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Eptinezumab for the Prevention of Episodic Migraine: Sustained Effect Through 1 Year of Treatment in the PROMISE-1 Study

Open AccessPublished:November 26, 2020DOI:https://doi.org/10.1016/j.clinthera.2020.11.007

      Abstract

      Purpose

      The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy 1 (PROMISE-1) study was a phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, tolerability, and pharmacokinetic properties of repeat intravenous (IV) doses of the calcitonin gene–related peptide‒targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with episodic migraine. Here we present the results of PROMISE-1 through 1 year of treatment (up to 4 doses).

      Methods

      Patients received up to 4 IV administrations of eptinezumab 30 mg, 100 mg, 300 mg, or placebo every 12 weeks. Patients recorded migraine and headache in an electronic diary daily. Additional assessments, including the patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 56-week study period.

      Findings

      A total of 888 adults (mean age, 39.8 years; 84.3% female; 83.8% white) received treatment: eptinezumab 30 mg, n = 219; eptinezumab 100 mg, n = 223; eptinezumab 300 mg, n = 224; and placebo, n = 222. During the primary 12-week study evaluation period, single doses of eptinezumab 100 mg and 300 mg led to significant reductions in mean monthly migraine-days versus placebo, beginning as early as the first day after the initial dose. The reduction in mean monthly migraine-days was maintained throughout the study (100 mg, −3.9, −4.5, −4.7, and −4.5 days; 300 mg, −4.3, −4.8, −5.1, and −5.3 days; and placebo, −3.2, −3.8, −4.0, and −4.0 days during weeks 1–12, 13–24, 25–36, and 37–48, respectively). Overall, the number of patients with a ≥50% or ≥75% reduction in migraine for each 12-week interval during the entire study was consistently numerically higher in the eptinezumab groups than in the placebo group. The proportions of patients with ≥50% reduction in migraine were similar across the eptinezumab groups. Eptinezumab was well tolerated throughout the study. Adverse events were similar across dosing periods, and there were no serious tolerability signals identified with continued dosing.

      Implications

      IV eptinezumab administered every 12 weeks for up to 4 doses was associated with early and sustained migraine-preventive effects and a favorable safety profile in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.

      Key words

      Introduction

      Migraine is a prevalent neurologic disorder
      GBD 2017 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      with symptoms that can cause substantial disability and limit the ability to function in everyday life.
      GBD 2016 Neurology Collaborators
      Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ,
      • Martelletti P.
      • Schwedt T.J.
      • Lanteri-Minet M.
      • et al.
      My Migraine Voice survey: a global study of disease burden among individuals with migraine for whom preventive treatments have failed.
      Episodic migraine (EM) is a nondiagnostic term commonly used to describe when patients experience headache and migraine frequency below diagnostic thresholds for chronic migraine (ie, <15 headache-days per month and <8 migraine-days per month).
      • Katsarava Z.
      • Buse D.C.
      • Manack A.N.
      • Lipton R.B.
      Defining the differences between episodic migraine and chronic migraine.
      • Lipton R.B.
      • Silberstein S.D.
      Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention.
      • Marmura M.J.
      Triggers, protectors, and predictors in episodic migraine.
      EM is commonly underdiagnosed, and individuals with EM are frequently undertreated.
      • Lipton R.B.
      • Silberstein S.D.
      Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention.
      ,
      • Diamond S.
      • Bigal M.E.
      • Silberstein S.
      • et al.
      Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study.
      ,
      • Silberstein S.D.
      • Holland S.
      • Freitag F.
      • et al.
      Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American academy of neurology and the American headache society.
      Conversely, in those patients who are prescribed preventive migraine medications, adherence is generally poor.
      • Woolley J.M.
      • Bonafede M.M.
      • Maiese B.A.
      • Lenz R.A.
      Migraine prophylaxis and acute treatment patterns among commercially insured patients in the United States.
      Previous studies have indicated that the most common reasons for discontinuation of preventive migraine treatment are lack of efficacy and the occurrence of adverse effects.
      • Blumenfeld A.M.
      • Bloudek L.M.
      • Becker W.J.
      • et al.
      Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II).
      ,
      • Ford J.H.
      • Jackson J.
      • Milligan G.
      • et al.
      A real-world analysis of migraine: a cross-sectional study of disease burden and treatment patterns.
      The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy 1 (PROMISE-1) study was a phase III, randomized, double-blind, placebo-controlled study conducted in adults with EM.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      PROMISE-1 was designed to evaluate the efficacy, tolerability, and pharmacokinetic properties of repeat intravenous administrations of the calcitonin gene–related peptide‒targeted monoclonal antibody eptinezumab
      Trademark: Vyepti™ (Lundbeck Seattle BioPharmaceuticals Inc, Bothell, Washington).
      for migraine prevention in this population of patients with EM.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      During the initial 12-week treatment period, single doses of eptinezumab 100 mg and 300 mg led to significant reductions in mean monthly migraine days (MMDs; 100 mg, −3.9, P = 0.0182 vs placebo; 300 mg, −4.3, P = 0.0001 vs placebo). The efficacy benefits associated with eptinezumab treatment were seen as early as the first day after the initial dose.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      Both doses led to clinically meaningful migraine-preventive effects over multiple efficacy measures and were well tolerated. The purpose of this report is to describe the results of PROMISE-1 through 1 year of treatment, delivering 4 administrations of eptinezumab every 12 weeks.

