Twelve-months prospective real-world assessment of effectiveness and safety of eptinezumab in migraine patients difficult-to-treat and naïve to CGRP monoclonal antibodies: results of the French FHU INOVPAIN Registry

Twelve-months prospective real-world assessment of effectiveness and safety of eptinezumab in migraine patients difficult-to-treat and naïve to CGRP monoclonal antibodies: results of the French FHU INOVPAIN Registry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Twelve-months prospective real-world assessment of effectiveness and safety of eptinezumab in migraine patients difficult-to-treat and naïve to CGRP monoclonal antibodies: results of the French FHU INOVPAIN Registry S Ferrao-Malheiro, R Fabre, T Jiacomini, M Lanteri-Minet This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9588176/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background . Randomized clinical trials have demonstrated the efficacy and safety of eptinezumab. The aim of this study was to evaluate the effectiveness and safety of eptinezumab in a real-world setting among patients with difficult-to-treat migraine in France. Methods . This is a one year-prospective real-word study including all consecutive adult patients from the FHU InovPain registry who received intravenous eptinezumab 100 mg. Results . Three hundred and two patients (83.8% female / mean age of 48.0 ± 13.9 years) were included. Patients had at least 8 monthly migraine days, had failed at least 3 previous prophylactic treatments across amitryptiline, betablockers, botulinum toxin, candesartan, and topiramate and were CGRP monoclonal antibodies naïve. Among them, 184 patients (60.9%) had chronic migraine and 118 (39.1%) had episodic migraine, whereas 229 patients (75.8%) presented a medication overuse. Regarding the primary endpoint, 50% responder rate at M3, M6, and M12 was 35.4% (107/302), 39.0% (96/246), and 45.7% (63/138), respectively. ≥30% responder rate at M3, M6, and M12 was 48.7% (147/302), 56.1% (138/246), and 63.0% (87/138), respectively. ≥75% responder rates at M3, M6, and M12 was 10.9% (33/302), 15.4% (38/246), and 23.2% (32/138), respectively. The effectiveness of eptinezumab was confirmed by significant changes in the values of all PRO measures at all assessment time points compared with baseline, demonstrating improvement in functional impact (HIT-6), emotional impact (HADS-A and HADS-D), interictal burden (MIBS-4), and quality of life (EQ-5D index and EQ-5D VAS). According to PGIC, the proportions of patients reporting being “much improved” or “very much improved” were 41.9% at M3, 54.8% at M6 and 74.4% at M12. Overall, effectiveness appeared similar in episodic migraine and chronic migraine except at M12, where rates of 50% and 75% response were significantly higher in the chronic migraine (50% response: 53.8% vs 34.5%, p = 0.025; 75% response: 30% vs 13.8%, p = 0.026). Adverse events were uncommon and mostly mild, transient, and self-limited with few expected hypersensitivity reactions. Conclusions . This French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who and have failed non-specific preventive migraine treatments and are naïve to CGRP monoclonal antibodies. Clinical trial number: not applicable. Migraine eptinezumab migraine prevention real-world evidence anti-CGRP monoclonal antibody-naive chronic migraine episodic migraine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 BACKGROUND Migraine is a highly prevalent and disabling neurologic disorder affecting more than one billion people worldwide and ranking among the leading causes of years lived with disability ( 1 ). Its burden extends well beyond headache frequency alone, encompassing substantial impairment in daily functioning, reduced quality of life, marked interictal burden, and frequent psychiatric comorbidity ( 2 ). Preventive treatment is recommended for patients experiencing frequent migraine attacks to reduce attack frequency and severity, and ultimately to decrease migraine-associated disability and the risk of progression to more severe forms ( 3 ). Previously, migraine prevention relied on oral non-specific medications, originally developed for other conditions, such as tricyclic antidepressants, β-blockers, and antiepileptic drugs. ( 4 ). Although these treatments have demonstrated a certain degree of efficacy, most are poorly tolerated due to off-target side effects leading to high treatment discontinuation rates ( 5 ). The high discontinuation rates ultimately result in poor disease control and have contributed to the underuse of preventive treatments ( 6 ). Advances in our understanding of migraine pathophysiology have led to the identification of calcitonin gene-related peptide (CGRP) as a key target for migraine treatment ( 7 ). Consequently, a new class of drugs specifically designed to target CGRP or its receptor has become available, including CGRP monoclonal antibodies (CGRP mAbs) and gepants ( 8 ). Large randomized clinical trials (RCTs) and meta-analyses have provided strong evidence on the efficacy and safety of CGRP-targeting therapies ( 9 , 10 ). Despite this evidence, regulators and health-care payers still consider nonspecific drugs as the standard of care for migraine prevention and oppose reimbursement for CGRP-targeting therapies as first-line treatment, even in patients suffering from severe forms of migraine such as high-frequency episodic migraine (EM) or chronic migraine (CM). A shift in healthcare decision-making requires additional evidence and real-world data are particularly valuable because of their higher generalizability to clinical practice ( 11 ). Although real-world data on CGRP-targeting therapies have been accumulating since their introduction, part of it was not collected in accordance with the International Headache Society guidelines for real-world studies ( 12 ), and fewer real-world data is available for CGRP-targeting therapies that last obtained marketing authorization, such as eptinezumab. Eptinezumab is a humanized monoclonal antibody that binds CGRP and is administered intravenously, a route that distinguishes it from subcutaneous CGRP mAbs and confers rapid systemic bioavailability, quarterly dosing, and an early onset of therapeutic effect as early as the first day post-infusion ( 13 ). Pivotal phase 3 RCTs have demonstrated the efficacy and safety of eptinezumab in EM ( 14 ), CM ( 15 ), migraine with previous failure for non-specific migraine drugs ( 16 ) and, more recently, migraine associated with medication overuse (MO) ( 17 ). Since 2023 real-world evidence has begun to support these trial findings ( 18 – 31 ). However, important limitations remain, as most existing real-world studies of eptinezumab have involved small patient populations and relied on retrospective data collection. Only three studies involved more than 100 patients and used prospective data collection in the United Kingdom ( 25 ), Greece ( 26 ), and Italy ( 31 ). Furthermore, these more robust studies included a significant proportion of patients previously exposed to other CGRP mAbs, who may therefore have been non-responders to CGRP-targeting therapies. In France, patient access to CGRP mAbs is extremely limited: subcutaneous CGRP mAbs and gepants are not reimbursed, and eptinezumab is currently the only available CGRP-targeting therapy, provided free of charge in selected hospitals for patients with severe migraine who have failed non-specific oral preventive treatments ( 32 ). This unique situation makes it possible to consider conducting real-world studies of eptinezumab in migraine patients who are naïve to prior CGRP-targeted therapies. In that respect, the aim of this study was to assess the effectiveness and safety/tolerability of eptinezumab over 12 months in a large cohort of patients with severe migraine (≥ 8 migraine days per month) enrolled in the prospective French FHU InovPain registry, who had experienced at least 3 prior treatment failure of amitriptyline, beta-blockers, botulinum toxin, candesartan, and topiramate, and had no prior exposure to CGRP mAbs. METHODS Research context This study was conducted within FHU InovPain, a research network dedicated to innovation in chronic refractory pain, including headache disorders. FHU InovPain has been described previously ( 33 ) and is based on a prospective patient registry designed to facilitate real-world observational research, particularly through the collection of data on newly approved treatments after marketing authorization. Study Design This was a data analysis of a single-center, observational, longitudinal prospective cohort conducted at the Pain Department of Nice University Hospital. The study period extended from June 2023 to September 2025 and included all patients enrolled in the FHU InovPain registry who were naïve to CGRP mAbs prior to administration of eptinezumab for migraine prevention. Real-world effectiveness and safety/tolerability of eptinezumab were evaluated, with outcomes assessed at 3, 6, and 12 months after treatment initiation. Participants All consecutive patients in the FHU InovPain registry who received eptinezumab for migraine prevention had no prior exposure to CGRP-targeting therapies and had at least one documented follow-up assessment at month 3 were considered for enrolment. The inclusion criteria for receiving eptinezumab at the Pain Department of Nice University Hospital were : i) age over 18 years; ii) a diagnosis of migraine according to the International Classification of Headache Disorders, 3rd edition ( 34 ); iii) at least 8 migraine days per month confirmed in a prospectively maintained headache diary for at least one month before treatment initiation; iv) failure of at least 3 previous prophylactic non-specific migraine treatments across amitriptyline, beta-blockers, botulinum toxin, candesartan, or topiramate (efficacy failure after administration of drug for at least 2–3 months at generally accepted therapeutic doses / tolerability failure defined as discontinuation due to adverse event / contraindication). The exclusion criteria for receiving eptinezumab et the Pain Department of Nice University Hospital were: i) hypersensitivity to the active substance or any of its excipients; ii) pregnancy or breastfeeding; and iii) a history of cardiovascular disease (this criterion did not include patients with high blood pressure [HBP], provided it as well controlled by antihypertensive treatment). Treatment Patients received intravenous eptinezumab in routine clinical practice at our institution. Eptinezumab (Vyepti®, Lundbeck A/S) was administered at a dose of 100 mg every 12 weeks as a 30-minute infusion in a hospital setting, in accordance with standard clinical practice. In cases of insufficient response to the 100 mg dose, escalation to 300 mg was not performed due to institutional financial constraints. Concomitant preventive treatments, except for other CGRP mAbs and gepants, were permitted, and acute migraine medications could be used as needed. Assessment Baseline assessment was performed at treatment initiation (M0), and follow-up assessments were performed at month 3 (M3), 6 (M6), and 12 (M12). These assessments were conducted during outpatient visits corresponding to the first, second, third, and fifth eptinezumab infusions, respectively. During each outpatient visit, data was collected prior to the infusion, based on a prospectively completed headache diary covering the preceding month and on the standardized FHU InovPain questionnaire including all assessment items. Following each outpatient visit, data were entered into the FHU InovPain registry database. Between visits, scheduled monitoring was performed to ensure data quality and verify the accuracy of the FHU InovPain registry entries. At M0, baseline descriptive demographic and clinical data were recorded, including age, sex, migraine subtype (EM/CM), existence of aura, presence of continuous headache pain, concomitant preventive migraine treatments, previous failure of onabotulinumtoxinA, triptan resistance, MO, and body mass index (BMI). At M0, M3, M6, and M12, assessment data were collected using the prospective headache diary and the FHU InovPain standardized questionnaire. Adverse events (AEs) were collected at M3, M6, and M12. The prospective headache diary was used to record the monthly number of headache days (MHDs), migraine days (MMDs) and days with acute migraine treatment use during the month preceding each outpatient visit. A headache day was defined as