Pozo‑Rosich et al. BMC Neurology (2022) 22:394 https://doi.org/10.1186/s12883-022-02914-9 RESEARCH Open Access Shift in diagnostic classification of migraine after initiation of preventive treatment with eptinezumab: post hoc analysis of the PROMISE studies Patricia Pozo‑Rosich1,2*, David W. Dodick3,4, Anders Ettrup5, Joe Hirman6 and Roger Cady7,8,9 Abstract Background: Monthly headache frequency directly correlates with personal/societal burden and impacts severity and preventive treatment decisions. This post hoc analysis identified shifts from higher to lower frequency headache categories over 6 months in patients with migraine participating in the PROMISE clinical trials receiving two eptin‑ ezumab doses. Methods: Headache frequency at baseline and over study months 1–6 was categorized into 4 groups: chronic migraine (CM; ≥ 15 monthly headache days [MHDs]), high-frequency episodic migraine (HFEM; 10–14 MHDs), low- frequency episodic migraine (LFEM; 4–9 MHDs), and ≤ 3 MHDs. Outcomes included the percentage of patients within each MHD category, the percentage of patients improving by ≥ 1 MHD category, and the number of months with reduction of ≥ 1 MHD category. Data from patients who received approved eptinezumab doses (100 mg or 300 mg) or placebo were included. Results: Mean headache frequency at baseline in PROMISE-1 was 10 MHDs; most patients were classified as having HFEM (48.6%) or LFEM (43.9%). At Month 1, 62/221 (28.1%), 75/222 (33.8%), and 45/222 (20.3%) patients who received eptinezumab 100 mg, 300 mg, and placebo had ≤ 3 MHDs, with 97/221 (43.9%), 108/222 (48.6%), and 84/222 (37.8%), respectively, falling below the diagnostic EM threshold at Month 6. More than one-third (79/221 [35.7%], 83/222 [37.4%], and 68/222 [30.6%] of patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively), had 6 months of reduction of ≥ 1 frequency category. At baseline in PROMISE-2, mean headache frequency was 20.5 MHDs. All patients (100%) in the eptinezumab 100 mg and placebo groups had CM, as did 99.4% of patients receiving eptinezumab 300 mg. At Month 1, 209/356 (58.7%), 216/350 (61.7%), and 167/366 (45.6%) patients treated with eptin‑ ezumab 100 mg, 300 mg, and placebo had ≤ 14 MHDs, with 240/356 (67.4%), 249/350 (71.1%), and 221/366 (60.4%), respectively, falling below CM threshold at Month 6. Additionally, 153/356 (43.0%), 169/350 (48.3%), and 116/366 (31.7%) patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, had 6 months of reduction of ≥ 1 frequency category. *Correspondence: patricia.pozo@vhir.org 1 Neurology Department, Headache Unit, Vall d’Hebron, University Hospital and Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 2 of 10 Conclusion: In the PROMISE studies, episodic and chronic migraine patients treated with eptinezumab were more likely to reduce their headache frequency versus placebo, which directly and in a sustained way improved their diag‑ nostic category classification. Trial registration: ClinicalTrials.gov Identifier: NCT02559895, NCT02974153. Keywords: Migraine, Prevention, Efficacy, Eptinezumab Introduction Methods Headache frequency varies widely across the migraine Data were from the randomized, double-blind, pla- spectrum and, in individual patients, may increase or cebo-controlled PROMISE studies [17, 18]. PROM- decrease as their migraine worsens or improves [1, 2]. ISE-1 (NCT02559895) evaluated the safety and efficacy Because the individual and societal impacts of migraine of eptinezumab 30 mg, 100 mg, and 300 mg in adults increase with monthly headache day frequency [3–8], (18‒75 years of age) with a greater than 12-month his- it is important to quantify changes in frequency occur- tory of EM, defined as ≤ 14 headache days per month, ring with preventive treatment. Furthermore, access with ≥ 4 migraine days per month in the 3 months prior to preventive treatment remains largely driven by the to screening [18]. Only data from patients who received number of headache days and diagnostic migraine approved doses (100 mg or 300 mg) were included in the classification (e.g., episodic migraine [EM] or chronic current analysis. PROMISE-2 (NCT02974153) evaluated migraine [CM]), despite calls to consider factors other the safety and efficacy of eptinezumab 100 mg or 300 mg than headache frequency when determining the need in adults (18‒65 years of age, inclusive) with a greater Eptinezumab (Vyepti™, Lundbeck Seattle BioPhar- for preventive intervention [9–12]. than 12-month history of CM, defined as ≥ 15 to ≤ 26 headache days and ≥ 8 migraine days during the 28-day maceuticals, Inc., Bothell, WA, USA) is a calcitonin screening period [17]. In both studies, eptinezumab was gene-related peptide antagonist approved for migraine administered intravenously once every 12 weeks [17, 18]. prevention in adults [13–15]. The preventive effi- Headache frequency at baseline and over study Months cacy and safety of eptinezumab 100 mg and 300 mg 1–6 was categorized into four groups for migraine cat- administered intravenously every 12 weeks have been egory: CM (≥ 15 MHDs), high-frequency episodic demonstrated across the spectrum of 4–26 migraine migraine (HFEM; 10–14 MHDs), low-frequency episodic days per month [16–24]. In the phase 3 randomized, migraine (LFEM; 4–9 MHDs), and ≤ 3 MHDs [6, 8, 25]. double-blind, placebo-controlled PROMISE studies, Outcomes included