      Patients and Methods

       Study Design and Patients

      Full study details of PROMISE-1 have been published previously, including all inclusion and exclusion criteria.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      Briefly, PROMISE-1 was a parallel-group, double-blind, randomized, placebo-controlled efficacy and tolerability study performed between September 30, 2015, and December 14, 2017. Adults aged 18 through 75 years with a diagnosis of migraine per the International Classification of Headache Disorders criteria
      Headache Classification Subcommittee of the International Headache Society
      The international classification of headache disorders.
      at or before the age of 50 years were eligible for participation. Key inclusion criteria were a history of migraine for at least 12 months, with no more than 14 headache days per month, including 4 or more migraine-days, in the 3 months before screening. The study was approved by the independent ethics committee or institutional review board for each study site. All clinical work was conducted in compliance with current Good Clinical Practices as referenced in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline E6, local regulatory requirements, and the principles of the Declaration of Helsinki. All patients enrolled in the study provided written informed consent before their participation.

       Study Procedures

      Patients were instructed to complete an electronic diary (eDiary) each study day whether or not they experienced a headache in the previous 24-h period. Eligible patients were randomly assigned to receive eptinezumab 30 mg, 100 mg, 300 mg, or placebo in a 1:1:1:1 ratio. Randomization was stratified by the number of migraine-days recorded during the screening period (≤9 vs >9 days). Stratification at 9 days was performed because it was expected that the median number of baseline migraine days would be approximately 9.
      The total duration of the study was 60 weeks, with 12 scheduled visits (screening, day 0 [randomization], and weeks 4, 8, 12, 16, 20, 24, 28, 36, 48, and 56 [5 t½ after the final dose at 36 weeks]). As stated in the primary report,
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      after the last patient completed the week 24 study visit, the study data were analyzed, and unblinded aggregated study results for the primary efficacy and tolerability data were provided by the statistician to clinical development and safety leadership within the company, pursuant to the investigational plan and protocol. However, to ensure blinding was adequately maintained for the entire study duration, the study site personnel and patients remained blinded to individual treatment assignments until study completion.
      Patients received up to 4 doses of eptinezumab or placebo (administered on day 0 and at weeks 12, 24, and 36). Treatments were reconstituted by unblinded personnel in a total volume of 100 mL 0.9% saline and administered intravenously for a mean (SD) period of 1 h (±15 min) by the blinded investigator or designated health care professional at each study site. Patients were monitored in the clinic for up to 4 h after the end of dosing.

       Outcome Measures

      A migraine-day was defined as any day on which the patient had a migraine or probable migraine. The criteria for a migraine included duration (4–72 h), presence of at least 2 pain-related symptoms (unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or causing avoidance of routine physical activity), and presence of ≥1 additional feature (nausea and/or vomiting, photophobia, and/or phonophobia).
      Headache Classification Subcommittee of the International Headache Society
      The international classification of headache disorders.
      A probable migraine was a headache that met only 2 of these 3 criteria.
      Details of the primary end point in PROMISE-1 (change from baseline in MMDs during weeks 1–12) have been reported previously.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      For this 1-year analysis, the outcome measures (assessed using eDiary data) included MMDs from weeks 1–48 and during each 12-week dosing interval, migraine responder rates (MRRs; ≥50%, ≥75%, mean monthly 100% response [defined as patients with no migraine-days for the entire prespecified study month]), and short-term medication use. In addition, the Medical Outcomes Study Short-Form Health Survey (SF-36, version 2.0)
      • Ware J.E.
      • Kosinski M.
      The SF-36 health survey (version 2.0) technical note.
      ,
      • Ware Jr., J.E.
      SF-36 health survey update.
      was administered at screening, day 0, weeks 4, 12, 16, 24, and 32, and the week 56 end of study visit. The SF-36 contains 36 questions designed to measure quality of life during the preceding 4 weeks in 8 key domains (vitality, physical functioning, bodily pain, general health perceptions, physical role–functioning, emotional role–functioning, social role–functioning, and mental health), which are also combined into mental component summary and physical component summary scores. Norm-based scores <50 represent health status below average.
      Tolerability was assessed throughout the study via adverse event monitoring, physical and laboratory measurements, and concomitant medication use. Adverse events and treatment-emergent adverse events (TEAEs) were classified according to the Medical Dictionary for Regulatory Activities (MedDRA), version 20.1.
      Blood samples were collected on scheduled visits for analysis of immunogenicity, including monitoring the development of antidrug antibodies (ADAs) and assessment for neutralizing antibodies.

       Statistical Analysis

      All randomly assigned patients who received study medication were included in the tolerability and efficacy populations. For the tolerability analyses, patients’ results were summarized within the treatment group for which they received treatment. For the efficacy analyses, patients’ results were summarized within the treatment group to which they were randomly assigned.
      Migraine and headache data from the eDiary were summarized in 4-week, 12-week, and 24-week intervals. Results during the 12-week and 24-week intervals were calculated by averaging data in the corresponding 4-week intervals, then calculating the respective end point. For the mean monthly 100% MRR, the treatment group results for each 4-week interval were averaged.
      Summary statistics were used to summarize results for the efficacy end points (change in MMDs from weeks 1–48 and during each 12-week dosing interval, MRRs, and change in short-term medication use). A serial testing procedure was applied to account for multiplicity associated with testing multiple dose strengths and multiple end points. This procedure resulted in statistical significance for most end points and dose groups specified within the algorithm as reported in the primary article.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      Additional end points have been summarized here with descriptive statistics. Because the α-controlled end points have been previously summarized, testing without α control has not been added within this manuscript. Least-squares means from the ANCOVA model used to test the primary end point have been used to summarize the MMDs. Post hoc analysis of short-term headache medication use by baseline short-term medication use (1–9 vs ≥10 days) was also performed. Short-term headache medication-days were calculated for individual types of medications and combined, meaning that if ≥2 types of medications were used on the same calendar-days, they were counted as separate medication-days. Medication classes included triptans, ergots, opioids, simple analgesics, and combination analgesics.
      Tolerability end points were summarized using descriptive statistics and conducted using the tolerability population. A post hoc analysis was conducted for a temporal analysis of TEAEs, which evaluated each 12-week dosing interval separately. For the immunogenicity analyses, the number and percentage of patients with preexisting antibodies at baseline and patients who developed ADAs to eptinezumab during the study were summarized at each scheduled visit, along with the overall incidence of ADA-positive patients.
      All analyses were conducted using SAS software, version 9.2 or higher (SAS Institute Inc, Cary, North Carolina).

