PDF: ARISE
(2018)Objective
Erenumab - To evaluate the efficacy and safety of erenumab 70 mg monthly in patients with episodic migraine.
Study Summary
• More patients achieved ≥50% reduction in migraine frequency.
• Acute migraine-specific medication use was reduced.
• Erenumab was well tolerated with a similar safety profile to placebo.
Intervention
Randomized, double-blind, placebo-controlled phase 3 trial across 69 global centers. Adults with episodic migraine (4–14 migraine days/month) received monthly subcutaneous injections of 70 mg erenumab or placebo for 12 weeks. Efficacy and patient-reported outcomes were assessed, including migraine days, medication use, and quality-of-life scales (MPFID, HIT-6, MSQ).
Inclusion Criteria
Adults aged 18–65 years with ≥4 and <15 migraine days/month for ≥12 months. Patients with prior preventive treatment failure were allowed, except those with failure of >2 drug classes.
Study Design
Arms: Erenumab 70 mg vs. Placebo
Patients per Arm: Erenumab: 286; Placebo: 291
Outcome
• ≥50% reduction in monthly migraine days: 39.7% (erenumab) vs. 29.5% (placebo); OR 1.59 (95% CI 1.12–2.27), p=0.010
• Monthly acute migraine-specific medication days: −1.2 (erenumab) vs. −0.6 (placebo); difference −0.6 days, p=0.002
• Safety: Similar adverse event profile to placebo; most common AEs were URTI, injection site pain, and nasopharyngitis.
Bottom Line
Erenumab 70 mg monthly significantly reduced migraine frequency (by 1.0 day beyond placebo), increased the proportion of patients achieving ≥50% reduction in monthly migraine days (39.7% vs 29.5%), and reduced acute migraine-specific medication use (by 0.6 days beyond placebo) in adults with episodic migraine over 12 weeks. Safety and adverse event profiles were similar to placebo with high treatment completion rates (95%), supporting erenumab as a potential new preventive therapy for episodic migraine
Major Points
- Phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 69 sites across North America and Europe (including Russia) from July 2015 to July 2016
- 577 adults with episodic migraine randomized 1:1 to erenumab 70 mg or placebo; 570 included in efficacy analyses, 546 (95%) completed week 12
- Patient population: mean age 42 years, 85.3% female, mean disease duration 21 years, baseline 8.3 monthly migraine days, 61% using acute migraine-specific medication
- 46.1% had prior preventive treatment use; 87.2% of those failed ≥1 medication due to lack of efficacy or poor tolerability
- Primary endpoint: Erenumab superior to placebo with LSM 2.9-day reduction in monthly migraine days vs 1.8 days for placebo (difference -1.0 days, 95% CI -1.6 to -0.5, p<0.001)
- Treatment effect apparent from first month and maintained throughout 12-week double-blind phase
- ≥50% responder rate significantly higher with erenumab: 39.7% vs 29.5% (OR 1.59, 95% CI 1.12-2.27, p=0.010)
- Monthly acute migraine-specific medication days reduced by LSM 1.2 days with erenumab vs 0.6 days with placebo (difference -0.6 days, 95% CI -1.0 to -0.2, p=0.002)
- Among baseline users of acute migraine-specific medications only, reduction was 2.1 vs 1.2 days respectively
- MPFID 5-point reduction rates not statistically significant: Physical Impairment 33.0% vs 27.1% (p=0.13), Everyday Activities 40.4% vs 35.8% (p=0.26)
- Improvements in patient-reported outcomes: MSQ-RFR difference 5.5 points (exceeding MID of 3.2), HIT-6 difference -2.3 points (exceeding MID of 1.5)
- Modified MIDAS total score reduced by 5.5 with erenumab vs 3.8 with placebo (difference -1.7, p=0.021)
- Safety profile favorable: treatment-emergent AEs in 48.1% erenumab vs 54.7% placebo; most common were upper respiratory tract infection (6.4% vs 4.8%), injection site pain (6.0% vs 4.2%), nasopharyngitis (5.3% vs 5.9%)
- Very low discontinuation rates due to AEs: 1.8% erenumab vs 0.3% placebo
- Serious AEs rare: 3 patients (1.1%) in erenumab group vs 5 (1.7%) in placebo group; no deaths
- Anti-erenumab binding antibodies developed in 4.3% through week 12; only 1 patient (0.4%) transiently positive for neutralizing antibodies
- No clinically significant changes in laboratory values, vital signs, ECG, or liver enzymes
- Results consistent with phase 2 study (1.1-day placebo-adjusted reduction) and STRIVE phase 3 trial (1.3-1.8 day placebo-adjusted reduction with 70-140 mg doses)
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, site personnel, and study sponsor personnel blinded to treatment assignment; erenumab and placebo packaged identically in size and color; randomization stratified by region (North America vs other) and preventive migraine medication status
- Sample Size
- 1113
- Follow-up
- Study comprised screening phase (up to 3 weeks), 4-week baseline phase, 12-week double-blind treatment phase (reported here), 28-week open-label extension, and 12-week safety follow-up after last dose
- Centers
- 69
- Countries
- Argentina, Canada, Czech Republic, Germany, Israel, Italy, Mexico, Netherlands, Spain, Taiwan, United Kingdom, United States
Primary Outcome
Definition: Change from baseline in monthly migraine days (MMD) in last month (month 3) of double-blind treatment phase. Migraine day defined as calendar day with headache ≥30 minutes meeting ICHD-3 beta criteria for migraine or probable migraine with ≥2 pain features and/or ≥1 non-pain feature, or use of acute migraine-specific medication on that day
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| LSM -1.8 days (SE 0.2) | LSM -2.9 days (SE 0.2) | - (Difference from placebo: -1.0 days (95% CI -1.6 to -0.5)) | p<0.001 (statistically significant after multiplicity adjustment) |
Limitations & Criticisms
- Relatively short 12-week double-blind phase may not assess long-term efficacy or durability of treatment effect; 28-week open-label extension will provide additional data
- Exclusion of patients with no therapeutic response to >2 classes of migraine preventives limits generalizability to most refractory population
- Only 70 mg dose tested in this trial; STRIVE phase 3 trial showed additional efficacy with 140 mg dose
- MPFID 5-point reduction categorical analysis had limited sensitivity as high proportion of patients had baseline scores <5; continuous score analysis may be more appropriate
- Minimally important difference (MID) for MPFID domain scores not yet established; work ongoing to determine optimal approach
- Study population predominantly white (89-91%) and female (85%), limiting generalizability to more diverse populations
- Exclusion of patients with serious/unstable medical conditions limits real-world applicability
- Protocol amendment during study allowed concomitant preventive use (initially prohibited), though only 15% remained on concurrent preventive
- No head-to-head comparison with other preventive treatments like onabotulinumtoxinA or topiramate
- Placebo response rates high in migraine trials; magnitude of placebo-adjusted treatment effects dependent on placebo response
- MPFID is novel instrument assessed daily with electronic diary; further validation and MID determination needed
- Longer follow-up in large numbers needed to detect rare adverse events and fully understand safety profile
- 28-week open-label extension and 12-week safety follow-up not yet reported
- Cost-effectiveness analysis not performed; monthly injections may have economic implications
- Theoretical cardiovascular risk with CGRP pathway blockade requires further real-world assessment in patients with cardiovascular comorbidities
- Low frequency of anti-erenumab antibodies and transient nature requires pooled data analysis across studies for fuller assessment
- No assessment of whether benefits persist after discontinuation or duration of washout period needed
Citation
Cephalalgia 2018;38(6):1026-1037