the percentage of patients within eptinezumab administered every 12 weeks significantly each MHD category, the percentage of patients improv- reduced migraine frequency, with onset of preven- ing by ≥ 1 MHD category, and the sustained response tive efficacy demonstrated on Day 1 after dosing [17, with reduction of ≥ 1 MHD category. Data from patients 18]. In patients with EM (PROMISE-1), eptinezumab who received approved eptinezumab doses (100 mg or 100 mg and 300 mg reduced monthly migraine days 300 mg) or placebo were included. For PROMISE-2, out- (MMDs) over Weeks 1–12 by 3.9 (P = 0.0182 vs pla- comes in the subgroup of patients with medication-over- cebo) and 4.3 (P = 0.0001 vs placebo) days, respectively use headache (MOH) were also examined. [18]. In patients with CM (PROMISE-2), eptinezumab 100 mg and 300 mg reduced MMDs over Weeks 1–12 by 7.7 (P < 0.0001 vs placebo) and 8.2 (P < 0.0001 vs pla- Results cebo) days, respectively, and reduced monthly head- Patients ache days (MHDs) over the same time period (–8.2 and A total of 443 adults received eptinezumab 100 mg or 300 mg –8.8 days, respectively; differences vs placebo [95% in PROMISE-1 (100 mg, n = 221; 300 mg, n = 222) and 222 CI], –1.7 [–2.6, –0.9] and –2.3 [–3.2, –1.4], respec- received placebo [18]. In PROMISE-2, 706 adults received tively) [17]. The objective of this post hoc analysis of eptinezumab (100 mg, n = 356; 300 mg, n = 350) and 366 data from the PROMISE studies was to identify the received placebo [17]. Selected baseline demographic and proportions of patients with migraine shifting from clinical characteristics are summarized in Table 1; additional higher-frequency classification headache categories characteristics have been previously reported [17, 18]. to lower-frequency headache categories over the first Mean headache frequency at baseline in PROM- 6 months of treatment. ISE-1 was 10 headache days per month, where 8.6 were Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 3 of 10 Table 1 Select baseline demographic and clinical characteristics PROMISE-1 PROMISE-2 Eptinezumab Eptinezumab Placebo n = 222 Eptinezumab Eptinezumab Placebo n = 366 100 mg n = 223 300 mg n = 224 100 mg n = 356 300 mg n = 350 Mean (SD) age, years 40.0 (10.7) 40.2 (11.7) 39.9 (11.7) 41.0 (11.7) 41.0 (10.4) 39.6 (11.3) Sex, n (%) female 179 (80.3) 199 (88.8) 186 (83.8) 307 (86.2) 314 (89.7) 325 (88.8) Mean (SD) MHDs 10.0 (3.0) 10.1 (3.1) 9.9 (2.8) 20.4 (3.1) 20.4 (3.2) 20.6 (3.0) ‒ ‒ ‒ Mean (SD) MMDs 8.7 (2.9) 8.6 (2.9) 8.4 (2.7) 16.1 (4.6) 16.1 (4.8) 16.2 (4.6) MOH diagnosis, n (%) 139 (39.0) 147 (42.0) 145 (39.6) Diagnostic category, n (%) CM (≥ 15 MHDs) 16 (7.2) 20 (9.0) 14 (6.3) 356 (100) 348 (99.4) 366 (100) HFEM (10–14 MHDs) 102 (46.2) 107 (48.2) 114 (51.4) 0 (0) 2 (0.6) 0 (0) LFEM (4–9 MHDs) 103 (46.6) 95 (42.8) 94 (42.3) 0 (0) 0 (0) 0 (0)    ≤ 3 MHDs 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) CM Chronic migraine, HFEM High-frequency episodic migraine, LFEM Low-frequency episodic migraine, MHD Monthly headache days, MMD Monthly migraine days, MOH Medication-overuse headache, SD Standard deviation migraine days [18]. For the purpose of this analysis, (70.6%), 163/222 (73.4%), and 138/222 (62.2%) at Month most patients in PROMISE-1 were classified as having 6 (Fig. 2). Furthermore, 79/221 (35.7%), 83/222 (37.4%), HFEM or LFEM (eptinezumab 100 mg, 46.2% HFEM and 68/222 (30.6%) patients in the eptinezumab 100-mg, and 46.6% LFEM; eptinezumab 300 mg, 48.2% HFEM 300-mg, and placebo groups, respectively, had 6 months and 42.8% LFEM; placebo, 51.4% HFEM and 42.3% of sustained reduction of ≥ 1 frequency category (Fig. 3). LFEM). A small number of patients in PROMISE-1 were classified as having CM at baseline; this is because Changes in diagnostic category in PROMISE‑2 the classification system for the current analysis was Changes from baseline in frequency category over not completely consistent with how diagnoses were Months 1–6 in PROMISE-2 are summarized in Fig. 1. captured during the 28-day screening period. At Month 1, 209/356 (58.7%) patients treated with At baseline in PROMISE-2, mean headache fre- eptinezumab 100 mg and 216/350 (61.7%) treated with quency was 20.5 MHDs, where 16.1 were migraine days eptinezumab 300 mg had ≤ 14 MHDs, with 240/356 [17]. All patients (100%) in the eptinezumab 100-mg (67.5%) and 249/350 (71.1%), respectively, falling below and placebo groups had CM, as did 99.4% of patients this diagnostic threshold at Month 6. The proportions receiving eptinezumab 300 mg. A total of 431/1072 of patients in the placebo group achieving this status (40.2%) patients in PROMISE-2 had an MOH diagnosis were numerically lower (45.6% [167/366] and 60.4% at baseline [17]. [221/366]) at Months 1 and 6, respectively. At Month 1, 25.8%, 23.1%, and 23.2% of patients in the eptinezumab Changes in diagnostic category in PROMISE‑1 100-mg, 300-mg, and placebo groups met the frequency Changes from baseline in frequency category over criteria for HFEM and 23.9%, 26.9%, and 20.5% met the Months 1–6 in PROMISE-1 are illustrated in Fig. 1. At criteria from LFEM, respectively. At Month 6, the shift Month 1, 62/221 (28.1%) patients treated with eptine- to LFEM was more pronounced (34.3%, 29.1%, and zumab 100 mg and 75/222 (33.8%) patients treated with 25.1%, respectively). eptinezumab 300 mg had ≤ 3 MHDs, with 97/221 (43.9%) A total of 209/356 (58.7%), 216/350 (61.7%), and and 108/222 (48.6%), respectively, falling below this diag- 167/366 (45.6%) patients in the eptinezumab 100-mg, nostic EM threshold at Month 6. The proportions of 300-mg, and placebo groups, respectively, had a reduc- patients in the placebo group achieving this status were tion of ≥ 1 frequency category at Month 1 and 240/356 numerically lower, at 20.3% (45/222) and 37.8% (84/222) (67.4%), 249/350 (71.1%), and 221/366 (60.4%) at Month at Months 1 and 6, respectively. 