      Results

       Patients

      A total of 898 patients were randomly assigned to treatment. Of these, 888 received treatment and were included in the efficacy population (eptinezumab 30 mg, n = 223; eptinezumab 100 mg, n = 221; eptinezumab 300 mg, n = 222; placebo, n = 222). The tolerability population, in which patients were categorized according to the actual treatment received, also comprised 888 patients (eptinezumab 30 mg, n = 219; eptinezumab 100 mg, n = 223; eptinezumab 300 mg, n = 224; placebo, n = 222). The mean patient age was 39.8 years, with 61.4% of patients 35 years or older. Most patients were female (84.3%), white (83.8%), and not Hispanic or Latino (81.9%). Additional patient details are summarized in the primary publication.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      Of the 888 patients treated, 835 (93.0%), 771 (85.9%), 772 (80.4%), and 694 (78.2%) patients attended the week 12, 24, 36, and 48 visits, respectively, with most patients (691 [77.8%]) receiving a total of 4 doses of randomized treatment. This group included 167 of 219 patients (76.3%) treated with eptinezumab 30 mg, 177 of 223 (79.4%) treated with eptinezumab 100 mg, and 180 of 224 (80.4%) treated with eptinezumab 300 mg; retention in the placebo group was 74.7%. Lack of efficacy was cited as a reason for study discontinuation by slightly more patients in the placebo group (3.6%) compared with the eptinezumab 30 mg, 100 mg, and 300 mg groups (<1%, 1.4%, and <1%, respectively). Full details of study discontinuations have been previously reported.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).

       Migraine-Preventive Effects

      Efficacy outcomes (MMDs, ≥50% MRRs, ≥75% MRRs, and mean monthly 100% MRRs) across weeks 1–48 are summarized in Table I. All eptinezumab doses reduced MMDs relative to placebo through week 48, with the therapeutic effect consistently sustained throughout the study. Because the 30-mg dose did not achieve statistical significance on the primary efficacy end point per the statistical hierarchy and was not approved by the US Food and Drug Administration, results for this dose will not be further discussed. In the approved eptinezumab doses (100 and 300 mg), mean reductions during weeks 1 to 12, 13 to 24, 25 to 36, and 37 to 48 were −3.9, −4.5, −4.7, and −4.5 days with 100 mg and −4.3, −4.8, −5.1, and −5.3 days with 300 mg compared with −3.2, −3.8, −4.0, and −4.1 days with placebo, respectively (Figure 1). Sensitivity analyses conducted to evaluate the impact of eDiary adherence on efficacy outcomes found a similar separation from placebo over time, with little difference between nonadherence in the placebo arm compared with the active treatment arms (data not shown).
      Table ISummary of efficacy by 12-week dosing interval.
      VariableWeeks 1–12Weeks 13–24Weeks 25–36Weeks 37–48
      EptinezumabPlacebo (n = 222)EptinezumabPlacebo (n = 222)EptinezumabPlacebo (n = 222)EptinezumabPlacebo (n = 222)
      300 mg n = 222100 mg n = 22130 mg n = 223300 mg n = 222100 mg n = 22130 mg n = 223300 mg n = 222100 mg n = 22130 mg n = 223300 mg n = 222100 mg n = 22130 mg n = 223
      Mean MMDs4.34.74.65.43.84.14.14.83.53.94.04.63.34.13.64.5
      Change from baseline
       Mean−4.3−3.9−4.0−3.2−4.8−4.5−4.5‒3.8−5.1−4.7−4.6−4.0−5.3−4.5−5.0−4.1
       Difference from placebo (95% CI)−1.11 (−1.68 to −0.54)−0.69 (−1.25 to −0.12)−0.82 (−1.39 to −0.25)−1.02 (−1.66 to −0.37)−0.76 (−1.40 to −0.11)−0.75 (−1.39 to −0.11)−1.13 (−1.84 to −0.42)−0.72 (−1.43 to −0.01)−0.66 (−1.37 to 0.05)−1.20 (−1.95 to −0.46)−0.38 (−1.13 to 0.37)−0.86 (−1.61 to −0.11)
      ≥50% MRR
       Patients, n (%)125 (56.3)110 (49.8)112 (50.2)83 (37.4)145 (65.3)137 (62.0)139 (62.3)114 (51.4)155 (69.8)141 (63.8)143 (64.1)129 (58.1)155 (69.8)143 (64.7)155 (69.5)123 (55.4)
       Difference from placebo (95% CI)18.9 (9.8, 28.0)12.4 (3.2, 21.5)12.8 (3.7, 22.0)14.0 (4.9, 23.0)10.6 (1.5, 19.8)11.0 (1.8, 20.1)11.7 (2.8, 20.6)5.7 (–3.4, 14.8)6.0 (–3.0, 15.1)14.4 (5.5, 23.3)9.3 (0.2, 18.4)14.1 (5.2, 23.0)
      ≥75% MRR
       Patients, no. (%)66 (29.7)49 (22.2)55 (24.7)36 (16.2)89 (40.1)74 (33.5)75 (33.6)55 (24.8)96 (43.2)89 (40.3)80 (35.9)66 (29.7)120 (54.1)87 (39.4)107 (48.0)88 (39.6)
       Difference from placebo (95% CI)13.5 (5.8–21.2)6.0 (−1.4 to 13.3)8.4 (1.0–15.9)15.3 (6.7–23.9)8.7 (0.3–17.1)8.9 (0.4–17.3)13.5 (4.6–22.4)10.5 (1.7–19.4)6.1 (−2.6 to 14.8)14.4 (5.2–23.6)−0.3 (−9.4 to 8.8)8.3 (−0.8 to 17.5)
      Mean monthly 100% MRR
      Calculated as the mean percentage of patients with 100% migraine response for any given month during the respective dosing interval.
       Patients, %16.7911.4310.749.1424.4519.7118.0514.2627.4525.7821.5018.2833.7627.7327.8022.67
       Difference from placebo (95% CI)7.65 (2.97–12.33)2.29 (−1.74 to 6.31)1.59 (−2.53 to 5.71)10.19 (4.38–16.00)5.46 (−0.04 to 10.96)3.80 (−1.65 to 9.24)9.1 (2.66–15.67)7.49 (1.33–13.66)3.22 (−2.73 to 9.17)11.09 (4.00–18.19)5.07 (−1.82 to 11.95)5.13 (−1.73 to 11.99)
      MMD = monthly migraine day; MRR = migraine responder rate.
      a Calculated as the mean percentage of patients with 100% migraine response for any given month during the respective dosing interval.
      Figure 1
      Figure 1Change from baseline in mean monthly migraine-days (MMDs). Eptinezumab 100 mg and 300 mg are the dose levels approved by the US Food and Drug Administration.
      Overall, the percentage of patients with a ≥50% or ≥75% reduction in MMDs from weeks 1–48 was consistently higher with eptinezumab 100 mg and 300 mg than with placebo (Table I). The ≥50% MRRs were similar across the eptinezumab groups during each 12-week dosing interval, ranging from 50% to 56% (vs 37% with placebo) during the first dosing interval and from 65% to 70% (vs 55% with placebo) during the fourth interval. During the study, almost 70% of patients treated with eptinezumab experienced a ≥50% migraine response during at least 6 study months (4-week intervals), and >20% of patients treated with eptinezumab experienced a ≥50% migraine response during all 12 study months (Figure 2A). In comparison, ≥6-month and 12-month rates in the placebo group were 60% and 15%, respectively.
      Figure 2
      Figure 2Cumulative monthly ≥50% (A) and ≥75% (B) migraine responder rates. Eptinezumab 100 mg and 300 mg are the dose levels approved by the US Food and Drug Administration. Migraine responder rates were evaluated during 4-week intervals with the first day of dosing used as the reference point.
      The ≥75% MRRs ranged from 22% to 30% among patients treated with eptinezumab (vs 16% with placebo) during the first dosing interval and tended to increase with subsequent doses (Table I). Approximately 45% of patients treated with eptinezumab experienced a ≥75% migraine response during at least 6 study months (4-week intervals) compared with 34% of placebo patients (Figure 2B).
      An increase in the mean monthly 100% MRRs was also observed, ranging from 11% to 17% (vs 9% with placebo) during weeks 1–12 and from 28% to 34% (vs 23% with placebo) during weeks 37–48 (Figure 3).
      Figure 3
      Figure 3Mean monthly 100% migraine responder rates. Eptinezumab 100 mg and 300 mg are the dose levels approved by the US Food and Drug Administration.

