Eptinezumab With Patient Education for Chronic Migraine and Medication-Overuse Headache

Abstract

Background and Objectives

Medication-overuse headache (MOH) commonly co-occurs with and complicates chronic migraine (CM). This trial evaluated efficacy and safety of eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention—combined with a standardized brief educational intervention (BEI)—in adults with CM and MOH. We report results from the 12-week placebo-controlled period, of which weeks 1–4 was the primary time point.

Methods

The phase 4, double-blind, placebo-controlled RESOLUTION trial was conducted at 76 specialist clinics across 11 countries. Eligible participants were adults diagnosed with CM and MOH and were randomized 1:1 to eptinezumab 100 mg IV with BEI or placebo IV with BEI. The primary end point was mean change from baseline in monthly migraine days (MMDs; weeks 1–4). Key secondary end points (multiplicity-controlled) included changes from baseline in monthly headache days, monthly days with acute migraine medication use, and average daily pain, as well as fulfillment of thresholds defining CM and MOH. Treatment-emergent adverse events (TEAEs) were assessed.

Results

Between July 2022 and March 2025, 608 participants were randomized, and 596 (98%) completed the placebo-controlled period. Of 604 participants treated, 517 (86%) were female and 87 (14%) were male; the mean age was 45.5 years (SD 12.0). The primary end point, mean change from baseline in MMDs (weeks 1–4), favored eptinezumab with BEI vs placebo with BEI (−6.9 vs −3.7; group difference −3.2; 95% CI −4.2 to −2.2; p < 0.0001). All key secondary end points showed statistically significant improvements with eptinezumab with BEI vs placebo with BEI; the greater reductions in disease burden observed during weeks 1–4 were sustained through weeks 1–12. The proportion of participants with TEAEs was similar with eptinezumab (41.9%) and placebo (36.9%); no new safety signals were identified.

Discussion

In adults with CM and MOH who also received patient education, eptinezumab was statistically superior to placebo on the primary and all key secondary end points, reducing disease burden as early as weeks 1–4 and throughout weeks 1–12. Eptinezumab was generally well tolerated, with no new safety signals identified. Together, data from this trial indicate that eptinezumab in combination with patient education is an effective treatment for reducing disease burden in patients living with CM complicated by medication overuse.

Trial Registration Information

ClinicalTrials.gov Identifier: NCT05452239 (clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40); EU CTR Number: 2024-510729-24-00 (euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-510729-24-00). EudraCT Number obtained: May 25, 2021. ClinicalTrials.gov Identifier obtained: July 6, 2022. First patient enrolled: July 1, 2022.

Classification of Evidence

This clinical trial provides Class I evidence that eptinezumab with patient education is superior to placebo with patient education in reducing MMDs in adults with CM and MOH.

Introduction

According to the International Classification of Headache Disorders, third edition (ICHD-3), medication overuse headache (MOH) is diagnosed when a person with an existing headache disorder develops a new or worsened headache disorder associated with overusing acute medication.¹ MOH occurs on ≥15 days per month with regular use of acute headache medications for over 3 months, defined as ≥10 days per month for triptans, ergots, opioids, or combinations, or ≥15 days per month for nonsteroidal anti-inflammatory drugs (NSAIDs) and simple analgesics.^1,2 MOH is the fourth most common headache disorder (estimated prevalence of 1%–2% worldwide).^2-4 People meeting the criteria for both chronic migraine (CM) and MOH are given both diagnoses.^5-7

Clinical approaches for the treatment of MOH include patient education, preventive treatment alone, medication withdrawal alone, and combined medication withdrawal and preventive therapy.^5,7,8 Evidence assessing the efficacy of the different approaches alone or in combination is not yet available from large double-blind, randomized trials. The efficacy of simple counselling is supported by a 60-participant, double-blind, cluster-randomized, controlled trial in the primary care setting in Norway,⁹ a 120-participant, open-label, randomized clinical trial in a tertiary care center in Denmark,¹⁰ and prospective cohort studies in specialist headache centers in Italy (N = 100–120 participants),^11,12 or primary care settings in Norway (N = 109).¹³ In the absence of robust and controlled evidence, European guidelines recommend education about MOH as the primary approach, followed by withdrawal from overused medications and, if these are ineffective, adding preventive treatment.⁶

Eptinezumab is an IV-administered, high-affinity anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) approved for migraine prevention, offering full bioavailability and rapid CGRP inhibition.^14-16 The efficacy of eptinezumab has been demonstrated to start from day 1 across multiple migraine-prevention trials^17-22 and from 2 hours when administered during a migraine attack.²³ Its migraine-preventive efficacy, including reductions in migraine frequency, acute migraine medication use frequency, and disease-related burden, was observed in post hoc analyses in the subgroup of participants with CM and MOH from the PROMISE-2 clinical trial.^24-26 The primary objective of this randomized controlled trial (RESOLUTION) was to assess the efficacy of eptinezumab compared with placebo in combination with a standardized brief educational intervention (BEI) in the treatment of dual diagnoses of CM and MOH.²⁷ We hypothesized that eptinezumab with patient education would reduce monthly migraine days (MMDs) more than placebo in combination with patient education.

Methods

RESOLUTION was a phase 4, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 76 specialist clinics across 11 countries (Australia, Denmark, France, Georgia, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and the United States). The first patient, first visit occurred July 1, 2022, with final completion on March 13, 2025. This report covers the screening period and placebo-controlled period (primary completion date: October 22, 2024).

Standard Protocol Approvals, Registrations, and Patient Consents

The trial was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki and applicable regulatory requirements. The appropriate ethics committees and institutional review boards approved the trial for each site before any recruitment was initiated. Participants provided written informed consent before any trial-related procedures. The RESOLUTION trial is registered with EudraCT (2021-003049-40 and 2024-510729-24-00) and ClinicalTrials.gov (NCT05452239). The final protocol and statistical analysis plan are provided in eSAP 1 and eSAP 2, respectively.

