This post hoc secondary analysis of 4 randomized clinical trials evaluates changes in migraine frequency, medication use, and patient-reported outcomes associated with erenumab use.
Key Points
Question
Is erenumab therapy effective for patients with migraine and a history of aura?
Findings
In this post hoc secondary analysis of 4 randomized clinical trials involving 2682 patients, erenumab treatment was associated with reduced migraine frequency and fewer days of acute migraine-specific medication use in patients with migraine with and without history of aura. No differences were observed in the safety profiles of patients in either group.
Meaning
Findings of this analysis suggest that erenumab may be safe and effective for patients with migraine with and without history of aura.
Abstract
Importance
Migraine with aura may respond differently to therapies than migraine without aura. Individuals with migraine with aura have an elevated vascular risk, necessitating a safety assessment of migraine preventive treatments in this patient subgroup.
Objective
To assess the efficacy and safety profiles of erenumab in patients with migraine with aura.
Design, Setting, and Participants
This post hoc secondary analysis evaluated 4 double-blind, placebo-controlled randomized clinical trials that were conducted in treatment centers in North America, Europe, Russia, and Turkey between August 6, 2013, and November 12, 2019. Participants were adults aged 18 to 65 years with episodic migraine or chronic migraine and were randomized to receive either erenumab or placebo.
Interventions
One or more dose of erenumab (70 mg or 140 mg once per month) or placebo was administered by subcutaneous injection in the double-blind treatment phase and open-label or dose-blinded active treatment, and erenumab, 70 mg or 140 mg, was administered once per month by subcutaneous injection during extension phases.
Main Outcomes and Measures
Efficacy assessments included change from baseline monthly migraine days (MMDs) and monthly acute migraine–specific medication (AMSM) days. Safety end points included patient incidences of adverse events. Subgroups of patients were categorized according to their history of aura.
Results
Of the 2682 patients who were randomized in the 4 trials, 1400 (52.2%) received 1 or more dose of erenumab, 70 mg or 140 mg, and 1043 (38.9%) received placebo. Patients had a mean (SD) age of 41.7 (11.2) years and were predominantly women (n = 2055 [84.1%]). Reductions from baseline MMDs and AMSM days were greater in the erenumab than placebo groups in patients with and without a history of aura during the double-blind treatment phase, and these reductions were maintained throughout the extension phases. In patients with episodic migraine and a history of aura, least-squares mean differences in change from baseline MMDs at week 12 were –1.1 (95% CI, –1.7 to –0.6) in those who received erenumab, 70 mg, and –0.9 (95% CI, –1.6 to –0.2) in those who received erenumab, 140 mg, compared with placebo. In patients with chronic migraine with a history of aura, the least-squares mean differences from placebo treatment were –2.1 (95% CI, –3.8 to –0.5) in those who received erenumab, 70 mg, and –3.1 (95% CI, –4.8 to –1.4) in those who received erenumab, 140 mg. Overall safety profiles were similar across treatment groups regardless of aura history and were comparable to that of placebo over 12 weeks, with no increased emergence of adverse events over time.
Conclusions and Relevance
Results of this secondary analysis of 4 randomized clinical trials showed reduced migraine frequency and AMSM days with erenumab treatment in patients with migraine with and without a history of aura. The findings support the efficacy and safety of using erenumab in this patient population.
Trial Registration
ClinicalTrials.gov Identifiers: NCT01952574, NCT02456740, NCT02483585, NTCT02066415, and NCT02174861
Introduction
Migraine with aura occurs in as many as one-third of patients with migraine (with prevalence estimated at 20%-40% of all people with migraine), although most of these patients do not experience aura with every migraine attack.1 Currently, no well-established treatments are available to abort or prevent aura symptoms,2 and therapeutic responses to acute therapy, specifically sumatriptan, may be different in migraine with aura compared with migraine without aura.2,3 The evidence is mixed on the association of aura with preventive treatments for migraine.2 Cortical spreading depression-like events are widely considered to be the underlying substrate of a migraine aura.4 Thus, it is unclear whether monoclonal antibodies, which are generally believed to be substantially restricted to the periphery, would be equally effective in migraine with aura vs without aura. Given the importance of calcitonin gene-related peptide (CGRP) in the regulation of vascular tone5 and the associations between migraine with aura and cardiovascular disease,6,7,8 well-established safety data on patients with migraine with aura are needed.