6 (Fig. 2). Furthermore, 153/356 (43.0%), 169/350 A total of 130/221 (58.8%), 138/222 (62.2%), and (48.3%), and 116/366 (31.7%) patients in the eptin- 116/222 (52.3%) patients in the eptinezumab 100-mg, ezumab 100-mg, 300-mg, and placebo groups, respec- 300-mg, and placebo groups, respectively, had a reduc- tively, had 6 months of reduction of ≥ 1 frequency tion of ≥ 1 frequency category at Month 1 and 156/221 category (Fig. 3). Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 4 of 10 Fig. 1 Percentage of patients in each diagnostic category, by month, in A) PROMISE-1 and B) PROMISE-2. MHDs, monthly headache days Changes from baseline in frequency category over Discussion Months 1–6 in the subset of patients with MOH in In this post hoc analysis of data from the PROMISE PROMISE-2 are summarized in Fig. 4. At Month 1, studies, eptinezumab use was associated with down- 93/139 (63.3%) patients treated with eptinezumab 100 mg ward shifts in frequency-based classifications that and 93/147 (63.3%) patients treated with eptinezumab were sustained across two dosing intervals (6 months). 300 mg had ≤ 14 MHDs, with 95/139 (68.4%) and 105/147 The results reported here are in alignment with the (71.4%), respectively, falling below this diagnostic thresh- responses observed in previous work [26], which old at Month 6. The proportions of patients in the placebo showed consistency in percent reduction across sub- group achieving this status were lower, at 45.5% (66/145) groups which were defined by baseline headache/ and 60.0% (87/145) at Months 1 and 6, respectively. migraine frequency. In PROMISE-1, reductions in Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 5 of 10 Fig. 2 Percentage of patients with reduction of ≥ 1 MHD frequency category in A) PROMISE-1 and B) PROMISE-2. MHDs, monthly headache days migraine frequency were evident the first month after [27], we would also expect some patients to fluctuate eptinezumab initiation and were of sufficient mag- between categories despite treatment. nitude to render nearly one-third (30.9%) of patients In addition, whereas these findings are suggestive of below the threshold of ≤ 4 MHDs often used as the clinically meaningful changes in headache frequency, threshold for initiating preventive treatment. Main- they raise some interesting questions for future research. tenance of this benefit was demonstrated by the simi- In both studies, marked differences between Months lar or greater proportions of patients experiencing ≤ 3 3 and 4 suggest that the administration of the second headache days during each subsequent month of the dose may not only sustain improvements, but further analysis period (36.6%, 38.8%, 46.5%, 49.0%, and 46.3% reduce headache frequency, i.e., an additive effect. These during Months 2, 3, 4, 5, and 6, respectively). Among results are supportive of the updated American Head- those treated with eptinezumab remaining above this ache Society [11] and European Headache Federation threshold, fewer experienced ≥ 10 headache days each [28] guidelines recommending that trials with monoclo- month (HFEM or CM) relative to baseline (55.3% at nal antibodies targeting calcitonin gene-related peptide baseline; 19.9%, 18.5%, 18.1%, 13.3%, 14.4%, and 14.9% last for at least 3 to 6 months. Furthermore, observed during Months 1, 2, 3, 4, 5, and 6, respectively). improvements in the placebo groups of both studies sug- In patients with CM (PROMISE-2), sustained reduc- gest that factors other than eptinezumab administration tions in headache frequency with eptinezumab were likely contributed to observed benefits. Lastly, because of sufficient magnitude and duration to permit many lower-frequency categories are associated with better patients to fall within the range typically considered quality of life and lower burden/healthcare resource uti- EM (≤ 14 MHDs) beginning the first month after treat- lization [3–8], examination of the impact of the observed ment initiation. Specifically, more than half (60.2%) changes on quality of life and healthcare resource con- had ≤ 14 MHDs during the first month after eptin- sumption are warranted. The latter may be particularly ezumab initiation and 66.0%, 64.7%, 71.5%, 68.4%, and relevant, as access to preventive treatments is often based 69.3% had ≤ 14 MHDs during Months 2, 3, 4, 5, and 6, on diagnostic classification. respectively. Some CM patients even improved to the point that they fell below the frequency threshold typi- cally used for the indication of preventive treatment Limitations (≤ 4 MHDs), with 10.3% achieving this status during Frequency-based classification of migraine is com- Month 1 and 15.3%, 15.3%, 23.4%, 22.5%, and 22.9% plex, and factors such as severity and associated dis- during Months 2, 3, 4, 5, and 6, respectively. While ability are an important