Trial Design and Interventions

The 36-week trial included a screening period (4 weeks), placebo-controlled period (12 weeks), open-label period (12 weeks), and safety follow-up period (8 weeks) (eFigure 1). At the end of the screening period, eligible participants were randomized (1:1 ratio) to receive eptinezumab 100 mg with BEI, or placebo with BEI at the baseline visit (day 0), with eptinezumab or placebo administered IV over 30–45 minutes. For masking purposes, participants randomized to placebo with BEI received 100 mL of IV 0.9% saline during the infusion visits. Randomization was performed using a centralized interactive response technology system and stratified by country and number of previous preventive treatment failures (≤2, >2) occurring up to 5 years before baseline visit.

The BEI was a standardized intervention performed at the baseline visit (before administration of eptinezumab or placebo) by trained clinicians. The ∼10-minute BEI comprised 3 components: (1) assessment of dependency-like behavior (Severity of Dependence Scale for Headache medication); (2) education on the association between medication overuse and chronic headache; and (3) an agreed-upon plan to discontinue the overused medication (through abrupt cessation or tapering). The BEI has been previously shown to be effective.⁹ Further details are presented in eFigure 2 and the published protocol.²⁷

Participants attended on-site visits for the screening visit, visits with IV infusions (baseline and end of week 12), and the week 24 end-of-trial visit/withdrawal visit. All other visits were conducted through telephone or telemedicine. Participants completed a daily electronic diary (eDiary) from the screening visit until the week 24 end-of-trial visit/withdrawal visit. For infusion visits, safety assessments were performed before and after infusion, with eDiary completion of patient-reported outcomes (PROs) required before infusion. Adherence to eDiary completion was monitored remotely on daily basis.

Eligibility Criteria

Full inclusion and exclusion criteria are detailed in the protocol, as well as restricted/disallowed concomitant medications (eSAP 1, pp. 44–47, 98–99). Eligible participants included adults aged 18–75 years (inclusive) diagnosed with CM and MOH, both as defined by the ICHD-3 criteria.¹ Participants were required to have migraine onset ≤50 years of age and a history of migraine onset of ≥12 months before the screening visit. Eligible participants had ≥1 preventive treatment failure within the past 5 years defined as treatment discontinuation due to lack of efficacy (no clinically meaningful improvement at the recommended or prescribed dose for ≥3 months), side effects, or generally poor tolerability of the treatment. During the 4-week screening period, eligible participants must have reported ≥15 headache days (of which ≥8 were assessed as migraine days) and overuse of acute and/or symptomatic headache medication (≥10 days per month or ≥15 days per month depending on medication class).

Key exclusion criteria included treatment failure with a previous preventive treatment targeting the CGRP pathway within the previous 5 years and history or diagnosis of any other type of headache, migraine, or other diagnoses listed in eSAP 1, p. 46.

Permitted concomitant medications included prescription or over-the-counter hormonal therapy (e.g., contraceptives, hormone replacement therapy), anti-impotence agents, barbiturates, opiates, and nonpharmacological interventions. Acute headache medications (i.e., paracetamol/acetaminophen, triptans, ergots, nonopioid analgesics, NSAIDs, and combination analgesics) were allowed throughout the trial for participants in severe need, with the advice not to exceed 9 days per month of use. Barbiturates and/or opioid analgesics were allowed provided use did not exceed 4 days per month during the screening period and throughout the trial. Other disallowed treatments are listed in eSAP 1 (pp. 98–99).

Assessments

Participants completed a daily headache eDiary from the screening visit until end-of-trial or withdrawal visit to assess headache and migraine variables (headache start/stop time, severity, associated symptoms, and acute headache/migraine medication use). Headache items were assessed with a yes/no response, except severity of pain (rated as none, mild, moderate, or severe). An evening eDiary was completed each evening to report acute headache medication use, regardless of whether the participant experienced a headache; acute medications included triptans, ergotamines, nonopioid analgesics, NSAIDs, nonopioid combination analgesics, and opioids/barbiturates. At the screening visit, trial site staff trained the participant in eDiary use and compliance. The recording of headache and migraine information was required to be completed by the participant in the eDiary daily before IV infusion (for those that were ongoing and not yet recorded on the day of the infusion). The data collected were used to verify eligibility criteria, baseline values, and eDiary compliance during the screening period.

Efficacy was also assessed using 2 electronic PRO measures associated with the primary objective: Patient Global Impression of Change (PGIC)²⁸ and patient-identified most bothersome symptom (PI-MBS).²⁹ The PGIC, a single patient-reported item, evaluated the participants' impression of change in their disease status from the baseline visit after treatment.²⁸ The scale measures overall change in disease severity from very much improved, much improved, minimally improved, no change, minimally worse, much worse, to very much worse. The PI-MBS for each participant was obtained verbally during the screening visit and categorized, and participants were required to rate the improvement in this symptom on the same 7-point scale used for PGIC.²⁹ For both scales, lower scores are better. Both measures were captured at week 12, with PGIC also captured at week 4. Other electronic PROs, associated with the secondary objective, were also included in this trial (results to be reported separately).

End Points

All primary, key secondary, secondary, exploratory, and safety end points are listed in eSAP 2, pp. 10–13. This report focuses on primary, key secondary, and secondary end points associated with the primary objective (to evaluate the efficacy of eptinezumab in combination with BEI), and end points associated with safety objective (to evaluate the safety and tolerability of eptinezumab); other end points (including other secondary end points related to specific classes of acute medication use and end points over the open-label period) will be reported separately. The primary end point was change from baseline in number of MMDs over weeks 1–4. Key secondary end points (in sequential, hierarchical order of testing) were change from baseline in MMDs over weeks 1–12, change from baseline in the number of monthly headache days (MHDs) over weeks 1–4 and weeks 1–12, not fulfilling threshold criteria for CM nor MOH criteria over weeks 1–4 and weeks 1–12 (eTable 1), change from baseline in average daily pain assessment score over weeks 1–2, and change from baseline in monthly days with acute migraine medication use over weeks 1–4 and weeks 1–12. The 4-week time point for the primary end point reflects that an early effect with eptinezumab was expected^17-24; the 12-week placebo-controlled period addresses ethical concerns of having participants affected by MOH undergo long-term placebo treatment.