Erenumab, which is known in the US as erenumab-aooe, is a human anti-CGRP receptor monoclonal antibody that was developed for migraine prevention. Erenumab has demonstrated clinical efficacy in episodic migraine and chronic migraine, reducing both monthly migraine days (MMDs) and acute migraine–specific medication (AMSM) use.9,10,11,12,13 To understand the efficacy and safety profiles of erenumab in patients with migraine with aura, we conducted a post hoc subgroup analysis of clinical data from 4 pivotal randomized clinical trials of erenumab. We believe this analysis provides Class II evidence (according to the Levels of Evidence for Primary Research Question from the North American Spine Society), as the evidence showed a reduction in MMDs and a reduction in AMSM use.
Methods
Given that this study was a subgroup analysis, it is covered under the approval granted and the patient consent provided for the original study protocols. The 4 randomized clinical trials included in this analysis were conducted in compliance with the Declaration of Helsinki,14 International Council on Harmonisation Good Clinical Practice guidelines, and local or country regulations. Their trial protocols (Supplements 1-5) were approved by the institutional review board or independent ethics committee at each participating treatment center. Participants provided written informed consent before study initiation. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Data Sources and Study Participants
In September 2020, we analyzed 4 double-blind trials and extension phases with varying erenumab regimens and treatment durations. These studies were conducted in treatment centers in North America, Europe, Russia, and Turkey between August 6, 2013, and November 12, 2019.10,11,12,13,15,16 The methods, primary and secondary outcomes, and other details (such as inclusion and exclusion criteria) of these studies have been reported elsewhere.10,11,12,13,15,16
All studies comprised a screening visit; a 4-week baseline phase; a 12- or 24-week placebo-controlled, double-blind treatment phase; an extension phase consisting of an open-label treatment phase or dose-blinded active treatment phase ranging from 28 weeks to 5 years; and safety follow-up visits 12 to 16 weeks after the last dose of erenumab. Participants were randomized to receive erenumab, 70 mg or 140 mg, or placebo in the double-blind treatment phase and open-label or dose-blinded active treatment, with erenumab, 70 mg or 140 mg, during the extension phases (Figure 1). Erenumab or placebo was administered by subcutaneous injection once per month (every 4 weeks).
Figure 1. Study Schema and Patient Flow.
aFour hundred sixty-four patients received erenumab, 70 mg, and 276 received erenumab, 140 mg.
bFour hundred twenty-nine patients received erenumab, 70 mg, and 231 received erenumab, 140 mg.
The studies enrolled adult patients aged 18 to 65 years who had episodic migraine (≥4 to <15 migraine days per month and <15 headache days per month) or chronic migraine (≥15 headache days per month, of which ≥8 were migraine days). Patients were excluded if they had had a myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary artery bypass surgery or another revascularization procedure within 12 months before study screening. Two clinical trials excluded patients if they had poorly controlled hypertension.10,11
The efficacy analyses we performed included pooled data from the 3 episodic migraine trials10,12,13; data from the 1 chronic migraine trial11 were assessed separately. Our safety analyses used data that were pooled from all 4 clinical trials. Race and ethnicity data were self-reported by participants and included the following categories: Black or African American, White, and other (ie, American Indian/Alaska Native, Asian, Native Hawaiian/Other Pacific Islander, multiple, or other).
Efficacy Outcomes and Statistical Analysis
We conducted efficacy assessments throughout the double-blind treatment phase at week 12 (including data from weeks 9-12) and throughout the open-label treatment phase or active treatment phase. Patients used a daily electronic diary to report information about their migraine and nonmigraine headaches, acute medication use, and, in the chronic migraine trial, aura symptoms. Efficacy end points for this subgroup analysis included changes in MMD, proportion of patients achieving 50% or greater reduction in MMD, and changes in monthly AMSM days.
