Benefits of eptinezumab on patient-reported disease burden and health-related quality of life in adults with chronic migraine and medication-overuse headache: Results from the placebo-controlled RESOLUTION trial

Abstract

Aim

The phase 4 RESOLUTION trial showed that, in comparison with placebo, adding eptinezumab—an anti-calcitonin gene-related peptide monoclonal antibody—to a brief educational intervention (BEI) reduced the monthly frequency of migraine, headache, and acute medication use in participants with chronic migraine (CM) and medication-overuse headache (MOH). Herein, we report data from multiple patient-reported outcomes (PROs) evaluating treatment impact on disease burden and health-related productivity and quality of life in the RESOLUTION trial.

Methods

RESOLUTION was a multi-national (conducted at 76 sites across 11 countries), double-blind, randomized, placebo-controlled trial. The trial comprised a 4-week screening period; a 12-week, double-blind, placebo-controlled period; a 12-week, open-label, extension period; and an 8-week, safety follow-up period, with results of the placebo-controlled period presented in this paper. Adults diagnosed with CM and MOH received a BEI and were randomized 1:1 to intravenous infusion with either eptinezumab 100 mg or placebo. Several PROs were assessed at baseline, Week 4, and Week 12, including the six-item Headache Impact Test (HIT-6), modified Migraine Disability Assessment (mMIDAS), Migraine-specific Work Productivity and Activity Impairment questionnaire (WPAI:M), Patient Global Impression of Change (PGIC; assessed only at follow-up), patient-identified most bothersome symptom (PI-MBS; assessed only at follow-up), Migraine-Specific Quality-of-Life questionnaire version 2.1 (MSQ v2.1), EQ-5D-5L visual analogue scale, and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; assessed only at follow-up). Post hoc analyses included responder rates for HIT-6 (i.e., participants with ≥5-point reduction from baseline), as well as for PGIC and PI-MBS (i.e., participants who reported “much improved” or “very much improved”).

Results

Of 608 participants randomized, the full-analysis set included 302 participants in the eptinezumab arm and 300 in the placebo arm. Eptinezumab with BEI was associated with more favorable PRO scores compared to placebo with BEI, starting at Week 4 (p < 0.05 for all comparisons) and up to Week 12 (p < 0.01 for all comparisons except WPAI:M absenteeism). Responder rates for HIT-6, PGIC, and PI-MBS also favored eptinezumab versus placebo.

Conclusions

In participants with CM and MOH who also received patient education, eptinezumab treatment resulted in greater reductions in headache impact and migraine disability than placebo, with greater improvements in productivity, quality of life, overall disease status, and treatment satisfaction starting from Week 4 and sustained to Week 12. Eptinezumab in combination with patient education is an effective treatment for reducing disease burden and improving overall quality of life in people with CM and MOH.

Trial registration

ClinicalTrials.gov Identifier: NCT05452239 (https://clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40)

Graphical abstract

This is a visual representation of the abstract.

Keywords

eptinezumab patient education patient-reported outcomes chronic migraine medication-overuse headache

Introduction

Migraine is a prevalent neurological disorder characterized by headache of at least moderate or severe pain intensity, accompanied by features such as phonophobia, photophobia, nausea, or vomiting, in various combinations.^1,2 The disorder is associated with health-related disability and burden,³ with reduced quality of life generally associated with increased frequency of monthly headache days.⁴ Although acute medication is commonly used for migraine relief, in many cases management of migraine exclusively using acute medications may not be sufficient for adequate control of the disease.⁵ In addition, frequent intake of acute medications may decrease their effectiveness over time.⁵ Episodic migraine (EM) can progress to chronic migraine (CM); this progression is associated with risk factors, including overuse of acute medications, and may result in development of medication-overuse headache (MOH).^3,6–8 MOH is a highly disabling disorder occurring in about 60 million people worldwide and causes substantial burden for individuals and the economy.^8–12 The primary headache disorder for approximately 80% of people with MOH is migraine, and people are given diagnoses of CM and MOH when meeting both criteria.^11,13

The International Classification of Headache Disorders, 3^rd edition (ICHD-3) defines MOH as a new type of headache or significantly worsening headache occurring ≥15 days per month in people with pre-existing headache and associated with regular overuse of symptomatic and/or acute headache medication for ≥3 months.^2,13 MOH can contribute to various negative outcomes, including decreased health-related quality of life, reduced productivity, increased life impact due to headaches, increased anxiety and depression symptoms, and frequent healthcare use.^8,14 The high incidence and burden of MOH emphasizes the importance of identifying an effective treatment strategy to prevent CM and reduce occurrence of MOH.¹⁵

The three treatment approaches for MOH that can be used are patient education, withdrawal from overused medication, and initiation of preventive therapy (pharmacological and non-pharmacological), sometimes used in various combinations.^{11,13,15–17} Medication withdrawal continues to be an established treatment method for MOH, with evidence that withdrawal can be achieved and medication days and headache disability can be improved using patient education.^18–20 A brief educational intervention (BEI) demonstrated efficacy for treatment of MOH; however, this may be insufficient to achieve optimal treatment results and may be more effective coupled with preventive treatment, although this is debated.^{16,18,21–23}

Eptinezumab, a high-affinity, humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb), is an approved preventive treatment for migraine.^24–26 Intravenous (IV) infusion of eptinezumab allows rapid binding to CGRP to inhibit its action and demonstrate efficacy in reducing migraine burden in participants as early as Day 1 of treatment.^24,25,27,28 Exploratory post hoc subgroup analysis in the PROMISE-2 trial demonstrated that eptinezumab reduced number of monthly migraine days (MMDs) and improved a variety of electronic patient-reported outcomes (ePROs) more than placebo for participants with both CM and MOH prospectively diagnosed at screening.^29,30

The phase 4 RESOLUTION trial evaluated the efficacy and safety of eptinezumab as an add-on to BEI for the treatment of migraine in participants diagnosed with CM and MOH, as defined by ICHD-3 criteria.^6,31 In the 12-week placebo-controlled period of the RESOLUTION trial,³¹ administration of eptinezumab 100 mg after BEI showed a similar safety profile as previously observed for eptinezumab alone.²⁷ The trial met the primary endpoint, with considerably greater reductions from baseline in MMDs at Weeks 1–4 with IV eptinezumab versus placebo as add-ons to BEI.³¹ All key secondary and most secondary endpoints were also met, with effects as early as Weeks 1–4 and across Weeks 1–12, collectively suggesting the benefits of not delaying effective anti-CGRP treatment, but rather initiating eptinezumab concurrently with BEI in patients with CM and MOH.³¹ Here, we report the effects of eptinezumab treatment on ePROs reflecting headache-related life impact, migraine-related disability, work productivity and activity impairment, overall and migraine-specific quality of life, and treatment satisfaction, at Week 4 and Week 12 of the RESOLUTION trial.