part of defining migraine. these reductions in MHD associated with eptinezumab Analysis of data from the PROMISE-2 study indicated use likely reduce migraine-related burden, it is impor- that reductions in headache frequency were associ- tant to note that these data should not be interpreted ated with decreases in pain severity; common symp- as indicating a patient should discontinue preven- toms such as nausea, phonophobia, and photophobia; tive migraine treatment. Based on previous analyses and activity limitations [29]. The categories used in this Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 6 of 10 Fig. 3 Cumulative number of months with reduction of ≥ 1 MHD frequency category in A) PROMISE-1 and B) PROMISE-2. MHDs, monthly headache days analysis were based on the conceptional framework MHDs) [11]. To date, no clear definitions of LFEM for transitions in migraine put forth by Bigal and col- and HFEM exist, and there is some variability in the leagues (2008) [1], with the LFEM category being fur- range of each category [30–34]. Further, CM subgroups ther broken down to identify patients who fall below could have been further subdivided into two categories the threshold for initiating migraine prevention (≤ 4 (15–23 MHDs and 24–28 MHDs) which may better Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 7 of 10 Fig. 4 Percentage of patients in each diagnostic category, by month, in the subgroup of patients with MOH diagnosis at baseline in PROMISE-2: A) eptinezumab 100 mg; B) eptinezumab 300 mg; C) placebo. MHDs, monthly headache days; MOH, medication-overuse headache Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 8 of 10 capture differences in disease burden, as was described Declarations in Ishii et al. 2021 [35]. Although changes in classifica- Ethics approval and consent to participate tion based on migraine days were not explored, previ- The PROMISE-1 study was approved by the independent ethics committee or ous data indicate that MMD reduction parallels MHD institutional review board for each of the 87 study sites: Birmingham, Alabama, reduction and thus would be expected to demonstrate United States, 35216; Phoenix, Arizona, United States, 85013; Tucson, Arizona, United States, 85712; Little Rock, Arkansas, United States, 72205; Anaheim, similar improvements. Future work would be needed to California, United States, 92801; Fresno, California, United States, 93702; determine if sociodemographic or baseline character- Fullerton, California, United States, 92835; Long Beach, California, United istics can be used to predict which patients experience States, 90806; Montclair, California, United States, 91763; Oceanside, California, United States, 92056; Redlands, California, United States, 92374; two sites in the greatest shifts in diagnostic classification; however, San Diego, California, United States: 92103; 92108; Santa Monica, California, previous work has suggested that such predictors are United States, 90404; Sherman Oaks, California, United States, 91403; Colorado not easily identified [26, 36]. Springs, Colorado, United States, 80918; Fort Collins, Colorado, United States, 80528; Stamford, Connecticut, United States, 06905; Waterbury, Connecticut, United States, 06708; Bradenton, Florida, United States, 34201; DeLand, Florida, United States, 32720; Fort Myers, Florida, United States, 33912; Hallandale Beach, Florida, United States, 33009; Hialeah, Florida, United States, 33012; Conclusion Maitland, Florida, United States, 32751; three sites in Miami, Florida, United Changes in headache frequency during the first States: 33143; 33155; 33173; Naples, Florida, United States, 34102; Orlando, 6 months of eptinezumab treatment in the PROMISE Florida, United States, 32801; Sunrise, Florida, United States, 33351; Winter studies were frequently of sufficient magnitude and Haven, Florida, United States, 33880; two sites in Atlanta, Georgia, United States: 30331; 30342; Stockbridge, Georgia, United States, 30281; Chicago, duration to permit a shift in frequency and reclassify Illinois, United States, 60607; Lisle, Illinois, United States, 60532; Prairie Village, to categories associated with better quality of life and Kansas, United States, 66206; Lexington, Kentucky, United States, 40509; reduced healthcare resource utilization. Owensboro, Kentucky, United States, 42303; New Orleans, Louisiana, United States, 70115; Boston, Massachusetts, United States, 02131; North Attleboro, Massachusetts, United States, 02760; Springfield, Massachusetts, United States, 01104; Watertown, Massachusetts, United States, 02472; Ann Arbor, Michigan, Abbreviations United States, 48104; Farmington Hills, Michigan, United States, 48334; CM: Chronic migraine; EM: Episodic migraine; HFEM: High-frequency episodic Jackson, Michigan, United States, 49201; Minneapolis, Minnesota, United migraine; LFEM: Low-frequency episodic migraine; MMDs: Monthly migraine States, 55402; Flowood, Mississippi, United States, 39232; Saint Louis, Missouri, days; MOH: Medication-overuse headache; MHD: Monthly headache day. United States, 63141; Springfield, Missouri, United States, 65807; Las Vegas, Nevada, United States, 89119; Reno, Nevada, United States, 89502; Albuquer‑ Acknowledgements que, New Mexico, United States, 87102; two sites in Brooklyn, New York, The authors thank Mary Tom, PharmD, and