APPRAISE
12-Month Prospective, Interventional, Global, Multicenter, Active-Controlled, Randomized Clinical Trial Comparing Sustained Benefit of 2 Treatment Paradigms (Erenumab qm vs Oral Prophylactics) in Adult Episodic Migraine Patients
Year of Publication: 2024
Authors: Patricia Pozo-Rosich, David Dolezil, Koen Paemeleire, ..., Raquel Gil-Gouveia
Journal: JAMA Neurology
Citation: JAMA Neurol. 2024;81(5):461-470. doi:10.1001/jamaneurol.2024.0368
Link: https://jamanetwork.com/journals/jamaneu...article/2816800
PDF: Clinical Question
Does early initiation of erenumab in patients with episodic migraine who failed 1 or 2 previous preventive treatments provide improved long-term efficacy, tolerability, adherence, and patient satisfaction compared with nonspecific oral migraine preventive medication?
Study Overview
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
- Erenumab met the composite primary endpoint (≥50% MMD reduction + completion at 12 months) in 56.2% vs 16.8% for OMPMs (OR 6.48, 95% CI 4.28–9.82).
- Completion on initially assigned drug: 86.9% (erenumab) vs 37.5% (OMPM) (OR 11.27, 95% CI 7.53–16.87).
- 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.
Patients per Arm
Erenumab: 413; OMPM: 208
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 achieved primary endpoint in 56.2% vs 16.8% for OMPMs (OR 6.48, 95% CI 4.28–9.82) and completion on initially assigned drug in 86.9% vs 37.5% (OR 11.27, 95% CI 7.53–16.87)
- 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
- Higher PGIC responder rate at 12 months: 76.0% vs 18.8% (OR 13.75, 95% CI 9.08–20.83), 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
Design
Study Type: Interventional, randomized controlled trial
Blinding: Open-label (physicians and patients aware of treatment assignment)
Sample Size: 621
Centers: 84
Follow-up Duration: 12 months (52 weeks)
Inclusion Criteria
- Age ≥18 years
- Documented history of migraine (with or without aura) for ≥12 months before screening according to ICHD-3 criteria
- 4 or more but fewer than 15 monthly migraine days on average across 3 months before screening
- 1 or 2 documented preventive treatment failures in past 6 months due to lack of efficacy or poor tolerability
- Prior treatment failures from: TCAs, valproate, divalproex, topiramate, flunarizine, β-blockers, or others
- eDiary compliance ≥80% during baseline period
Exclusion Criteria
- Age ≥50 years at migraine onset
- History of cluster headache or hemiplegic migraine
- Failure of 2 or more approved migraine preventive therapies
- Use of CGRP-targeted monoclonal antibodies within 3 months of baseline period
- Use of devices or invasive interventions within 2 months of baseline period
- Overuse of acute medications: ergotamine or triptans (≥10 days/month), simple analgesics (≥15 days/month), or opioid/butalbital-containing analgesics (≥4 days/month) within 2 months of baseline
Arms
| Field | Erenumab | Control |
|---|---|---|
| Intervention | Erenumab, subcutaneous injection once monthly | Non-specific oral migraine preventive medication (e.g., beta-blocker, topiramate, TCA) |
| Duration | 12 months | 12 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| 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 | Primary | 35/208 (16.8%) | 232/413 (56.2%) | 39.35% | <0.001 |
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
- Overall discontinuation was 15.8% (98/621) but strongly imbalanced between arms: erenumab 36/413 (8.7%) vs OMPMs 62/208 (29.8%), raising concern about differential dropout in an open-label trial
- 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
Funding
Novartis Pharma AG, Basel, Switzerland
Based on: APPRAISE (JAMA Neurology, 2024)
Authors: Patricia Pozo-Rosich, David Dolezil, Koen Paemeleire, ..., Raquel Gil-Gouveia
Citation: JAMA Neurol. 2024;81(5):461-470. doi:10.1001/jamaneurol.2024.0368
Reviewed by: Ahmed Koriesh, MD
Content summarized and formatted by NeuroTrials.ai.