Methods

Trial design

RESOLUTION was a multi-center, parallel-group, double-blind, randomized, placebo-controlled phase 4 clinical trial conducted at 76 sites across 11 countries (Australia, Denmark, France, Georgia, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and the United States) from 1 July 2022 to 13 March 2025. This report describes results from the placebo-controlled period, with a primary completion date of 22 October 2024 and follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized controlled trials. The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable regulatory requirements. The appropriate ethics committee or institutional review board for each site approved the trial protocol, and all participants provided written informed consent before trial participation. The RESOLUTION trial is registered with ClinicalTrials.gov (NCT05452239) and EudraCT (2021-003049-40).

The protocol and statistical analysis plan for RESOLUTION have been published,^6,31 with key details summarized here. The trial consisted of a 4-week screening period, 12-week placebo-controlled period, 12-week open-label period, and 8-week safety follow-up period; further results of the placebo-controlled period are reported in this paper. Participants were randomized with stratification by country and number of previous preventive treatment failures (≤2, >2) over the past five years before baseline. The screening visit, IV infusion visits (i.e., baseline and Week 12), and Week 24 end-of-trial/withdrawal visit required on-site attendance; all other visits occurred through telephone or telemedicine. Participants completed an electronic diary (eDiary) for reporting migraine characteristics daily and completed ePROs at predefined time points in a remote setting throughout the trial period; completion of the eDiary was monitored regularly at on-site and decentralized visits to ensure adherence.

Eligibility criteria

Full exclusion and inclusion criteria, including disallowed or restricted concomitant medications, are detailed in the published protocol.^6,31 Eligible participants included adults aged 18−75 years (inclusive) with diagnoses of both CM and MOH, as defined by ICHD-3 criteria.² The trial investigators assessed CM and MOH based on ICHD-3 criteria, with the diagnostic criteria detailed in the published protocol (section 10.1.2 of eSAP1³¹). Participants were required to have a history of migraine onset for ≥12 months before the screening visit and a migraine onset at ≤50 years of age, as well as ≥8 MMDs and ≥15 monthly headache days within the three months before the screening visit. Eligibility also included >3 months of regular overuse of ≥1 drug that can be taken for symptomatic and/or acute treatment of headache and ≥1 preventive treatment failure within ≤5 years before the screening visit. Barbiturates and/or opioid analgesics were allowed, provided ≤4 intakes per month for ≥12 weeks before the screening visit and during the entire trial duration. Before randomization, participants were required to demonstrate compliance with the eDiary for ≥24 of 28 days.

Key exclusion criteria included previous anti-CGRP treatment failure; history or diagnosis of other headache disorders (including new daily persistent headache); severe psychiatric conditions with symptoms not adequately treated for ≥6 months before the screening visit; confounding and clinically significant pain syndromes (i.e., chronic low back pain, fibromyalgia, and complex regional pain syndrome); clinically significant cardiovascular disease; and acute or active temporomandibular disorders.

Treatments

At the baseline visit (Day 0), participants eligible for the trial were randomized 1:1 to receive an infusion with eptinezumab 100 mg or placebo, administered over 30–45 min. Before infusion of eptinezumab or placebo, all participants received a BEI performed by a trained clinician during the baseline visit to replicate treatment situations in the real world. The approximately 10-min BEI semi-structured conversation consisted of questions based on the Severity of Dependence Scale adapted for Headache medication, and presentations with the goal to educate participants on the consequences of medication overuse and to support a plan of ending acute migraine medication overuse while treatment with eptinezumab or placebo was initiated.²¹

Patient-reported outcome measures

The primary trial objective was to evaluate efficacy of eptinezumab compared to placebo as IV treatments added on to BEI for prevention of migraine. A secondary trial objective was to evaluate efficacy of eptinezumab on health-related quality of life and work productivity. The ePRO measures addressing the primary and secondary objectives included the six-item Headache Impact Test (HIT-6); modified Migraine Disability Assessment (mMIDAS); Migraine-specific Work Productivity and Activity Impairment questionnaire (WPAI:M); Patient Global Impression of Change scale (PGIC); patient-identified most bothersome symptom scale (PI-MBS); Migraine-Specific Quality-of-Life questionnaire, version 2.1 (MSQ v2.1); EuroQol EQ-5D-5L visual analogue scale (VAS); Hospital Anxiety and Depression Scale (results to be reported separately); and nine-item Treatment Satisfaction Questionnaire for Medicine (TSQM-9). PGIC and TSQM-9 were captured at Week 4 and Week 12, whereas PI-MBS was captured only at Week 12; all other ePROs were captured at baseline, Week 4, and Week 12. Changes from baseline at Weeks 4 and 12 for the ePROs total or domain score (or change from baseline at Week 12 only for WPAI:M domain scores, scores at Weeks 4 and 12 for PGIC and TSQM-9, and score at Week 12 for PI-MBS) were predefined secondary endpoints; PGIC score (Weeks 4 and 12) and PI-MBS score (Week 12) have been reported previously.³¹ Responder rates for HIT-6, PGIC, and PI-MBS were generated post hoc.