       Short-term Headache Medication Use

      A total of 301 patients in the eptinezumab 100 mg group, 314 in the 300 mg group, and 309 in the placebo group reported taking ≥1 day of headache medication during the 28-day baseline period for the post hoc analysis. Among these, patients in the eptinezumab groups had greater decreases in headache medication use compared with placebo as early as weeks 1–4 after treatment and across 24 weeks of treatment.
      When stratified by baseline use (1–9 days vs ≥ 10 days per month), greater improvements were observed in the subgroup with the higher baseline use. At week 24, reductions in patients with baseline use of 1–9 days per month were −0.8, −2.6, and −1.3 days in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively; reductions in patients with baseline use of ≥10 days per month were −8.9, −11.1, and −7.9 days, respectively.

       Short-form Health Survey

      Baseline scores and changes from baseline in all SF-36 component summaries and domains are presented in Supplemental Table I. At baseline, there were noticeable impairments in the bodily pain and physical role–functioning domains of the SF-36, as well as mean scores below the normative health-related quality of life line (score of 50) in the social role–functioning domain; all other domains and the 2 component summary scores were at or above normative levels. For domains with impairment noted at baseline, mean scores across the four 12-week dosing intervals are presented in Supplemental Figure I. At the end of the study, patients who received eptinezumab had improvements of 3.1 to 5.2 points on the bodily pain domain (vs 2.1 with placebo), 2.1 to 2.9 points on the physical role–functioning domain (vs 1.9 with placebo), and 1.4 to 3.4 points on the social role–functioning domain (vs 1.5 with placebo).

