Abstract
Background and Objectives
Migraine is a significant disabling neurologic headache disorder globally. Evaluating patient-related outcomes (PROs) is necessary to assess the impact of therapeutic interventions in preventive therapy. An exploratory analysis of data from the EMPOwER study examined the effect of erenumab on PROs in patients with episodic migraine (EM) in regions underrepresented in the pivotal Phase 3 trials of erenumab, specifically Asia, the Middle East, and Latin America.
Methods
Patients (N = 900) were randomized (2:3:3) to receive monthly subcutaneous injections of erenumab 140 mg, erenumab 70 mg, or placebo. Adjusted mean changes from baseline in the Headache Impact Test (HIT-6), Migraine Physical Function Impact Diary (MPFID), modified Migraine Disability Assessment (mMIDAS), and EuroQoL 5-dimension 5-level scale (EQ-5D-5L) scores were assessed during the double-blind treatment phase of 3 months.
Results
A statistically significant reduction from baseline in the HIT-6 total score was observed for erenumab 140 mg (−9.34, p < 0.001) and 70 mg (−8.39, p = 0.004) vs placebo (−6.62) at Month 3. Improvement in MPFID scores was also greater in the erenumab groups vs the placebo group (Everyday Activity: 140 mg, −5.61 [p = 0.002]; 70 mg, −4.94 [p = 0.011]; placebo, −3.19; Physical Impairment: 140 mg, −4.27 [p = 0.014]; 70 mg, −3.95 [p = 0.021]; placebo, −2.31) at Month 3. Similar findings were observed for mMIDAS scores (140 mg −8.99 [p < 0.001], 70 mg −8.11 [p = 0.011] vs placebo [−6.59]) and the EQ-5D-5L quality-of-life visual analog scale scores (140 mg 8.13 [p = 0.017], 70 mg 7.08 [p = 0.088] vs placebo [5.22]), although no meaningful between-group difference was noted for index values.
Discussion
Erenumab showed favorable effects on PROs when compared with placebo in patients with EM. These results enhance the evidence for erenumab as an effective preventive therapy for patients with EM.
Trial Registration Information
Introduction
Migraine is among the most common neurologic disorders, with worldwide prevalence ranging from 14% to 15%.1-4 Recurring migraine attacks may adversely affect individuals' quality of life (QoL) by influencing social, psychological, and daily functioning.2-5
Patient-reported outcomes (PROs) are designed to collect information regarding the burden of disease and the impact of treatment from the patient's perspective.6 PROs have been acknowledged by regulators, physicians, and patients as valuable tools to complement traditional clinical data.6 PROs that are commonly used in migraine trials include the Headache Impact Test (HIT-6), Migraine-Specific Quality of Life Questionnaire (MSQ), Migraine Disability Assessment (MIDAS), and Migraine Physical Function Impact Diary (MPFID).7-9 These PROs broadly aim to assess the negative effects of headache/migraine on normal activities (such as attending school/work and performing household chores), their impact on emotional/physical functioning over different recall periods, and the overall burden of disease.7-9
Erenumab is a fully human monoclonal antibody (mAb) that has demonstrated its efficacy and safety in patients with episodic migraine (EM)10-12 and chronic migraine (CM).13,14 It selectively blocks the calcitonin gene-related peptide (CGRP) receptor.15 The Phase 3, double-blind, placebo-controlled Study to Reduce the Incidence of migraine Via Erenumab (STRIVE) (n = 955) demonstrated that once-monthly treatment with erenumab (140 mg or 70 mg) clinically improved PROs, as measured by the MIDAS, HIT-6, and MSQ, in patients with EM.11 In addition, the Phase 3b, randomized, double-blind, placebo-controlled, parallel-group LIBERTY study (n = 246) showed that once-monthly treatment with erenumab 140 mg improved PROs, including the MPFID, HIT-6, and Work Productivity and Activity Impairment, in patients with EM who had failed 2 to 4 previous preventive treatments.16
Migraine is the second leading cause of global disability, with a higher impact in women than in men according to the Global Burden of Disease (2019).17 However, a limited number of studies have assessed the impact of treatment with CGRP pathway–targeted mAbs on PROs in patients with EM. Recently, we evaluated the efficacy of erenumab in the Phase 3 EMPOwER study (clinicaltrials.gov/study/NCT03333109), which was conducted in patients with EM (n = 900) across regions inadequately included in the pivotal Phase 3 trials of erenumab (i.e., Asia, the Middle East, and Latin America).18
We further assessed the effect of erenumab on PROs in patients with EM through exploratory and post hoc analyses of the data obtained from the EMPOwER study.