Subgroups of patients with and without a history of aura were determined from medical history provided by the investigators during screening. In the chronic migraine clinical trial, patients were instructed to record their aura symptoms daily during the baseline and treatment phases. Because some patients with a history of aura did not experience aura during the 4-week baseline period, we calculated change in monthly aura days in patients with 1 or more or 3 or more aura days during baseline regardless of their history of aura. In the episodic migraine trials, aura information was not routinely collected; therefore, we did not calculate changes in aura days.
The efficacy analysis in the episodic migraine clinical trials included pooled data on patients who received 1 or more erenumab dose (70 mg or 140 mg) or placebo during the double-blind treatment phase (short-term analysis) and completed 1 or more postbaseline monthly measurement. Long-term analysis included data on patients who received 1 or more erenumab dose (70 mg or 140 mg) and completed 1 or more measurement during the extension periods. The efficacy analysis in the chronic migraine trial included patients who received 1 or more erenumab dose (70 mg or 140 mg) or placebo during the double-blind treatment phase (short-term analysis) or 1 or more dose of erenumab (70 mg or 140 mg) during the extension periods (long-term analysis) and completed 1 or more postbaseline measurement.
In the adjusted analyses of continuous efficacy outcomes in the short-term analyses, we used a generalized linear mixed model, including treatment, visit, treatment-by-visit interaction, stratification factors, and baseline value as covariates and assuming a first-order autoregressive covariance structure. Binary efficacy outcomes in the short-term analyses were assessed using a Cochran-Mantel-Haenszel test, after the missing data were imputed as nonresponse, classified by stratification factors. P values were not adjusted for multiple comparisons. Descriptive summaries were provided for efficacy outcomes in the long-term analyses. We performed a sensitivity analysis of efficacy outcomes in the short-term analyses of the pooled episodic migraine trials for patients who were treated at headache specialty centers (ie, those with ongoing clinical activities related to migraine care outside of a migraine trial) to account for potential misclassification of patients with migraine and aura; however, we did not perform a similar sensitivity analysis in the chronic migraine trial because of the low numbers of patients from non–headache specialty sites.
Safety End Points and Statistical Analysis
Safety end points included patient incidences or exposure-adjusted patient incidences of adverse events (AEs) and serious AEs. Data were collected and coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 20.0 (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use)17 and graded according to Common Terminology Criteria for Adverse Events, version 4.03 (National Cancer Institute).18 Double-blind treatment phase data were used to assess the overall safety profile by treatment group. Open-label treatment phase data were used to assess the overall long-term safety profile of erenumab. Cardiovascular risk factors at baseline were identified from predefined search strategies or dedicated case report form pages for diabetes, history of hypertension, high blood pressure at screening (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg measured on ≥2 occasions), cigarette use, history of dyslipidemia, high cholesterol level (total cholesterol >5.17 mmol/L, low-density lipoprotein >3.36 mmol/L, or high-density lipoprotein <1.03 mmol/L), high lipid level (triglyceride >1.69 mmol/L), and body mass index of 30 or higher (calculated as weight in kilograms divided by height in meters squared). Cardiovascular, cerebrovascular, and hypertension AEs were identified using a narrow standardized MedDRA query for ischemic central nervous system vascular conditions, a narrow standardized MedDRA query for ischemic heart disease, a narrow Amgen MedDRA query for peripheral arterial disease, and a narrow and broad standardized MedDRA query for hypertension.
Safety analysis sets included pooled data on all patients from the 4 clinical trials who received 1 or more erenumab dose (70 mg or 140 mg) or placebo during the double-blind treatment phase (short-term analysis) or 1 or more dose of erenumab (70 mg or 140 mg) during the extension periods (long-term analysis).19 Events that spanned the double-blind treatment phase and extension phases were counted as a single occurrence in the short-term period unless the event worsened in the extension phase. Exposure-adjusted incidence rates (per 100 patient-years) of AEs were calculated as the total number of patients who reported 1 or more AEs divided by the total time at risk for reporting the AEs (in years, summed across all patients) multiplied by 100. Time at risk included only the time to first occurrence of the AE. If a patient did not have the corresponding AE to report, then time at risk included time to safety follow-up visit for long-term analysis. All statistical calculations were performed with SAS, version 9.4 (SAS Institute Inc).
