PROMISE-1
Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1)
Year of Publication: 2020
Authors: Ashina M, Saper J, Cady R, ..., Smith J
Journal: Cephalalgia
Citation: Cephalalgia 2020;40(3):241-254
Link: https://doi.org/10.1177/0333102420905132
PDF: https://journals.sagepub.com/doi/pdf/10....333102420905132
PDF: Clinical Question
Does intravenous eptinezumab reduce monthly migraine days in adults with episodic migraine?
Study Overview
Objective
Eptinezumab 30 mg, 100 mg, and 300 mg intravenously every 12 weeks — to evaluate preventive efficacy and safety in episodic migraine.
Study Summary
- Eptinezumab 100 mg and 300 mg IV every 12 weeks reduced monthly migraine days in adults with episodic migraine.
- Mean MMD reduction over weeks 1-12: 30 mg -4.0 (unadjusted p=0.0046, NS per hierarchy), 100 mg -3.9 (p=0.0182), 300 mg -4.3 (p=0.0001) vs placebo -3.2.
- Benefit was apparent from day 1 after the first infusion, reflecting rapid onset with IV administration.
- 30 mg did not achieve significance under the prespecified serial testing hierarchy (raw reduction similar to 100 mg; no clear dose-response for the primary endpoint).
- Safety profile favorable; TEAE rates comparable across arms (~57.6-63.2% eptinezumab vs 59.5% placebo).
- Established eptinezumab as the first IV-administered CGRP pathway antibody (q12-weekly dosing) for migraine prevention.
Intervention
Eptinezumab 30 mg, 100 mg, 300 mg, or placebo IV every 12 weeks for up to 4 doses over 56 weeks.
Patients per Arm
Placebo 222; Eptinezumab 30 mg 223; 100 mg 221; 300 mg 222 (N=888)
Bottom Line
Intravenous eptinezumab 100 mg and 300 mg dosed every 12 weeks significantly reduced monthly migraine days vs placebo over weeks 1-12 in adults with episodic migraine, with benefit evident from day 1. The 30 mg dose did not reach significance under the prespecified testing hierarchy. Established eptinezumab as the first IV CGRP pathway antibody for migraine prevention with a quarterly infusion schedule.
Major Points
- Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial at 84 sites in the USA and Republic of Georgia
- 888 adults with episodic migraine (≤14 headache days/month including ≥4 migraine days) randomized 1:1:1:1
- Four arms: placebo, eptinezumab 30 mg, 100 mg, and 300 mg IV every 12 weeks
- Up to 4 IV doses over 56-week study duration
- Primary endpoint: mean change from baseline in MMD over weeks 1-12 (ANCOVA)
- Mean baseline MMD: 8.4 (placebo), 8.7 (30 mg), 8.7 (100 mg), 8.6 (300 mg)
- Primary result: MMD reduction weeks 1-12 — placebo -3.2; 30 mg -4.0 (diff -0.82, unadjusted p=0.0046, NS per hierarchy); 100 mg -3.9 (diff -0.69, p=0.0182); 300 mg -4.3 (diff -1.11, p=0.0001)
- Benefit evident from day 1 after first infusion (rapid onset with IV route)
- ≥50% MMD responder rates weeks 1-12: 50.2% / 49.8% / 56.3% vs 37.4% placebo (ORs 1.691, 1.662, 2.158)
- URTI: 7.2% (placebo), 11.4% (30 mg), 9.9% (100 mg), 10.3% (300 mg)
- Fatigue: <1% (placebo) vs 2.3-3.6% (eptinezumab arms)
- No hepatotoxicity, anaphylaxis, or cardiovascular adverse event signals
- TEAE-related withdrawal higher in 30 mg (5.5%) than other arms (2.2-2.7%)
- Led to FDA approval of eptinezumab (Vyepti) in 2020 for migraine prevention (episodic and chronic)
- Companion PROMISE-2 trial (chronic migraine) also positive
Design
Study Type: Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: 30 September 2015 to 14 December 2017
Follow-up Duration: 56 weeks (primary at weeks 1-12)
Centers: 84
Sample Size: 888
Analyzed: 888
Analysis: ANCOVA for primary endpoint (change from baseline as response; treatment and baseline migraine days as covariates). Key secondary endpoints tested via Cochran-Mantel-Haenszel (CMH)/extended CMH tests, stratified by randomization stratification factor. Serial testing procedure to control study-wide two-sided 5% alpha.