Methods
Study Design and Patient Population
This exploratory analysis was conducted using data obtained from the randomized, double-blind, placebo-controlled, parallel-group, Phase 3 EMPOwER study. This study was conducted at 83 sites across 11 countries in Asia, the Middle East, and Latin America (February 8, 2018, to January 13, 2020). Detailed study design and eligibility criteria of the EMPOwER study have been published previously.18 In brief, the study period was divided into a screening period (2 weeks), baseline period (4 weeks), double-blind treatment phase (DBTP; 3 months), and safety follow-up period (3 months). In the DBTP, patients were randomized (2:3:3) to receive monthly subcutaneous injections of erenumab 140 mg, erenumab 70 mg, or placebo, respectively. The study included patients aged 18–65 years, with a diagnosis of migraine as per the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta),19 who had an average of ≥4 to <15 monthly migraine days (MMDs) and <15 monthly headache days (MHDs) across the 3 months before screening and during baseline.
Outcomes and Assessments
The primary and secondary efficacy outcomes of the EMPOwER study have been published previously.18 Change from baseline over the 3-month DBTP was assessed for the following PROs: HIT-6, MPFID, modified MIDAS (mMIDAS), and EuroQoL 5-dimension 5-level scale (EQ-5D-5L).
Patients completed the PRO questionnaires using a daily electronic diary (eDiary). The site study staff trained the patients on the use of eDiary (e.g., turning it on/off, charging, navigating screens, transmitting data, and contacting the help desk for technical assistance) and completing the questionnaires. Patients were encouraged to complete the eDiary at the same time every day during the baseline period (to confirm the relevant inclusion and exclusion criteria) and DBTP.
HIT-6
The HIT-6 is a short-form self-administered questionnaire derived from the Internet-HIT question pool.20 The HIT-6 is widely used as a global measure of adverse headache impact to determine headache severity in the previous month and changes in a patient's clinical status. The following 6 items were assessed with the HIT-6 tool: frequency of pain severity; headaches limiting daily activity (household, work, school, and social); wanting to lie down when a headache is experienced; feeling too tired to work or perform daily activities because of a headache; feeling “fed up” or irritated because of a headache; and headaches limiting the ability to concentrate or work on daily activities. Each of the 6 questions had one of 5 response categories: “never,” “rarely,” “sometimes,” “very often,” or “always.” For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, were assigned to the response provided. These points were summed up to produce a total HIT-6 score that ranged from 36 to 78. The HIT-6 scores were then categorized into 4 grades: little or no impact (49 or less), some impact (50–55), substantial impact (56–59), and severe impact (60–78) due to headache. No recall period was specified for the first 3 items. The recall period was the past 4 weeks for the last 3 items. The HIT-6 was assessed in patients at Day 1 and every 4 weeks until the visit at 3 months. The between-group difference of at least 1.5 points in HIT-6 scores was considered minimally important difference (MID). The MID was defined as the smallest difference in scores between groups that patients perceived as beneficial or important.2,21
MPFID
The MPFID is a self-administered 13-item instrument designed to measure physical functioning; it contains 2 domains: impact on Everyday Activity (EA; 7 items) and Physical Impairment (PI; 5 items). In addition, a stand-alone global question in MPFID is used to assess overall impact of migraine on EA. Patients responded to items using a 5-point scale, with difficulty items ranging from “without any difficulty” to “unable to do” and frequency items ranging from “none of the time” to “all of the time.” These were assigned scores from 1 to 5, with 5 representing the greatest burden. For each domain, the scores were calculated as the sum of the item responses and the sum was rescaled to a 0–100 scale, with higher scores representing a greater impact of migraine (i.e., higher burden). A score was calculated for each of the 2 domains, and a third score was calculated for the stand-alone item. Patients with a reduction of ≥5 points in either of the 2 domains were considered to have a clinically meaningful reduction/improvement.22 The recall period was the last 24 hours. The MPFID was completed by patients daily using the eDiary during the 28-day baseline period and then throughout the 3-month treatment period.