Beth Reichard, PhD, of The Medi‑ United States: 11213; 11229; Hartsdale, New York, United States, 10530; cine Group, LLC (New Hope, PA, United States) for providing medical writing Rochester, New York, United States, 14609; Staten Island, New York, United support, which was funded by H. Lundbeck A/S (Copenhagen, Denmark) in States, 10312; Durham, North Carolina, United States, 27713; Greensboro, accordance with Good Publication Practice guidelines. North Carolina, United States, 27405; High Point, North Carolina, United States, 27265; Wilmington, North Carolina, United States, 28401; Dayton, Ohio, United Authors’ contributions States, 45424; Edmond, Oklahoma, United States, 73034; Norman, Oklahoma, PP-R, DD, AE, and RC contributed to the conception and design of the United States, 73069; Oklahoma City, Oklahoma, United States, 73112; study. JH contributed to data visualization and statistical analysis. All authors Portland, Oregon, United States, 97210; Allentown, Pennsylvania, United reviewed and provided critical revision of all manuscript drafts for important States, 18104; Smithfield, Pennsylvania, United States, 15478; Anderson, South intellectual content, as well as approved the final manuscript for submission. Carolina, United States, 29621; two sites in Chattanooga, Tennessee, United States: 37404; 37421; Kingsport, Tennessee, United States, 37660; Memphis, Funding Tennessee, United States, 38119; Austin, Texas, United States, 78745; Dallas, The PROMISE trials were funded by Lundbeck Seattle BioPharmaceuticals, Texas, United States, 75231; two sites in Houston, Texas, United States: 77074; Inc., Bothell, WA, USA. The sponsor participated in the design and conduct 77081; Richmond, Virginia, United States, 23294; Virginia Beach, Virginia, United of the study; data collection, management, analysis, and interpretation; and States, 23454; Bellevue, Washington, United States, 98007; and four sites in preparation, review, and approval of the manuscript. All statistical analyses Tbilisi, Georgia: 0112; 0160; 0179; 0186. The PROMISE-2 study was approved by were performed by a contracted research organization and were directed the independent ethics committee or institutional review board for each of or designed by Pacific Northwest Statistical Consulting under contractual the 145 study sites: Birmingham, Alabama, United States, 35235; Phoenix, agreement with Lundbeck Seattle BioPharmaceuticals, Inc. All authors and Arizona, United States, 85032; Little Rock, Arkansas, United States, 72211; H. Lundbeck A/S and Lundbeck Seattle BioPharmaceuticals, Inc. prepared, Carlsbad, California, United States, 92011; Oceanside, California, United States, reviewed, and approved the manuscript and made the decision to submit 92056; Orange, California, United States, 92868; Oxnard, California, United the manuscript for publication. Editorial support for the development of this States, 93030; Palo Alto, California, United States, 94304; Redlands, California, manuscript was funded by H. Lundbeck A/S. United States, 92374; San Diego, California, United States, 92108; Santa Monica, California, United States, 90404; Torrance, California, United States, 90502; Availability of data and materials Colorado Springs, Colorado, United States, 80918; New London, Connecticut, Data Sharing Statement: In accordance with EFPIA’s and PhRMA’s “Prin‑ United States, 06320; Jacksonville, Florida, United States, 32256; Miami, Florida, ciples for Responsible Clinical Trial Data Sharing” guidelines, Lundbeck is United States, 33155; Orlando, Florida, United States, 32806; Tampa, Florida, committed to responsible sharing of clinical trial data in a manner that is United States, 33606; West Palm Beach, Florida, United States, 33407; Winter consistent with safeguarding the privacy of patients, respecting the integ‑ Haven, Florida, United States, 33880; two sites in Atlanta, Georgia, United rity of national regulatory systems, and protecting the intellectual property States: 30328; 30342; Decatur, Georgia, United States, 30030; Champaign, of the sponsor. The protection of intellectual property ensures continued Illinois, United States, 61820; two sites in Chicago, Illinois, United States: 60607; research and innovation in the pharmaceutical industry. Deidentified data 60642; Anderson, Indiana, United States, 46011; Des Moines, Iowa, United are available to those whose request has been reviewed and approved States, 50309; Overland Park, Kansas, United States, 66212; Prairie Village, through an application submitted to https://​www.​lundb​eck.​com/​global/​ Kansas, United States, 66208; Wichita, Kansas, United States, 67207; Marrero, our-​scien​ce/​clini​cal-​data-​shari​ng. Louisiana, United States, 70072; Waldorf, Maryland, United States, 20603; Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 9 of 10 Boston, Massachusetts, United States, 02135; North Attleboro, Massachusetts, Headache Society. She has edited the Guidelines for the Diagnosis and Treat‑ United States, 02740; Watertown, Massachusetts, United States, 02472; Ann ment of Headache of the Spanish Neurological Society. She is the founder of Arbor, Michigan, United States, 48104; Minneapolis, Minnesota, United States, www.​midol​ordec​abeza.