PDF: APPRAISE
(2024)Objective
Erenumab - To evaluate whether early initiation of erenumab provides superior efficacy, tolerability and adherence in patients with episodic migraine who failed 1–2 prior preventive.
Study Summary
• Patients were 11 times more likely to complete treatment on erenumab than OMPMs.
• Erenumab had lower rates of switching, adverse events, and discontinuation.
• Supports early use of CGRP monoclonal antibodies for migraine prevention.
Intervention
12-month, phase 4, open-label, multicenter, randomized clinical trial (n=621) comparing erenumab (monthly SC injection) vs. nonspecific OMPMs (e.g., β-blockers, topiramate, TCAs) in patients with episodic migraine and 1–2 prior treatment failures. Primary outcome combined efficacy (≥50% MMD reduction) and treatment adherence at 12 months.
Inclusion Criteria
Adults ≥18 years with episodic migraine (4–14 MMDs/month), ≥1 but ≤2 prior preventive failures due to inefficacy or intolerance.
Study Design
Arms: Erenumab (SC monthly) vs. OMPMs (oral prophylactics)
Patients per Arm: Erenumab: 413; OMPM: 208
Outcome
• PGIC responders at 12 months: 76.0% (erenumab) vs. 18.8% (OMPM); OR 13.75 (95% CI, 9.08–20.83), p<0.001
• Change in MMDs: –4.32 (erenumab) vs. –2.65 (OMPM); difference –1.67 days, p<0.001
• Treatment discontinuation due to AEs: 2.9% (erenumab) vs. 23.3% (OMPM)
• Switch rate: 2.2% (erenumab) vs. 34.6% (OMPM)
• No new safety signals identified
Bottom Line
Earlier use of erenumab in patients with episodic migraine who failed 1 or 2 previous preventive treatments provided significantly greater and sustained efficacy, safety, tolerability, and adherence compared with continuous oral preventive medications over 12 months
Major Points
- First pragmatic head-to-head trial comparing erenumab vs standard-of-care oral preventives in patients with 1-2 prior treatment failures
- Novel composite primary endpoint combining efficacy (≥50% MMD reduction) with sustained adherence at 12 months
- Erenumab patients 6 times more likely to achieve primary endpoint (56.2% vs 16.8%) and 11 times more likely to complete treatment on first assigned drug
- Significantly lower switching rates with erenumab (2.2%) vs OMPMs (34.6%), with most OMPM switches due to lack of tolerability (50%)
- Sustained superiority in MMD reduction throughout 12 months, with treatment difference stable over time
- Erenumab showed 13-fold higher PGIC responder rate (76% vs 18.8%), indicating greater patient satisfaction
- Better tolerability profile: 8-fold lower discontinuation due to adverse events (2.9% vs 23.3%) and lower exposure-adjusted AE rate
- Open-label design mimicked real-world clinical practice with physician autonomy in treatment decisions
Study Design
- Study Type
- Interventional, randomized controlled trial
- Blinding
- Open-label (physicians and patients aware of treatment assignment)
- Sample Size
- 621
- Follow-up
- 12 months (52 weeks)
- Centers
- 84
Primary Outcome
Definition: Composite endpoint: proportion of patients completing 1 year of initially assigned treatment AND achieving reduction of 50% or greater from baseline in monthly migraine days (MMDs) at month 12
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 35/208 (16.8%) | 232/413 (56.2%) | - | <0.001 |
Limitations & Criticisms
- Open-label design may have introduced placebo effect and bias, though authors argue this reflects real-world practice and placebo effect typically peaks at 3 months
- Heterogeneous choice of OMPMs across geographies and dependent on individual physician experience, as no standardized treatment algorithms exist
- Only locally approved OMPMs at study onset were used, limiting generalizability to newer oral preventives
- Unequal randomization (2:1) favoring erenumab may have affected statistical power for comparisons
- 19% overall discontinuation rate (15.8%), though similar between groups
- 30% cap on patients with 2 prior treatment failures may limit applicability to more refractory patients
- Results may not apply to patients with >2 prior treatment failures or chronic migraine
- Subcutaneous administration in clinic setting may have enhanced satisfaction outcomes independently of drug effect
- Erenumab patients received dose at week 48 while OMPM patients continued to week 52, creating slight difference in treatment duration
- Limited ethnic diversity (98.9% White) limits generalizability
- Study funded by manufacturer (Novartis) with several authors as employees
Citation
JAMA Neurol. 2024;81(5):461-470. doi:10.1001/jamaneurol.2024.0368