-week placebo-controlled period is relatively short for a chronic condition; longer-term controlled data are not available from this design
- The assumed treatment effect for power calculation was −1.5 MMDs, but the observed effect was −3.2 MMDs, suggesting the trial was substantially overpowered for the primary endpoint
Citation
Neurology 2026;106:e214863