mMIDAS Questionnaire
The MIDAS is a 5-item, self-administered questionnaire that assesses loss of productive days and disability in family, social, and leisure activities. The MIDAS score is calculated from the sum of missed days due to a headache from paid work, housework, and nonwork (family, social, and leisure) activities, as well as days in the past 3 months when productivity at paid work or housework was reduced by at least half. The intergroup MID for MIDAS (3-month recall period) is at least a 5-point reduction (−5 points).20,23 In patients with EM, a change of ≥4.5 points represents a clinically important difference.24 Migraine-related disability may also be categorized into 4 severity grades based on the MIDAS scores: Grade I, score of 0–5 (defined as minimal or infrequent disability); Grade II, score of 6–10 (mild or infrequent disability); Grade III, score of 11–20 (moderate disability); and Grade IV, score of 21 and over (severe disability).
The original MIDAS questionnaire requires a 3-month recall period. However, because the patients in this 3-month study were evaluated monthly, we have used modified MIDAS (mMIDAS), in which the recall period was changed from 3 months to 4 weeks to reduce recall bias and improve the accuracy of the results; patients completed the mMIDAS questionnaire at Weeks 4, 8, and 12.24-26 The intergroup MID for mMIDAS has not been established yet.
Converted MIDAS
To allow better interpretation of the results for the evaluation of change in disability categories defined using the 3-month recall period, the mMIDAS score was converted into a MIDAS score, with the baseline score calculated as 3 times the baseline mMIDAS score and 3-month score as the sum of the mMIDAS scores reported at the Week 4, Week 8, and Week 12 visits. The converted MIDAS total score was categorized into 4 disability grades based on the scoring system for the 3-month MIDAS (represented in this article as converted MIDAS).
EuroQoL 5-Dimension 5-Level Scale
The EQ-5D-5L consists of a short descriptive system questionnaire and a visual analog scale (EQ VAS). The EQ-5D-5L comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension takes one of 5 responses, which “record” 5 levels of severity within a particular EQ-5D dimension: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records self-rated health on a 20-cm vertical VAS, with end points labeled “the best health you can imagine” and “the worst health you can imagine.” This information was used as a quantitative measure of health, as assessed by the patient. There was no recall period (i.e., responses related to the patient's situation at the time of completion). The EQ-5D-5L was assessed in patients at Day 1 and every 4 weeks until 3 months.
Statistical Analysis
This exploratory evaluation used the full analysis set, which comprised all patients who started study treatment and completed at least 1 postbaseline efficacy measurement during the DBTP. PRO data were analyzed using the linear mixed-effects repeated-measures model based on observed monthly data during the DBTP, and pairwise comparisons with placebo were conducted. The model was fitted using a linear mixed-effects repeated-measures approach, with treatment group, baseline value, stratification factor, scheduled visit, and the interaction between treatment group and scheduled visit. An unstructured covariance matrix was assumed. Descriptive p values were reported for PRO end points, which were not adjusted for multiple comparisons. No missing data were imputed for the mixed-effects model. Treatment difference and odds ratio (OR) compared with placebo were generated. Nominal 95% CIs and p values were reported. Categorical efficacy end points such as achievement of at least a ≥5-point reduction from baseline in MPFID or HIT-6 scores were analyzed using the stratified Cochran-Mantel-Haenszel (CMH) method, with missing data imputed as nonresponders (i.e., not achieved). No sensitivity analyses were performed for the exploratory end points. The p values reported for the exploratory outcomes are intended only as descriptive measures and should be interpreted with caution.
Standard Protocol Approvals, Registrations, and Patient Consents
The study was conducted in compliance with the International Council for Harmonisation E6 Guideline for Good Clinical Practice, the principles of the Declaration of Helsinki, and all applicable local regulations and guidelines. Informed consent was obtained from all patients before participation in the study. The final study protocol, informed patient consent forms, and accompanying materials were reviewed and approved by the relevant ethics committee/institutional review board at each participating site.