Participants received training on the daily headache eDiary and ePROs at the screening visit. The ePROs scheduled for baseline and Week 12 visits were to be completed at the clinical site on the visit date and before IV infusion of eptinezumab or placebo. ePROs scheduled for Week 4 were to be completed in a remote setting and completed on the day of or within three days before the scheduled date.

Participants reported headache-related impact on ability to function in daily life using HIT-6, an approximately five-minute questionnaire that assesses the effect of an occurring headache on ability to function in daily life. HIT-6 contains six questions (half with a four-week recall, half with no specified recall period), with each item rated as never (6), rarely (8), sometimes (10), very often (11), or always (13). HIT-6 total score ranges between 36 and 78 and is the sum of each response score, and is used to grade headache-related impact on life: severe (≥60), substantial (56–59), some (50–55), and little to none (≤49).^32,33 In people with CM, a ≥5-point reduction from baseline in HIT-6 total score is considered a clinically meaningful improvement.³³ In addition to the changes from baseline, a post hoc analysis of the percentage of participants with ≥5-point reduction from baseline in HIT-6 total score (i.e., HIT-6 responder rate) was conducted.

The mMIDAS questionnaire has a one-month recall period that assesses data of missed activities and days of reduced ability to engage in activities (reduced participation) in multiple domains, including school, work, social, family, and leisure activities during the past four weeks; five questions related to these domains are included in the total score.³⁴ The original Migraine Disability Assessment (MIDAS) scale has a three-month recall period, rendering it less suitable for clinical trials.³⁵ MIDAS also includes a question on monthly headache day frequency and another on pain intensity, which are not included in the total score.

WPAI:M assesses activities over the preceding seven days and consists of six questions: employment status (one item); number of hours worked, the number of hours missed from work due to the patient's condition, or due to other reasons (three items); and how much the participant's condition affects their ability to complete normal daily activities and their productivity at work (two visual numerical scales).³⁶ From these questions, four domains are calculated to quantify impairment due to migraine: absenteeism (percentage of work time missed), presenteeism (percentage of impairment while working), work productivity loss (percentage of overall work impairment), and activity impairment (percentage of activity impairment).

PGIC evaluates participants’ impression of change in their disease status related to activity limitations, emotions, symptoms, and overall quality of life since the baseline visit after treatment.³⁷ This single patient-reported item is rated on a seven-point scale where 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. The investigators also verbally obtained the most bothersome symptom (including nausea, vomiting, light or sound sensitivity, mental cloudiness, fatigue, pain during activity, mood changes, and other symptoms) associated with the participant's migraine during the screening visit. For the PI-MBS, participants rated the symptom improvement after treatment, using the same seven-point scale as the PGIC scale.³⁸ For both measures, a responder was defined as a participant who reported “much improved” or “very much improved”.

MSQ v2.1 assesses migraine-related quality of life in the past four weeks, with higher scores indicating better quality of life. It consists of 14 items that lead to scores in three domains: role function–restrictive (seven items); role function–preventive (four items); and emotional function (three items). Each item is scored on a six-point scale ranging from 1 (never) to 6 (always); raw domain scores are summed and transformed to a scale ranging from 0–100.³⁹

Participants reported their overall current health state using the short VAS assessment from the EQ-5D-5L instrument. VAS scores range from 0 (worst imaginable) to 100 (best imaginable health state).⁴⁰ Participants were asked to report on their health state on the day they completed the item.

The TSQM-9 generic questionnaire, consisting of nine items addressing convenience, effectiveness, and overall satisfaction, assessed participants’ treatment satisfaction.⁴¹ Each item is rated on a seven-point scale from 1 (extremely dissatisfied) to 7 (extremely satisfied), with each domain score ranging from 0 to 100 and higher scores representing higher satisfaction.

Statistical analyses

The ePRO data were analyzed in the full-analysis set (all treated participants who had a valid baseline assessment and had ≥1 valid four-weekly post-baseline assessment of MMDs during Weeks 1–12). Similar to the approach for the primary endpoint, continuous ePRO endpoints were analyzed using mixed models for repeated measures (MMRM). These models included the following fixed effects: baseline score as a continuous covariate, treatment group (eptinezumab vs. placebo), month (Month 1: Weeks 1–4; Month 2: Weeks 5–8; Month 3: Weeks 9–12), country, and previous preventive treatment failures (≤2, >2) as factors. The interaction terms treatment-by-month and previous treatment failures (≤2, >2) by month and baseline score-by-month were included. An unstructured covariance matrix was used to model between- and within-participant covariance. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. Least-squares (LS) means, LS mean changes from baseline, treatment differences, and 95% confidence intervals (CI) were derived from this model. The treatment difference estimates and 95% CI were built on LS means presented throughout this paper. For TSQM-9, no baseline score was included in the model.

Comparisons for post hoc analyses of HIT-6, PGIC, and PI-MBS responder rates were based on a logistic regression model using Firth's penalized likelihood and included treatment, country, and stratification as factors and baseline number of MMDs as a continuous covariate. Odds ratios for eptinezumab compared to placebo were estimated from the model and presented with 95% CIs based on the profile-likelihood and p-values based on the penalized likelihood ratio test.

The derivation of ePRO sub-scale and total scores was detailed in the statistical analysis plan, including strategies for calculating sub-scale and total scores with missing item scores.³¹ As prespecified, only analyses for primary and key secondary efficacy endpoints were controlled for multiplicity; thus, all other p-values are descriptive and not adjusted for multiplicity. P-values were based on two-sided tests. All statistical analyses were done using SAS (version 9.4; SAS Institute, Inc., Cary, NC).

Results

Participants

Of 608 randomized adults who met eligibility criteria, 596 (98.0%) completed the 12-week placebo-controlled period. The all-participants-treated set comprised 604 participants (eptinezumab, n = 303; placebo, n = 301) and the full-analysis set comprised 602 participants (eptinezumab, n = 302; placebo, n = 300) (Table 1). Detailed demographics were reported previously.³¹

Table 1.