Secondary end points associated with the primary objective included: not fulfilling threshold criteria for CM (weeks 1–4, weeks 1–12), not fulfilling threshold criteria for MOH (weeks 1–4, weeks 1–12), change from baseline in MMDs with use of acute migraine medication (weeks 1–12), migraine on the day after dosing (day 1), rate of ≥50% reduction from baseline in MMDs (weeks 1–4, weeks 1–12), rate of ≥75% reduction from baseline in MMDs (weeks 1–4, weeks 1–12), rate of ≥50% reduction from baseline in MHDs (weeks 1–4, weeks 1–12), rate of ≥75% reduction from baseline in MHDs (weeks 1–4, weeks 1–12), change from baseline in rate of migraine attacks with severe pain intensity (weeks 1–4, weeks 1–12), change from baseline in rate of headache episodes with severe pain intensity (weeks 1–4, weeks 1–12), PGIC score at week 4 and week 12, and PI-MBS score at week 12.

To evaluate the safety and tolerability of eptinezumab, adverse events were assessed, as well as absolute values, changes from baseline, and potentially clinically significant values for vital signs.

Statistical Methods

Sample size assumptions were based on previous trials in MOH and/or CM with preventive treatment and withdrawal. In the DEFINE-3 trial, the differences in MMDs between pharmacologic preventive treatment (before anti-CGRPs were available) and withdrawal vs withdrawal alone were approximately −1.7 and −1.4 days, respectively, after 2 and 4 months.¹⁰ In the PROMISE-2 trial, the difference in MMDs (weeks 1–4) was −3.1 days between eptinezumab and placebo in the CM and MOH subpopulation,²⁴ without any MOH-specific intervention. Based on these findings, the treatment effect of eptinezumab 100 mg compared with placebo in change from baseline in MMDs (weeks 1–4) was assumed to be −1.5 MMDs. Based on averaged SD on the change from baseline in MMDs (weeks 1–4) across treatment groups in the PROMISE-2 MOH subpopulation,²⁴ the SD was assumed to be 6.2. With the assumed effect size and SD, 270 participants per treatment group were estimated to provide 80% power using a 2-sided 5% significance level for showing an effect on the primary end point. Assuming 5% of participants would not contribute data to the analysis, 285 participants randomized per treatment group (or 570 total participants randomized) were the estimated requirement for the trial.

Demographics and safety end points were analyzed using data from all randomized participants who received an infusion in the placebo-controlled period (all-participants-treated set). Efficacy end points were analyzed using data from all participants in the all-participants-treated set who had a valid baseline assessment and ≥1 valid postbaseline 4-week assessment of MMDs in weeks 1–12 (full-analysis set; modified intent-to-treat). Demographics and efficacy were summarized by planned treatment, and safety was summarized by treatment received.

The primary end point was analyzed using a mixed model for repeated measures with the number of MMDs at baseline as a continuous covariate; treatment group, study month, country, and previous treatment failures (≤2, >2) as categorical factors; and interaction terms for treatment-by-month, previous treatment failures-by-month, and MMDs at baseline-by-month. The model assumed an unstructured covariance matrix to model the between-participant and within-participant variance. Change from baseline in average daily pain was analyzed using an analysis of covariance with the average daily pain at baseline as a covariate and including treatment group, country, and previous treatment failures as categorical variables. The binary key secondary end points were analyzed using logistic regression with baseline MMDs as a covariate and treatment and previous treatment failures as categorical variables. Primary and key secondary end points were tested sequentially in the order listed above, using the gatekeeper approach to avoid false-positive discovery. Only if an end point demonstrated a statistically significant effect would the formal testing continue to the next end point; this was continued until an end point failed to reach statistical significance. In all statistical comparisons, the null hypothesis of equal treatment effect in the 2 treatment groups was tested using a 2-sided 5% significance level. No additional multiplicity control was applied to any outcomes outside the statistical hierarchy of primary and key secondary efficacy end points using the gatekeeper plan.

For eDiary-based end points, prorating was used to impute missing data. For 28-day (4-week) intervals, missing data from the eDiary were imputed as follows, using MMDs as the example: If the number of days with eDiary data entry was ≥14 days, then the MMDs for the 28-day interval were calculated as 28×(number of migraine days observed)/(number of eDiary days observed), rounded off to 2 decimals. If there was <14 days of eDiary data, the number of MMDs for that period was set to missing. For other end points, such as MHDs and migraine attacks/headache episodes with severe intensity, the “migraine days observed” in the above prorating formula was replaced with the outcome of interest (e.g., headache days, days with use of acute headache/migraine medication). All statistical analyses were performed using SAS (version 9.4 or later).

Data Availability

In accordance with EFPIA's and PhRMA's “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 lundbeck.com/global/our-science/clinical-data-sharing.

Results

Participants

The trial was conducted between July 2022 and March 2025. A total of 928 participants were screened; 608 participants met eligibility criteria and were randomized, of which 604 received an infusion following BEI (all-participants-treated set; eptinezumab, n = 303; placebo, n = 301) and 4 were not treated (Figure 1). The full-analysis set included 302 participants in the eptinezumab group and 300 in the placebo group. Completion rates for the 12-week placebo-controlled period were 99% (301/305) for eptinezumab and 98% (295/303) for placebo. Figure 1 shows reasons for withdrawal.

Figure 1. Participant Disposition.