Results
A total of 2682 patients were randomized during the double-blind treatment phase of the 4 trials, of whom 1400 (52.2%) received 1 or more dose of erenumab (70 mg or 140 mg) and 1043 (38.9%) received placebo; 239 patients (8.9%) who received 7 mg or 21 mg erenumab were not part of the short-term analysis (Figure 1). Of the 2443 patients who were treated with erenumab (70 mg or 140 mg) or placebo, 1140 (46.7%) had a history of aura (Table).
Table. Patient Demographic and Baseline Disease Characteristics by History of Aura .
| Characteristic | No. (%) | |||||
|---|---|---|---|---|---|---|
| Without history of aura (N = 1303) | With history of aura (N = 1140) | |||||
| Placebo (n = 563) | Erenumab, 70 mg (n = 464) | Erenumab, 140 mg (n = 276) | Placebo (n = 480) | Erenumab, 70 mg (n = 429) | Erenumab, 140 mg (n = 231) | |
| Age, mean (SD), y | 42.1 (11.2) | 42.1 (11.4) | 41.3 (11.2) | 41.4 (11.1) | 41.4 (11.0) | 41.4 (11.2) |
| Sex | ||||||
| Female | 464 (82.4) | 391 (84.3) | 236 (85.5) | 405 (84.4) | 364 (84.8) | 195 (84.4) |
| Male | 99 (17.6) | 73 (15.7) | 40 (14.5) | 75 (15.6) | 65 (15.2) | 36 (15.6) |
| Race and ethnicitya | ||||||
| Black or African American | 30 (5.3) | 27 (5.8) | 11 (4.0) | 44 (9.2) | 32 (7.5) | 13 (5.6) |
| White | 521 (92.5) | 430 (92.7) | 261 (94.6) | 413 (86.0) | 383 (89.3) | 214 (92.6) |
| Otherb | 12 (2.2) | 7 (1.5) | 4 (1.4) | 23 (4.8) | 14 (3.2) | 4 (1.8) |
| Episodic migraine | 404 (71.8) | 354 (76.3) | 159 (57.6) | 357 (74.4) | 349 (81.4) | 160 (69.3) |
| Chronic migraine | 159 (28.2) | 110 (23.7) | 117 (42.4) | 123 (25.6) | 80 (18.6) | 71 (30.7) |
| Disease duration, mean (SD), y | 20.8 (12.3) | 21.1 (12.5) | 19.8 (11.4) | 20.7 (12.1) | 20.5 (12.3) | 21.3 (13.0) |
| Headache specialty site | 214 (38.0) | 174 (37.5) | 99 (35.9) | 116 (24.2) | 121 (28.2) | 34 (14.7) |
| Previous use of preventive treatment | ||||||
| Naïve | 231 (41.0) | 194 (41.8) | 115 (41.7) | 251 (52.3) | 231 (53.8) | 125 (54.1) |
| Previous or current use | 332 (59.0) | 270 (58.2) | 161 (58.3) | 229 (47.7) | 198 (46.1) | 106 (45.9) |
| Previous preventive treatment failure | 304 (54.0) | 232 (50.0) | 144 (52.2) | 191 (39.8) | 170 (39.6) | 97 (42.0) |
| MMDs, mean (SD) | 11.1 (5.7) | 10.6 (5.1) | 12.5 (5.9) | 11.0 (5.3) | 10.0 (4.8) | 11.1 (5.5) |
| AMSM use | 415 (73.7) | 325 (70.0) | 194 (70.3) | 275 (57.3) | 247 (57.6) | 145 (62.8) |
Abbreviations: AMSM, acute migraine–specific medication; MMDs, monthly migraine days.
Race and ethnicity were self-reported.
Other race and ethnicity included American Indian/Alaska Native, Asian, Native Hawaiian/Other Pacific Islander, multiple, or other.