Demographics and baseline ePRO scores.

	Eptinezumab with BEI	Placebo with BEI	Total
Demographics,* N	303	301	604
Age (years), mean (SD)	45.7 (12.0)	45.2 (12.0)	45.5 (12.0)
Sex, n (%)
Female	264 (87.1%)	253 (84.1%)	517 (85.6%)
Male	39 (12.9%)	48 (15.9%)	87 (14.4%)
Geographic region, n (%)
Europe	296 (97.7%)	295 (98.0%)	591 (97.8%)
Australia	5 (1.7%)	4 (1.3%)	9 (1.5%)
United States	2 (0.7%)	2 (0.7%)	4 (0.7%)
Baseline disease characteristics,* N	303	301	604
Acute headache medication taken during screening period,^† n (%)
Triptan/ergotamine	264 (87.1%)	271 (90.0%)	535 (88.6%)
Opioid analgesics	11 (3.6%)	5 (1.7%)	16 (2.6%)
Combination of analgesics	58 (19.1%)	50 (16.6%)	108 (17.9%)
Non-opioid analgesics	249 (82.2%)	238 (79.1%)	487 (80.6%)
Baseline clinical characteristics,^‡ N	302	300	602
MMDs, mean (SD)	21.0 (4.3)	20.9 (4.3)	20.9 (4.3)
MHDs, mean (SD)	21.8 (3.9)	21.7 (4.0)	21.7 (3.9)
Monthly days with use of acute migraine medication, mean (SD)	20.1 (4.3)	20.1 (4.5)	20.1 (4.4)
HIT-6 total score, mean (SD)	66.4 (5.0)	66.5 (5.0)	66.5 (5.0)
mMIDAS total score, mean (SD)	33.1 (19.5)	29.9 (19.8)	31.5 (19.7)
WPAI:M domain score: Absenteeism, mean (SD)	19.2 (28.7)	13.9 (23.5)	16.5 (26.3)
WPAI:M domain score: Presenteeism, mean (SD)	56.3 (21.2)	57.7 (21.2)	57.0 (21.2)
WPAI:M domain score: Work productivity loss, mean (SD)	60.5 (22.7)	61.0 (22.2)	60.8 (22.4)
WPAI:M domain score: Activity impairment, mean (SD)	62.1 (20.1)	62.6 (20.2)	62.4 (20.2)
MSQ v2.1 domain score: Role function–restrictive, mean (SD)	34.5 (17.6)	34.9 (18.9)	34.7 (18.2)
MSQ v2.1 domain score: Role function–preventive, mean (SD)	52.3 (22.1)	51.3 (22.4)	51.8 (22.2)
MSQ v2.1 domain score: Emotional function, mean (SD)	43.2 (25.8)	41.3 (26.4)	42.3 (26.1)
EQ-5D-5L VAS score, mean (SD)	65.3 (20.1)	67.2 (19.4)	66.3 (19.8)

Percentage values may not add to 100% due to rounding.

*Data were collected at the first screening visit and analyzed in the all-participants-treated set.

†

Participants may have taken more than one type of medication. Opioid analgesics were only permitted up to 4 days per month.

‡

Baseline values calculated from the eDiary during the screening period (MMDs, MHDs, and monthly days with use of acute migraine medication) or during the baseline visit (all ePROs) and analyzed in the full-analysis set.

Abbreviations: BEI, brief educational intervention; eDiary, electronic diary; ePRO, electronic patient-reported outcome; HIT-6, six-item Headache Impact Test; MHDs, monthly headache days; MMDs, monthly migraine days; mMIDAS, modified Migraine Disability Assessment; MSQ, Migraine-Specific Quality of Life questionnaire (version 2.1); SD, standard deviation; VAS, visual analogue scale; WPAI:M, Migraine-specific Work Productivity and Activity Impairment questionnaire.

Participants were predominantly female (517/604 [85.6%]), based in Europe (591/604 [97.8%]), and had a mean age of 45.5 years. Baseline mean scores for ePROs were similar between both treatment groups, with participants experiencing moderate to severe disease burden from CM and MOH on average (Table 1).

Disease-specific effect on functioning (disability scales)

Table S1 details the impact of treatment across ePRO endpoints.

HIT-6 total scores improved more in the eptinezumab arm compared with the placebo arm at both Week 4 (−6.3 and −2.3, respectively; difference vs. placebo: −4.0, p < 0.0001) and Week 12 (−7.1 and −3.6, respectively; difference vs. placebo: −3.5, p < 0.0001) (Figure 1(a)).

Figure 1.

Change from baseline in (a) HIT-6 total score and (b) mMIDAS total score. HIT-6 contains six questions; each item is rated with the following response scores: never (6), rarely (8), sometimes (10), very often (11), and always (13). The total score is the sum of each response score and ranges between 36 and 78. Life impact derived from the total score is described as follows: severe (≥60), substantial (56–59), some (50–55), little to none (≤49). A decrease from baseline in the HIT-6 total score indicates improvement. HIT-6 total score was analyzed in the full-analysis set using a mixed model for repeated measures, which included baseline HIT-6 total score as a continuous covariate, treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week as well as HIT-6 total score at baseline-by-week. mMIDAS measures the total number of days with disability. A decrease from baseline in the mMIDAS total score indicates improvement. mMIDAS total score was analyzed in the full-analysis set using a mixed model for repeated measures, which included the following fixed effects: baseline mMIDAS total score as a continuous covariate, treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week, as well as mMIDAS total score at baseline-by-week. Abbreviations: HIT-6, six-item Headache Impact Test; mMIDAS, modified Migraine Disability Assessment; SE, standard error.

The mMIDAS total score improved more in the eptinezumab arm than in the placebo arm at both Week 4 (−14.7 and −6.6, respectively; difference vs. placebo: −8.1, p < 0.0001) and Week 12 (−13.8 and −8.8, respectively; difference vs. placebo: −5.1, p < 0.001) (Figure 1(b)).

