Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial

Abstract

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden.

Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments.

Design, setting, and participants: The 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 (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included.

Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent).

Main outcomes and measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment.

Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified.

Conclusions and relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM.

Trial registration: ClinicalTrials.gov Identifier: NCT03927144.

Figure 1.. Flow Diagram of Patient Disposition (Full Analysis Set)

Patients were enrolled at 84 centers across 17 countries (Argentina, Austria, Belgium, Czech Republic, Finland, France, Germany, Greece, Israel, Italy, Netherlands, Poland, Portugal, Slovakia, Spain, UK, and US), and the full analysis set included all randomized patients (413 in the erenumab group and 208 in the oral migraine preventive medicines [OMPMs] group). The safety analysis set included all patients who received 1 or more doses of any study treatment (408 initially given erenumab; 206 given OMPMs [197 initially given nonspecific oral preventive treatment plus 9 who switched from the erenumab group]). ^aPatients could have more than 1 reason for screen failure. Other reasons for exclusion at screening included the patient's or physician's decision, loss to follow-up, protocol deviation, or technical problems.

Figure 2.. Patients With 50% or Greater Reduction in Monthly Migraine Days (MMDs)

A, Proportion of patients completing 12 months receiving the initially assigned treatment and achieving 50% or greater MMD reduction from baseline. Statistical analysis uses a Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor (number of prior prophylactic migraine treatment failures = 1 vs 2) after missing data are imputed using multiple imputation assuming MAR. Odds ratio (OR) and corresponding 95% CI are based on imputed data. B, Proportion of completers on initially assigned treatment and switchers achieving 50% or greater MMD reduction from baseline at quarterly intervals (full analysis set).^a OMPM indicates oral migraine preventive medicine. ^aCompleters were defined as patients who completed the study taking the initially assigned treatment (erenumab or nonspecific oral preventive therapy). In total, 9 patients in erenumab arm switched and were counted in switcher group.

Figure 3.. Change From Baseline in Cumulative Average Monthly Migraine Days (MMDs)

A, Patients receiving initially assigned treatment.^a,b B, Completers vs switchers of erenumab by visit (full analysis set).^a,b C, Completers vs switchers of oral migraine preventive medicine by visit (full analysis set).^a,b D, Proportion of Patient Global Impression of Change (PGIC) responders at month 12^a,c Statistical analysis utilized a Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor (number of prior prophylactic migraine treatment failures = one vs two) after missing data were imputed as nonresponse. OMPM indicates oral migraine preventive medication; TD, treatment difference. ^aCompleters were defined as patients who completed the study taking the initially assigned treatment (erenumab or nonspecific oral preventive therapy). ^bThe linear mixed-effects model includes treatment groups, baseline value, stratification factor, scheduled visit, and the interaction of treatment group per scheduled visit; an unstructured covariate matrix was assumed. ^cPatients were considered as PGIC responders if completed 12 months taking initially assigned treatment and the PGIC score was 5 or higher at month 12.