any day on which the patient experienced headache, regardless of characteristics or duration. A migraine day was defined according to ICHD-3 criteria as a day with headache fulfilling criteria for migraine without aura, a day with symptoms fulfilling criteria for migraine with aura, or a day considered by the patient to be migraine at onset and relieved by migraine-specific acute medication ( 34 ). Migraine subtype (EM or CM) and medication overuse were also defined according to ICHD-3 criteria ( 34 ). For this study, patient-reported outcomes (PROs) included in the FHU InovPain standardized questionnaire were used to assess emotional impact, functional impact, interictal burden, quality of life, and patients’ overall perceived change. Emotional impact was assessed using the Hospital Anxiety and Depression Scale (HADS), a 14-item self-report instrument comprising 2 subscales (HADS-A and HADS-D), each ranging from 0 to 21, with higher scores indicating greater symptom burden. HADS-A and HADS-D scores > 7 were considered indicative of clinically relevant anxiety and depressive symptoms, respectively ( 35 ). Headache-related functional impact was evaluated using the Headache Impact Test-6 (HIT-6), with total scores ranging from 36 to 78, with higher scores indicating greater headache-related impact; scores were classified as little or no impact (36–49), some impact (50–55), substantial impact (56–59), and severe impact (≥ 60) ( 36 ). Interictal burden was measured using the 4-item Migraine Interictal Burden Scale (MIBS-4), with total scores ranging from 0 to 12, with higher scores indicating greater interictal burden; scores were categorized as none (0), mild ( 1 – 2 ), substantial ( 3 – 4 ), and severe (≥ 5) ( 38 ). Quality of life was evaluated using the EuroQol 5-Dimension questionnaire (EQ-5D), including the EQ-5D index and the EQ-5D visual analogue scale (EQ-5D VAS), with higher values indicating better perceived health status ( 37 ). Patient global impression of change (PGIC) was assessed using a single-item 7-point scale ranging from “very much worse” to “very much improved.” Given the known placebo effect in migraine, the two highest categories (“much improved” and “very much improved”) were used as the threshold for defining clinical improvement ( 39 ). Outcomes The primary effectiveness endpoint was the 50% responder rate at M3, M6, and M12, defined as the proportion of patients achieving at least a 50% reduction in MMD compared with baseline. Secondary effectiveness endpoints included the 30% and 75% responder rates at M3, M6, and M12, as well as changes from baseline in MMDs, MHDs, and the monthly number of days with acute migraine treatment use. Additional secondary endpoints included changes from baseline in headache-related impact assessed using HIT-6, emotional burden assessed using HADS-A and HADS-D, interictal burden assessed using MIBS-4 and quality of life assessed using the EQ-5D index and EQ-5D VAS. Further secondary outcomes included the evolution of PGIC and conversion from ‘MO’ to ‘non-MO’. A prespecified subgroup analysis compared patients with EM and CM at baseline using the same effectiveness endpoints at each time point. Among patients classified as having CM at baseline, conversion to EM during follow-up was also evaluated. Safety and tolerability outcomes included the occurrence of AEs during follow-up and discontinuations due to treatment-emergent adverse events (TEAEs). Statistics Statistical analyses were performed using standard statistical software R (version R-4.5.1). Continuous variables are presented as mean ± standard deviation (SD), and categorical variables as number and percentage. Distributional assumptions were assessed using the Shapiro–Wilk test. Baseline comparisons between patients with CM and EM were performed using the unpaired Student’s t-test for approximately normally distributed continuous variables and the Mann–Whitney U test otherwise. Comparisons of categorical variables between subgroups were performed using the χ² test or Fisher’s exact test, as appropriate. Responder rates are reported descriptively for the overall population at each follow-up time point. Comparisons of responder rates between CM and EM subgroups at each time point were performed using the χ² test or Fisher’s exact test, as appropriate. Changes from baseline to follow-up in continuous outcomes were assessed using the paired Student’s t-test for approximately normally distributed variables and the Wilcoxon signed-rank test otherwise. This applied to MHDs, MMDs, monthly acute treatment days, HIT-6, HADS-A, HADS-D, EQ-5D index, EQ-5D VAS, MIBS-4. For subgroup analyses according to migraine subtype at baseline, within-group changes over time were assessed using the same approach. Changes from baseline to follow-up in dichotomous outcomes as medication overuse and migraine subtype, McNemar tests were performed. Effectiveness analyses at M3, M6, and M12 were primarily performed using available-case analyses at each time point, including only patients with evaluable data for the corresponding outcome. Because availability of a documented M3 follow-up was part of the inclusion criteria, all included patients were evaluable for the 3-month assessment. In addition, sensitivity analyses using a last observation carried forward (LOCF) approach were performed for responder rates and diary-based outcomes, including MHDs, MMDs, and monthly acute treatment days, to assess the robustness of the results in the presence of treatment discontinuation and missing follow-up data. All tests were two-sided, and p-values < 0.05 were considered statistically significant. No adjustment for multiple comparisons was performed; p-values should therefore be interpreted as nominal. Ethics and Regulatory Considerations This observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l’Informatique et des Libertés; CNIL; CIL register no. 278, dated 11/09/2017). Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes This study was conducted in accordance with the STROBE guidelines ( 40 ). RESULTS Demographics and clinical characteristics at baseline Three hundred and two patients were included in the analysis. All 302 patients were evaluable for effectiveness and safety assessment at M3, whereas 246 and 138 patients were evaluable at M6 and M12, respectively. Reasons for non-evaluable status at M6 and M12 are shown in Fig. 1 . The cohort comprised 253 women (83.8%) with a mean age of 48.0 ± 13.9 years. At baseline, 184 patients (60.9%) had CM and 118 (39.1%) had EM. Migraine with aura was present in 54 patients (17.9%). Mean baseline MHDs and MMDs were 18.6 ± 7.7 and 17.0 ± 7.6, respectively. Continuous headache pain was reported by 102 patients (33.8%). Mean monthly acute treatment days were 16.2 ± 8.1. MO was present in 229/302 patients (75.8%). Baseline demographic and clinical characteristics of the overall population and according to migraine subtype are detailed in Table 1 . Mean HIT-6 score was 67.0 ± 6.4. Mean EQ-5D index and EQ-5D VAS were 0.56 ± 0.29 and 56.0 ± 18.7, respectively. Mean MIBS-4 score was 6.3 ± 4.0. Mean HADS-A and HADS-D scores were 10.0 ± 4.4 and 7.3 ± 4.5, respectively; clinically relevant anxious symptoms were present in 131 patients (43.4%) and clinically relevant depressive symptoms in 93 (30.8%). Mean body mass index was 24.0 ± 4.2 kg/m² (n = 255), with overweight and obesity present in 69/255 (27.1%) and 22/255 (8.6%) patients, respectively. Table 1 Baseline demographic and clinical characteristics of the overall population and according to migraine subtype at baseline. Data are presented as mean ± SD or n (%), as appropriate. Percentages were calculated using the number of valid observations for the corresponding variable. p-values refer to comparisons between patients with chronic migraine (CM) and episodic migraine (EM). BMI, Body Mass Index; CM, chronic migraine; EM, episodic migraine; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; HIT-6, Headache Impact Test-6; EQ-5D, EuroQol 5-Dimension questionnaire; VAS, visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days; MOH, medication overuse headache. Characteristic n valid Total (n = 302) CM (n = 184) EM (n = 118) p-value Sex, female, n (%) 302 253 (83.8) 143 (77.7) 110 (93.2) < 0.001 Age, years 302 48.0 ± 13.9 47.8 ± 14.6 48.3 ± 12.6 0.940 Migraine subtype, n (%) 302 CM, n 302 184 (60.9) — — — EM, n 302 118 (39.1) — — — Aura, n (%) 298 54 (178.1) 36 (19.9) 18 (15.4) 0.324 MHD 302 18.6 ± 7.7 23.5 ± 5.1 10.8 ± 3.3 < 0.001 MMD 302 17.0 ± 7.6 21.4 ± 6.2 10.0 ± 3.0 < 0.001 MATD 302 16.2 ± 8.1 19.9 ± 8.0 10.4 ± 3.9 < 0.001 Continuous headache pain, n (%) 301 102 (34.9) 96 (54.5) 6 (5.2) < 0.001 MOH, n (%) 302 229 (75.8) 161 (87.5) 68 (57.6) < 0.001 Simple overuse, n (%) 302 118 (39.1) 82 (44.6) 36 (30.5) 0.015 Multiple overuse, n (%) 302 112 (37.1) 79 (42.9) 33 (28.0) 0.009 Triptan overuse, n (%) 302 188 (62.3) 125 (67.9) 63 (53.4) 0.011 Opioid overuse, n (%) 302 15 (5.0) 12 (6.5) 3 (2.5) 0.120 Triptan resistance, n (%) 299 41 (13.7) 32 (17.6) 9 (7.7) 0.015 Current preventive treatment, n (%) 301 166 (55.1) 101 (55.2) 65 (55.1) 0.986 Previous onabotulinumtoxinA exposure, n (%) 302 123 (40.7) 93 (50.5) 30 (25.4) < 0.001 Previous onabotulinumtoxinA failure among exposed, n (%) 123 69 (56.1) 53 (57.0) 16 (53.3) 0.726 HIT-6 301 67.0 ± 6.4 67.2 ± 5.7 66.6 ± 7.5 0.693 HADS-A 301 10.0 ± 4.4 9.7 ± 4.4 10.4 ± 4.4 0.186 Anxious symptoms, n (%) 301 131 (43.45) 78 (42.6) 53 (44.9) 0.695 HADS-D 301 7.3 ± 4.5 7.6 ± 4.8 6.9 ± 4.1 0.368 Depressive symptoms, n (%) 301 93 (30.9) 52 (28.4) 41 (34.7) 0.246 EQ-5D 298 0.56 ± 0.29 0.50 ± 0.30 0.64 ± 0.25 < 0.001 EQ-5D VAS 295 56.0 ± 18.7 53.9 ± 19.2 59.3 ± 17.4 0.017 MIBS-4 287 6.3 ± 4.0 6.7 ± 4.0 5.7 ± 4.0 0.038 BMI, kg/m² 255 24.0 ± 4.2 24.1 ± 4.3 24.0 ± 3.9 0.960 Overweight, n (%) 256 69 (27.0) 41 (26.5) 28 (27.7) 0.823 Obesity, n (%) 255 22 (8.6) 14 (9.1) 8 (7.9) 0.745 Percentages were calculated using the number of valid observations for the corresponding variable. p-values refer to comparisons between patients with chronic migraine (CM) and episodic migraine (EM). BMI, Body Mass Index; CM, chronic migraine; EM, episodic migraine; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; HIT-6, Headache Impact Test-6; EQ-5D, EuroQol 5-Dimension questionnaire; VAS, visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days; MOH, medication overuse headache. Primary effectiveness endpoint The proportion of 50% responders at M3, M6 and M12 was 35.4% (107/302), 39.1% (96/246) and 45.7% (63/138), respectively (Fig. 2 ). Secondary effectiveness endpoints The proportions of ≥ 30% responders at M3, M6 and M12 were 48.7% (147/302), 56.1% (138/246) and 63.0% (87/138), respectively. The proportions of ≥ 75% responders at M3, M6 and M12 were 10.9% (33/302), 15.4% (38/246) and 23.2% (32/138), respectively (Fig. 2 ). Changes in continuous effectiveness outcomes over time are presented in Table 2 , and the longitudinal evolution of diary-based outcomes is shown in Fig. 3 . Table 2 Evolution of continuous effectiveness outcomes in the overall population. Data are presented in mean ± standard deviation. Negative change-from-baseline values indicate an increase from baseline. *Wilconson signed rank test vs M0, p < 0.001, ** Wilconson signed rank test vs M0, p < 0.05. Change/M0, change from baseline; HIT-6, Headache Impact Test-6; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; EQ-5Di, EuroQol 5-Dimension index utility; EQ-5Dvas: EuroQol 5-Dimension visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days. Outcomes M0 (302) M3 (302) M6 (246) M12 (138) MHDs change/M0 18.6 ± 7.7 - 14.1 ± 9.1* 4.5 ± 7.7 12.6 ± 9.0* 5.6 ± 8.0 10.8 ± 8.0* 7.1 ± 8.3 MMDs change/M0 17.0 ± 7.6 - 12.5 ± 8.7* 4.4 ± 8.2 11.4 ± 8.6* 5.2 ± 8.3 9.2 ± 7.6* 7.0 ± 8.5 MATD change/M0 16.2 ± 8.1 - 11.6 ± 9.1* 4.5 ± 8.0 10.5 ± 8.7* 5.2 ± 8.3 9.1 ± 7.7* 6.8 ± 8.4 HIT-6 change/M0 67.0 ± 6.4 - 62.1 ± 8.4* 4.8 ± 8.3 60.0 ± 9.2* 7.0 ± 9.0 58.4 ± 8.8* 7.8 ± 8.3 HADS-A change/M0 10.0 ± 4.4 - 9.2 ± 4.2* 0.8 ± 2.9 8.7 ± 4.3* 1.2 ± 3.3 8.1 ± 3.9* 1.6 ± 3.4 HADS-D change/M0 7.3 ± 4.5 - 6.8 ± 4.6** 0.5 ± 3.2 6.5 ± 4.6* 0.8 ± 3.4 5.5 ± 4.0* 1.9 ± 3.5 EQ-5D i change/M0 0.6 ± 0.3 - 0.7 ± 0.3* -0.1 ± 0.2 0.7 ± 0.3* -0.1 ± 0.2 0.7 ± 0.2* -0.1 ± 0.3 EQ-5D vas change/M0 56.0 ± 18.7 - 62.3 ± 18.5* -6.0 ± 17.1 65.9 ± 19.0* -9.1 ± 18.7 69.5 ± 17.2* -12.7 ± 17.6 MIBS-4 change/M0 6.3 ± 4.0 - 5.2 ± 4.0* 1.1 ± 3.5 4.6 ± 3.9* 1.5 ± 3.3 4.3 ± 3.8* 1.9 ± 3.9 For MHDs, mean values decreased