The eptinezumab arm showed greater improvements than the placebo arm in WPAI:M domain scores at Week 4 and Week 12, except for WPAI:M absenteeism at Week 12 (Figure 2(a)). The change in the WPAI:M presenteeism score was −20.3 with eptinezumab and −7.2 with placebo, with a difference of −13.1 from placebo (p < 0.0001) at Week 4; at Week 12, the change was −19.1 with eptinezumab and −10.1 with placebo, with a difference of −9.0 from placebo (p = 0.001) (Figure 2(b)). Similar results to WPAI:M presenteeism were observed for WPAI:M work productivity loss (Figure 2(c)) and WPAI:M activity impairment (Figure 2(d)).

Figure 2.

Change from baseline in WPAI:M domain scores: (a) absenteeism, (b) presenteeism, (c) work productivity loss, and (d) activity impairment. WPAI:M assesses activities over the preceding seven days and consists of six items: one item assesses employment status; three items assess the number of hours worked/number of hours missed from work due to the patient’s migraine condition or due to other reasons; and two visual numerical scales assess how much the patient’s condition affects their productivity at work and their ability to complete normal daily activities. A decrease from baseline in WPAI:M domain score indicates improvement. WPAI:M sub-scores were analyzed in the full-analysis set using a mixed model for repeated measures, which included the following fixed effects: baseline WPAI:M sub-score as a continuous covariate, treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week as well as WPAI:M sub-score at baseline-by-week. Abbreviations: SE, standard error; WPAI:M, Migraine-specific Work Productivity and Activity Impairment questionnaire.

Effect on headache-related life impact, most bothersome symptom, and global impression of change in disease status

A higher proportion of participants in the eptinezumab arm than in the placebo arm achieved a clinically meaningful reduction in HIT-6 total score at both Week 4 (144/276 [52.2%] vs. 75/268 [28.0%], with an odds ratio of 2.9 vs. placebo [p < 0.0001]) and Week 12 (148/279 [53.0%] vs. 98/274 [35.8%], with an odds ratio of 2.1 vs. placebo [p < 0.0001]) (Figure 3(a)).

Figure 3.

Proportion of (a) HIT-6 responders, (b) PGIC responders, and (c) PI-MBS responders. Participants were considered HIT-6 responders if they experienced ≥5-point reduction from baseline in HIT-6 total score. Both the PGIC and PI-MBS were rated using an identical seven-point scale ranging from 1 (very much improved) to 7 (very much worse). Participants were considered PGIC responders if they rated the PGIC “very much improved” or “much improved” and were PI-MBS responders if they rated the PI-MBS “very much improved” or “much improved”. Post hoc analyses. For each measure, the proportion of responders was analyzed in the full-analysis set; comparisons were based on a logistic regression model using Firth's penalized likelihood and included treatment, country, and stratification as factors and baseline number of monthly migraine days as a continuous covariate. The odds ratio for eptinezumab compared to placebo was estimated from the model and presented with p-values based on the penalized likelihood ratio test and 95% confidence intervals based on the profile-likelihood. Odds ratios (95% confidence interval) and p-values for eptinezumab vs. placebo are reported above the bars. Abbreviations: HIT-6, six-item Headache Impact Test; PGIC, Patient Global Impression of Change scale; PI-MBS, patient-identified most bothersome symptom scale.

Reported previously, the eptinezumab arm demonstrated better PGIC (both Weeks 4 and 12) and PI-MBS (Week 12) scores compared to the placebo arm.³¹ Post hoc analyses here found a greater percentage of PGIC responders (i.e., participants who reported “very much improved” or “much improved”) in the eptinezumab arm than in the placebo arm at Week 4 (139/279 [49.8%] vs. 41/274 [15.0%], with an odds ratio of 6.3 vs. placebo [p < 0.0001]). At Week 12, a greater percentage of participants in the eptinezumab arm than in the placebo arm were PGIC responders (Figure 3(b)) and PI-MBS responders (Figure 3(c)).

Effect of treatment on migraine-specific quality of life

Improvements in MSQ scores were greater for the eptinezumab arm than the placebo arm in all three domains at both Week 4 and Week 12 (Figure 4). The change in role function–restrictive score was 24.0 with eptinezumab vs. 10.2 with placebo (difference vs. placebo: 13.9, p < 0.0001) at Week 4; at Week 12, the change was 22.6 with eptinezumab and 11.8 with placebo (difference vs. placebo: 10.8, p < 0.0001) (Figure 4(a)). Similar improvements were observed for role function–preventive (Figure 4(b)) and emotional function (Figure 4(c)) scores.

Figure 4.

Change from baseline in MSQ v2.1 domain scores: (a) role function–restrictive, (b) role function–preventive, and (c) emotional function. MSQ v2.1 consists of 14 items assessing migraine-specific quality of life, which cover three domains: role function-restrictive (seven items); role function-preventive (four items); and emotional function (three items). Each item is scored on a six-point scale ranging from 1 (none of the time) to 6 (all the time). Scores range from 0–100, with higher scores indicating better quality of life. MSQ v2.1 sub-scale scores were analyzed in the full-analysis set using a mixed model for repeated measures, which included the following fixed effects: baseline MSQ v2.1 sub-score as a continuous covariate, treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week as well as MSQ v2.1 sub-score at baseline-by-week. Abbreviations: MSQ v2.1, Migraine-Specific Quality of Life questionnaire version 2.1; SE, standard error.

The change in EQ-5D-5L VAS score was greater for the eptinezumab arm than the placebo arm at both Week 4 (5.1 and 0.5, respectively [difference vs. placebo: 4.6, p < 0.01]) and Week 12 (7.4 and 2.2, respectively [difference vs. placebo: 5.2, p < 0.001]) (Figure 5).

Figure 5.

Change from baseline in EQ-5D-5L VAS score. The EQ-5D-5L VAS ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Increase from baseline in EQ-5D-5L VAS score indicates improvement. EQ-5D-5L VAS score was analyzed in the full-analysis set using a mixed model for repeated measures, which included the following fixed effects: baseline EQ-5D-5L VAS score as a continuous covariate, treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week as well as EQ-5D-5L VAS score at baseline-by-week. Abbreviations: SE, standard error; VAS, visual analogue scale.