Data Availability
The data presented in this report are available on request from the author/investigators or Novartis Pharma AG, the company sponsoring this clinical research.
Results
Demographics and Disease Characteristics
In the EMPOwER study, 900 patients were randomized to receive either erenumab 140 mg (n = 224), erenumab 70 mg (n = 338), or placebo (n = 338).18 Of 900 patients, 865 (96.1%) completed the DBTP and 840 (93.3%) completed the study.18 Baseline and disease characteristics were comparable across treatment groups (Table). The mean (SD) age of patients was 37.5 (9.9) years.18 At baseline, the mean (SD) MMD was 8.3 (3.1) in the erenumab 140-mg group, 8.1 (2.6) in the erenumab 70-mg group, and 8.4 (2.7) in the placebo group. Most of the patients (68.0%) had either not received preventive migraine treatment or failed to benefit from such treatments previously. Baseline PRO scores were also comparable between the treatment groups (Table). Detailed patient demographics and disease characteristics are published elsewhere.18
Table.
Patient Demographic and Disease Characteristics in the EMPOwER Study
| Baseline demographic and clinical characteristics | |||
| Erenumab 140 mg (N = 224) | Erenumab 70 mg (N = 338) | Placebo (N = 338) | |
| Age, y, mean (SD) | 37.1 (9.6) | 37.3 (10.0) | 38.0 (10.1) |
| Female, n (%) | 184 (82.1) | 272 (80.5) | 281 (83.1) |
| Race, n (%) | |||
| Asian | 184 (82.1) | 278 (82.2) | 269 (79.6) |
| Black or African American | 0 (0) | 1 (0.3) | 0 |
| Native Hawaiian or Other Pacific Islander | 0 (0) | 0 (0) | 0 (0) |
| American Indian or Alaskan native | 0 (0) | 1 (0.3) | 1 (0.3) |
| Multiple | 8 (3.6) | 9 (2.7) | 5 (1.5) |
| Other | 13 (5.8) | 9 (2.7) | 13 (3.8) |
| White | 35 (15.6) | 58 (17.2) | 60 (17.8) |
| Ethnicity, n (%) | |||
| Not hispanic or latino | 198 (88.4) | 295 (87.3) | 280 (82.8) |
| Hispanic or latino | 18 (8.0) | 36 (10.7) | 51 (15.1) |
| Not reported | 2 (0.9) | 4 (1.2) | 4 (1.2) |
| Unknown | 6 (2.7) | 3 (0.9) | 3 (0.9) |
| Country | |||
| India | 94 (42.0) | 133 (39.3) | 124 (36.7) |
| Korea | 31 (13.8) | 46 (13.6) | 42 (12.4) |
| Taiwan | 30 (13.4) | 44 (13.0) | 56 (16.6) |
| Asia (excluding India, Korea, and Taiwan) | 37 (16.5) | 61 (18.0) | 51 (15.1) |
| Malaysia | 7 (3.1) | 17 (5.0) | 13 (3.8) |
| Philippines | 8 (3.6) | 8 (2.4) | 9 (2.7) |
| Singapore | 5 (2.2) | 6 (1.8) | 2 (0.6) |
| Thailand | 11 (4.9) | 24 (7.1) | 18 (5.3) |
| Vietnam | 6 (2.7) | 6 (1.8) | 9 (2.7) |
| Others | 32 (14.3) | 54 (16.0) | 65 (19.2) |
| Argentina | 14 (6.3) | 29 (8.6) | 38 (11.2) |
| Lebanon | 14 (6.3) | 20 (5.9) | 15 (4.4) |
| Mexico | 4 (1.8) | 5 (1.5) | 12 (3.6) |
| Body mass index, kg/m2 | 24.8 (4.3) | 24.4 (4.4) | 24.6 (4.5) |
| Previous prophylactic migraine treatment, n (%) | |||
| Yes | 119 (53.1) | 181 (53.6) | 179 (53.0) |
| No | 105 (46.9) | 157 (46.4) | 159 (47.0) |
| Previous prophylactic migraine treatment failure, n (%) | |||
| Yes | 72 (32.1) | 108 (32.0) | 108 (32.0) |
| No | 152 (67.9) | 230 (68.0) | 230 (68.0) |
| Monthly migraine d, mean (SD) | 8.3 (3.1) | 8.1 (2.6) | 8.4 (2.8) |