from 18.6 ± 7.7 at baseline to 14.1 ± 9.1, 12.6 ± 9.0, and 10.8 ± 8.0 at M3, M6, and M12, respectively. For MMDs, mean values decreased from 17.0 ± 7.6 at baseline to 12.5 ± 8.7, 11.4 ± 8.6, and 9.2 ± 7.6 at M3, M6, and M12, respectively. For monthly acute medication days, mean values decreased from 16.2 ± 8.1 at baseline to 11.6 ± 9.1, 10.5 ± 8.7, and 9.1 ± 7.7 at M3, M6, and M12, respectively. Differences from baseline were significant at all time points for MHDs, MMDs and monthly acute medication days (all p < 0.001). For HIT-6 score, mean values decreased from 67.0 ± 6.4 at baseline to 62.1 ± 8.4, 60.0 ± 9.2 and 58.4 ± 8.8 at M3, M6 and M12, respectively. For HADS-A score, mean values decreased from 10.0 ± 4.4 at baseline to 9.2 ± 4.2, 8.7 ± 4.3 and 8.1 ± 3.9 at M3, M6 and M12, respectively. For HADS-D score, mean values decreased from 7.3 ± 4.5 at baseline to 6.8 ± 4.6, 6.5 ± 4.6 and 5.5 ± 4.0 at M3, M6 and M12, respectively. For MIBS-4 score, mean values decreased from 6.3 ± 4.0 at baseline to 5.2 ± 4.0, 4.6 ± 3.9 and 4.3 ± 3.8 at M3, M6 and M12, respectively. For EQ-5D index, mean values increased from 0.6 ± 0.3 at baseline to 0.7 ± 0.3, 0.7 ± 0.3 and 0.7 ± 0.2 at M3, M6 and M12, respectively. For EQ-5D VAS, mean values increased from 56.0 ± 18.7 at baseline to 62.3 ± 18.5, 65.9 ± 19.0 and 69.5 ± 17.2 at M3, M6 and M12, respectively. Differences from baseline were significant at all time points for HIT-6, HADS-A, MIBS-4, EQ-5D index and EQ-5D VAS (all p < 0.001), whereas for HADS-D the differences were significant at M3 (p < 0.05), M6 (p < 0.001) and M12 (p < 0.001). According to PGIC, the proportions of patients reporting themselves as “much improved” or “very much improved” were 41.9% at M3, 54.8% at M6 and 74.4% at M12 (Fig. 4 ). The proportion of patients with MO was reduced from 75.8% (229/302) at baseline to 41.9% (124/302), 36.4% (87/246) and 31.6% (43/138) at M3, M6 and M12, respectively (Fig. 5 ). Differences from baseline were significant at all time points (all p < 0.001). Prespecified subgroup analysis according to baseline migraine subtype Baseline demographic and clinical characteristics according to migraine subtype are presented in Table 1 . Compared with patients with EM, those with CM were less frequently female (77.7% vs 93.2%; p < 0.001) and had a greater headache burden, with higher MHDs (23.5 ± 5.1 vs 10.9 ± 3.3; p < 0.001), higher MMDs (21.4 ± 6.2 vs 10.0 ± 3.0; p < 0.001), and more monthly acute treatment days (19.9 ± 8.0 vs 10.4 ± 3.9; p < 0.001). Patients with CM also more frequently reported continuous headache pain, MO, simple and multiple medication overuse, triptan overuse, and triptan resistance, and had lower EQ-5D index values, lower EQ-5D VAS scores, higher MIBS-4 scores, and higher systolic blood pressure. No significant between-group differences were observed for age, aura, HIT-6, HADS-A, HADS-D, current preventive treatment, previous onabotulinumtoxinA failure, overweight, obesity, or opioid overuse. For the primary effectiveness endpoint, the proportions of 50% responders at M3, M6 and M12 were 35.9% (66/184), 41.4% (60/145) and 53.8% (43/80) in patients with CM, and 34.7% (41/118), 35.6% (36/101) and 34.5% (20/58) in patients with EM. Between-group differences were not significant at M3 (p = 0.842) or M6 (p = 0.364) but were significant at M12 (p = 0.025). For the secondary responder endpoints, the proportions of 30% responders at M3, M6 and M12 were 48.4% (89/184), 53.8% (78/145) and 63.8% (51/80) in patients with CM, and 49.2% (58/118), 59.4% (60/101) and 62.1% (36/58) in patients with EM, with no significant between-group differences at any time point (p = 0.894, p = 0.383 and p = 0.840, respectively). The proportions of 75% responders were 10.3% (19/184), 16.6% (24/145) and 30.0% (24/80) in patients with CM, and 11.9% (14/118), 13.9% (14/101) and 13.8% (8/58) in patients with EM. These did not differ significantly at M3 (p = 0.676) or M6 (p = 0.566) but were significantly higher in the CM subgroup at M12 (p = 0.026). Evolution of continuous effectiveness outcomes according to baseline migraine subtype are presented in Supplementary Table S1 , and the longitudinal evolution of key diary-based outcomes in each subgroup is shown in Supplementary Fig. S1 . In both subgroups, MHDs, MMDs and monthly acute treatment days decreased significantly from baseline at all follow-up time points (all p < 0.001). Patient-reported outcomes also improved in both subgroups. HADS-A decreased significantly from baseline at all time points in both groups, whereas HADS-D decreased significantly from M6 onward in patients with CM and from M3 onward in patients with EM. MO decreased in both subgroups over time. In patients with CM, the proportion with MO decreased from 87.5% (161/184) at baseline to 53.6% (96/184), 48.9% (68/145) and 39.2% (31/80) at M3, M6 and M12, respectively. In patients with EM, the corresponding proportions were 57.6% (68/118), 23.9% (28/118), 19.0% (19/101) and 21.1% (12/58). Reductions from baseline were significant at all time points in both subgroups (all p < 0.001). Conversion from chronic to episodic migraine. Among patients in the effectiveness population classified as having CM at baseline (n = 184), phenotypic conversion to EM was assessed at each follow-up visit using observed-case data. At M3, 87/184 patients (47.3%) no longer fulfilled criteria for CM and were classified as EM. Among baseline CM patients with available data at M6 (n = 145), 77/145 patients (53.1%) were classified as EM. Among baseline CM patients with available data at M12 (n = 80), 55/80 patients (68.8%) were classified as EM. In the overall population, the proportion of patients classified as having EM increased from 39.1% at baseline to 65.0% at M3, 67.8% at M6 and 79.7% at M12, whereas the proportion classified as having CM decreased from 60.9% to 35.0%, 32.2% and 20.3%, respectively (Fig. 6 ). Differences from baseline were significant at all follow-up time points (McNemar test vs M0: p < 0.001). LOCF analysis LOCF sensitivity analysis yielded results broadly consistent with those of the available-case analysis. In the overall population (N = 302), the proportions of ≥ 50% responders at M3, M6 and M12 were 35.4% (107/302), 36.1% (109/302) and 36.8% (111/302), respectively. The corresponding proportions of ≥ 30% responders were 48.7% (147/302), 53.6% (162/302) and 52.3% (158/302), whereas the proportions of ≥ 75% responders were 10.9% (33/302), 14.2% (43/302) and 16.6% (50/302), respectively. Mean MHDs decreased from 18.6 ± 7.7 at baseline to 14.1 ± 9.1, 13.3 ± 9.1 and 13.5 ± 9.3 at M3, M6 and M12, respectively. Mean MMDs decreased from 17.0 ± 7.6 at baseline to 12.5 ± 8.7, 12.1 ± 8.9 and 12.0 ± 9.1, respectively. Mean monthly acute treatment days decreased from 16.2 ± 8.1 at baseline to 11.8 ± 9.2, 11.5 ± 9.1 and 11.2 ± 9.2 at M3, M6 and M12, respectively. Differences from baseline remained significant at all time points for MHDs, MMDs and monthly acute treatment days (all p < 0.001). Detailed results of LOCF subgroup analyses according to migraine subtype at baseline are presented in Supplementary Table S2. Safety and tolerability AEs were uncommon and mostly mild, transient, and self-limited. Reported events included allergic and non-allergic AEs. Non-allergic AEs occurring during eptinezumab infusion and resolving within 24 hours included asthenia (n = 3, 1.0%), nausea (n = 1, 0.3%), scalp pruritus (n = 1, 0.3%), transient “brain fog” (n = 1, 0.3%), and transient symmetric lower-limb paresthesia (n = 1, 0.3%). Non-allergic AEs that persisted between infusions included alopecia (n = 3, 1.0%). Allergic AEs occurring during or immediately after eptinezumab infusion included bronchospasm (n = 1, 0.3%), pruritic erythematous rash (n = 1, 0.3%), urticaria (n = 3, 1.0%). One patient (0.3%) developed severe generalized urticaria leading to treatment discontinuation, representing the only TEAE resulting in treatment withdrawal. After 1 year of treatment, 1 patient (0.3%) developed ANCA-associated vasculitis, but with no confirmed causal relationship with eptinezumab. DISCUSSION Our study is a real-world study to evaluate the effectiveness and safety of eptinezumab 100 mg in difficult-to-treat patients with migraine based on the prospective French InovPain registry. Compared with previous large prospective real-world studies on eptinezumab conducted in the United Kingdom ( 25 ), Greece ( 26 ), and Italy ( 31 ), our study is distinguished by its larger sample size and its 12-month follow-up period. It is also the first prospective real-world study to evaluate eptinezumab exclusively in patients with migraine who were naïve to CGRP-targeting therapies. In this population of difficult-to-treat, CGRP-targeting therapy-naïve patients treated with eptinezumab 100 mg, our study has shown 50% responder rates (in terms of MMDs) of 35.4%, 39%, and 45.7% at M3, M6, and M12, respectively. Comparison with previous prospective real-world studies on eptinezumab remains challenging because those studies involved smaller sample sizes, among which at least 50% of patients had failed previous CGRP mAbs ( 25 , 26 , 31 ). Our findings may therefore be more appropriately compared with those of the DELIVER trial, a RCT that evaluated the efficacy of eptinezumab in a large population of patients who were difficult to treat with non-specific migraine therapies but had not previously failed CGRP-targeting treatments ( 16 ). In that RCT, the 50% responder rate following initiation of treatment with 100 mg of eptinezumab was 42%, 52%, and 62.6% in weeks 1–12, 13–24, and 49–60, respectively ( 16 , 41 ). Those responder rates were higher than those observed in our study, but it should be noted that our patients likely had more prophylactic treatment resistance than those included in the DELIVER study. In DELIVER, the inclusion criterion regarding patients’ treatment history specified a prior failure of 2 to 4 treatments and less than 38% of included patients had at least 3 previous preventive treatment failures ( 16 ). In contrast, all patients included in our study had failed at least three preventive treatments among amitriptyline, beta-blockers, candesartan, topiramate, and botulinum toxin before receiving eptinezumab. The population included in our study was also characterized by more severe migraine than the DELIVER population ( 16 ), in terms of MMDs (17.0 ± 7.6 vs 13.8 ± 5.6), CM/EM ratio (60.9%/39.1% vs 46%/54%), MO (75.8% vs 13%), and HIT-6 scores(67.0 ± 6.4 vs 66.6 ± 4.7). Differences in assessment methodology may also have contributed to the lower responder rates observed in our study. Unlike DELIVER, which evaluated the average MMDs over the entire three-month period between two eptinezumab infusions, our study assessed only the last month of the three-month period. This approach may have reduced observed treatment response in patients experiencing a wearing-off effect toward the end of the dosing interval. Although wearing off was not specifically assessed in RCTs of eptinezumab, Alssadi et al. reported this phenomenon in 36.1% of patients treated with CGRP mAbs in a real-world cohort ( 43 ). Similarly, approximately one-quarter of responders in our cohort reported a decline in therapeutic effect that consistently occurred during the last two weeks before reinfusion (data not presented because they are declarative and not supported by any quantitative analysis of prospective headache diary). At the three assessment time points, the 30% responder rates (M3: 48.7%, M6: 56.1%, M12: 63%) and the 75% responder rates (M3: 10.9%, M6: 15.4%, M12: 23.2%) increased in the same proportions as the 50% responder rates. The effectiveness of eptinezumab was confirmed by significant changes in the values of all PRO measures at all assessment time points compared with baseline, demonstrating improvements in functional impact (HIT-6), emotional impact (HADS-A and HADS-D), interictal burden (MIBS-4), and consequently quality of life (EQ-5D index and EQ-5D VAS). This reduction in the number of migraine days and in the burden of migraine resulted in a clinically relevant Patient Global Impression of Change, with 41.9%, 54.8%, and 74.4% of patients in the overall population reporting that they were ‘much improved’ or ‘very much improved’ at M3, M6, and M12, respectively. Given its large sample size, our study allowed us to compare the effectiveness of eptinezumab in high-frequency EM (all patients included in our study experienced at least 