Baseline demographic characteristics were generally similar within and between the subgroups of patients with and without a history of aura. Patients had a mean (SD) age of 41.7 (11.2) years, identified as primarily White individuals (n = 2222 [91.0%]), were predominantly women (n = 2055 [84.1%]), and had a mean (SD) disease duration of 20.7 (12.3) years. The mean (SD) baseline MMDs were 10.6 (5.1) in patients with a history of aura and 11.2 (5.6) in patients without a history of aura. Previous or current use of preventive treatment and use of AMSM at baseline were higher in patients without a history of aura than patients with a history of aura as were previous preventive treatment failure (Table).
Multiple cardiovascular risk factors were more prominent in patients with vs patients without a history of aura (eFigure in Supplement 6), including diabetes, history of hypertension, high blood pressure, high lipids, and body mass index of 30 or higher. The proportion of patients with high cholesterol level at baseline was high in both subgroups. More patients with a history of aura than those without had 2 or more cardiovascular risk factors at baseline (eFigure in Supplement 6).
Outcomes
Reductions in MMDs were greater in patients who received erenumab than in those who received placebo (Figure 2 and Figure 3). In patients with episodic migraine without a history of aura, least-squares mean (LSM) differences in MMD change from baseline at week 12 were –1.2 (95% CI, –1.6 to –0.7) in those who received 70 mg of erenumab and –2.5 (95% CI, –3.2 to –1.8) in those who received 140 mg of erenumab compared with the placebo. In patients with episodic migraine and a history of aura, the LSM differences were –1.1 (95% CI, –1.7 to –0.6) in those who received 70 mg of erenumab and –0.9 (95% CI, –1.6 to –0.2) in those who received 140 mg of erenumab compared with those who received placebo (Figure 2). The treatment difference from placebo was more homogeneous in the headache specialty site subset between patients with a history of aura and those without a history of aura (eTable 1 in Supplement 6). In patients with chronic migraine without a history of aura, the LSM differences were –2.7 (95% CI, –4.1 to –1.3) in those who received 70 mg of erenumab and –2.1 (95% CI, –3.5 to –0.7) in those who received 140 mg of erenumab compared with those who received placebo. In patients with chronic migraine and a history of aura, the LSM differences were –2.1 (95% CI, –3.8 to –0.5) in those who received 70 mg of erenumab and –3.1 (95% CI, –4.8 to –1.4) in those who received 140 mg of erenumab compared with those who received placebo (Figure 3). The changes in MMD in both episodic migraine and chronic migraine groups were sustained across both history of aura subgroups throughout the long-term analysis (eTable 2 in Supplement 6).
Figure 2. Monthly Migraine Days (MMDs) and Acute Migraine–Specific Medication (AMSM) Days by History of Aura in Episodic Migraine .
Error bars represent 95% CIs. LSM indicates least-squares mean.
Figure 3. Monthly Migraine Days (MMDs) and Acute Migraine–Specific Medication (AMSM) Days by History of Aura in Chronic Migraine.
Error bars represent 95% CIs. LSM indicates least-squares mean.
A greater proportion of patients who received erenumab achieved 50% or greater MMD reduction from baseline than placebo in both history of aura subgroups (Figure 2 and Figure 3). In patients with episodic migraine without a history of aura, the 50% or greater response rates at week 12 were 24.8% for placebo, 36.8% for the 70-mg erenumab, and 50.6% for 140-mg erenumab groups. In patients with episodic migraine with a history of aura, the response rates were 32.3% for placebo, 44.5% for the 70-mg erenumab, and 45.6% for 140-mg erenumab groups (Figure 2). In patients with chronic migraine without a history of aura, the response rates were 22.8% for placebo and 38.5% for both erenumab doses, whereas in patients with chronic migraine and a history of aura the rates were 24.4% for placebo, 41.8% for the 70-mg erenumab, and 45.7% for 140-mg erenumab groups (Figure 3). The treatment difference from placebo was more homogeneous in the headache specialty site subset between the 2 subgroups (eTable 1 in Supplement 6).