​org. PP-R does not own stocks from any pharmaceuti‑ 55402; Flowood, Mississippi, United States, 39232; Saint Louis, Missouri, United cal company. States, 63141; Saint Peters, Missouri, United States, 63303; Springfield, Missouri, DD has been a consultant for Amgen, Allergan/Abbvie, Atria Health, AYYA Bio‑ United States, 65810; Las Vegas, Nevada, United States, 89113; Lebanon, New sciences, Biohaven, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, Cooltech, Hampshire, United States, 03756; Princeton, New Jersey, United States, 08540; Ctrl M, Eli Lilly, GSK, Impel, Lundbeck, Nocira, Novartis, Perfood, Pfizer, Praxis, Albuquerque, New Mexico, United States, 87102; Amherst, New York, United Revance, Satsuma, Theranica, and WL Gore. He has received payment or hono‑ States, 14226; Brooklyn, New York, United States, 11229; two sites in New York, raria from Amgen, Allergan/Abbvie, Biohaven, Cambridge University Press, New York, United States: 10016; 10019; Plainview, New York, United States, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Eli 11803; Rochester, New York, United States, 14609; Durham, North Carolina, Lilly, Global Access Meetings, KLJ Associates, Lundbeck, Majallin LLC, Medlogix United States, 27705; High Point, North Carolina, United States, 27262; Canton, Communications, Miller Medical Communications, MJH Lifesciences, Novartis, Ohio, United States, 44718; Dayton, Ohio, United States, 45432; Oklahoma City, Oxford University Press, Pfizer, Vector Psychometric Group, WebMD Health/ Oklahoma, United States, 73116; Scottdale, Pennsylvania, United States, 15683; Medscape, and Wolters Kluwer. He has participated on Data Safety Monitoring Smithfield, Pennsylvania, United States, 15478; Mount Pleasant, South Carolina, or Advisory Boards for Allergan/Abbvie, Academy for Continued Healthcare United States, 29464; two sites in Chattanooga, Tennessee, United States: Learning, Amgen, and Biohaven. He has received research support from Amer‑ 37404; 37421; Memphis, Tennessee, United States, 38119; Nashville, Tennessee, ican Migraine Foundation, Department of Defense, Henry Jackson Foundation, United States, 37203; Dallas, Texas, United States, 75214; Houston, Texas, National Institutes of Health, Patient Centered Outcomes Research Institute United States, 77058; Houston, Texas, United States, 77081; North Richland (PCORI), and Sperling Foundation. He has a leadership or fiduciary role with Hills, Texas, United States, 76180; San Antonio, Texas, United States, 78258; two American Brain Foundation, American Migraine Foundation, International sites in Salt Lake City, Utah, United States: 84109; 84123; Richmond, Virginia, Headache Society, and Global Patient Advocacy Coalition. He owns stock or United States, 23294; Bellevue, Washington, United States, 98007; Spokane, stock options in Atria Health, Aural Analytics, AYYA Biosciences, Epien, ExSano, Washington, United States, 99202; Brussels, Belgium, 1090; two sites in Liege, Healint, King-Devick Technologies, Man and Science, Matterhorn, Nocira, Belgium, 4000; Brno, Czechia, 61500; Choceň, Czechia, 565 01; Prague, Czechia, Ontologics, Precon Health, Second Opinion/Mobile Health, and Theranica. 18200; Praha, Czechia, 100 34; Glostrup, Denmark, 2600; Viborg, Denmark, He holds a patent, 17189376.1–1466:vTitle: Botulinum Toxin Dosage Regimen 8800; four sites in Tbilisi, Georgia: 0112; 0160; 0179; 0186; Berlin, Germany, for Chronic Migraine Prophylaxis without fee, and has a patent application 10117; Erlangen, Germany, 91054; Hamburg, Germany, 20246; Nordheim, submitted, Synaquell (Precon Health). AE is a full-time employee of H. Lund‑ Germany, 45122; Unterhaching, Germany, 82008; three sites in Budapest, beck A/S. JH is an employee of Pacific Northwest Statistical Consulting, Inc., a Hungary: 1033; 1083; 1145; Pecs, Hungary, 7623; Ancona, Italy, 60020; two sites contracted service provider of biostatistical resources for Lundbeck. RC was an in Milano, Italy: 20132; 20133; Napoli, Italy, 80131; Pavia, Italy, 27100; Roma, employee of Lundbeck at the time of manuscript development. Italy, 00163; Ekaterinburg, Russian Federation, 620102; Kazan’, Russian Federation, 420064; Krasnoyarsk, Russian Federation, 660037Moscow, Russian Author details 1 Federation, 121467; two sites in Novosibirsk, Russian Federation, 630051; Neurology Department, Headache Unit, Vall d’Hebron, University Hospi‑ 630054; three sites in Saint Petersburg, Russian Federation: 191144; 194044; tal and Research Institute, Universitat Autonoma de Barcelona, Barcelona, 194223; Yaroslavl’, Russian Federation, 150030; Banska Bystrica, Slovakia, Spain. 2 Headache and Neurological Pain Research Group, Department de 97404Dolný Kubín, Slovakia, 026 01; Dubnica nad Vahom, Slovakia, 01841; Medicina, Vall d’Hebron, University Hospital and Research Institute, Universitat Krompachy, Slovakia, 053 42; Alicante, Spain, 03010; Barcelona, Spain, 08035; Autonoma de Barcelona, Barcelona, Spain. 3 Mayo Clinic, Scottsdale, AZ, USA. 4 Guadalajara, Spain, 19002; Lleida, Spain, 25198; four sites in Madrid, Spain: Atria Institute, New York, NY, USA. 5 H. Lundbeck A/S, Copenhagen, Denmark. 