8 migraine days per month) and CM. Overall, effectiveness appeared similar in both groups except at M12, where 50% and 75% responder rates were significantly higher in patients with CM than in those with high frequency EM (50% response: 53.8% vs 34.5%, p = 0.025 and 75% response: 30% vs 13.8%, p = 0.026). Such improved effectiveness in CM had not been demonstrated in a subgroup analysis of the DELIVER study, which instead showed higher responder rates for patients with high-frequency EM than for those with CM, although no statistical comparison between groups was performed and this subgroup analysis was limited to weeks 1–12 and weeks 13–24 ( 42 ). The effectiveness of eptinezumab in CM was further reflected by significant rates of conversion from CM to EM, as illustrated by the evolution of the CM/EM ratio: 60.9%/39.1% at baseline, 35%/65% at M3, 32.2%/67.8% at M6, and 20.3%/79.7% at M12. Similarly, the proportion of patients with MO decreased from 75.8% at baseline to 31.6% at 12 months. The safety and tolerability of eptinezumab were good in our cohort. Allergic AEs were expected, as hypersensitivity reactions were reported in 23 (1.1%) patients among a pooled population of 2,076 patients with migraine treated with eptinezumab across 5 RCTs ( 44 ). With 5/302 patients experiencing a hypersensitivity reaction, the proportion of patients who experienced this type of adverse event in our cohort (1.6%) was comparable to that observed in controlled trials. In one patient, severe urticaria led to permanent discontinuation of eptinezumab treatment. In remaining patients, eptinezumab treatment was continued using a desensitization protocol previously developed and published by our group ( 45 ). The primary strength of this study is its large sample size, making it currently the largest real-world study of eptinezumab in terms of patient number. A second major strength is that the study was conducted in accordance with the International Headache Society guidelines for real-world evidence studies ( 12 ), with Data Quality that may be considered Level 1 owing to the use of a structured data collection method, validated assessment measures and validated PRO instruments. This study also has several limitations. First, its single-center design may call into question the generalizability of the findings to the broader French population. Another weakness is the use of a paper headache diary rather than an electronic diary, as recommended by the International Headache Society ( 12 ). Similarly, our study may be criticized for assessing MHDs and MMDs only during the last 4 weeks of the three-month period between two eptinezumab infusions. This methodological choice was deliberate, given the low rate of adherence to headache diary completion among migraine sufferers, even those with frequent attacks ( 46 ). Finally, it is important to note that our study focused solely on the 100 mg dose of eptinezumab. Due to financial constraints, escalation to the 300 mg dose was not possible. Consequently, we have no data to determine what proportion of non-responders to 100 mg would respond to 300 mg, or whether higher dosing could be a way to limit the wearing-off effect observed in some patients. CONCLUSION This French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who had previously failed non-migraine specific treatments and are naïve to CGRP mAbs. For the international migraine community, these findings, which are consistent with those obtained with other CGRP mAbs, further support the clinical value of this innovative class of migraine therapies. More specifically for the French migraine community, these results give us hope that the ongoing negotiations will yield favorable outcomes, potentially leading to easier treatment access, particularly for patients with the most severe forms of migraine. Declarations Ethic approval and consent to participate This observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l’Informatique et des Libertés; CNIL; CIL register no. 278, dated 11/09/2017). Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes Consent for publication Not applicable Available data and materials The material used for this work are available from the corresponding author on reasonable request Competing interests FRS has no conflict of interest. FR had no conflict of interest. JT had no conflict of interest. LMM received personal fees for consultancy activities from: Abbvie/Allergan, Amgen, Eli Lilly, IPSEN, Lundbeck, Medtronic, Novartis, Orion Pharma, Perfood, Pfizer, Reckitt-Benckiser, Savia, Bioelectronics, Teva, UPSA. . Funding This study was supported by FHU InovPain Authors’ contribution FRS and LMM conceived the study. JT and MLM collected the data FR performed statistical analysis. FRS and LMM drafted the manuscript. All authors revised and approved the final manuscript References GBD 2021 Nervous System Disorders Collaborators. 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PMID: 41331996; PMCID: PMC12849520 Argyriou AA, Dermitzakis EV, Chondrogianni M, Foska A, Rikos D, Soldatos P, Vikelis M, Greek Research Alliance for the Study of Headache and Pain (GRASP) Study Group (2025) Testing the Efficacy of Eptinezumab 100 mg in the Early Prevention of Chronic Migraine over Weeks 1 to 4: Prospective Real-World Data from the GRASP Study Group. J Clin Med 14(24):8793. 10.3390/jcm14248793 PMID: 41464695; PMCID: PMC12733432 Dermitzakis EV, Argyriou AA, Chondrogianni M, Foska A, Rikos D, Athanasopoulos D, Tsironis C, Soldatos P, Koutsokera M, Tsitsaras N, Litsardopoulos P, Mavraki E, Vikelis M, Greek Research Alliance for the Study of Headache and Pain (GRASP) Study Group (2026) Eptinezumab to prevent difficult-to-treat migraine: prospective, six-month, real-world multicenter evidence from the GRASP study group. J Headache Pain 27(1):48. 10.1186/s10194-026-02275-5 PMID: 41578184; PMCID: PMC12918022 Iannone LF, Piella EM, Montisano DA, Fasano C, Sebastianelli G, Coppola G, Ferrandi D, Lanni C, Prudenzano MP, de Tommaso M, Merlo P, De Cesaris F, Chiarugi A, Munafò A, Pistoia F, Ornello R, Doretti A, Grazzi L, Lo Castro F, De Icco R, Vaghi G, Avino G, Romozzi M, Calabresi P, Battistini S, Rufa A, Albanese M, Trimboli M, Carlucci G, Silvestro M, Russo A, Rainero I, Valente MR, Fofi L, Marcosano M, Geppetti P, Altamura C, Vernieri F, Tassorelli C, Sacco S, Guerzoni S (2026) Italian Headache Registry (RICe) Study Group. Levels of migraine controls following International Headache Society (IHS) recommendations with eptinezumab: Effectiveness and tolerability in a 24-week, prospective multicenter study (the TACHIS study). Cephalalgia 46(2):3331024251414659. 10.1177/03331024251414659 Epub 2026 Feb 12. PMID: 41684106 Moisset X, Demarquay G, de Gaalon S, Roos C, Donnet A, Giraud P, Guégan-Massardier E, Lucas C, Mawet J, Valade D, Corand V, Gollion C, Moreau N, Grangeon L, Lantéri-Minet M, Ducros A (2024) Migraine treatment: Position paper of the French Headache Society. Rev Neurol (Paris). ;180(10):1087–1099. doi: 10.1016/j.neurol.2024.09.008. Epub 2024 Oct 15. PMID: 39406556 Lanteri-Minet M, Fabre R, Martin C, Pradat K, Alchaar A, Bozzolo E, Duchene ML, Van Obberghen EK, Donnet A, Fontaine D (2023) One-year prospective real-world assessment of effectiveness and safety of erenumab in migraine prevention: results of the French FHU INOVPAIN registry study. J Headache Pain 24(1):152. 10.1186/s10194-023-01680-4. PMID: 37940860; PMCID: PMC10633983 Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia (2018) ;38(1):1-211. 10.1177/0333102417738202 . PMID: 29368949 Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand. ;67(6):361 – 70. 10.1111/j.1600-0447.1983.tb09716.x . PMID: 6880820 Kosinski M, Bayliss MS, Bjorner JB, Ware JE Jr, Garber WH, Batenhorst A, Cady R, Dahlöf CG, Dowson A, Tepper S (2003) A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res. ;12(8):963 – 74. 10.1023/a:1026119331193 . PMID: 14651415 EuroQol Group. EuroQol–a new facility for the measurement of health-related quality of life. Health Policy (1990) ;16(3):199–208. 10.1016/0168-8510(90)90421-9 . PMID: 10109801 Buse DC, Rupnow MF, Lipton RB (2009) Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. Mayo Clin Proc. ;84(5):422 – 35. 10.1016/S0025-6196(11)60561-2 . PMID: 19411439; PMCID: PMC2676125 Yalinay Dikmen P, Ozge A, Martelletti P (2023) The use of clinical scales and PROMs in headache disorders and migraine, summarizing their dissemination and operationalization. Heliyon 9(5):e16187. 10.1016/j.heliyon.2023.e16187. PMID: 37251845; PMCID: PMC10220237 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, STROBE Initiative (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 335(7624):806–808. 10.1136/bmj.39335.541782.AD. PMID: 17947786; PMCID: PMC2034723 Ashina M, Tepper SJ, Gendolla A, Sperling B, Ettrup A, Josiassen MK, Starling AJ (2023) Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial. J Headache Pain 24(1):155. 10.1186/s10194-023-01688-w. PMID: 37985968; PMCID: PMC10662788 Ashina M, Lanteri-Minet M, Ettrup A, Christoffersen CL, Josiassen MK, Phul R, Sperling B, Pozo-Rosich P (2023) Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study. Cephalalgia. ;43(5):3331024231170807. 10.1177/03331024231170807 . PMID: 37125484 Alsaadi T, Adel F, Alsaffarini K, El Jadam C, Alkhateri A, Pagdato B, Suliman R (2025) Bridging CGRP mAbs with Gepants: An innovative approach to address the wearing-off phenomenon. Clin Neurol Neurosurg 258:109183. 10.1016/j.clineuro.2025.109183. Epub 2025 Oct 5. PMID: 41056647 Smith TR, Spierings ELH, Cady R, Hirman J, Schaeffler B, Shen V, Sperling B, Brevig T, Josiassen MK, Brunner E, Honeywell L, Mehta L (2021) Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials. J Headache Pain. ;22(1):16. doi: 10.1186/s10194-021-01227-5. Erratum in: J Headache Pain. 2021;22(1):46. 10.1186/s10194-021-01253-3 . PMID: 33781209; PMCID: PMC8008612 Gerard B, Praudel H, Lanteri-Minet M, Van Obberghen E, Rocher-Moreau F, Rousset J, Jacquier U, Leroy S, Delin M (2026) First successful protocol for desensitization to eptinezumab. Headache 66(2):556–559. 10.1111/head.70000. Epub 2025 Dec 19. PMID: 41420316; PMCID: PMC12916455 Phillip D, Lyngberg A, Jensen R (2007) Assessment of headache diagnosis. A comparative population study of a clinical interview with a diagnostic headache diary. Cephalalgia. ;27(1):1–8. 10.1111/j.1468-2982.2007.01239.x . PMID: 17212676 Additional Declarations Competing interest reported. SFM has no conflict of interest. RF had no conflict of interest. TJ had no conflict of interest. MLM received personal fees for consultancy activities from: Abbvie/Allergan, Amgen, Eli Lilly, IPSEN, Lundbeck, Medtronic, Novartis, Orion Pharma, Perfood, Pfizer, Reckitt-Benckiser, Savia, Bioelectronics, Teva, UPSA. . Supplementary Files SUPPLEMENTARYMATERIALLanteriMinetetal.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 06 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers invited by journal 05 May, 2026 Editor assigned by journal 05 May, 2026 Submission checks completed at journal 05 May, 2026 First submitted to journal 01 May, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9588176","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":638390958,"identity":"aeac76ca-f60e-4634-9a84-88a4152b25a7","order_by":0,"name":"S Ferrao-Malheiro","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Nice","correspondingAuthor":false,"prefix":"","firstName":"S","middleName":"","lastName":"Ferrao-Malheiro","suffix":""},{"id":638390959,"identity":"feb9bbb2-9071-48b2-b3e6-688dc1d2f2f4","order_by":1,"name":"R Fabre","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Nice","correspondingAuthor":false,"prefix":"","firstName":"R","middleName":"","lastName":"Fabre","suffix":""},{"id":638390960,"identity":"4650394b-88db-44d5-b484-51990eb9892c","order_by":2,"name":"T Jiacomini","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Nice","correspondingAuthor":false,"prefix":"","firstName":"T","middleName":"","lastName":"Jiacomini","suffix":""},{"id":638390961,"identity":"a494fb32-d766-473c-a279-e08a808cddaa","order_by":3,"name":"M Lanteri-Minet","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIiWNgGAWjYBACPgglwcDADGHJgdgMDAZAzHwAqxY2BgbGBrgWoBpjhBa2BHxaoACoJbFBAi6HQwv72eMPPu6xYNBt5z34+APDtvT+2T0GzAUFdnIMbLwPsGrhyUtsnPFMgsHsMF+ywQGG27kz7pwxYJ5hkGwMNM4Au8NyDJt5DkjUbzvMYyYB0rJBIsf8N4/BgcQG+TbsDuN/Y9j85wDIFh7zH0At6QYSOQbMQC31DWxs2LVIAG1hgGgxA3r/dgJMSwIDTi1vDGf2QLQYS5wxuG0440ZaAVBLsmEbDi38/DkGH34cqGMwO3/G8ENFxW15/hnJG5h5/tjJ8+PQggaQg4goDaNgFIyCUTAKsAIAlSlR0gSRAZAAAAAASUVORK5CYII=","orcid":"","institution":"Centre Hospitalier Universitaire de Nice","correspondingAuthor":true,"prefix":"","firstName":"M","middleName":"","lastName":"Lanteri-Minet","suffix":""}],"badges":[],"createdAt":"2026-05-01 17:11:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9588176/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9588176/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109297947,"identity":"ee6a7f2b-9087-4c1f-a0bb-577d47d4b3c8","added_by":"auto","created_at":"2026-05-15 09:07:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":117369,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow-chart of patients from inclusion to study end, with initial evaluation at baseline (M0), follow-up assessments at month 3 (M3), month 6 (M6), and month 12 (M12), and reasons for non-evaluable status at M6 and M12.