       Treatment-emergent Adverse Events

      Tolerability data for the full study have been presented previously.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      The overall incidence of TEAEs was generally balanced among treatment groups and tended to decrease across dosing intervals (Table II). No clear dose–response trend emerged with any specific TEAEs. No serious tolerability signals were observed with continued eptinezumab dosing.
      Table IINumber (percentage) of treatment-emergent adverse events reported in ≥2% of patients by 12-week dosing interval.
      Italicized indicates ≥2% of patients.
      EventEptinezumab 300 mgEptinezumab 100 mgEptinezumab 30 mgPlacebo
      Dose 1 (n = 224)Dose 2 (n = 218)Dose 3 (n = 206)Dose 4 (n = 189)Dose 1 (n = 223)Dose 2 (n = 214)Dose 3 (n = 199)Dose 4 (n = 184)Dose 1 (n = 219)Dose 2 (n = 210)Dose 3 (n = 196)Dose 4 (n = 182)Dose 1 (n = 222)Dose 2 (n = 212)Dose 3 (n = 195)Dose 4 (n = 179)
      Any event73 (32.6)64 (29.4)44 (21.4)40 (21.2)74 (33.2)75 (35.0)48 (24.1)34 (18.5)74 (33.8)41 (19.5)45 (23.0)35 (19.2)85 (38.3)63 (29.7)36 (18.5)31 (17.3)
      URTI9 (4.0)12 (5.5)2 (1.0)3 (1.6)12 (5.4)7 (3.3)3 (1.5)5 (2.7)15 (6.8)5 (2.4)3 (1.5)4 (2.2)6 (2.7)8 (3.8)2 (1.0)1 (0.6)
      Nasopharyngitis3 (1.3)5 (2.3)3 (1.5)3 (1.6)6 (2.7)5 (2.3)3 (1.5)5 (2.7)5 (2.3)2 (1.0)5 (2.6)2 (1.1)7 (3.2)2 (0.9)4 (2.1)1 (0.6)
      Sinusitis4 (1.8)4 (1.8)3 (1.5)03 (1.3)2 (0.9)1 (0.5)01 (0.5)3 (1.4)3 (1.5)08 (3.6)5 (2.4)3 (1.5)0
      Dizziness2 (0.9)01 (0.5)2 (1.1)6 (2.7)04 (2.0)06 (2.7)2 (1.0)1 (0.5)2 (1.1)4 (1.8)1 (0.5)1 (0.5)2 (1.1)
      Nausea3 (1.3)02 (1.0)1 (0.5)1 (0.4)03 (1.5)1 (0.5)6 (2.7)02 (1.0)1 (0.5)3 (1.4)3 (1.4)2 (1.0)1 (0.6)
      Fatigue6 (2.7)01 (0.5)1 (0.5)4 (1.8)4 (1.9)003 (1.4)1 (0.5)01 (0.5)01 (0.5)00
      URTI = upper respiratory tract infection.
      Italicized indicates ≥2% of patients.

       Immunogenicity

      The incidence of ADAs was transient and similar in patients receiving 100 or 300 mg eptinezumab, with the maximal incidence of ADAs being detected at week 24 (18.5% and 17.5% of patients, respectively). The incidence of ADAs subsequently decreased in both the 100 and 300 mg treatment groups (6.9% and 4.1% at week 56, respectively), despite administration of additional scheduled doses at weeks 24 and 36. The ADA titers were low across all eptinezumab dose groups, with no trend of increasing titer related to dose throughout the study period. The overall neutralizing antibody–positive incidence across the 56 weeks was 7.8% (52 of 666 patients) among all eptinezumab-treated patients, with 22 patients who received the 100 mg dose and 16 patients who received the 300 mg dose reporting ADA-positive results with neutralizing potential.
      Patients who tested positive for antieptinezumab antibodies at the end-of-study visit (week 56) continued with immunogenicity testing at approximately 12-week intervals for up to 24 weeks (ie, follow-up visits) to evaluate sustainability of the antibody response. At the 12-week follow-up visit, 9 of the 26 ADA-positive patients tested remained positive. All 9 patients had low titer antibodies (<300), with 4 having titers of 50—the lowest titer that can be scored as positive. Two of these 9 patients had antibodies that were characterized as having neutralizing potential. At the 24-week follow-up analysis, all patients were ADA negative.