Reductions in monthly AMSM days were greater in the erenumab vs placebo groups in both history of aura subgroups (Figure 2 and Figure 3). In the episodic migraine clinical trials, among patients using AMSM at baseline and without a history of aura, the LSM differences in change from baseline monthly AMSM days were –1.3 (95% CI, –1.8 to –0.8) in those who received 70 mg of erenumab, and −2.4 (95% CI, −3.1 to −1.8) in those who received 140 mg of erenumab compared with those who received placebo. For patients with a history of aura, the LSM differences from placebo treatment were –0.9 (95% CI, –1.4 to –0.3) in those who received 70 mg of erenumab and −1.3 (95% CI, −2.0 to −0.5) in those who received 140 mg of erenumab (Figure 2). The change from baseline AMSM days was more homogeneous in the headache specialty site subset between the 2 subgroups (eTable 3 in Supplement 6). In patients with chronic migraine and without a history of aura, the LSM differences from placebo were –2.3 (95% CI, –3.5 to –1.0) in those who received 70 mg of erenumab and −3.0 (95% CI, −4.2 to −1.7) in those who received 140 mg of erenumab. In patients with chronic migraine and a history of aura, the LSM differences were –2.4 (95% CI, –3.9 to –1.0) in those who received 70 mg of erenumab and −3.7 (95% CI, −5.0 to −2.3) in those who received 140 mg of erenumab compared with those who received placebo (Figure 3). The changes in AMSM days in both episodic migraine and chronic migraine groups were equally sustained across the 2 subgroups throughout the long-term analysis (eTable 2 in Supplement 6).
In the chronic migraine trial, the mean (SE) number of baseline monthly aura days ranged from 6.5 (0.5) to 7.5 (0.4) days among patients with 1 or more aura days during baseline (eTable 4 in Supplement 6). The change from baseline in monthly aura days did not substantially differ among treatment groups (eTable 4 in Supplement 6).
Safety
Overall safety profiles were similar across treatment groups regardless of aura history (Figure 4; eTable 5 in Supplement 6). In patients without a history of aura, 49.7% (n = 280) in the placebo group vs 46.4% (n = 343) in the erenumab group reported an AE during the double-blind treatment phase. In patients with a history of aura, the AE rates were 47.9% (n = 230) in the placebo group vs 47.7% (n = 315) in the erenumab group. Most AEs that were reported were mild or moderate in severity. Discontinuations because of AEs during the double-blind treatment phase were low in both subgroups but slightly higher in patients with a history of aura who received erenumab (2.3% [n = 15] vs 1.4% [n = 10]) (eTable 5 in Supplement 6).
Figure 4. Incidence Rate of Adverse Events (AEs).
BP indicates blood pressure; CK-MB, creatine kinase MB.
The total erenumab exposure during the long-term analysis was 2002.5 patient-years with a median (IQR) 69.4 (28.1-63.4) weeks of erenumab treatment for patients without a history of aura (n = 1352). This exposure was 1479.5 patient-years with a median (IQR) 44.3 (28.0-52.3) weeks of erenumab treatment for patients with a history of aura (n = 1147). A total of 2499 patients received 1 or more dose of erenumab, 70 mg or 140 mg, including patients in the 7-mg or 21-mg dose group from the double-blind treatment phase who received 70 mg or 140 mg during the extension phases. Overall exposure-adjusted AE rates in the extension phases remained low, with no apparent association with aura history (Figure 4; eTable 6 in Supplement 6). Exposure-adjusted patient incidences (per 100 patient-years) of all AEs were 140.8 in patients without a history of aura (n = 968) and 160.6 in patients with a history of aura (n = 829). Treatment discontinuation because of AEs remained low throughout the long-term analysis and was comparable between subgroups (2.5-2.7 per 100 patient-years) (eTable 6 in Supplement 6).
Cardiovascular, cerebrovascular, and hypertension AE rates in the extension phases were low, with no differences among subgroups (Figure 4; eTable 6 in Supplement 6). Adverse events mapped to cardiovascular, cerebrovascular, and peripheral arterial disease standardized or Amgen MedDRA queries were all less than 0.1 per 100 patient-years.