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/d6b0a83db2f0f42440f4b658.png"},{"id":109216007,"identity":"4a33c894-30ae-4e3c-82c2-bb3499fe0386","added_by":"auto","created_at":"2026-05-13 17:59:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74116,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eResponder rates (≥30%, ≥50% and ≥75% reduction from baseline in monthly migraine days) at month 3 (M3), month 6 (M6), and month 12 (M12).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/df2fe1f2bedc7384ed417b8c.png"},{"id":109216008,"identity":"3da6fb4d-22f8-42ac-ab1c-bb4290e4aecd","added_by":"auto","created_at":"2026-05-13 17:59:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95497,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal evolution of key diary-based outcomes in the overall population. \u003c/strong\u003e\u003cem\u003e*\u003c/em\u003eWilcoxon signed-rank test vs M0: p \u0026lt; 0.001 MHDs, monthly headache days; MMDs, monthly migraine days\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/12a6e9b9d5725b5fe8793b37.png"},{"id":109222242,"identity":"eec9ab96-1946-422a-88be-c5f9556a04dd","added_by":"auto","created_at":"2026-05-13 21:06:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":17127,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of Patient Global Impression of Change (PGIC) categories at month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/b0b4ae07c7d49e52f4069759.png"},{"id":109216010,"identity":"4f0d7ca9-c3f9-4817-b0ee-9a562c0baff7","added_by":"auto","created_at":"2026-05-13 17:59:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":963810,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of patients with medication-overuse at baseline (M0), month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population. \u003c/strong\u003e\u003cem\u003e*\u003c/em\u003eMcNemar test vs M0: p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/e8adbfe7d2bb359806b8611e.png"},{"id":109216012,"identity":"3f9f8125-7abd-4167-9ca6-cc52ed0acf3a","added_by":"auto","created_at":"2026-05-13 17:59:07","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":960171,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of patients classified as having episodic migraine or chronic migraine at baseline (M0), month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population\u003c/strong\u003e. *McNemar test vs M0: p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/d5a3fb811fa8825d39b3d811.png"},{"id":109299378,"identity":"3906447f-eae7-4238-84a6-1c23580888ac","added_by":"auto","created_at":"2026-05-15 09:18:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2790372,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/818a27f2-61c5-460a-9dbb-3a82b8124ff6.pdf"},{"id":109216006,"identity":"4d49d6b5-2d12-4ea1-8fd7-031073fd711f","added_by":"auto","created_at":"2026-05-13 17:59:07","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":150568,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYMATERIALLanteriMinetetal.docx","url":"https://assets-eu.researchsquare.com/files/rs-9588176/v1/655020a01a94db3ac1f501c9.docx"}],"financialInterests":"Competing interest reported. SFM has no conflict of interest.\nRF had no conflict of interest.\nTJ had no conflict of interest.\nMLM received personal fees for consultancy activities from: Abbvie/Allergan, Amgen, Eli Lilly, IPSEN, Lundbeck, Medtronic, Novartis, Orion Pharma, Perfood, Pfizer, Reckitt-Benckiser, Savia, Bioelectronics, Teva, UPSA. .","formattedTitle":"Twelve-months prospective real-world assessment of effectiveness and safety of eptinezumab in migraine patients difficult-to-treat and naïve to CGRP monoclonal antibodies: results of the French FHU INOVPAIN Registry","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eMigraine is a highly prevalent and disabling neurologic disorder affecting more than one billion people worldwide and ranking among the leading causes of years lived with disability (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Its burden extends well beyond headache frequency alone, encompassing substantial impairment in daily functioning, reduced quality of life, marked interictal burden, and frequent psychiatric comorbidity (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePreventive treatment is recommended for patients experiencing frequent migraine attacks to reduce attack frequency and severity, and ultimately to decrease migraine-associated disability and the risk of progression to more severe forms (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Previously, migraine prevention relied on oral non-specific medications, originally developed for other conditions, such as tricyclic antidepressants, β-blockers, and antiepileptic drugs. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Although these treatments have demonstrated a certain degree of efficacy, most are poorly tolerated due to off-target side effects leading to high treatment discontinuation rates (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The high discontinuation rates ultimately result in poor disease control and have contributed to the underuse of preventive treatments (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAdvances in our understanding of migraine pathophysiology have led to the identification of calcitonin gene-related peptide (CGRP) as a key target for migraine treatment (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Consequently, a new class of drugs specifically designed to target CGRP or its receptor has become available, including CGRP monoclonal antibodies (CGRP mAbs) and gepants (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Large randomized clinical trials (RCTs) and meta-analyses have provided strong evidence on the efficacy and safety of CGRP-targeting therapies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Despite this evidence, regulators and health-care payers still consider nonspecific drugs as the standard of care for migraine prevention and oppose reimbursement for CGRP-targeting therapies as first-line treatment, even in patients suffering from severe forms of migraine such as high-frequency episodic migraine (EM) or chronic migraine (CM). A shift in healthcare decision-making requires additional evidence and real-world data are particularly valuable because of their higher generalizability to clinical practice (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Although real-world data on CGRP-targeting therapies have been accumulating since their introduction, part of it was not collected in accordance with the International Headache Society guidelines for real-world studies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), and fewer real-world data is available for CGRP-targeting therapies that last obtained marketing authorization, such as eptinezumab.\u003c/p\u003e \u003cp\u003eEptinezumab is a humanized monoclonal antibody that binds CGRP and is administered intravenously, a route that distinguishes it from subcutaneous CGRP mAbs and confers rapid systemic bioavailability, quarterly dosing, and an early onset of therapeutic effect as early as the first day post-infusion (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Pivotal phase 3 RCTs have demonstrated the efficacy and safety of eptinezumab in EM (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), CM (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), migraine with previous failure for non-specific migraine drugs (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and, more recently, migraine associated with medication overuse (MO) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Since 2023 real-world evidence has begun to support these trial findings (\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). However, important limitations remain, as most existing real-world studies of eptinezumab have involved small patient populations and relied on retrospective data collection. Only three studies involved more than 100 patients and used prospective data collection in the United Kingdom (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), Greece (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and Italy (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Furthermore, these more robust studies included a significant proportion of patients previously exposed to other CGRP mAbs, who may therefore have been non-responders to CGRP-targeting therapies.\u003c/p\u003e \u003cp\u003eIn France, patient access to CGRP mAbs is extremely limited: subcutaneous CGRP mAbs and gepants are not reimbursed, and eptinezumab is currently the only available CGRP-targeting therapy, provided free of charge in selected hospitals for patients with severe migraine who have failed non-specific oral preventive treatments (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). This unique situation makes it possible to consider conducting real-world studies of eptinezumab in migraine patients who are na\u0026iuml;ve to prior CGRP-targeted therapies.\u003c/p\u003e \u003cp\u003eIn that respect, the aim of this study was to assess the effectiveness and safety/tolerability of eptinezumab over 12 months in a large cohort of patients with severe migraine (\u0026ge;\u0026thinsp;8 migraine days per month) enrolled in the prospective French FHU InovPain registry, who had experienced at least 3 prior treatment failure of amitriptyline, beta-blockers, botulinum toxin, candesartan, and topiramate, and had no prior exposure to CGRP mAbs.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eResearch context\u003c/h2\u003e \u003cp\u003eThis study was conducted within FHU InovPain, a research network dedicated to innovation in chronic refractory pain, including headache disorders. FHU InovPain has been described previously (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) and is based on a prospective patient registry designed to facilitate real-world observational research, particularly through the collection of data on newly approved treatments after marketing authorization.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eThis was a data analysis of a single-center, observational, longitudinal prospective cohort conducted at the Pain Department of Nice University Hospital. The study period extended from June 2023 to September 2025 and included all patients enrolled in the FHU InovPain registry who were na\u0026iuml;ve to CGRP mAbs prior to administration of eptinezumab for migraine prevention. Real-world effectiveness and safety/tolerability of eptinezumab were evaluated, with outcomes assessed at 3, 6, and 12 months after treatment initiation.\u003c/p\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eAll consecutive patients in the FHU InovPain registry who received eptinezumab for migraine prevention had no prior exposure to CGRP-targeting therapies and had at least one documented follow-up assessment at month 3 were considered for enrolment. The inclusion criteria for receiving eptinezumab at the Pain Department of Nice University Hospital were : i) age over 18 years; ii) a diagnosis of migraine according to the International Classification of Headache Disorders, 3rd edition (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e); iii) at least 8 migraine days per month confirmed in a prospectively maintained headache diary for at least one month before treatment initiation; iv) failure of at least 3 previous prophylactic non-specific migraine treatments across amitriptyline, beta-blockers, botulinum toxin, candesartan, or topiramate (efficacy failure after administration of drug for at least 2\u0026ndash;3 months at generally accepted therapeutic doses / tolerability failure defined as discontinuation due to adverse event / contraindication). The exclusion criteria for receiving eptinezumab et the Pain Department of Nice University Hospital were: i) hypersensitivity to the active substance or any of its excipients; ii) pregnancy or breastfeeding; and iii) a history of cardiovascular disease (this criterion did not include patients with high blood pressure [HBP], provided it as well controlled by antihypertensive treatment).