      Discussion

      The 1-year results of PROMISE-1 indicate that IV eptinezumab administered every 12 weeks for up to 4 doses provides sustained migraine-preventive effects in adults with EM. These data confirm and extend the positive results of the 12-week primary analysis
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      in which eptinezumab had an early preventive migraine effect. Taken together, these data indicate that eptinezumab can provide clinically meaningful migraine reductions for patients with EM, with an acceptable safety profile.
      The current analyses indicate that the >50% reduction in migraine versus baseline observed on the first day after eptinezumab dosing described in the initial study report
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      was sustained throughout all four 12-week dosing intervals. The proportions of patients experiencing ≥50% and ≥75% migraine response were higher during the second half of the study (weeks 24–48) relative to the first half (weeks 1–24). As reported in the primary analysis,
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      on the first day after dosing, the percentages of patients with migraine were reduced by 44%, 52%, and 55% in the eptinezumab 30 mg, 100 mg, and 300 mg groups, respectively (vs 27% in the placebo group). During the last dosing interval, ≥50% migraine response was achieved by 65%–70% of the eptinezumab groups compared with 55% of the placebo group. During the last month of the treatment period (weeks 37–48), 14% of patients who received eptinezumab 30 mg, 15% of patients who received eptinezumab 100 mg, 20% of patients who received eptinezumab 300 mg, and 13% of patients who received placebo reported no migraine days (100% MRR). Eptinezumab was well tolerated throughout the study. Rates of TEAEs were similar across dose levels and dosing intervals, and the temporal analysis of exposure reported herein did not identify any serious tolerability signals compared with the overall tolerability analysis.
      • Ashina M.
      • Saper J.
      • Cady R.
      • et al.
      Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
      The sustained preventive benefit of eptinezumab observed in this study may contribute to improved persistence with therapy, as does the acceptable tolerability profile. During the first half of the study (weeks 1–24), eptinezumab reduced MMDs by 0.7–1 day more than placebo; reductions relative to placebo during weeks 25–48 ranged from 0.6 to 1 day. Lack of efficacy and the occurrence of adverse effects are 2 common reasons cited for the discontinuation of migraine-preventive medications.
      • Blumenfeld A.M.
      • Bloudek L.M.
      • Becker W.J.
      • et al.
      Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II).
      Although the impact of quarterly versus monthly or daily migraine-preventive medication administration on persistence remains to be established as an obvious benefit, both physicians and patients recognize the potential benefits of the longer dosing interval. In a survey designed to assess patient preferences for monthly or quarterly administration, patients who preferred administration every 12 weeks cited convenience, fewer treatments to keep track of, need to pay for medication less often, perception that the higher dose is more efficacious, and fewer reminders of disease.
      • Cowan R.
      • Cohen J.M.
      • Rosenman E.
      • Iyer R.
      Physician and patient preferences for dosing options in migraine prevention.
      Leading reasons for physicians choosing administration every 12 weeks were the potential for improved adherence, reduced monthly injection burden, and fewer injection-days. Additional research will provide greater insight into the potential benefits of eptinezumab and other migraine preventive measures designed to reduce or eliminate the need for daily therapy.
      The SF-36 findings reported herein suggest that eptinezumab treatment is associated with meaningful improvements in quality of life, particularly with respect to bodily pain, physical role–functioning, and social role–functioning. It seems reasonable to suspect that such improvements in patient well-being would translate into an increased ability to fulfill work, school, and family or social obligations. Migraine is also associated with high financial costs to the individual, to society, and to health care systems,
      • Silberstein S.D.
      • Lee L.
      • Gandhi K.
      • et al.
      Health care resource utilization and migraine disability along the migraine continuum among patients treated for migraine.
      • Saylor D.
      • Steiner T.J.
      The global burden of headache.
      • Messali A.
      • Sanderson J.C.
      • Blumenfeld A.M.
      • et al.
      Direct and indirect costs of chronic and episodic migraine in the United States: a web-based survey.
      and we can speculate that improvements in health and functioning may also contribute in reducing the economic burden associated with this disabling disorder.
      The presence of a large placebo effect in our study is not surprising; similar results have been reported in previous clinical trials of migraine treatments.
      • Dodick D.W.
      • Ashina M.
      • Brandes J.L.
      • et al.
      ARISE: a phase 3 randomized trial of erenumab for episodic migraine.
      • Detke H.C.
      • Goadsby P.J.
      • Wang S.
      • et al.
      Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study.
      • Goadsby P.J.
      • Reuter U.
      • Hallstrom Y.
      • et al.
      A controlled trial of erenumab for episodic migraine.
      • Dodick D.W.
      • Silberstein S.D.
      • Bigal M.E.
      • et al.
      Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial.
      • Reuter U.
      • Goadsby P.J.
      • Lanteri-Minet M.
      • et al.
      Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study.
      • Skljarevski V.
      • Matharu M.
      • Millen B.A.
      • et al.
      Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial.
      • Stauffer V.L.
      • Dodick D.W.
      • Zhang Q.
      • et al.
      Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial.
      • Silberstein S.D.
      • Dodick D.W.
      • Bigal M.E.
      • et al.
      Fremanezumab for the preventive treatment of chronic migraine.
      This result may reflect the regular attention and care that clinical study participants receive; alternatively, it may be attributable to the well-documented placebo phenomenon among patients with migraine.
      • Autret A.
      • Valade D.
      • Debiais S.
      Placebo and other psychological interactions in headache treatment.
      ,
      • Speciali J.G.
      • Peres M.
      • Bigal M.E.
      Migraine treatment and placebo effect.
      In addition, the placebo effect observed in PROMISE-1 may be attributable to the route of administration, frequency of on-site visits, patient expectations and beliefs, or other contextual factors.
      • Di Blasi Z.
      • Harkness E.
      • Ernst E.
      • Georgiou A.
      • Kleijnen J.
      Influence of context effects on health outcomes: a systematic review.
      • Meissner K.
      • Fässler M.
      • Rücker G.
      • et al.
      Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis.
      • Mitsikostas D.D.
      • Benedetti F.
      Placebos and Nocebos in Headaches.
      • Forbes R.B.
      • McCarron M.
      • Cardwell C.R.
      Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-Analysis.
      While nonadherence with the eDiary may play a factor in the placebo response, sensitivity analyses found a similar separation from placebo over time and similar rates of nonadherence across treatment arms. Despite the placebo response, eptinezumab 100 mg and 300 mg produced statistically and nominally greater improvements in migraine frequency across 48 weeks of treatment.
      Overall, the results from the study provide no evidence of an impact from development of antieptinezumab antibodies, including neutralizing antibodies, on the safety and efficacy profiles of eptinezumab. The ADA and neutralizing antibody profiles observed in this study, where a peak response occurs at 24 weeks followed by a consistent decrease despite subsequent dosing, suggest that any impact from immunogenicity is likely to manifest by week 24 of long-term administration. Continued immunogenicity testing at approximately 12-week intervals for patients who were ADA positive at week 56 supported the transient nature of the response and that it was not sustained over time.

       Study Limitations

      As might be expected with a year-long study, patients did not remain fully adherent with the eDiary during the full year, and nearly 1 in 4 patients discontinued the study early. Although no clear bias is known to exist within the resulting missing data, the unknown but potential impact on the results should be considered when interpreting the long-term data from this study.

      Conclusion

      IV eptinezumab administered every 12 weeks for up to 4 doses provides early and sustained migraine-preventive efficacy and improvements in health-related quality of life in adults with EM and is well tolerated with an acceptable safety profile. These attributes could potentially facilitate improved adherence.

      Disclosures

      T.R. Smith has been a consultant and/or scientific advisor for Alder/Lundbeck, Amgen, Biohaven, Eli Lilly, Impel Neuropharma, and Theranica, and has received research support from Alder/Lundbeck, Allergan, Amgen, Biohaven, Charleston Labs, Eli Lilly, Electrocore, Novartis, Novo Nordisk, Satsuma, Theranica, and Vorso. M. Janelidze and G. Chakhava report no conflicts of interest. R. Cady and S. Pederson are full-time employees of Lundbeck Seattle BioPharmaceuticals. J. Hirman is a contracted service provider of biostatistical resources for Lundbeck Seattle BioPharmaceuticals. B. Allan and J. Smith were full-time employees and stockholders of Alder BioPharmaceuticals (now known as Lundbeck Seattle BioPharmaceuticals) at the time of study and were contracted service providers for Lundbeck Seattle BioPharmaceuticals during manuscript development. B. Schaeffler was a full-time employee of Lundbeck Seattle BioPharmaceuticals at the time of study and during manuscript preparation.