6 28046; 28050; 28222; 28223; Navarrés, Spain, 31008; Santander, Spain, 39008; Pacific Northwest Statistical Consulting, Inc., Woodinville, WA, USA. 7 Lundbeck Sevilla, Spain, 41013; Terrassa, Spain, 08221; Valencia, Spain, 46026; Valladolid, LLC, Deerfield, IL, USA. 8 RK Consults, Ozark, MO, USA. 9 Missouri State University, Spain, 47005; two sites in Dnipropetrovs’k, Ukraine: 49045; 49027; Ivano- Springfield, MO, USA. Frankivs’k, Ukraine, 76008; two sites in Kharkiv, Ukraine: 61068; 61103; L’viv, Ukraine, 79010; Odessa, Ukraine, 65014; Vinnytsia, Ukraine, 21005; Zapor‑ Received: 9 June 2022 Accepted: 11 October 2022 izhzhya, Ukraine, 69065; Glasgow, United Kingdom, G51 4TF; Inverness, United Kingdom, IV2 3UJ; London, United Kingdom, SE5 9PL; Newcastle, United Kingdom, NE1 4LP; Salford, United Kingdom, M8 8HD; and Stoke-on-Trent, United Kingdom, ST4 7LN. Both studies were conducted in accordance with standards of Good Clinical Practice as defined by the International Conference References on Harmonisation and all applicable federal and local regulations. All study 1. Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine documentation was approved by the local review board at each site or by a transformation. Neurol. 2008;71:848–55. https://​doi.​org/​10.​1212/​01.​wnl.​ central institutional review board or ethics committee. All patients provided 00003​25565.​63526.​d2. written informed consent prior to participation in their respective study. 2. Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treat‑ Consent for publication ment and clinical trial design. J Headache Pain. 2017;18:101. https://​doi.​ Not applicable. org/​10.​1186/​s10194-​017-​0787-1. 3. Buse DC, Reed ML, Fanning KM, et al. Demographics, headache features, Competing interests and comorbidity profiles in relation to headache frequency in people with PP-R has received honoraria as a consultant and speaker from Allergan/ migraine: results of the American Migraine Prevalence and Prevention (AMPP) AbbVie, Biohaven, Chiesi, Eli Lilly, Medscape, Lundbeck, Novartis, and Teva study. Headache. 2020;60:2340–56. https://​doi.​org/​10.​1111/​HEAD.​13966. Pharmaceuticals. Her research group has received research grants from 4. Buse DC, Fanning KM, Reed ML, et al. Life with migraine: effects on rela‑ AGAUR, Allergan/AbbVie, EraNet Migraine Research Foundation, FEDER tionships, career, and finances from the chronic migraine epidemiology RIS3CAT, Instituto Investigación Carlos III, International Headache Society, la and outcomes (CaMEO) study. Headache. 2019;59:1286–99. https://​doi.​ Caixa foundation, MICINN, Neuron, Novartis, PERIS, and Teva; and has received org/​10.​1111/​head.​13613. funding for clinical trials from Alder, Allergan/AbbVie, Amgen, electroCore, 5. Buse DC, Reed ML, Fanning KM, et al. Comorbid and co-occurring Eli Lilly, Lundbeck, Novartis, and Teva. She is the Honorary Secretary of the conditions in migraine and associated risk of increasing headache pain International Headache Society. She is on the editorial board of Revista de intensity and headache frequency: results of the migraine in America Neurologia. She is an associate editor for Cephalalgia, Headache, Neurologia, symptoms and treatment (MAST) study. J Headache Pain. 2020;21:23. and Frontiers of Neurology and an advisory Scientific member of the Editorial https://​doi.​org/​10.​1186/​s10194-​020-​1084-y. Board of The Journal of Headache and Pain. She is a member of the Clinical 6. Torres-Ferrús M, Quintana M, Fernandez-Morales J, et al. When does Trials Guidelines Committee and Scientific Committee of the International chronic migraine strike? A clinical comparison of migraine according to Pozo‑Rosich et al. BMC Neurology (2022) 22:394 Page 10 of 10 the headache days suffered per month. Cephalalgia. 2017;37:104–13. 28. Sacco S, Amin FM, Ashina M, et al. European Headache Federation https://​doi.​org/​10.​1177/​03331​02416​636055. guideline on the use of monoclonal antibodies targeting the calcitonin 7. Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource gene related peptide pathway for migraine prevention – 2022 update. J use among chronic and episodic migraineurs: Results from the Inter‑ Headache Pain. 2022;23:67. https://​doi.​org/​10.​1186/​s10194-​022-​01431-x. national Burden of Migraine Study (IBMS). Cephalalgia. 2011;31:301–15. 29. McAllister P, Kudrow D, Cady R, et al. Reduction in migraine-associated https://​doi.​org/​10.​1177/​03331​02410​381145. burden after eptinezumab treatment in patients with chronic migraine. 8. Silberstein SD, Lee L, Gandhi K, et al. Health care resource utilization and Cephalalgia. 2022;42:1005. https://​doi.​org/​10.​1177/​03331​02422​10895​67. migraine disability along the migraine continuum among patients treated for 30. Doane MJ, Gupta S, Fang J, et al. The humanistic and economic burden of migraine. Headache. 2018;58:1579–92. https://​doi.​org/​10.​1111/​head.​13421. migraine in Europe: a cross-sectional survey in five countries. Neurol Ther. 9. National Headache Foundation Position Statement on the Treatment 2020;9:535–49. https://​doi.​org/​10.​1007/​S40120-​020-​00196-2/​TABLES/3. of Migraine and Access to Care. National Headache Foundation; 2022. 31. Lipton RB, Serrano D, Pavlovic JM, et al. Improving the classification of https://​heada​ches.​org/​natio​nal-​heada​che-​found​ation-​posit​ion-​state​ migraine subtypes: an empirical approach based on factor mixture mod‑ ment-​on-​the-​treat​ment-​of-​migra​ine/. Accessed 28 Feb 2022. els in the american migraine prevalence and prevention (AMPP) study. 10. Pringsheim T, Davenport W, Mackie G, et al. Canadian headache society Headache. 2014;54:830–49. https://​doi.