\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003ePatients received intravenous eptinezumab in routine clinical practice at our institution. Eptinezumab (Vyepti\u0026reg;, Lundbeck A/S) was administered at a dose of 100 mg every 12 weeks as a 30-minute infusion in a hospital setting, in accordance with standard clinical practice. In cases of insufficient response to the 100 mg dose, escalation to 300 mg was not performed due to institutional financial constraints. Concomitant preventive treatments, except for other CGRP mAbs and gepants, were permitted, and acute migraine medications could be used as needed.\u003c/p\u003e\n\u003ch3\u003eAssessment\u003c/h3\u003e\n\u003cp\u003eBaseline assessment was performed at treatment initiation (M0), and follow-up assessments were performed at month 3 (M3), 6 (M6), and 12 (M12). These assessments were conducted during outpatient visits corresponding to the first, second, third, and fifth eptinezumab infusions, respectively. During each outpatient visit, data was collected prior to the infusion, based on a prospectively completed headache diary covering the preceding month and on the standardized FHU InovPain questionnaire including all assessment items.\u003c/p\u003e \u003cp\u003eFollowing each outpatient visit, data were entered into the FHU InovPain registry database. Between visits, scheduled monitoring was performed to ensure data quality and verify the accuracy of the FHU InovPain registry entries.\u003c/p\u003e \u003cp\u003eAt M0, baseline descriptive demographic and clinical data were recorded, including age, sex, migraine subtype (EM/CM), existence of aura, presence of continuous headache pain, concomitant preventive migraine treatments, previous failure of onabotulinumtoxinA, triptan resistance, MO, and body mass index (BMI).\u003c/p\u003e \u003cp\u003eAt M0, M3, M6, and M12, assessment data were collected using the prospective headache diary and the FHU InovPain standardized questionnaire. Adverse events (AEs) were collected at M3, M6, and M12.\u003c/p\u003e \u003cp\u003eThe prospective headache diary was used to record the monthly number of headache days (MHDs), migraine days (MMDs) and days with acute migraine treatment use during the month preceding each outpatient visit. A headache day was defined as any day on which the patient experienced headache, regardless of characteristics or duration. A migraine day was defined according to ICHD-3 criteria as a day with headache fulfilling criteria for migraine without aura, a day with symptoms fulfilling criteria for migraine with aura, or a day considered by the patient to be migraine at onset and relieved by migraine-specific acute medication (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Migraine subtype (EM or CM) and medication overuse were also defined according to ICHD-3 criteria (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor this study, patient-reported outcomes (PROs) included in the FHU InovPain standardized questionnaire were used to assess emotional impact, functional impact, interictal burden, quality of life, and patients\u0026rsquo; overall perceived change.\u003c/p\u003e \u003cp\u003eEmotional impact was assessed using the Hospital Anxiety and Depression Scale (HADS), a 14-item self-report instrument comprising 2 subscales (HADS-A and HADS-D), each ranging from 0 to 21, with higher scores indicating greater symptom burden. HADS-A and HADS-D scores\u0026thinsp;\u0026gt;\u0026thinsp;7 were considered indicative of clinically relevant anxiety and depressive symptoms, respectively (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHeadache-related functional impact was evaluated using the Headache Impact Test-6 (HIT-6), with total scores ranging from 36 to 78, with higher scores indicating greater headache-related impact; scores were classified as little or no impact (36\u0026ndash;49), some impact (50\u0026ndash;55), substantial impact (56\u0026ndash;59), and severe impact (\u0026ge;\u0026thinsp;60) (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInterictal burden was measured using the 4-item Migraine Interictal Burden Scale (MIBS-4), with total scores ranging from 0 to 12, with higher scores indicating greater interictal burden; scores were categorized as none (0), mild (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), substantial (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), and severe (\u0026ge;\u0026thinsp;5) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eQuality of life was evaluated using the EuroQol 5-Dimension questionnaire (EQ-5D), including the EQ-5D index and the EQ-5D visual analogue scale (EQ-5D VAS), with higher values indicating better perceived health status (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatient global impression of change (PGIC) was assessed using a single-item 7-point scale ranging from \u0026ldquo;very much worse\u0026rdquo; to \u0026ldquo;very much improved.\u0026rdquo; Given the known placebo effect in migraine, the two highest categories (\u0026ldquo;much improved\u0026rdquo; and \u0026ldquo;very much improved\u0026rdquo;) were used as the threshold for defining clinical improvement (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary effectiveness endpoint was the 50% responder rate at M3, M6, and M12, defined as the proportion of patients achieving at least a 50% reduction in MMD compared with baseline.\u003c/p\u003e \u003cp\u003eSecondary effectiveness endpoints included the 30% and 75% responder rates at M3, M6, and M12, as well as changes from baseline in MMDs, MHDs, and the monthly number of days with acute migraine treatment use. Additional secondary endpoints included changes from baseline in headache-related impact assessed using HIT-6, emotional burden assessed using HADS-A and HADS-D, interictal burden assessed using MIBS-4 and quality of life assessed using the EQ-5D index and EQ-5D VAS. Further secondary outcomes included the evolution of PGIC and conversion from \u0026lsquo;MO\u0026rsquo; to \u0026lsquo;non-MO\u0026rsquo;.\u003c/p\u003e \u003cp\u003eA prespecified subgroup analysis compared patients with EM and CM at baseline using the same effectiveness endpoints at each time point. Among patients classified as having CM at baseline, conversion to EM during follow-up was also evaluated.\u003c/p\u003e \u003cp\u003eSafety and tolerability outcomes included the occurrence of AEs during follow-up and discontinuations due to treatment-emergent adverse events (TEAEs).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eStatistical analyses were performed using standard statistical software R (version R-4.5.1). Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical variables as number and percentage. Distributional assumptions were assessed using the Shapiro\u0026ndash;Wilk test.\u003c/p\u003e \u003cp\u003eBaseline comparisons between patients with CM and EM were performed using the unpaired Student\u0026rsquo;s t-test for approximately normally distributed continuous variables and the Mann\u0026ndash;Whitney U test otherwise. Comparisons of categorical variables between subgroups were performed using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test, as appropriate.\u003c/p\u003e \u003cp\u003eResponder rates are reported descriptively for the overall population at each follow-up time point. Comparisons of responder rates between CM and EM subgroups at each time point were performed using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test, as appropriate.\u003c/p\u003e \u003cp\u003eChanges from baseline to follow-up in continuous outcomes were assessed using the paired Student\u0026rsquo;s t-test for approximately normally distributed variables and the Wilcoxon signed-rank test otherwise. This applied to MHDs, MMDs, monthly acute treatment days, HIT-6, HADS-A, HADS-D, EQ-5D index, EQ-5D VAS, MIBS-4. For subgroup analyses according to migraine subtype at baseline, within-group changes over time were assessed using the same approach. Changes from baseline to follow-up in dichotomous outcomes as medication overuse and migraine subtype, McNemar tests were performed.\u003c/p\u003e \u003cp\u003eEffectiveness analyses at M3, M6, and M12 were primarily performed using available-case analyses at each time point, including only patients with evaluable data for the corresponding outcome. Because availability of a documented M3 follow-up was part of the inclusion criteria, all included patients were evaluable for the 3-month assessment. In addition, sensitivity analyses using a last observation carried forward (LOCF) approach were performed for responder rates and diary-based outcomes, including MHDs, MMDs, and monthly acute treatment days, to assess the robustness of the results in the presence of treatment discontinuation and missing follow-up data.\u003c/p\u003e \u003cp\u003eAll tests were two-sided, and p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. No adjustment for multiple comparisons was performed; p-values should therefore be interpreted as nominal.\u003c/p\u003e\n\u003ch3\u003eEthics and Regulatory Considerations\u003c/h3\u003e\n\u003cp\u003eThis observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l\u0026rsquo;Informatique et des Libert\u0026eacute;s; CNIL; CIL register no. 278, dated 11/09/2017). Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes\u003c/p\u003e \u003cp\u003eThis study was conducted in accordance with the STROBE guidelines (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDemographics and clinical characteristics at baseline\u003c/h2\u003e \u003cp\u003eThree hundred and two patients were included in the analysis. All 302 patients were evaluable for effectiveness and safety assessment at M3, whereas 246 and 138 patients were evaluable at M6 and M12, respectively. Reasons for non-evaluable status at M6 and M12 are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe cohort comprised 253 women (83.8%) with a mean age of 48.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9 years. At baseline, 184 patients (60.9%) had CM and 118 (39.1%) had EM. Migraine with aura was present in 54 patients (17.9%). Mean baseline MHDs and MMDs were 18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 and 17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6, respectively. Continuous headache pain was reported by 102 patients (33.8%). Mean monthly acute treatment days were 16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1. MO was present in 229/302 patients (75.8%).\u003c/p\u003e \u003cp\u003eBaseline demographic and clinical characteristics of the overall population and according to migraine subtype are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eMean HIT-6 score was 67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4. Mean EQ-5D index and EQ-5D VAS were 0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29 and 56.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7, respectively. Mean MIBS-4 score was 6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0. Mean HADS-A and HADS-D scores were 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 and 7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5, respectively; clinically relevant anxious symptoms were present in 131 patients (43.4%) and clinically relevant depressive symptoms in 93 (30.8%). Mean body mass index was 24.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 kg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;255), with overweight and obesity present in 69/255 (27.1%) and 22/255 (8.6%) patients, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eBaseline demographic and clinical characteristics of the overall population and according to migraine subtype at baseline.\u003c/b\u003e Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%), as appropriate. Percentages were calculated using the number of valid observations for the corresponding variable.