      Acknowledgments

      We thank the patients, their families, and the study sites that participated in this study. We also thank Mary Tom, PharmD, Nicole Coolbaugh, CMPP, and Philip Sjostedt, BPharm, of The Medicine Group LLC (New Hope, Pennsylvania), for providing medical writing support, which was funded by H. Lundbeck A/S (Copenhagen, Denmark) in accordance with Good Publication Practice guidelines.

      APPENDIX.

      Supplemental Table IMean (SD) baseline and changes from baseline in Short-Form Health Survey component and domain scores.
      Eptinezumab 30 mg

      n = 223
      Eptinezumab 100 m

      gn = 221
      Eptinezumab 300 m

      gn = 222
      Placebo

      n = 222
      Physical Functioning
       Baseline52.5 (7.44)52.0 (7.02)52.1 (7.15)52.8 (6.24)
       Change from baseline
      Week 40.7 (6.50)1.2 (6.00)0.5 (5.01)0.6 (4.95)
      Week 241.3 (7.22)1.2 (6.73)1.7 (4.82)0.3 (6.41)
      Week 560.7 (7.02)1.3 (7.24)1.3 (5.20)0.3 (7.14)
      Role-Physical
       Baseline49.4 (8.04)48.8 (8.24)48.9 (8.16)49.0 (7.36)
       Change from baseline
      Week 42.6 (6.60)2.6 (7.20)2.1 (7.92)1.5 (6.64)
      Week 243.2 (7.85)2.4 (8.05)3.1 (7.48)1.5 (7.46)
      Week 562.1 (9.23)2.9 (8.28)2.4 (8.42)1.9 (7.46)
      Bodily Pain
       Baseline4.78 (9.30)45.8 (9.46)46.6 (9.26)47.2 (9.33)
       Change from baseline
      Week 43.8 (9.06)4.5 (9.04)4.1 (8.36)2.3 (8.07)
      Week 243.4 (9.79)4.4 (9.97)4.9 (9.35)2.8 (9.37)
      Week 563.1 (10.42)5.2 (10.66)4.8 (9.92)2.1 (9.62)
      General Health
       Baseline53.4 (9.22)53.1 (9.91)52.2 (10.04)53.1 (9.37)
       Change from baseline
      Week 40.5 (6.90)0.9 (6.68)1.5 (6.62)0.0 (6.08)
      Week 240.8 (7.57)0.6 (7.31)1.5 (7.61)0.1 (7.59)
      Week 560.6 (8.05)0.4 (7.76)1.9 (8.40)0.1 (7.93)
      Vitality
       Baseline53.0 (8.30)53.1 (9.21)53.0 (9.01)52.8 (8.17)
       Change from baseline
      Week 40.7 (7.98)1.7 (8.04)0.9 (7.55)1.3 (6.69)
      Week 241.8 (8.43)1.2 (9.11)2.3 (8.83)0.8 (7.90)
      Week 561.4 (9.33)2.4 (9.13)1.7 (9.66)0.6 (7.93)
      Physical Component
       Baseline50.1 (7.85)49.4 (7.15)49.4 (7.65)50.1 (6.71)
       Change from baseline
      Week 42.5 (6.38)2.6 (6.10)2.1 (5.77)1.0 (5.42)
      Week 243.0 (7.69)2.7 (6.84)3.2 (6.02)1.3 (6.42)
      Week 562.1 (7.63)3.0 (7.46)3.1 (6.49)1.4 (7.51)
      Social Functioning
       Baseline50.2 (8.26)48.6 (9.11)49.8 (8.88)49.9 (8.45)
       Change from baseline
      Week 41.7 (8.12)3.0 (8.09)1.9 (7.51)1.8 (7.05)
      Week 242.5 (7.78)2.8 (9.45)2.6 (9.21)0.7 (8.43)
      Week 561.7 (9.55)3.4 (8.77)1.4 (9.07)1.5 (7.93)
      Role-Emotional
       Baseline51.9 (7.40)50.8 (8.32)50.6 (8.58)50.8 (7.96)
       Change from baseline
      Week 4−0.2 (7.07)1.3 (7.14)1.0 (7.96)1.5 (6.89)
      Week 240.3 (7.01)−0.1 (8.98)1.3 (8.25)0.7 (8.01)
      Week 56−0.1 (8.15)0.7 (7.82)1.0 (9.22)0.7 (7.90)
      Mental Health
       Baseline53.1 (7.68)52.1 (9.82)52.5 (9.00)52.6 (8.99)
       Change from baseline
      Week 40.5 (7.56)1.5 (7.78)1.6 (6.48)1.4 (6.03)
      Week 240.1 (8.29)1.0 (8.65)1.8 (7.42)0.9 (7.60)
      Week 560.3 (8.91)1.1 (9.38)0.8 (9.18)−0.3 (7.53)
      Mental Component
       Baseline52.7 (7.06)51.8 (9.33)52.1 (9.02)52.0 (8.60)
       Change from baseline
      Week 4−0.1 (7.09)1.4 (7.59)1.1 (6.29)1.6 (6.17)
      Week 240.2 (6.79)0.5 (8.89)1.4 (7.86)0.6 (7.63)
      Week 560.1 (8.21)1.2 (8.81)0.5 (8.98)0.2 (7.28)
      SD = standard deviation.
      Supplementary Figure I
      Supplementary Figure IMean SF-36 Domain Scores for (A) Bodily Pain, (B) Role-Physical, and (C) Social Functioning. Eptinezumab 100 mg and 300 mg are the dose levels approved by the US Food & Drug Administration.