| Monthly headache d, mean (SD) | 9.5 (3.9) | 9.2 (2.7) | 9.2 (2.8) |
| Acute headache medication use, n (%) | |||
| Any acute medication | 207 (92.4) | 308 (91.1) | 313 (92.6) |
| Migraine specific | 81 (36.2) | 123 (36.4) | 127 (37.6) |
| Patient-reported outcomes at baseline | |||
| Mean (SD) | Erenumab 140 mg (n = 219) | Erenumab 70 mg (n = 329) | Placebo (n = 330) |
| HIT-6 score | 58.71 (7.0) | 58.79 (6.9) | 59.36 (6.7) |
| mMIDAS score | 12.69 (11.5) | 12.56 (10.6) | 13.91 (12.1) |
| MPFID-PI score | 11.11 (11.9) | 10.43 (8.9) | 11.14 (9.7) |
| MPFID-EA score | 11.97 (11.2) | 11.41 (8.4) | 12.44 (9.2) |
| EQ-5D-5L quality-of-life VAS score | 76.9 (17.4) | 78.3 (18.7) | 78.5 (16.5) |
| EQ-5D-5L quality-of-life index value | 0.938 (0.094) | 0.937 (0.113) | 0.924 (0.124) |
Abbreviations: EQ-5D-5L = EuroQoL 5-dimension 5-level scale; HIT-6 = Headache Impact Test; mMIDAS = modified Migraine Disability Assessment; MPFID-EA = Migraine Physical Function Impact Diary–Everyday Activity; MPFID-PI = Migraine Physical Function Impact Diary–Physical Impairment; VAS = visual analog scale.
HIT-6
At Month 3, the adjusted mean reductions from baseline in the HIT-6 total score were −9.34 for erenumab 140 mg, −8.39 for erenumab 70 mg, and −6.62 for placebo. Improvement in the adjusted mean HIT-6 scores observed for erenumab 140 mg was statistically significantly greater by 2.71 points (95% CI−4.07 to −1.36; p < 0.001) and for erenumab 70 mg by 1.77 points (95% CI −2.99 to −0.56; p = 0.004) compared with placebo (Figure 1). The intergroup difference in the mean HIT-6 scores exceeded the MID of −1.5 points at all time points, i.e., Months 1, 2, and 3 (p < 0.001).
Figure 1. Adjusted Mean Change From Baseline in HIT-6 Total Score by Visit (FAS).
HIT-6 total score. BL = baseline; FAS = full analysis set; HIT-6 = Headache Impact Test; PBO = placebo; SE = standard error; TD = treatment difference; vs = versus.
The proportion of patients with at least a 5-point reduction in the HIT-6 total score from baseline at Month 3 was 63.9% in the erenumab 140-mg group and 59.9% in the erenumab 70-mg group, compared with 52.9% in the placebo group; the corresponding ORs were 1.58 (95% CI 1.11–2.25; p = 0.010) and 1.33 (95% CI 0.98–1.82; p = 0.071), respectively.
MPFID
At Month 3, observed reduction from baseline in the mean MPFID PI scores was greater for erenumab 140 mg (−4.27) and erenumab 70 mg (−3.95) than for placebo (−2.31) (Figure 2A). The adjusted mean difference in the mean MPFID-PI scores at Month 3 was statistically significant for erenumab 140 mg (−1.96 [p = 0.014]) and for erenumab 70 mg (−1.64 [p = 0.021]) compared with placebo. At Months 1 and 2, the adjusted mean differences for erenumab 140 mg vs placebo were −1.52 and −1.91, respectively, and for erenumab 70 mg vs placebo were −1.40 and −2.16, respectively.
Figure 2. Adjusted Mean Change From Baseline in (A) MPFID-PI and (B) MPFID-EA Scores by Visit (FAS).
BL = baseline; EA = Everyday Activity; FAS = full analysis set; MPFID = Migraine Physical Function Impact Diary; PBO = placebo; PI = Physical Impairment; SE = standard error; TD = treatment difference; vs = versus.