Medication satisfaction

TSQM-9 effectiveness scores for the eptinezumab arm compared with the placebo arm at Week 4 were 58.2 versus 39.0, with a mean difference of 19.2 (p < 0.0001); at Week 12, the score was 58.0 versus 40.9, with a mean difference of 17.1 (p < 0.0001) (Figure 6(a)). TSQM-9 scores for convenience (Figure 6(b)) and overall satisfaction (Figure 6(c)) were also higher with the eptinezumab arm than with the placebo arm at both Week 4 and Week 12.

Figure 6.

TSQM-9 domain scores: (a) effectiveness, (b) convenience, and (c) overall satisfaction. TSQM-9 consists of nine items, which address effectiveness, convenience, side effects, and overall participant satisfaction of the treatment. Higher TSQM-9 domain scores are better. TSQM-9 score was analyzed in the full-analysis set using a mixed model for repeated measures, which included the following fixed effects: treatment group, week (Week 4, Week 12), country, and previous treatment failures (≤2, >2) as factors. The following interaction terms were included: treatment-by-week and previous treatment failures-by-week. Abbreviations: SE, standard error; TSQM-9, 9-item Treatment Satisfaction Questionnaire for Medicine.

Discussion

Patient education about MOH is a safe intervention that can be effective in reducing medication use in people with MOH.^18,19 However, preventive therapy combined with education may be necessary for further improving outcomes.^16,31 RESOLUTION is the first randomized, double-blinded, placebo-controlled trial to demonstrate that the addition of eptinezumab, an anti-CGRP mAb, to patient education about MOH is associated with better outcomes than placebo with patient education for participants with CM and MOH. Indeed, the primary results of RESOLUTION demonstrated that, compared with placebo as an add-on to BEI, eptinezumab 100 mg as an add-on to BEI led to statistically significant reductions in the primary and all key secondary efficacy outcomes, with effects observed as early as Weeks 1–4 and across Weeks 1–12, as well as more favorable PGIC (both Weeks 4 and 12) and PI-MBS (Week 12) scores.³¹ In the present analysis, eptinezumab with BEI demonstrated advantages compared with placebo with BEI across multiple ePROs capturing various aspects of disease burden. These results support the value of eptinezumab with patient education as a preventive treatment for CM with MOH.

Utilization of ePROs is valuable for assessing effects of CM and MOH on associated disability and health-related quality of life.^29,42 Eptinezumab-treated participants reported greater improvements compared with placebo-treated participants in many ePROs measuring headache-related life impact, migraine-related disability, work productivity and activity impairment, migraine-specific quality of life, overall disease status, and treatment satisfaction. Beneficial effects were seen across all ePRO measures as early as Week 4 (p < 0.05 for all comparisons), with results generally sustained at Week 12 (p < 0.01 for all comparisons, except p = 0.19 for WPAI:M absenteeism).

The decreases observed in HIT-6 total score, mMIDAS total score, and WPAI:M domain scores (presenteeism, work productivity loss, and activity impairment) with eptinezumab treatment indicated greater improvements than placebo in disability, disease-related productivity, and functioning. Post hoc analyses demonstrated that a greater proportion of participants in the eptinezumab arm compared with the placebo arm were responders on HIT-6, PGIC, and PI-MBS measures, indicating clinically meaningful, multidimensional impacts of treatment on overall disease status. Improvements in overall quality of life were also shown by greater increases in MSQ v2.1 domain scores (role function–restrictive, role function–preventive, and emotional function) and EQ-5D-5L VAS score in eptinezumab-treated participants than with placebo-treated participants. The TSQM-9 domain scores were also better with eptinezumab than with placebo at both Week 4 and Week 12, indicating higher effectiveness, convenience, and overall satisfaction.

The beneficial effect of eptinezumab on the mMIDAS score in comparison to placebo was of particular interest because MIDAS is the most widely used PRO in migraine prevention clinical trials and provides an efficient assessment of migraine disability.³⁵ Moreover, the four-week recall period of the mMIDAS limits recall bias and may improve accuracy of results.³⁴ Because CM and MOH can cause debilitating life impact, reductions in mMIDAS scores represent valuable clinical benefit.

Despite improvements in most ePROs, the WPAI:M domain scores for absenteeism did not differ between treatment groups at Week 12, although they trended in the expected direction. WPAI:M has a seven-day recall period and absenteeism was only reported in a small percentage of participants in the trial, in agreement with available literature on people with CM.^10,36,43 Additionally, employed people with frequent migraine tend to go to work and experience reduced effectiveness in the form of presenteeism, which might lead to more lost productivity time than that captured by absenteeism.^10,43 Given that differences were demonstrated at Week 4 for absenteeism and at Week 4 and Week 12 for presenteeism and total work productivity loss, the data presented suggest that, in comparison with people treated with placebo, those treated with eptinezumab have better outcomes overall in the domain of workplace productivity.

Previous clinical trials of anti-CGRP mAbs demonstrated improved quality-of-life outcomes for people with MOH.^29,42 A ≥5-point improvement in HIT-6 total score was established as a clinically meaningful threshold,³³ indicating that mean changes in HIT-6 total score at both Week 4 and Week 12 (−6.3 and −7.1, respectively for eptinezumab, compared with −2.3 and −3.6 for placebo) of the RESOLUTION trial, were of notable magnitude. These results validate findings from the CM and MOH subgroup in the 24-week phase 3 PROMISE-2 trial, which demonstrated clinically meaningful improvements in mean HIT-6 total scores with eptinezumab treatment (−6.9 at Week 4, with benefits sustained at Week 12 and up to Week 24).²⁹ Moreover, HIT-6 scores in the RESOLUTION trial parallel those in the phase 4 randomized controlled trial for the anti-CGRP mAb erenumab.⁴² In participants diagnosed with both CM and MOH, erenumab 140 mg resulted in a mean change in HIT-6 total score of −8.8 (−3.8 relative to placebo [p < 0.001]) over Weeks 13–24.⁴² Together, these findings indicate that treatment with an anti-CGRP mAb can improve quality of life for people with CM and MOH, although longer-term clinical trials are lacking. When added to the other findings, the RESOLUTION trial suggests a paradigm change for optimal CM and MOH management.