^aAll participants received a brief educational intervention at the baseline visit before the infusion of eptinezumab or placebo. All participants received treatment as planned. ^bFour participants were not treated: 3 participants were randomized despite not meeting the inclusion criteria and 1 participant was randomized, but the trial medication was not dispensed due to non-availability of adequate trial medication at the pharmacy. Safety was analyzed in all randomized participants who received an infusion of eptinezumab or placebo in the placebo-controlled period (all-participants-treated set). Efficacy was analyzed in participants in the all-participants-treated set who had a valid baseline assessment and ≥1 valid postbaseline 4-week assessment of monthly migraine days for weeks 1–12 (full-analysis set).

Baseline demographics and disease characteristics were similar between treatment groups (Table 1). Most participants were female (517/604 [85.6%]) and based in Europe (591/604 [97.8%]), and the mean age was 45.5 years. Almost half of participants were White (298/604 [49.3%]); however, race was not collected/unknown for nearly half of participants (291/604 [48.2%]) due to local legislation in several European countries. At baseline, the mean (SD) numbers of MMDs and MHDs were 20.9 (4.3) and 21.7 (3.9), respectively, with a mean of 20.1 (4.4) monthly days with acute migraine medication use. The most common types of acute medication treatment taken during the screening period were triptans (535/604 [88.6%], including 4 participants in total who used ergotamine) and nonopioid analgesics (487/604 [80.6%]). Furthermore, 44.0% (266/604) of participants had tried >2 preventive migraine treatments before the screening visit that failed to work (Table 1).

Table 1.

Demographics and Baseline Characteristics

	Eptinezumaba (N = 303)	Placeboa (N = 301)	Total (N = 604)
Demographicsb
Age, y, 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)
Race, n (%)
White	151 (49.8)	147 (48.8)	298 (49.3)
Black	3 (1.0)	4 (1.3)	7 (1.2)
Asian	1 (0.3)	1 (0.3)	2 (0.3)
Other	2 (0.7)	4 (1.3)	6 (1.0)
Unknown/not collectedc	146 (48.2)	145 (48.2)	291 (48.2)
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 characteristicsb
Age at first diagnosis of migraine, y, mean (SD)	25.4 (12.2)	25.8 (12.2)	25.6 (12.2)
Time since first diagnosis of migraine, y, mean (SD)	20.8 (13.1)	19.9 (13.9)	20.4 (13.5)
Age at first diagnosis of MOH, y, mean (SD)	40.8 (12.2)	41.2 (12.1)	41.0 (12.1)
Time since first diagnosis of MOH, y, mean (SD)	5.5 (6.6)	4.5 (4.8)	5.0 (5.8)
Participants suffering from aura, n (%)	72 (23.8)	67 (22.3)	139 (23.0)
Participants ever experiencing aura without headache, n (%)	10 (3.3)	8 (2.7)	18 (3.0)
Migraine started in relation to any event, n (%)	20 (6.6)	17 (5.6)	37 (6.1)
Previous preventive treatment failures, n (%)
≤2 previous preventive treatment failures	170 (56.1)	168 (55.8)	338 (56.0)
>2 previous preventive treatment failures	133 (43.9)	133 (44.2)	266 (44.0)
Acute medication taken during screening period,d n (%)
Triptans/ergotamines	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 characteristicse
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)

Abbreviations: eDiary = electronic diary; MHD = monthly headache day; MMD = monthly migraine day; MOH = medication-overuse headache.

Due to rounding, percentages may not sum to 100.0%.

^aAll participants received a brief educational intervention at the baseline visit prior to the infusion of eptinezumab or placebo.

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

^cRace data are only available for Australia, Denmark, Italy, the Netherlands, Spain, and the United States; collection of race is prohibited in several European countries due to local legislations. Ethnicity is only available for United States sites and therefore is not reported.

^dBased on the eDiary during the screening period. Participants may have taken more than 1 type of medication. A total of 4 participants used ergotamine during the screening period. Opioid analgesics were only permitted up to 4 days per month.

^eBaseline days calculated from the eDiary during the screening period and analyzed in the full-analysis set.

Compliance with the eDiary was high, with <3% of participants reporting <14 days during each of the 4-week intervals over weeks 1–12, with an average of <10% missing data in each arm across each 4-week interval.

Primary and Key Secondary Efficacy End Points

Primary and key secondary end points are summarized in Table 2. This trial met the primary trial end point; the eptinezumab with BEI group showed a statistically significant reduction in MMDs compared with placebo with BEI over weeks 1–4. The change from baseline was −6.9 with eptinezumab and −3.7 with placebo and a mean difference of −3.2 (95% CI −4.2 to −2.2; p < 0.0001) (Figure 2A).

Table 2.

Summary of Primary and Key Secondary End Points

	Eptinezumaba (n = 302)	Placeboa (n = 300)	Comparison (95% CI)b	p Valuec
Primary end point
Change from baseline in MMDs (weeks 1–4), LS mean (SE)	−6.9 (0.52)	−3.7 (0.52)	−3.2 (−4.2 to −2.2)	<0.0001
Key secondary end points
Change from baseline in MMDs (weeks 1–12), LS mean (SE)	−7.4 (0.51)	−4.5 (0.51)	−2.9 (−3.9 to −2.0)	<0.0001
Change from baseline in MHDs (weeks 1–4), LS mean (SE)	−6.5 (0.50)	−3.4 (0.50)	−3.2 (−4.1 to −2.2)	<0.0001
Change from baseline in MHDs (weeks 1–12), LS mean (SE)	−7.4 (0.50)	−4.5 (0.50)	−2.9 (−3.8 to −2.0)	<0.0001
No longer fulfilling criteria for neither CM nor MOH (weeks 1–4), n/N (%)	113/299 (37.8)	54/298 (18.1)	3.3 (2.2 to 4.9)	<0.0001
No longer fulfilling criteria for neither CM nor MOH (weeks 1–12), n/N (%)	82/302 (27.2)	38/300 (12.7)	3.1 (1.9 to 4.9)	<0.0001
Change from baseline in average daily pain assessment score (weeks 1–2), LS mean (SE)	−0.6 (0.05)	−0.3 (0.05)	−0.3 (−0.4 to −0.2)	<0.0001
Change from baseline in monthly days with acute migraine medication use (weeks 1–4), LS mean (SE)	−11.3 (0.51)	−7.7 (0.51)	−3.6 (−4.6 to −2.7)	<0.0001
Change from baseline in monthly days with acute migraine medication use (weeks 1–12), LS mean (SE)	−11.2 (0.49)	−7.8 (0.49)	−3.4 (−4.2 to −2.5)	<0.0001