The proportion of patients with at least a 5-point reduction from baseline in monthly average PI domain scores at Month 3 was 36.1% (OR, 1.03; 95% CI 0.72–1.47; p = 0.881) in the erenumab 140-mg group, 38.3% (OR, 1.13; 95% CI 0.82–1.55; p = 0.449) in the erenumab 70-mg group, and 35.5% in the placebo group.
At Month 3, the observed reduction from baseline in the mean MPFID-EA scores was greater in the erenumab treatment groups compared with the placebo group (erenumab 140 mg, −5.61; 70 mg, −4.94; placebo, −3.19) (Figure 2B). The adjusted mean difference in the mean MPFID-EA scores at Month 3 was statistically significant for erenumab 140 mg (−2.42 [p = 0.002]) and for erenumab 70 mg (−1.75 [p = 0.011]) compared with placebo. At Months 1 and 2, the adjusted mean differences for erenumab 140 mg vs placebo were −1.59 and −2.06, respectively, and for erenumab 70 mg vs placebo were −1.33 and −1.95, respectively.
The proportion of patients with at least a 5-point reduction from baseline in monthly average impact on MPFID-EA scores at Month 3 was 41.6% in the erenumab 140-mg group, 41.9% (OR, 1.10; 95% CI 0.80–1.50; p = 0.553) in the erenumab 70-mg group, and 39.7% in the placebo group.
mMIDAS Questionnaire
At Month 3, the adjusted mean change from baseline in mMIDAS scores was −8.99 for erenumab 140 mg, −8.11 for erenumab 70 mg, and −6.59 for placebo. A significant difference in adjusted means was observed for erenumab 140 mg vs placebo (−2.40 days; 95% CI −3.70 to −1.10; p < 0.001) and erenumab 70 mg vs placebo (−1.52 days; 95% CI −2.69 to −0.35; p = 0.011) (Figure 3).
Figure 3. Adjusted Mean Change From Baseline in mMIDAS scores by Visit (FAS).
BL = baseline; FAS = full analysis set; MIDAS = Migraine Disability Assessment; mMIDAS = modified MIDAS; OR = odds ratio; PBO = placebo; SE = standard error; TD = treatment difference; vs = versus.
Converted MIDAS
Because mMIDAS scoring relies on a 1-month recall period, the MIDAS disability categories were determined using converted MIDAS scores. A shift to a lower disability category compared with baseline was regarded as an improvement. At Month 3, the proportion of patients with improvement in MIDAS disability categories was greater in the erenumab 140-mg group (52.0%) and erenumab 70-mg group (55.1%) than in the placebo group (38.0%) (Figure 4).
Figure 4. Proportion of Patients With Improvement in Converted MIDAS Disability Categories at Month 3.
Converted MIDAS. MIDAS = Migraine Disability Assessment; OR = odds ratio; PBO = placebo; vs = versus.
EuroQoL 5-Dimension 5-Level Scale
At Month 3, the adjusted mean change from baseline in EQ-5D-5L QoL VAS score was 8.13 for erenumab 140 mg, 7.08 for erenumab 70 mg, and 5.22 for placebo. Greater improvement in adjusted means was observed for erenumab 140 mg vs placebo (2.91 days; 95% CI 0.52–5.29; p = 0.017) and erenumab 70 mg vs placebo (1.86 days; 95% CI −0.28 to 4.00; p = 0.088) (Figure 5A).
Figure 5. Adjusted Mean Change From Baseline in (A) EQ-5D-5L QoL VAS Scores (B) EQ-5D-5L QoL Index Values by Visit (FAS).
BL = baseline; EQ-5D-5L = EuroQoL 5-dimension 5-level scale; FAS = full analysis set; PBO = placebo; QoL = quality of life; SE = standard error; TD = treatment difference; VAS = visual analog scale; vs = versus.
The adjusted mean change from baseline in EQ-5D-5L QoL index values did not show significant differences between treatment groups at Month 3 (erenumab 140 mg, 0.032 [p = 0.830]; 70 mg, 0.037 [p = 0.268]; placebo, 0.030) (Figure 5B).
