PDF: HER-MES
(2022)Objective
Erenumab - To compare the tolerability and efficacy of erenumab versus topiramate in the prevention of migraine.
Study Summary
• Discontinuation due to adverse events was much lower with erenumab.
• Erenumab showed superior efficacy in reducing migraine frequency.
• Erenumab improved headache-related quality of life metrics more than topiramate.
Intervention
Phase 4, randomized, double-blind, double-dummy, controlled trial across 82 German sites. Adults with ≥4 monthly migraine days were randomized 1:1 to either subcutaneous erenumab (70 or 140 mg/month) or oral topiramate (50–100 mg/day) over 24 weeks.
Inclusion Criteria
Adults aged 18–65 years with migraine (with or without aura) for ≥12 months, ≥4 monthly migraine days, no prior use of topiramate or CGRP-targeting antibodies. Patients with chronic migraine were also included following protocol amendment.
Study Design
Arms: Erenumab vs. Topiramate
Patients per Arm: Erenumab: 388; Topiramate: 388
Outcome
• ≥50% reduction in monthly migraine days: 55.4% (erenumab) vs. 31.2% (topiramate); OR 2.76, p<0.001
• Mean change in monthly migraine days: -5.86 (erenumab) vs. -4.02 (topiramate); p<0.001
• HIT-6 score reduction: -10.9 (erenumab) vs. -7.7 (topiramate); p<0.001
• SF-36v2 physical score: +5.5 (erenumab) vs. +3.6 (topiramate); mental score: +1.0 vs. -1.2; both p<0.001
Bottom Line
Erenumab demonstrated significantly superior tolerability with 4-fold lower discontinuation due to adverse events and superior efficacy with nearly double the responder rate compared to topiramate, representing the first head-to-head comparison of a CGRP-targeted therapy versus standard oral migraine preventive treatment
Major Points
- First randomized head-to-head trial comparing CGRP receptor antibody (erenumab) to standard-of-care oral preventive (topiramate)
- Novel double-dummy design to maintain blinding despite different routes of administration (subcutaneous vs oral)
- Primary endpoint focused on tolerability: discontinuation due to adverse events significantly lower with erenumab (10.6% vs 38.9%)
- Erenumab showed nearly 4-fold lower odds of discontinuation due to AEs (OR 0.19, 95% CI 0.13-0.27)
- Efficacy superiority: 55.4% vs 31.2% achieved ≥50% reduction in monthly migraine days (OR 2.76)
- Greater reduction in monthly migraine days with erenumab (-5.86 vs -4.02 days, difference -1.84 days)
- Significant improvements in quality of life measures (HIT-6, SF-36v2) favoring erenumab
- By week 6 (end of topiramate up-titration), 26.6% had discontinued topiramate vs 8.3% erenumab
- Composite analysis included all randomized patients (on-drug and off-drug) to reflect real-world adherence
- Broad migraine population: 59.4% were preventive-naïve, 64.7% had 8-14 MMD, 11% had chronic migraine
Study Design
- Study Type
- Randomized, double-blind, double-dummy, active-controlled, parallel-group phase 4 trial
- Randomization
- Yes
- Blinding
- Double-blind using double-dummy design; patients, investigator staff, assessors, and Novartis personnel remained blinded until primary analysis completion
- Sample Size
- 777
- Follow-up
- 24 weeks double-blind treatment phase plus 4-week safety follow-up
- Centers
- 82
- Countries
- Germany
Primary Outcome
Definition: Proportion of patients who discontinued erenumab or topiramate medication due to an adverse event during the 24-week double-blind treatment phase
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 151/388 (38.9%) | 41/388 (10.6%) | - (OR 0.19 (0.13-0.27); RR 0.27 (0.20-0.37)) | <0.001 |
Limitations & Criticisms
- Lack of placebo group to judge nocebo and placebo effects; discontinuation rates higher than placebo-controlled trials for both drugs, possibly due to double-dummy design introducing nocebo effect
- Potential partial unblinding due to typical side effects of topiramate (paresthesia, cognitive effects), though elaborate double-dummy design employed to minimize this
- Open-label extension not included; long-term durability of tolerability and efficacy benefits unknown
- Topiramate dose reduction not permitted during double-blind phase (per regulatory requirements), which may have increased discontinuation rates compared to real-world clinical practice
- Conducted only in Germany; generalizability to other healthcare systems and populations uncertain
- Predominantly Caucasian population (99.2%) limits generalizability to other ethnic groups
- Unequal treatment exposure in final months: erenumab patients more likely to remain on medication (89.2% vs 63.4% on active drug during months 4-6)
- 59.4% were preventive-naïve; results may differ in more treatment-refractory populations
- Protocol amendment mid-trial to include chronic migraine patients (11% of final sample) after 43.8% already enrolled
- Composite analysis approach (including discontinued patients) is novel but may complicate comparison to traditional efficacy trials
- Mean topiramate dose (92.1 mg/day) lower than typical 100 mg target, potentially underestimating topiramate efficacy
- Industry-sponsored trial (Novartis) with several authors as employees or stockholders
- Only one patient discontinued erenumab for lack of efficacy, suggesting possible selective study population
Citation
Cephalalgia. 2022;42(2):108-118. doi:10.1177/03331024211053571