There are potential limitations to this trial. Secondary endpoints were not controlled for multiplicity, increasing risk of a false-positive result. However, consistency of positive findings across ePRO endpoints suggests these results are unlikely to be due to chance. The trial excluded people with frequent opioid and/or barbiturate use (with use before and during the trial limited to ≤4 days per month), introducing the possibility that the patient-reported benefits observed in the RESOLUTION trial may not be generalizable to those with opioid-overuse headache. Benefits of treatment were also limited by potential variations in how well participants adhered to the education about MOH. Moreover, cultural differences among the various countries where the trial was conducted could have affected treatment methods and results, including how patient education was implemented by physicians and how participants responded to ePROs. As most trial participants were from Europe, generalizability of the results to other regions is limited. Lastly, the short duration of the placebo-controlled period precludes conclusions about longer-term outcomes of the treatment.

Conclusions

In participants diagnosed with CM and MOH who also received a brief educational intervention, treatment with eptinezumab led to more favorable improvements than placebo in patient-reported outcomes capturing headache-related life impact, migraine-related disability, work productivity and activity impairment, overall and migraine-specific quality of life, and treatment satisfaction. Benefits were observed for all outcome measures as early as Week 4 (first post-baseline timepoint), with most measures sustained to Week 12. These findings support benefits of eptinezumab in combination with patient education in management of CM and MOH.

Highlights

The phase 4, randomized, double-blind, placebo-controlled RESOLUTION trial evaluated eptinezumab versus placebo when added to patient education for the treatment of chronic migraine and medication-overuse headache.

When added to patient education, eptinezumab was associated with more favorable improvements than placebo in patient-reported outcomes related to disease burden, work productivity, and quality of life at Week 4 and Week 12.

Supplemental Material

sj-docx-1-cep-10.1177_03331024261449814 - Supplemental material for Benefits of eptinezumab on patient-reported disease burden and health-related quality of life in adults with chronic migraine and medication-overuse headache: Results from the placebo-controlled RESOLUTION trial

Supplemental material, sj-docx-1-cep-10.1177_03331024261449814 for Benefits of eptinezumab on patient-reported disease burden and health-related quality of life in adults with chronic migraine and medication-overuse headache: Results from the placebo-controlled RESOLUTION trial by Stewart J. Tepper, Henrik W. Schytz, Rigmor H. Jensen, Christofer Lundqvist, Gisela M. Terwindt, Cristina Tassorelli, Fabrizio Vernieri, Michel Lantéri-Minet, Andrew Blumenfeld, Mette Krog Josiassen, Gary Jansson, Anders Ettrup, Aurélia Mittoux and Richard B. Lipton in Cephalalgia

Footnotes

Acknowledgements

The authors thank the participants, their families, and the sites that participated in this trial. Assistance with medical writing and manuscript preparation was funded by H. Lundbeck A/S and provided by Brittany Friedson, PhD, and Nicole Coolbaugh, CMPP, of The Medicine Group, LLC (New Hope, PA, USA) in accordance with Good Publication Practice guidelines.

ORCID iDs

Stewart J. Tepper

Henrik W. Schytz

Rigmor H. Jensen

Christofer Lundqvist

Gisela M. Terwindt

Cristina Tassorelli

Fabrizio Vernieri

Michel Lantéri-Minet

Andrew Blumenfeld

Mette Krog Josiassen

Gary Jansson

Anders Ettrup

Aurélia Mittoux

Richard B. Lipton

Author contributions

AB, AM, CL, CT, GMT, HWS, MKJ, RBL, RHJ, and SJT contributed to the conception or design of the trial.

AM contributed to obtaining funding.

CL, CT, FV, GMT, HWS, and ML-M were trial investigators, contributing to the acquisition of the data.

GJ and MKJ have directly accessed and verified the underlying data reported in the manuscript.

GJ and MKJ contributed to the statistical analyses, and all authors contributed to the interpretation of data.

All authors were involved in drafting the manuscript and critically reviewed the manuscript for important intellectual content.

Consent to participate

All participants provided written informed consent before trial participation.

Consent for publication

All authors confirm that they had full access to all the data in the trial, provided final approval of the manuscript content for submission, and had final responsibility for the decision to submit for publication.

Ethical considerations

The trial was designed in accordance with the Declaration of Helsinki and was conducted in compliance with the protocol, Good Clinical Practice guidelines, and all applicable regulatory requirements. The trial was approved by the ethics committee or institutional review board for each site. All participants provided written informed consent before trial participation.