Inclusion Criteria
- Adults 18-75 years
- Diagnosis of migraine per ICHD criteria at or before age 50
- ≥12 months migraine history with ≤14 headache days/month, including ≥4 migraine days, in the 3 months prior to screening
- eDiary completed on ≥25 of 28 screening days confirming ≤14 headache days and ≥4 migraine days
- Acute migraine medication use ≤14 days per 28-day period; triptan use ≤10 days per 28-day period
- Prophylactic headache medication use ≤7 days in the 2 months prior to and during screening (menstrual prophylaxis <7 days/month allowed; barbiturates/prescription opiates ≤4 days/month if stable ≥2 months; ≤16 mg/day codeine allowed; stable hormonal therapy allowed)
Exclusion Criteria
- Confounding pain syndromes or any pain syndrome requiring regular analgesia
- Uncontrolled or untreated psychiatric conditions
- Temporomandibular disorders (TMD)
- Headache or migraine disorders not meeting ICHD-III beta (2013) section 1.3 criteria for migraine with or without aura
- Current or prior malignancy
- Experimental/unregistered therapy within 30 days or five plasma half-lives before screening
- Any monoclonal antibody treatment within 6 months of screening
- Botulinum toxin (any type) in head, face, or neck within 4 months prior to or during screening
- Approved devices, neuromodulation, neurostimulation, or injectable prophylaxis within 2 months prior to or during screening
- Inability to differentiate migraine from other headaches
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| N | 222 | 666 |
| Age mean | 39.9 (11.67) | ~40 (30 mg 39.1, 100 mg 40.0, 300 mg 40.2) |
| Sex female | 83.8% | 84.5% (30 mg), 80.3% (100 mg), 88.8% (300 mg) |
| Baseline MMD | 8.4 (2.68) | 8.7 (30 mg), 8.7 (100 mg), 8.6 (300 mg) |
| Baseline headache days | 9.9 (2.83) | 10.2 (30 mg), 10.0 (100 mg), 10.1 (300 mg) |
| Duration of migraine (y) | 16.9 (11.23) | 17.0 (30 mg), 17.4 (100 mg), 18.2 (300 mg) |
Arms
| Field | Control | Eptinezumab 30 mg | Eptinezumab 100 mg | Eptinezumab 300 mg |
|---|---|---|---|---|
| N | 222 | 223 | 221 | 222 |
| Intervention | Matching placebo IV every 12 weeks | Eptinezumab 30 mg IV every 12 weeks | Eptinezumab 100 mg IV every 12 weeks | Eptinezumab 300 mg IV every 12 weeks |
| Duration | Up to 4 doses | Up to 4 doses | Up to 4 doses | Up to 4 doses |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Mean change from baseline in monthly migraine days (MMD) over weeks 1-12 | Primary | -3.2 (95% CI -3.60, -2.79) | -4.0 (30 mg; 95% CI -4.41, -3.61); -3.9 (100 mg; -4.28, -3.47); -4.3 (300 mg; -4.70, -3.90) | Difference vs placebo: 30 mg -0.82 (-1.39, -0.25); 100 mg -0.69 (-1.25, -0.12); 300 mg -1.11 (-1.68, -0.54) | 30 mg p=0.0046 (unadjusted; NS per prespecified hierarchy); 100 mg p=0.0182; 300 mg p=0.0001 |
| ≥50% MMD responder rate, weeks 1-12 | Secondary | 83/222 (37.4%) | 30 mg 112/223 (50.2%); 100 mg 110/221 (49.8%); 300 mg 125/222 (56.3%) | OR vs placebo: 30 mg 1.691; 100 mg 1.662; 300 mg 2.158 | 30 mg p=0.0064 (unadjusted); 100 mg p=0.0085 (unadjusted); 300 mg p=0.0001 |
| ≥75% MMD responder rate, weeks 1-4 and weeks 1-12 | Secondary | Weeks 1-4: 45/222 (20.3%); Weeks 1-12: 36/222 (16.2%) | Weeks 1-4: 30 mg 67 (30.0%), 100 mg 68 (30.8%), 300 mg 70 (31.5%); Weeks 1-12: 30 mg 55 (24.7%), 100 mg 49 (22.2%), 300 mg 66 (29.7%) | OR weeks 1-4: 30 mg 1.694, 100 mg 1.752, 300 mg 1.817; OR weeks 1-12: 30 mg 1.686, 100 mg 1.470, 300 mg 2.179 | Weeks 1-4: 30 mg p=0.0170 (unadjusted), 100 mg p=0.0112, 300 mg p=0.0066; Weeks 1-12: 30 mg p=0.0272 (unadjusted), 100 mg p=0.1126, 300 mg p=0.0007 |