Abbreviations: CM = chronic migraine; LS = least-squares; MHD = monthly headache day; MMD = monthly migraine day; MOH = medication-overuse headache; SE = standard error.

^aAll participants received a brief educational intervention at the baseline visit prior to the infusion of eptinezumab or placebo. Data were analyzed in the full-analysis set.

^bBetween-group differences for continuous end points (change from baseline) are reported as LS mean (95% CI) and for discrete end points (proportion of participants) are reported as odds ratio (95% CI).

^cp Values for the primary and key secondary end points were controlled for multiplicity.

Figure 2. (A) Change From Baseline in MMDs and (B) Percentage of Participants No Longer Fulfilling Threshold Criteria for CM and/or MOH .

All participants received a brief educational intervention at the baseline visit prior to the infusion of eptinezumab or placebo. Data were analyzed in the full-analysis set. (A) The change from baseline in number of MMDs (weeks 1–4) was analyzed using a restricted maximum likelihood–based MMRM that included baseline number of MMDs as a continuous covariate; treatment group, study month (weeks 1–4), country, and previous treatment failures (≤2, >2) as factors; and interaction terms for treatment-by-month, previous treatment failures-by-month, and number of MMDs at baseline-by-month. An unstructured covariance matrix was used to model the between-participant and within-participant covariance. The Kenward–Roger approximation was used to estimate denominator degrees of freedom. The change from baseline in number of MMDs (weeks 1–12) was analyzed using the same MMRM model as described for the primary analysis, except that the test will be based on the estimated mean MMDs averaged over weeks 1–4 (month 1), weeks 5–8 (month 2), and weeks 9–12 (month 3). The change from baseline in MMDs (weeks 1–12) was estimated as the average across the three 4-week intervals, and the treatment effect was calculated from the LS estimates from the MMRM model for the month × treatment interaction through a contrast: (1/3, 1/3, 1/3, −1/3, −1/3, −1/3) comparing the effect of eptinezumab to the effect of placebo across weeks 1–12. The LS mean differences (95% CI) and p values for eptinezumab vs placebo are reported below the bars. (B) Criteria for CM and/or MOH were checked at baseline, weeks 1–4, weeks 5–8, and weeks 9–12 using the protocol definition based on the International Classification of Headache Disorders, 3rd edition, criteria¹ (see Supplement 3, eTable 1). Conservative criteria were applied through weeks 1–12; a participant was considered as no longer fulfilling criteria for CM and/or MOH for weeks 1–12 only if they did not fulfill the respective CM and/or MOH criteria for all three 4-week intervals. Missing data after prorating were not used in the analysis. The treatment effect was analyzed using logistic regression with baseline MMDs as a covariate, and treatment group, country, and previous treatment failures as categorical variables based on the eDiary data collected over weeks 1–4 and weeks 1–12, separately. Odds ratios (95% CIs) and p values for eptinezumab vs placebo are reported below the x-axis. The proportion of participants no longer fulfilling either CM or MOH criteria was a key secondary end point (and thus the p values are controlled for multiplicity). The proportion of participants no longer fulfilling CM criteria and the proportion of participants no longer fulfilling MOH criteria were additional secondary end points (and thus the p values are descriptive). CM = chronic migraine; LS = least-squares; MMD = monthly migraine day; MMRM = mixed model for repeated measures; MOH = medication-overuse headache; SE = standard error.

All key secondary end points showed statistically significant improvements with eptinezumab with BEI compared with placebo with BEI (Table 2). Reductions in MMDs (weeks 1–12, Figure 2A) and MHDs (weeks 1–4 and 1–12) (eFigure 3) were statistically significantly greater with eptinezumab with BEI compared with placebo with BEI.

Eptinezumab with BEI resulted in more participants no longer fulfilling criteria for CM nor MOH compared with participants treated with placebo with BEI for weeks 1–4 (37.8% vs 18.1%, odds ratio 3.3, 95% CI 2.2–4.9, p < 0.0001) and weeks 1–12 (27.2% vs 12.7%, odds ratio 3.1, 95% CI 1.9–4.9, p < 0.0001) (Figure 2B).

The mean daily pain, assessed as none, mild, moderate, or severe, was also reduced statistically significantly more in the eptinezumab with BEI group compared with the placebo with BEI group over weeks 1–2 (mean difference of −0.3, 95% CI −0.4 to −0.2, p < 0.0001) (Figure 3A).

Figure 3. Change From Baseline in (A) Average Daily Pain Assessment Score and (B) Monthly Days With Acute Migraine Medication Use.