Declaration of conflicting interests

SJT reports grants for research from AbbVie, Aeon, Amgen, Annovis, Axsome, Cassava, Cognition, Eli Lilly, Inhibikase, Ipsen, Lundbeck, Merz, Neurolief, Pfizer, PrecisionMed, Revance, Scilex, Suven, and UCB; has served as a consultant and/or on advisory boards (honoraria) for AbbVie, Aeon, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, Catch Therapeutics, ClearView Healthcare Partners, Click Therapeutics, CoolTech, CRG, Decision Resources, Defined Health, DRG, Dr Reddy's, Eli Lilly, ExpertConnect, FCB Health, Fenix, Gilmartin Capital, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, Initiator Pharma, Interactive Forums, IQVIA, Keyquest, Ki Health Partners, Krog and Partners, Lundbeck, M3 Global Research, Magellan Health, Magnolia Innovation, Miravo Healthcare, MJH Holdings, Neurofront Therapeutics, Neurolief, Nocira, Novartis, P Value Communications, Pain Insights, Palion Medical, Perfood, Pfizer, Pulmatrix, Putnam Associates, Rehaler, SAI MedPartners, Satsuma, Scilex, Slingshot Insights, Spherix Global Insights, Strategy Inc, Synapse Medical Communication, System Analytic, Taylor and Francis, Tegus, Teva, Theranica, Third Bridge, Tonix, Trinity Partners, Unity HA, Vial, and Xoc; receives salary from Dartmouth-Hitchcock Medical Center, Thomas Jefferson University, and Ki Health Partners; serves as a speaker for AbbVie, Dr Reddy's, Eli Lilly, Lundbeck, Pfizer, Scilex, Teva, and Tonix; and received continuing medical education honoraria from the American Academy of Neurology, American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, HMP Global, Medical Education Speakers Network, Medical Learning Institute, Migraine Association of Ireland, Miller Medical Education, National Association for Continuing Education, North American Center for CME, The Ohio State University, PeerView, Physicians’ Education Resource, PlatformQ Education, Primed, Vindico Medical Education, and WebMD/Medscape.

HWS has received personal fees from AbbVie, Teva, Lundbeck, Novartis, and Eli Lilly, and research grants from Novartis and Novo Nordisk Foundation.

RHJ has given lectures for Allergan, ATI, Eli Lilly, Lundbeck, Merck, Novartis, Pfizer, and Teva; served as investigator in clinical trials with ATI, Eli Lilly, Lundbeck, Novartis, and Novo Nordisk; is the director of the Danish Headache Center, Lifting The Global Burden of Headache, and founder of Master of Headache Disorders at University of Copenhagen; and has received research funding from ATI, Lundbeck Foundation, Novo Nordisk Foundation, Rigshospitalet, The Medical Society in Copenhagen, Tryg Foundation, and University of Copenhagen.

CL has participated on advisory boards and received payment for lectures arranged by AbbVie, Lundbeck, Novartis AS, and Roche AS, Norway, and has received research sponsorship from AbbVie Pharma.

GMT reports grants or consultancy support from AbbVie, Lilly, Lundbeck, Novartis, Organon, Pfizer, Salvia, Teva, Interactive studios, and independent support from the IRRF, Dioraphte foundation, Clayco foundation, Dutch Research Council, Dutch Heart Foundation, Dutch Brain Foundation, and the European Community

CT in the past 3 years has received support (financial or pharmaceutical products) from AbbVie and Novartis for an investigator-initiated trial; consulting fees for the participation in advisory boards for AbbVie, Dompé, Eli Lilly, Ipsen, Lundbeck, Medscape, Organon, Pfizer, and Teva; honoraria for scientific lectures and presentations from AbbVie, Eli Lilly, Lundbeck, Pfizer, Organon and Teva; support for attending meetings from AbbVie, Dompé, Eli Lilly, Ipsen, Lundbeck, Pfizer, and Teva; has been Principal Investigator in clinical trials sponsored by AbbVie, Biohaven, Eli Lilly, Ipsen, Lundbeck, Pfizer, and Teva; and received grants from the European Commission, the Italian Ministry of Health, and the Italian Ministry of University.

FV has received financial support from AbbVie, Angelini, and Lundbeck for investigator-initiated trials; consulting fees for the participation in advisory boards from AbbVie, Angelini, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer, and Teva; honoraria for scientific lectures and presentations from AbbVie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva; support for attending meetings from AbbVie, Eli Lilly, Lundbeck, Organon, Pfizer, and Teva; has been Principal Investigator in clinical trials sponsored by AbbVie, Eli Lilly, Lundbeck, Pfizer, and Teva.

ML-M reports personal fees for advisory boards, speaker panels, or investigation studies from Allergan, Amgen, Astellas, ATI, BMS, Boehringer, Boston Scientific, CoLucid, Convergence, Eli Lilly, GlaxoSmithKline, Grunenthal, Eli Lilly, Ipsen, Lundbeck, Medtronic, MSD, Novartis, Orion, Perfood, Pfizer, Reckitt Benckiser, Saint-Jude, Salvia BioElectronics, Sanofi-Aventis, Teva, UCB, UPSA, and Zambon.

AB has served on advisory boards for AbbVie, Aeon, Alder, Amgen, Biohaven, Eaglet, Eli Lilly, Impel, Lundbeck, Novartis, Promius, Revance, Supernus, and Teva; and has received funding for speaking from AbbVie, Amgen, Avanir, Biohaven, Depomed, Eli Lilly, Impel, Lundbeck, Pernix, Promius, Supernus, and Teva.

MKJ is a full-time employee of H. Lundbeck A/S and owns stock or stock options in H. Lundbeck A/S.

GJ, AE, and AM are full-time employees of H. Lundbeck A/S.

RBL receives research support from the National Institutes of Health and the United States Food and Drug Administration. He serves as consultant for and/or advisory board member of—or has received honoraria or research support from—AbbVie/Allergan, Amgen, Axsome, Biohaven, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Vector, and Vedanta Research. He also holds stock/options in NuVieBio, Biohaven, CoolTech, and Manistee.

Funding

The clinical trial, post hoc data analysis, and medical writing support were sponsored and funded by H. Lundbeck A/S (Copenhagen, Denmark). In collaboration with the academic authors, the sponsor participated in design and conduct of the trial and in collection, management, analysis, and interpretation of data. Preparation and review of the manuscript were undertaken by all authors, the sponsor, and professional medical writers funded by the sponsor. All authors and the sponsor approved the final version of the manuscript for submission and for publication.

Data availability statement

Principles for Responsible Clinical Trial Data Sharing” guidelines, Lundbeck is committed to responsible sharing of clinical trial data in a manner that is consistent with safeguarding the privacy of participants, respecting the integrity of national regulatory systems, and protecting the intellectual property of the sponsor. The protection of intellectual property ensures continued research and innovation in the pharmaceutical industry. Deidentified data are available to those whose request has been reviewed and approved through an application submitted to .

Supplemental material

Supplemental material for this article is available online.

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