      References

        • GBD 2017 Disease and Injury Incidence and Prevalence Collaborators
        Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
        Lancet. 2018; 392: 1789-1858
        • GBD 2016 Neurology Collaborators
        Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
        Lancet Neurol. 2019; 18: 459-480
        • Martelletti P.
        • Schwedt T.J.
        • Lanteri-Minet M.
        • et al.
        My Migraine Voice survey: a global study of disease burden among individuals with migraine for whom preventive treatments have failed.
        J Headache Pain. 2018; 19: 115
        • Katsarava Z.
        • Buse D.C.
        • Manack A.N.
        • Lipton R.B.
        Defining the differences between episodic migraine and chronic migraine.
        Curr Pain Headache Rep. 2012; 16: 86-92
        • Lipton R.B.
        • Silberstein S.D.
        Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention.
        Headache. 2015; 55 (quiz 123–106): 103-122
        • Marmura M.J.
        Triggers, protectors, and predictors in episodic migraine.
        Curr Pain Headache Rep. 2018; 22: 81
        • Diamond S.
        • Bigal M.E.
        • Silberstein S.
        • et al.
        Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study.
        Headache. 2007; 47: 355-363
        • Silberstein S.D.
        • Holland S.
        • Freitag F.
        • et al.
        Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American academy of neurology and the American headache society.
        Neurology. 2012; 78: 1337-1345
        • Woolley J.M.
        • Bonafede M.M.
        • Maiese B.A.
        • Lenz R.A.
        Migraine prophylaxis and acute treatment patterns among commercially insured patients in the United States.
        Headache. 2017; 57: 1399-1408
        • Blumenfeld A.M.
        • Bloudek L.M.
        • Becker W.J.
        • et al.
        Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II).
        Headache. 2013; 53: 644-655
        • Ford J.H.
        • Jackson J.
        • Milligan G.
        • et al.
        A real-world analysis of migraine: a cross-sectional study of disease burden and treatment patterns.
        Headache. 2017; 57: 1532-1544
        • Ashina M.
        • Saper J.
        • Cady R.
        • et al.
        Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1).
        Cephalalgia. 2020; 40: 241-254
        • Headache Classification Subcommittee of the International Headache Society
        The international classification of headache disorders.
        Cephalalgia. 2004; 24 (2nd ed.): 9-160
        • Ware J.E.
        • Kosinski M.
        The SF-36 health survey (version 2.0) technical note.
        Health Assessment Lab, Boston, MA1996 (September 20 (updates September 27, 1997))
        • Ware Jr., J.E.
        SF-36 health survey update.
        Spine. 2000; 25: 3130-3139
        • Cowan R.
        • Cohen J.M.
        • Rosenman E.
        • Iyer R.
        Physician and patient preferences for dosing options in migraine prevention.
        J Headache Pain. 2019; 20: 50
        • Silberstein S.D.
        • Lee L.
        • Gandhi K.
        • et al.
        Health care resource utilization and migraine disability along the migraine continuum among patients treated for migraine.
        Headache. 2018; 58: 1579-1592
        • Saylor D.
        • Steiner T.J.
        The global burden of headache.
        Semin Neurol. 2018; 38: 182-190
        • Messali A.
        • Sanderson J.C.
        • Blumenfeld A.M.
        • et al.
        Direct and indirect costs of chronic and episodic migraine in the United States: a web-based survey.
        Headache. 2016; 56: 306-322
        • Dodick D.W.
        • Ashina M.
        • Brandes J.L.
        • et al.
        ARISE: a phase 3 randomized trial of erenumab for episodic migraine.
        Cephalalgia. 2018; 38: 1026-1037
        • Detke H.C.
        • Goadsby P.J.
        • Wang S.
        • et al.
        Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study.
        Neurology. 2018; 91: e2211-e2221
        • Goadsby P.J.
        • Reuter U.
        • Hallstrom Y.
        • et al.
        A controlled trial of erenumab for episodic migraine.
        N Engl J Med. 2017; 377: 2123-2132
        • Dodick D.W.
        • Silberstein S.D.
        • Bigal M.E.
        • et al.
        Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial.
        JAMA. 2018; 319: 1999-2008
        • Reuter U.
        • Goadsby P.J.
        • Lanteri-Minet M.
        • et al.
        Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study.
        Lancet. 2018; 392: 2280-2287
        • Skljarevski V.
        • Matharu M.
        • Millen B.A.
        • et al.
        Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial.
        Cephalalgia. 2018; 38: 1442-1454
        • Stauffer V.L.
        • Dodick D.W.
        • Zhang Q.
        • et al.
        Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial.
        JAMA Neurol. 2018; 75: 1080-1088
        • Silberstein S.D.
        • Dodick D.W.
        • Bigal M.E.
        • et al.
        Fremanezumab for the preventive treatment of chronic migraine.
        N Engl J Med. 2017; 377: 2113-2122
        • Autret A.
        • Valade D.
        • Debiais S.
        Placebo and other psychological interactions in headache treatment.
        J Headache Pain. 2012; 13: 191-198
        • Speciali J.G.
        • Peres M.
        • Bigal M.E.
        Migraine treatment and placebo effect.
        Expert Rev Neurother. 2010; 10: 413-419
        • Di Blasi Z.
        • Harkness E.
        • Ernst E.
        • Georgiou A.
        • Kleijnen J.
        Influence of context effects on health outcomes: a systematic review.
        Lancet. 2001; 357: 757-762
        • Meissner K.
        • Fässler M.
        • Rücker G.
        • et al.
        Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis.
        JAMA Intern Med. 2013; 173: 1941-1951
        • Mitsikostas D.D.
        • Benedetti F.
        Placebos and Nocebos in Headaches.
        Springer International Publishing, Cham, Switzerland2019
        • Forbes R.B.
        • McCarron M.
        • Cardwell C.R.
        Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-Analysis.
        Headache. 2020; 60: 1941-1951

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