All participants received a brief educational intervention at the baseline visit before the infusion of eptinezumab or placebo. Data were analyzed in the full-analysis set. As key secondary efficacy end points, p values were controlled for multiplicity. The LS mean difference (95% CI) and p value for eptinezumab vs placebo are reported below the bars. (A) Daily pain assessment data were collected in the headache eDiary using the question “What was the worst pain intensity of this headache today?” with the following possible ratings: mild (score = 1), moderate (score = 2), and severe (score = 3). For each day, the daily pain assessment score was derived by averaging the worst pain intensity over all headache episodes of that day. For days on which no headache took place during the relevant period, the daily pain score was given as a score of 0. The average daily pain score was calculated using the daily pain assessments collected during weeks 1–2. The change from baseline in average daily pain assessment score was analyzed using an analysis of covariance that included the average daily pain score at baseline as a covariate and treatment group, country, and previous treatment failures as categorical variables. (B) The weeks 1–4 end point was analyzed using the same methodology as that described for the primary analysis, except that the test was based on monthly days with acute migraine medication use. The baseline MMDs were replaced with monthly acute migraine medication use at baseline. For the weeks 1–12 end point, the estimated mean difference of monthly days with acute migraine medication use on eptinezumab and placebo were averaged over weeks 1–4 (month 1), weeks 5–8 (month 2), and weeks 9–12 (month 3). All medication collected in the eDiary as acute migraine medication regardless of whether they were taken to stop headache/migraine attacks were accounted for in the analysis. eDiary = electronic diary; LS = least-squares; MMD = monthly migraine day; SE = standard error.

The eptinezumab with BEI group demonstrated statistically significant decreases from baseline in monthly days with acute migraine medication use over weeks 1–4 and weeks 1–12 compared with the placebo with BEI group. The change from baseline over weeks 1–4 was −11.3 vs −7.7 for eptinezumab and placebo, respectively (mean difference of −3.6, 95% CI −4.6 to −2.7), which was sustained through weeks 1–12 (−11.2 and −7.8, respectively, with a mean difference of −3.4, 95% CI −4.2 to −2.5, p < 0.0001 for both comparisons) (Figure 3B).

Secondary Efficacy End Points

Secondary end points associated with the primary objective are summarized in eTable 2 and eFigures 4–9. The results favored eptinezumab with BEI compared with placebo with BEI across secondary end points: no longer fulfilling CM criteria (weeks 1–4 and weeks 1–12), no longer fulfilling MOH criteria (weeks 1–4 and weeks 1–12), change from baseline in MMDs with acute migraine medication use (weeks 1–12), migraine on day 1, ≥50% reduction from baseline in MMDs and MHDs (weeks 1–4 and weeks 1–12), ≥75% reduction from baseline in MMDs and MHDs (weeks 1–4 and weeks 1–12), change from baseline in rate of migraine attacks, and headache episodes with severe pain intensity (weeks 1–4 and weeks 1–12).

PGIC scores were lower with eptinezumab than for placebo at week 4 (2.6 and 3.6, respectively, with a mean difference of −1.0, 95% CI −1.2 to −0.8, p < 0.0001) and week 12 (2.6 and 3.5, respectively, with a mean difference of −0.9, 95% CI −1.1 to −0.7, p < 0.0001) (Figure 4A). The PI-MBS score at week 12 was also lower in the eptinezumab group than for the placebo group (2.9 vs 3.6, with a mean difference of −0.7, 95% CI −0.9 to −0.5, p < 0.0001) (Figure 4B).

Figure 4. (A) PGIC Score and (B) PI-MBS Score.

All participants received a brief educational intervention at the baseline visit prior to the infusion of eptinezumab or placebo. Data were analyzed in the full-analysis set. Both PGIC and PI-MBS were rated using the following 7-point scale: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. The LS mean differences (95% CI) and p values for eptinezumab vs placebo are reported above the bars. (A) The analysis was similar to the MMRM model defined in the primary analysis; however, no baseline covariate was included in the model. (B) The analysis was similar to the ANCOVA model defined in the analysis of the change from baseline in average daily pain assessment score; however, no baseline covariate was included in the model. ANCOVA = analysis of covariance; LS = least-squares; MMRM = mixed model for repeated measures; PGIC = Patient Global Impression of Change; PI-MBS = patient-identified most bothersome symptom; SE = standard error.

Safety

The overall incidence of treatment-emergent adverse events (TEAEs) across the placebo-controlled period was similar between the groups (eptinezumab, 41.9%; placebo, 36.9%) (Table 3). Most TEAEs were mild to moderate, and few led to treatment withdrawal (eptinezumab, 1/303 [0.3%]; placebo, 3/301 [1.0%]) or infusion interruption (eptinezumab, 2/303 [0.7%]; placebo, 1/301 [0.3%]). The most commonly reported TEAEs (≥2% incidence in any treatment arm) were nasopharyngitis, influenza, dizziness, and fatigue (Table 3). Serious TEAEs included appendicitis (1 participant) and recurrent breast cancer (1 participant) in the eptinezumab group and drug abuse (1 participant) in the placebo group; however, none was considered treatment-related, and no TEAEs led to death. Few participants experienced TEAEs of special interest related to immunogenicity and/or hypersensitivity (eptinezumab, 6/303 [2.0%]; placebo, 4/301 [1.3%]) (Table 3), and vital signs did not show new safety signals.

Table 3.