\np-values refer to comparisons between patients with chronic migraine (CM) and episodic migraine (EM). BMI, Body Mass Index; CM, chronic migraine; EM, episodic migraine; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; HIT-6, Headache Impact Test-6; EQ-5D, EuroQol 5-Dimension questionnaire; VAS, visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days; MOH, medication overuse headache.\n\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en valid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;302)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;118)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, female, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e253 (83.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e143 (77.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e110 (93.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.940\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMigraine subtype, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCM, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e184 (60.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEM, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e118 (39.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAura, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54 (178.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (19.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.324\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMATD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContinuous headache pain, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e102 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMOH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e229 (75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e161 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple overuse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e118 (39.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82 (44.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple overuse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriptan overuse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e188 (62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125 (67.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63 (53.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioid overuse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriptan resistance, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent preventive treatment, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e166 (55.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e101 (55.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65 (55.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.986\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious onabotulinumtoxinA exposure, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e123 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious onabotulinumtoxinA failure among exposed, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69 (56.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (53.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIT-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.693\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHADS-A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.186\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnxious symptoms, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e131 (43.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (42.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53 (44.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.695\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHADS-D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.368\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e93 (30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (28.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41 (34.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEQ-5D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEQ-5D VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.9\u0026thinsp;\u0026plusmn;\u0026thinsp;19.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMIBS-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverweight, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69 (27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28 (27.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.745\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePercentages were calculated using the number of valid observations for the corresponding variable.\u003c/p\u003e \u003cp\u003ep-values refer to comparisons between patients with chronic migraine (CM) and episodic migraine (EM). BMI, Body Mass Index; CM, chronic migraine; EM, episodic migraine; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; HIT-6, Headache Impact Test-6; EQ-5D, EuroQol 5-Dimension questionnaire; VAS, visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days; MOH, medication overuse headache.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrimary effectiveness endpoint\u003c/h2\u003e \u003cp\u003eThe proportion of 50% responders at M3, M6 and M12 was 35.4% (107/302), 39.1% (96/246) and 45.7% (63/138), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSecondary effectiveness endpoints\u003c/h2\u003e \u003cp\u003eThe proportions of \u0026ge;\u0026thinsp;30% responders at M3, M6 and M12 were 48.7% (147/302), 56.1% (138/246) and 63.0% (87/138), respectively. The proportions of \u0026ge;\u0026thinsp;75% responders at M3, M6 and M12 were 10.9% (33/302), 15.4% (38/246) and 23.2% (32/138), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Changes in continuous effectiveness outcomes over time are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and the longitudinal evolution of diary-based outcomes is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eEvolution of continuous effectiveness outcomes in the overall population.\u003c/b\u003e Data are presented in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Negative change-from-baseline values indicate an increase from baseline. *Wilconson signed rank test vs M0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, ** Wilconson signed rank test vs M0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Change/M0, change from baseline; HIT-6, Headache Impact Test-6; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; EQ-5Di, EuroQol 5-Dimension index utility; EQ-5Dvas: EuroQol 5-Dimension visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM0\u003c/p\u003e \u003cp\u003e(302)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM3\u003c/p\u003e \u003cp\u003e(302)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM6\u003c/p\u003e \u003cp\u003e(246)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM12\u003c/p\u003e \u003cp\u003e(138)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMHDs\u003c/b\u003e \u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1*\u003c/p\u003e \u003cp\u003e\u003cem\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0*\u003c/p\u003e \u003cp\u003e\u003cem\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0*\u003c/p\u003e \u003cp\u003e\u003cem\u003e7.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMMDs\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7*\u003c/p\u003e \u003cp\u003e\u003cem\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6*\u003c/p\u003e \u003cp\u003e\u003cem\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6*\u003c/p\u003e \u003cp\u003e\u003cem\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMATD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1*\u003c/p\u003e \u003cp\u003e\u003cem\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7*\u003c/p\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7*\u003c/p\u003e \u003cp\u003e\u003cem\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIT-6\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4*\u003c/p\u003e \u003cp\u003e\u003cem\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2*\u003c/p\u003e \u003cp\u003e\u003cem\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8*\u003c/p\u003e \u003cp\u003e\u003cem\u003e7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHADS-A\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2*\u003c/p\u003e \u003cp\u003e\u003cem\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHADS-D\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6**\u003c/p\u003e \u003cp\u003e\u003cem\u003e0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6*\u003c/p\u003e \u003cp\u003e\u003cem\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEQ-5D i\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEQ-5D vas\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;17.1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.9\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69.5\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2*\u003c/p\u003e \u003cp\u003e\u003cem\u003e-12.7\u0026thinsp;\u0026plusmn;\u0026thinsp;17.6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMIBS-4\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange/M0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8*\u003c/p\u003e \u003cp\u003e\u003cem\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor MHDs, mean values decreased from 18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 at baseline to 14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1, 12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0, and 10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0 at M3, M6, and M12, respectively. For MMDs, mean values decreased from 17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 at baseline to 12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7, 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6, and 9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 at M3, M6, and M12, respectively. For monthly acute medication days, mean values decreased from 16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 at baseline to 11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1, 10.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7, and 9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 at M3, M6, and M12, respectively. Differences from baseline were significant at all time points for MHDs, MMDs and monthly acute medication days (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eFor HIT-6 score, mean values decreased from 67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4 at baseline to 62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4, 60.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 and 58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 at M3, M6 and M12, respectively. For HADS-A score, mean values decreased from 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 at baseline to 9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2, 8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 and 8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9 at M3, M6 and M12, respectively. For HADS-D score, mean values decreased from 7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 at baseline to 6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6, 6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 and 5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 at M3, M6 and M12, respectively. For MIBS-4 score, mean values decreased from 6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 at baseline to 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0, 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9 and 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 at M3, M6 and M12, respectively. For EQ-5D index, mean values increased from 0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 at baseline to 0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3, 0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 and 0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 at M3, M6 and M12, respectively. For EQ-5D VAS, mean values increased from 56.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 at baseline to 62.