Discussion
Previous studies indicated that patients with migraine with aura may respond differently to acute therapies compared with those with migraine without aura.2 Furthermore, CGRP was found to provoke migraine attacks without aura in patients with a history of aura.18 Thus, it was not known whether erenumab was efficacious in patients with migraine with a history of aura. Findings of this post hoc secondary analysis support the safety and efficacy of erenumab in patients with migraine with or without a history of aura. Those who received erenumab in both subgroups attained greater reductions in MMDs from baseline than those who received placebo, with an increased proportion of patients achieving 50% or greater reductions in MMDs. Among patients who used AMSM, monthly AMSM days were reduced. These clinical responses were maintained in the longer term, with a treatment time frame ranging from 1 to 1.25 years and up to 5 years in some cases.
In this post hoc analysis, no differences were found in the safety profiles of patients with and without history of aura, and no unexpected safety findings were observed. Most of the reported AEs were mild or moderate.
Limitations
This study has some limitations. The results may not be generalizable to patients from racial and ethnic minority groups and those older than 65 years, as the representation of these populations was limited in this study. There were some imbalances in baseline characteristics, including higher exposure to previous preventive treatments and acute medications in patients with migraine without a history of aura, and time of exposure to erenumab that may confound any indirect comparisons between the 2 subgroups. However, we believe that these imbalances do not affect the main objective of this analysis. Patients with a history of aura in the development program were overrepresented. In contrast to the commonly reported 1-year prevalence of 25% to 40% of patients with migraine experiencing aura,1,20,21 almost half of the patients in the present analysis had a history of aura. This finding was largely based on lifetime prevalence but in some cases may have been interpreted as a current diagnosis. Differences between reported rates and rates found in the 4 clinical trials could be attributable to selection bias or diagnosis errors; thus, we performed a sensitivity analysis for patients in headache specialty centers, which would be expected to have more accurate aura diagnoses.
The ability to assess the association of erenumab with aura was limited to the chronic migraine trial, in which we were able to conduct a preliminary assessment of aura days in patients who reported experiencing aura during baseline. We did not observe a substantial treatment difference, but conclusions are limited because of the small number of patients available for analysis.
Conclusions
This post hoc secondary analysis of 4 randomized clinical trials found that erenumab reduced migraine frequency and AMSM days in patients with migraine with and without a history of aura. The safety profile of long-term erenumab treatment was similar in patients with and without a history of aura and was comparable to that of placebo over 12 weeks, with no increased emergence of adverse events over time. These findings suggest that erenumab may be safe and effective for this patient population.
Trial Protocol. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
Trial Protocol. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention
Statistical Analysis Plan for Supplement 1
Statistical Analysis Plan for Supplement 2
Trial Protocol. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
eTable 1. Change from Baseline in MMD and ≥50% MMD Responder by History of Aura Status (Headache Specialty Site)
eTable 2. Efficacy of Erenumab During the Extension Phases of the Episodic and Chronic Migraine Studies
eTable 3. Change From Baseline in Acute Migraine–Specific Medication Treatment Days Over Time by History of Aura Status (Headache Specialty Site)
eTable 4. Change in Monthly Aura Days in Chronic Migraine in Patients With Baseline Aura
eTable 5. Safety of Erenumab During the Double-Blind Treatment Phase by History of Aura Status
eTable 6. Safety in the Long-Term Analysis (Double-Blind Treatment Phase Plus Extensions)
eFigure. Clinical Characterization at Baseline by Risk Factors in Patients With Episodic Migraine and Chronic Migraine
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
Trial Protocol. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention
Statistical Analysis Plan for Supplement 1
Statistical Analysis Plan for Supplement 2
Trial Protocol. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
eTable 1. Change from Baseline in MMD and ≥50% MMD Responder by History of Aura Status (Headache Specialty Site)
eTable 2. Efficacy of Erenumab During the Extension Phases of the Episodic and Chronic Migraine Studies
eTable 3. Change From Baseline in Acute Migraine–Specific Medication Treatment Days Over Time by History of Aura Status (Headache Specialty Site)
eTable 4. Change in Monthly Aura Days in Chronic Migraine in Patients With Baseline Aura
eTable 5. Safety of Erenumab During the Double-Blind Treatment Phase by History of Aura Status
eTable 6. Safety in the Long-Term Analysis (Double-Blind Treatment Phase Plus Extensions)
eFigure. Clinical Characterization at Baseline by Risk Factors in Patients With Episodic Migraine and Chronic Migraine
Data Sharing Statement