Overview of TEAEs for the Placebo-Controlled Period

	Eptinezumaba (n = 303)	Placeboa (n = 301)
Any TEAE, n (%)	127 (41.9)	111 (36.9)
Any TEAE by intensity, n (%)
Mild	70 (23.1)	64 (21.3)
Moderate	50 (16.5)	41 (13.6)
Severe	7 (2.3)	6 (2.0)
Any treatment-emergent SAE, n (%)b	2 (0.7)	1 (0.3)
Any TEAE leading to withdrawal from treatment, n (%)	1 (0.3)	3 (1.0)
Any TEAE leading to infusion interruption, n (%)	2 (0.7)	1 (0.3)
Most common TEAEs (incidence ≥2% in any arm), n (%)
Nasopharyngitis	15 (5.0)	17 (5.6)
Influenza	11 (3.6)	10 (3.3)
Dizziness	8 (2.6)	9 (3.0)
Fatigue	6 (2.0)	11 (3.7)
Any treatment-emergent AESI, n (%)	13 (4.3)	9 (3.0)
Hypersensitivity and anaphylactic reactions	6 (2.0)	4 (1.3)
Angioedema	1 (0.3)	0
Eczema	1 (0.3)	1 (0.3)
Urticaria	1 (0.3)	0
Rash	0	2 (0.7)
Hypersensitivity	1 (0.3)	0
Infusion-related hypersensitivity reaction	1 (0.3)	0
Rhinitis allergic	1 (0.3)	1 (0.3)
Cardiovascular/cerebrovascular events	1 (0.3)	3 (1.0)
Hypertension	1 (0.3)	2 (0.7)
Venous thrombosis limb	0	1 (0.3)
Potentially associated with trial infusion	8 (2.6)	3 (1.0)
Oropharyngeal pain	1 (0.3)	0
Pharyngeal paresthesia	1 (0.3)	0
Rhinorrhea	1 (0.3)	0
Pruritis	3 (1.0)	2 (0.7)
Rash	0	1 (0.3)
Infusion site pain	1 (0.3)	0
Infusion site pruritis	1 (0.3)	0

Abbreviations: AESI = adverse events of special interest; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aAll participants received a brief educational intervention at the baseline visit prior to the infusion of eptinezumab or placebo. Data were analyzed in the all-participants-treated set and represent the number (percentage) of participants.

^bSAEs included appendicitis (1 participant) and recurrent breast cancer (1 participant) in the eptinezumab group, and drug abuse (1 participant) in the placebo group. None were considered treatment related.

Classification of Evidence

This clinical trial provides Class I evidence that eptinezumab with patient education is superior to placebo with patient education in reducing MMDs in adults with CM and MOH.

Discussion

RESOLUTION was a double-blind, randomized, controlled trial that evaluated the efficacy of the IV anti-CGRP mAb in combination with patient education as preventive migraine treatment in participants with CM and MOH. The trial met the primary end point, with a statistically significant greater mean change from baseline in MMDs (weeks 1–4) after eptinezumab in combination with BEI compared with placebo with BEI, as well as statistically significant advantages with eptinezumab compared with placebo for all key secondary end points. Participants treated with eptinezumab with BEI showed fast (within the first 4 weeks) improvements in MMDs, MHDs, monthly days with acute migraine medication use, and pain severity that were greater than changes observed for those who received placebo with BEI. A higher proportion of participants in the eptinezumab with BEI group no longer met criteria for MOH nor CM compared with the placebo with BEI group, with remission of both disorders demonstrating a qualitative shift in the diagnostic status of trial participants.

In addition to the primary and key secondary efficacy end points, the results from this trial provide robust evidence for the efficacy of eptinezumab with BEI compared with placebo with BEI in the treatment of CM and MOH across secondary end points associated with the primary objective. Greater improvements in secondary end points were observed in the eptinezumab group compared with the placebo group as early as weeks 1–4 for end points assessed within the first 4-week period, with effects sustained through weeks 1–12. The odds ratios between eptinezumab and placebo for ≥50% and ≥75% responder rates for MMDs and MHDs, clinically meaningful assessment tools recommended as key clinical outcomes in CM trials,³⁰ consistently favored eptinezumab. Larger proportions of participants no longer fulfilled the diagnostic criteria for CM or MOH across weeks 1–4 and weeks 1–12. Changes from baseline in the rates of migraine attacks and headache episodes with severe pain intensity were greater with eptinezumab than placebo. Better PGIC and PI-MBS scores were also observed with eptinezumab compared with placebo, which are of particular interest since these measures reflect the global impact of treatment and consider different components of improvement.

Since headache intensity may worsen after acute headache medication withdrawal, the early reductions in average daily pain and rate of migraine attacks and headache episodes with severe pain intensity represent valuable clinical benefits. Greater reductions in pain may have contributed to the higher rate of participants in eptinezumab with BEI group succeeding in reducing their acute headache/migraine medication use than the placebo with BEI group.

The results of this trial expand and augment the previous efficacy findings demonstrated in an exploratory subgroup analysis of the PROMISE-2 trial, in which eptinezumab reduced the number of MMDs and improved PROs (including PGIC and PI-MBS) compared with placebo for participants with a dual diagnosis of CM and MOH.^24-26 The present findings are also in line with the phase 4 trial investigating the subcutaneous anti-CGRP mAb erenumab in participants dually diagnosed with CM and MOH,³¹ although the differences in primary outcome measures between the trials preclude indirect comparisons. In the erenumab trial, a significantly greater proportion of participants no longer had MOH in the erenumab 140-mg arm compared with placebo (69.1% and 52.6%, respectively), with a greater reduction in mean monthly acute medication days (−9.4 and −6.6 days with erenumab and placebo, respectively) at 6 months.³¹ Here, we show that the efficacy of the eptinezumab group is superior to the placebo group at early time points, with benefits seen as early as weeks 1–4 and across weeks 1–12, when both are added to BEI.

Eptinezumab was well tolerated in this trial, with no new safety signals identified relative to its established profile in migraine prevention.¹⁴ The incidence of TEAEs was similar between eptinezumab-treated and placebo-treated participants and was of similar nature to the most common TEAEs observed in previous migraine trials.^14,32

Patient education has demonstrated long-term efficacy in reducing medication intake for people with MOH.^9-13 However, patient education alone may not be sufficient for reducing disease burden in all people with MOH.^8,9,13 Therefore, concurrent patient education with initiating preventive anti-CGRP therapy may, as the present trial suggests, provide a more effective treatment strategy for improved patient outcomes.