Discussion
The Phase 3 EMPOwER study assessed the efficacy and safety of erenumab in patients with EM from Asia, the Middle East, and Latin America.18 Exploratory analysis of PRO data from EMPOwER using HIT-6, MPFID, mMIDAS, and EQ-5D-5L showed greater improvement in the erenumab treatment groups (140 mg and 70 mg) than in the placebo group. Erenumab at the dose of 140 mg resulted in numerically higher improvements in PROs compared with the dose of 70 mg. However, formal statistical test was not performed to compare the efficacy between the 2 dose levels since it was not a part of original study design.
Growing evidence attributes the societal burden of migraine to the increased indirect costs due to migraine-related disability and impaired functioning.27,28 Hence, it is imperative that newly developed migraine preventive therapies are assessed for their ability to improve the QoL of patients with migraine, in addition to achieving the primary treatment goal of reduction in MMDs. The clinically meaningful reduction/improvement in PROs in the erenumab treatment groups compared with the placebo group was previously assessed using 2 complementary approaches: (1) by comparing well-established intergroup MIDs in patients with EM for the available PROs, i.e., HIT-6 (−1.5-point reduction)20 and MIDAS (−5-point reduction),20,24 and (2) by assessing improvement thresholds (i.e., proportion of patients achieving a ≥5-point reduction in HIT-6 and MPFID scores).20,22
In this study, the adjusted mean intergroup differences in HIT-6 scores exceeded the MIDs for both doses of erenumab compared with placebo at Month 1 and the results were sustained up to Month 3. In addition, a higher proportion of patients treated with erenumab achieved a ≥5-point reduction in HIT-6 scores. Furthermore, a numerically higher proportion of patients treated with erenumab achieved a ≥5-point reduction in MPFID-EA and MPFID-PI scores. Taken together, the results from this analysis confirm clinically meaningful improvements in migraine for individuals after erenumab treatment.
The observed reduction in functional outcome scores (MPFID, HIT-6) after each dose of erenumab vs placebo is in line with previous reports suggesting that the decrease in migraine frequency led to a reduced impact of migraine on an individual's physical functioning and other aspects of daily activities affected by headache.29 In this study, response to the treatment with erenumab could be observed from the first efficacy assessment time point at Month 1, suggesting that patients had an early benefit of treatment, which was sustained throughout the 3-month DBTP. At Month 3, the improvement from baseline in VAS scores was statistically significantly greater with erenumab 140 mg and numerically greater with erenumab 70 mg compared with placebo (the change was observed early after treatment initiation, starting from Month 1 [numerical difference]). These PRO parameters assess different aspects of an individual's social life and act as complementary data/evidence to the primary outcomes (MMDs, MHDs) for evaluating the effects of erenumab as a preventive therapy.
The PRO results from the EMPOwER study in patients with EM across Asia, the Middle East, and Latin America are consistent with the PRO data obtained from the pivotal erenumab studies (STRIVE and LIBERTY),30 which mostly included patients from North America and Europe.16,20 Of note, consistent with the STRIVE study,20 the improvement in PROs from baseline at Month 3 in the EMPOwER study was numerically greater in the erenumab 140-mg group than in the 70-mg group. The numerically greater improvements in PROs observed with erenumab 140 mg vs erenumab 70 mg support the findings from previously reported primary efficacy outcomes, i.e., reduction in MMDs, achievement of a ≥50% reduction from baseline in MMDs, and change from baseline in monthly acute migraine-specific medication treatment days.18
The study only included patients with EM; therefore, the results cannot be generalized to all patients with migraine, particularly those with CM. However, a double-blind, placebo-controlled study in patients with CM from the United States and European countries demonstrated that erenumab resulted in clinically relevant improvements across a broad range of PROs.31 In our study, the MID has not yet been established for mMIDAS and EQ-5D-5L scores, which limits the interpretation of the results. Our study used a 3-month duration for assessment, which was short. Further research is needed to assess the effect of erenumab on PROs over an extended period. Furthermore, PROs are prone to recall bias because they may not be recorded daily. To circumvent this, the site study staff trained the participants on how to use an eDiary, which was used to record the PROs, except for EQ-5D-5L. In addition, the participants were instructed to interact with the eDiary every day and to complete MPFID, during the baseline period and DBTP, as well as to bring the eDiary to every study visit.