| Percentage of patients with migraine on day 1 after first dose | Secondary | Baseline 29.8%; Day 1 22.5% | Baseline: 31.0% (30 mg), 31.0% (100 mg), 30.8% (300 mg); Day 1: 17.3% (30 mg), 14.8% (100 mg), 13.9% (300 mg) | 30 mg p=0.1539; 100 mg p=0.0312 (unadjusted); 300 mg p=0.0159 (unadjusted) | |
| Change in acute migraine medication days (weeks 1-12) | Secondary | Prespecified secondary endpoint; numeric results not reported in this publication | Prespecified secondary endpoint; numeric results not reported in this publication | Not reported | |
| Any treatment-emergent AE | Adverse | 132/222 (59.5%) | 30 mg 128/219 (58.4%); 100 mg 141/223 (63.2%); 300 mg 129/224 (57.6%) | Comparable across arms; no dose-related trend | |
| Upper respiratory tract infection | Adverse | 16/222 (7.2%) | 30 mg 25 (11.4%); 100 mg 22 (9.9%); 300 mg 23 (10.3%) | Slightly more with eptinezumab | |
| Fatigue | Adverse | 1/222 (<1%) | 30 mg 5 (2.3%); 100 mg 8 (3.6%); 300 mg 8 (3.6%) | More with eptinezumab | |
| Nasopharyngitis | Adverse | 12/222 (5.4%) | 30 mg 14 (6.4%); 100 mg 17 (7.6%); 300 mg 14 (6.3%) | Similar across arms | |
| Hypersensitivity/infusion reactions | Adverse | Low | 7 (1.1%) eptinezumab-treated patients had study drug withdrawn for hypersensitivity: 4 (1.8%) 30 mg, 1 (<1%) 100 mg, 2 (<1%) 300 mg; all mild-to-moderate, resolved same day | Uncommon | |
| Hepatotoxicity | Adverse | None | None observed | Not applicable | |
| Cardiovascular events | Adverse | None attributable | None attributable | Not applicable | |
| Discontinuation due to AEs | Adverse | 6/222 (2.7%) | 30 mg 12 (5.5%); 100 mg 6 (2.7%); 300 mg 5 (2.2%) | Numerically higher in 30 mg arm; similar to placebo at 100 and 300 mg |
Subgroup Analysis
Efficacy was consistent across prespecified subgroups by age, sex, baseline MMD frequency, and prior preventive medication use. The rapid-onset effect (benefit evident on day 1) is distinctive of IV administration and may be particularly advantageous for severe or uncontrolled migraine in the week after infusion compared to subcutaneous CGRP mAbs which have delayed onset.
Criticisms
- Placebo response was large (3.2-day reduction), reducing absolute effect size
- 30 mg dose did not meet significance under prespecified hierarchy despite raw reduction similar to 100 mg — no clear dose-response for primary endpoint
- No active comparator (subcutaneous CGRP mAb)
- IV administration requires infusion center access — may limit accessibility for some patients
- Study conducted only in USA and Republic of Georgia; low enrollment of non-Caucasians and men limits generalizability
- Numerically higher TEAE-related withdrawal in the 30 mg arm (5.5%) vs other arms (2.2-2.7%)
- Short 12-week primary window; longer 1-year data reported separately
- PRO instruments (SF-36, EQ-5D-5L, ASC-12) collected but results published separately (HIT-6 not reported)
Funding
H. Lundbeck A/S, Copenhagen, Denmark (formerly Alder BioPharmaceuticals, Inc.; manufacturer of eptinezumab/Vyepti).
Based on: PROMISE-1 (Cephalalgia, 2020)
Authors: Ashina M, Saper J, Cady R, ..., Smith J
Citation: Cephalalgia 2020;40(3):241-254
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