There are potential limitations associated with these data. Although BEI has shown effectiveness in prior trials from primary care and specialist settings,^9-13 this trial did not include a control arm that received eptinezumab or placebo without the BEI due to ethical concerns of participants undergoing placebo treatment for 3 months without education on the risk of medication overuse; therefore, we cannot determine how much the BEI contributed to the present results or if it augmented the efficacy benefits of eptinezumab. Nevertheless, as education about medication overuse is a mandatory step in the treatment of MOH,^6,33 its introduction in the trial design contributes to its translatability to clinical practice. Furthermore, this design supports the recent IHS position statement advocating for preventing disease progression early³⁴ by demonstrating the value of initiating effective preventive anti-CGRP therapy concurrently with behavioral withdrawal advice. Because improvements in migraine/headache end points and reductions in acute medication use occurred simultaneously, these analyses cannot fully disentangle the causal relationship between these outcomes or the specific contribution of medication withdrawal vs the direct effect of eptinezumab; further analyses are required to explore the temporal connections underlying these effects. As the design focused on people living with MOH and underlying migraine, the results are not generalizable to people with MOH with other underlying primary or secondary headache disorders. In addition, people with previous anti-CGRP therapy failures, barbiturate and/or opioid analgesic use for >4 days per month, clinically significant psychiatric or cardiovascular diseases, or confounding pain syndromes were excluded from participation, limiting generalizability to the general population of people with these or other excluded conditions. Finally, despite a large geographic spread of participating sites, most trial participants were from Europe, limiting generalizability to other regions.

The RESOLUTION trial met the primary end point, with statistically significant reductions from baseline in MMDs over weeks 1–4 with eptinezumab in combination with patient education compared with placebo with patient education. The trial also met all key secondary end points, with eptinezumab demonstrating greater reduction in disease burden compared with placebo over weeks 1–4, that was sustained through weeks 1–12. The demonstration of moving patients from CM and MOH to lower frequency migraine no longer fulfilling the criteria for MOH without a formal wean suggests a potential change for clinical practice in treating MOH. These results indicate that the combination of eptinezumab with patient education was effective in reducing disease burden in people living with CM and MOH, with the trial providing reliable evidence for an optimized approach to the management of patients with high-frequency migraine complicated by medication overuse.

Glossary

BEI

brief educational intervention

CGRP

calcitonin gene-related peptide

CM

chronic migraine

eDiary

electronic diary

PRO

patient-reported outcome

ICHD-3

International Classification of Headache Disorders, third edition

mAb

monoclonal antibody

MHD

monthly headache day

MMD

monthly migraine day

MOH

medication-overuse headache

NSAID

non-steroidal anti-inflammatory drug

PGIC

Patient Global Impression of Change

PI-MBS

patient-identified most bothersome symptom

TEAE

treatment-emergent adverse event

Author Contributions

R.H. Jensen: 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. C. Lundqvist: 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. H.W. Schytz: 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. C. Tassorelli: 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. F. Vernieri: 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. M. Lanteri-Minet: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. G.M. Terwindt: 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. Blumenfeld: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. S.J. Tepper: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. M.K. Josiassen: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. G. Jansson: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A. Ettrup: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A. Mittoux: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. R.B. Lipton: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

Study Funding

The trial was sponsored and funded by H. Lundbeck A/S, including medical writing support for the development of the manuscript. 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. All authors had access to the relevant data.

Disclosure

R.H. Jensen 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, Rigshospitalet, The Medical Society in Copenhagen, NovoNordisk Foundation, Tryg Foundation, and University of Copenhagen. C. Lundqvist has participated on an advisory board and received payment for lectures arranged by AbbVie Pharma AS, Lundbeck, Novartis AS, and Roche AS, Pfizer AS; and has received research sponsorship from AbbVie Pharma. H.W. Schtyz has received personal fees from AbbVie, Eli Lilly, Lundbeck, Novartis, and Teva; and has received research grants from Novartis and Novo Nordisk Foundation. C. Tassorelli in the past 3 years has received support (financial or drugs) from AbbVie and Novartis for an investigator-initiated trial; consulting fees for the participation in advisory boards for AbbVie, Dompé, Eli Lilly, Ipsen, Lundbeck, Organon, Pfizer, and Teva; honoraria for scientific lectures and presentations from AbbVie, Eli Lilly, Lundbeck, Pfizer, 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, Chordate, 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. F. Vernieri 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, Organon, Pfizer, and Teva; honoraria for scientific lectures and presentations from AbbVie, Eli Lilly, Lundbeck, Pfizer, and Teva; support for attending meetings from AbbVie, Eli Lilly, Lundbeck, Pfizer, and Teva; and has been Principal Investigator in clinical trials sponsored by AbbVie, Eli Lilly, Lundbeck, Pfizer, and Teva. M. Lanteri-Minet 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 Pharma, Perfood, Pfizer, Reckitt Benckiser, St. Jude, Salvia BioElectronics, Sanofi-Aventis, Teva, UCB, UPSA, and Zambon. G.M. Terwindt reports grants or consultancy support from AbbVie, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer, and Teva; and independent support from the Clayco Foundation, Dioraphte Foundation, Dutch Research Council, Dutch Heart Foundation, Dutch Brain Foundation, IRRF, and the European Community. A. Blumenfeld 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. S.J. Tepper 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. M.K. Josiassen is a full-time employee of H. Lundbeck A/S and owns stock/stock options in H. Lundbeck A/S. G. Jansson, A. Ettrup and A. Mittoux are full-time employees of H. Lundbeck A/S. R.B. Lipton has received research support from the NIH, the FDA, and the National Headache Foundation; serves as consultant, advisory board member, or has received honoraria or research support from AbbVie/Allergan, Amgen, Axon, Axsome, Biohaven, Eli Lilly, GlaxoSmithKline, Lilly, Lundbeck, Merck, Novartis, Pfizer, Teva, Vector, and Vedanta Research; receives royalties from Wolff's Headache, 8th edition (Oxford University Press, 2009) and Informa; and holds stock/options in Biohaven, Cooltech, Mainistee, and NuVieBio. Go to Neurology.org/N for full disclosures.