In conclusion, consistent with the pivotal studies, the EMPOwER study demonstrated favorable and clinically meaningful treatment effects of erenumab (140 mg and 70 mg) compared with placebo, particularly in improving physical functioning and various daily activities affected by headaches, as measured by specific PRO scales in individuals with EM. Overall, complementary to the primary efficacy results, the PRO results further validate erenumab as an efficacious preventive therapy for patients with EM.
TAKE-HOME POINTS
→ Patient-reported outcomes (PROs) are key to assessing unique aspects of an individual's life, including the impact of headache on daily life activities, migraine-related disability, and overall health-related quality of life.
→ Effects of erenumab on PROs were not evaluated previously in patients with migraine across Asia, the Middle East, and Latin America.
→ Erenumab 140 mg and 70 mg produce a clinically meaningful improvement in most PROs (HIT-6 score, MPFID, and MIDAS) compared with placebo at Month 3.
→ These results enhance the evidence for erenumab as an effective preventive therapy for patients with episodic migraine.
Acknowledgment
Medical writing support was provided by Shashank Jain, Preethi Bheereddy, Fatima Hasan, Parag Betkar, and Rachna Shukla from Novartis Healthcare Pvt. Ltd, Hyderabad, India, and Janis Noonan from Novartis Ireland Limited, Dublin, Ireland. The final responsibility for the content lies with the authors.
Author Contributions
S.-J. Wang: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. A.A. Roxas: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. B. Saravia: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. B.K. Kim: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. D. Chowdhury: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. N.J. Riachi: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. M.-L.S. Tai: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. S. Tanprawate: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. T.N. Tran: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. Y.J. Zhao: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. W. Su: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. S. Wen: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. S. Mondal: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. L. Ecochard: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. M. Arkuszewski: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.
Study Funding
The study was supported by Novartis Pharma AG, Basel, Switzerland. Erenumab is co-developed by Amgen and Novartis.
Disclosure
S.-J. Wang has served on the advisory boards of Taiwan Pfizer, AbbVie, and Hava-Biopharma; has received honoraria as a moderator from AbbVie, Pfizer, and Biogen; and has been the PI in clinical trials sponsored by AbbVie, Novartis, Lundbeck, and Pfizer. He has received research grants from the National Council of Technology and Science of Taiwan, Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, Taipei Veterans General Hospital, and Taiwan branches of Eli Lilly and Novartis. A.A. Roxas Jr served as a speaker and member of the advisory board of Novartis for erenumab and was involved in Novartis erenumab trials for episodic migraine (EMPOwER) and chronic migraine (DRAGON). B. Saravia reports no disclosures. Y.J. Zhao has received honoraria from Lundbeck, Teva, DKSH, and Novartis and is part of the advisory boards of Lundbeck, Teva, and DKSH. B-K. Kim reported receiving consulting fees and honoraria from the Center for New Health Technology Assessment, National Pension Service, Eli Lilly, Allergan, Teva, Lundbeck, Sanofi Korea, SK Pharm, Yuyu Pharma, and Ildong Pharm. D. Chowdhury, N. Riachi, and M.-L.S. Tai received funding from Novartis for conducting the study. S. Tanprawate received research grants from the Faculty of Medicine, Chiang Mai University, and National Innovation Agency of Thailand and received honoraria as a lecturer from Allergan, Pfizer, Eli Lilly, Novartis, and Eisai. T.N. Tran received consultation and/or honoraria/lecture fees from Abbott, Boehringer-Ingelheim, Ipsen Pharmaceuticals, Medtronic, and Novartis and funding from Novartis for the conduct of this study. Mahan Chehrenama is an employee of and stockholder in Amgen Inc. W. Su and S. Wen are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ, and may own Novartis stocks. S. Mondal is an employee of Novartis Healthcare Pvt. Ltd. Hyderabad, India. L. Ecochard and M. Arkuszewski are employees of Novartis Pharma AG, Basel, Switzerland, and may own Novartis stocks. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this report are available on request from the author/investigators or Novartis Pharma AG, the company sponsoring this clinical research.