​org/​10.​1111/​head.​12332. guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39:S1-59. 32. Serrano D, Buse DC, Kori SH, et al. Effects of switching acute treatment on 11. Ailani J, Burch RC, Robbins MS. The American headache society consensus disability in migraine patients using triptans. Headache: J Head Face Pain. statement: update on integrating new migraine treatments into clinical 2013;53:1419. https://​doi.​org/​10.​1111/​head.​12164. practice. Headache. 2021;61:1021–39. https://​doi.​org/​10.​1111/​head.​14153. 33. Caronna E, Gallardo VJ, Alpuente A, et al. Epidemiology, work and eco‑ 12. Silberstein SD. Preventive migraine treatment. Continuum (Minneap nomic impact of migraine in a large hospital cohort: time to raise aware‑ Minn). 2015;21:973–89. https://​doi.​org/​10.​1212/​CON.​00000​00000​000199. ness and promote sustainability. J Neurol. 2022;269:1456–62. https://​doi.​ 13. Vyepti [package insert]. Lundbeck Seattle BioPharmaceuticals Inc; 2021. org/​10.​1007/​s00415-​021-​10715-2. 14. Vyepti [EMA Authorization]. Lundbeck A/S Valby, Denmark; 2021. 34. Katsarava Z, Manack A, Yoon M-S, et al. Chronic migraine: classification 15. Product Monograph Including PatientMedication Information: Vyepti and comparisons. Cephalalgia. 2011;31:520–9. https://​doi.​org/​10.​1177/​ (Eptinezumab for injection). Lundbeck Canada Inc; 2021. 03331​02410​383590. 16. Dodick DW, Lipton RB, Silberstein S, et al. Eptinezumab for prevention 35. Ishii R, Schwedt TJ, Dumkrieger G, et al. Chronic versus episodic migraine: of chronic migraine: a randomized phase 2b clinical trial. Cephalalgia. The 15‐day threshold does not adequately reflect substantial differences in 2019;39:1075–85. https://​doi.​org/​10.​1177/​03331​02419​858355. disability across the full spectrum of headache frequency. Headache: J Head 17. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab and Face Pain. 2021;61:992–1003. https://​doi.​org/​10.​1111/​head.​14154. in patients with chronic migraine: PROMISE-2. Neurol. 2020;94:e1365–77. 36. Apelian R, Boyle L, Hirman J, Asher D. Measuring dose-related efficacy of https://​doi.​org/​10.​1212/​WNL.​00000​00000​009169. eptinezumab for migraine prevention: post hoc analysis of PROMISE-1 18. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a ran‑ and PROMISE-2. J Headache Pain. 2022;23:48. https://​doi.​org/​10.​1186/​ domized, double-blind, placebo-controlled study (PROMISE-1). Cephalal‑ S10194-​022-​01418-8. gia. 2020;40:241–54. https://​doi.​org/​10.​1177/​03331​02420​905132. 19. Smith TR, Janelidze M, Chakhava G, et al. Eptinezumab for the prevention of episodic migraine: sustained effect through 1 year of treatment in the Publisher’s Note PROMISE-1 study. Clin Ther. 2020;42:2254-2265.e3. https://​doi.​org/​10.​ Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 1016/j.​clint​hera.​2020.​11.​007. lished maps and institutional affiliations. 20. Silberstein S, Diamond M, Hindiyeh NA, et al. Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intrave‑ nous ALD403 safety and efficacy–2) study. J Headache Pain. 2020;21:1– 12. https://​doi.​org/​10.​1186/​s10194-​020-​01186-3. 21. Kudrow D, Cady RK, Allan B, et al. Long-term safety and tolerability of eptinezumab in patients with chronic migraine: a 2-year, open- label, phase 3 trial. BMC Neurol. 2021;21:126. https://​doi.​org/​10.​1186/​ s12883-​021-​02123-w. 22. Winner PK, McAllister P, Chakhava G, et al. Effects of intravenous eptin‑ ezumab vs placebo on headache pain and most bothersome symptom when initiated during a migraine attack: a randomized clinical trial. JAMA. 2021;325:2348–56. https://​doi.​org/​10.​1001/​jama.​2021.​7665. 23. Smith TR, Spierings ELH, Cady R, et al. Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials. J Headache Pain. 2021;22:1–11. https://​doi.​org/​10.​1186/​ s10194-​021-​01227-5. 24. Dodick DW, Gottschalk C, Cady R, et al. Eptinezumab demonstrated effi‑ cacy in sustained prevention of episodic and chronic migraine beginning on Day 1 after dosing. Headache. 2020;60:2220–31. https://​doi.​org/​10.​ Ready to submit your research ? Choose BMC and benefit from: 1111/​head.​14007. 25. Irimia P, Garrido-Cumbrera M, Santos-Lasaosa S, et al. Impact of monthly • fast, convenient online submission headache days on anxiety, depression and disability in migraine patients: results from the Spanish Atlas. Sci Rep. 2021;11:8286. https://​doi.​org/​10.​ • thorough peer review by experienced researchers in your field 1038/​s41598-​021-​87352-2. • rapid publication on acceptance 26. Martin V, Nagy AJ, Janelidze M, et al. Impact of baseline characteristics on • support for research data, including large and complex data types the efficacy and safety of Eptinezumab in patients with migraine: sub‑ group analyses of PROMISE-1 and PROMISE-2. Clin Ther. 2022;44:389–402. • gold Open Access which fosters wider collaboration and increased citations https://​doi.​org/​10.​1016/j.​clint​hera.​2022.​01.​006. • maximum visibility for your research: over 100M website views per year 27. Buse DC, Winner PK, Charleston L, et al. Early response to eptinezumab indicates high likelihood of continued response in patients with chronic At BMC, research is always in progress. migraine. J Headache Pain. 2022;23:1–12. https://​doi.​org/​10.​1186/​ S10194-​022-​01387-Y/​FIGUR​ES/5. Learn more biomedcentral.com/submissions