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5, 65.9\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0 and 69.5\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2 at M3, M6 and M12, respectively. Differences from baseline were significant at all time points for HIT-6, HADS-A, MIBS-4, EQ-5D index and EQ-5D VAS (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas for HADS-D the differences were significant at M3 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), M6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and M12 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eAccording to PGIC, the proportions of patients reporting themselves as \u0026ldquo;much improved\u0026rdquo; or \u0026ldquo;very much improved\u0026rdquo; were 41.9% at M3, 54.8% at M6 and 74.4% at M12 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe proportion of patients with MO was reduced from 75.8% (229/302) at baseline to 41.9% (124/302), 36.4% (87/246) and 31.6% (43/138) at M3, M6 and M12, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Differences from baseline were significant at all time points (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePrespecified subgroup analysis according to baseline migraine subtype\u003c/h2\u003e \u003cp\u003eBaseline demographic and clinical characteristics according to migraine subtype are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Compared with patients with EM, those with CM were less frequently female (77.7% vs 93.2%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and had a greater headache burden, with higher MHDs (23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1 vs 10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), higher MMDs (21.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2 vs 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and more monthly acute treatment days (19.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0 vs 10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with CM also more frequently reported continuous headache pain, MO, simple and multiple medication overuse, triptan overuse, and triptan resistance, and had lower EQ-5D index values, lower EQ-5D VAS scores, higher MIBS-4 scores, and higher systolic blood pressure. No significant between-group differences were observed for age, aura, HIT-6, HADS-A, HADS-D, current preventive treatment, previous onabotulinumtoxinA failure, overweight, obesity, or opioid overuse.\u003c/p\u003e \u003cp\u003eFor the primary effectiveness endpoint, the proportions of 50% responders at M3, M6 and M12 were 35.9% (66/184), 41.4% (60/145) and 53.8% (43/80) in patients with CM, and 34.7% (41/118), 35.6% (36/101) and 34.5% (20/58) in patients with EM. Between-group differences were not significant at M3 (p\u0026thinsp;=\u0026thinsp;0.842) or M6 (p\u0026thinsp;=\u0026thinsp;0.364) but were significant at M12 (p\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e \u003cp\u003eFor the secondary responder endpoints, the proportions of 30% responders at M3, M6 and M12 were 48.4% (89/184), 53.8% (78/145) and 63.8% (51/80) in patients with CM, and 49.2% (58/118), 59.4% (60/101) and 62.1% (36/58) in patients with EM, with no significant between-group differences at any time point (p\u0026thinsp;=\u0026thinsp;0.894, p\u0026thinsp;=\u0026thinsp;0.383 and p\u0026thinsp;=\u0026thinsp;0.840, respectively). The proportions of 75% responders were 10.3% (19/184), 16.6% (24/145) and 30.0% (24/80) in patients with CM, and 11.9% (14/118), 13.9% (14/101) and 13.8% (8/58) in patients with EM. These did not differ significantly at M3 (p\u0026thinsp;=\u0026thinsp;0.676) or M6 (p\u0026thinsp;=\u0026thinsp;0.566) but were significantly higher in the CM subgroup at M12 (p\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e \u003cp\u003eEvolution of continuous effectiveness outcomes according to baseline migraine subtype are presented in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, and the longitudinal evolution of key diary-based outcomes in each subgroup is shown in Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. In both subgroups, MHDs, MMDs and monthly acute treatment days decreased significantly from baseline at all follow-up time points (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patient-reported outcomes also improved in both subgroups. HADS-A decreased significantly from baseline at all time points in both groups, whereas HADS-D decreased significantly from M6 onward in patients with CM and from M3 onward in patients with EM.\u003c/p\u003e \u003cp\u003eMO decreased in both subgroups over time. In patients with CM, the proportion with MO decreased from 87.5% (161/184) at baseline to 53.6% (96/184), 48.9% (68/145) and 39.2% (31/80) at M3, M6 and M12, respectively. In patients with EM, the corresponding proportions were 57.6% (68/118), 23.9% (28/118), 19.0% (19/101) and 21.1% (12/58). Reductions from baseline were significant at all time points in both subgroups (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cb\u003eConversion from chronic to episodic migraine.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong patients in the effectiveness population classified as having CM at baseline (n\u0026thinsp;=\u0026thinsp;184), phenotypic conversion to EM was assessed at each follow-up visit using observed-case data. At M3, 87/184 patients (47.3%) no longer fulfilled criteria for CM and were classified as EM. Among baseline CM patients with available data at M6 (n\u0026thinsp;=\u0026thinsp;145), 77/145 patients (53.1%) were classified as EM. Among baseline CM patients with available data at M12 (n\u0026thinsp;=\u0026thinsp;80), 55/80 patients (68.8%) were classified as EM.\u003c/p\u003e \u003cp\u003eIn the overall population, the proportion of patients classified as having EM increased from 39.1% at baseline to 65.0% at M3, 67.8% at M6 and 79.7% at M12, whereas the proportion classified as having CM decreased from 60.9% to 35.0%, 32.2% and 20.3%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Differences from baseline were significant at all follow-up time points (McNemar test vs M0: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLOCF analysis\u003c/h2\u003e \u003cp\u003eLOCF sensitivity analysis yielded results broadly consistent with those of the available-case analysis. In the overall population (N\u0026thinsp;=\u0026thinsp;302), the proportions of \u0026ge;\u0026thinsp;50% responders at M3, M6 and M12 were 35.4% (107/302), 36.1% (109/302) and 36.8% (111/302), respectively. The corresponding proportions of \u0026ge;\u0026thinsp;30% responders were 48.7% (147/302), 53.6% (162/302) and 52.3% (158/302), whereas the proportions of \u0026ge;\u0026thinsp;75% responders were 10.9% (33/302), 14.2% (43/302) and 16.6% (50/302), respectively. Mean MHDs decreased from 18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 at baseline to 14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1, 13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 and 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 at M3, M6 and M12, respectively. Mean MMDs decreased from 17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 at baseline to 12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7, 12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9 and 12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1, respectively. Mean monthly acute treatment days decreased from 16.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 at baseline to 11.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2, 11.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 and 11.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 at M3, M6 and M12, respectively. Differences from baseline remained significant at all time points for MHDs, MMDs and monthly acute treatment days (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Detailed results of LOCF subgroup analyses according to migraine subtype at baseline are presented in Supplementary Table S2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSafety and tolerability\u003c/h2\u003e \u003cp\u003eAEs were uncommon and mostly mild, transient, and self-limited. Reported events included allergic and non-allergic AEs.\u003c/p\u003e \u003cp\u003eNon-allergic AEs occurring during eptinezumab infusion and resolving within 24 hours included asthenia (n\u0026thinsp;=\u0026thinsp;3, 1.0%), nausea (n\u0026thinsp;=\u0026thinsp;1, 0.3%), scalp pruritus (n\u0026thinsp;=\u0026thinsp;1, 0.3%), transient \u0026ldquo;brain fog\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;1, 0.3%), and transient symmetric lower-limb paresthesia (n\u0026thinsp;=\u0026thinsp;1, 0.3%). Non-allergic AEs that persisted between infusions included alopecia (n\u0026thinsp;=\u0026thinsp;3, 1.0%).\u003c/p\u003e \u003cp\u003eAllergic AEs occurring during or immediately after eptinezumab infusion included bronchospasm (n\u0026thinsp;=\u0026thinsp;1, 0.3%), pruritic erythematous rash (n\u0026thinsp;=\u0026thinsp;1, 0.3%), urticaria (n\u0026thinsp;=\u0026thinsp;3, 1.0%). One patient (0.3%) developed severe generalized urticaria leading to treatment discontinuation, representing the only TEAE resulting in treatment withdrawal. After 1 year of treatment, 1 patient (0.3%) developed ANCA-associated vasculitis, but with no confirmed causal relationship with eptinezumab.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study is a real-world study to evaluate the effectiveness and safety of eptinezumab 100 mg in difficult-to-treat patients with migraine based on the prospective French InovPain registry.\u003c/p\u003e \u003cp\u003eCompared with previous large prospective real-world studies on eptinezumab conducted in the United Kingdom (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), Greece (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and Italy (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), our study is distinguished by its larger sample size and its 12-month follow-up period. It is also the first prospective real-world study to evaluate eptinezumab exclusively in patients with migraine who were na\u0026iuml;ve to CGRP-targeting therapies. In this population of difficult-to-treat, CGRP-targeting therapy-na\u0026iuml;ve patients treated with eptinezumab 100 mg, our study has shown 50% responder rates (in terms of MMDs) of 35.4%, 39%, and 45.7% at M3, M6, and M12, respectively.\u003c/p\u003e \u003cp\u003eComparison with previous prospective real-world studies on eptinezumab remains challenging because those studies involved smaller sample sizes, among which at least 50% of patients had failed previous CGRP mAbs (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Our findings may therefore be more appropriately compared with those of the DELIVER trial, a RCT that evaluated the efficacy of eptinezumab in a large population of patients who were difficult to treat with non-specific migraine therapies but had not previously failed CGRP-targeting treatments (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In that RCT, the 50% responder rate following initiation of treatment with 100 mg of eptinezumab was 42%, 52%, and 62.6% in weeks 1\u0026ndash;12, 13\u0026ndash;24, and 49\u0026ndash;60, respectively (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Those responder rates were higher than those observed in our study, but it should be noted that our patients likely had more prophylactic treatment resistance than those included in the DELIVER study. In DELIVER, the inclusion criterion regarding patients\u0026rsquo; treatment history specified a prior failure of 2 to 4 treatments and less than 38% of included patients had at least 3 previous preventive treatment failures (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In contrast, all patients included in our study had failed at least three preventive treatments among amitriptyline, beta-blockers, candesartan, topiramate, and botulinum toxin before receiving eptinezumab. The population included in our study was also characterized by more severe migraine than the DELIVER population (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), in terms of MMDs (17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 \u003cem\u003evs\u003c/em\u003e 13.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6), CM/EM ratio (60.9%/39.1% \u003cem\u003evs\u003c/em\u003e 46%/54%), MO (75.8% \u003cem\u003evs\u003c/em\u003e 13%), and HIT-6 scores(67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4 \u003cem\u003evs\u003c/em\u003e 66.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7).\u003c/p\u003e \u003cp\u003eDifferences in assessment methodology may also have contributed to the lower responder rates observed in our study. Unlike DELIVER, which evaluated the average MMDs over the entire three-month period between two eptinezumab infusions, our study assessed only the last month of the three-month period. This approach may have reduced observed treatment response in patients experiencing a wearing-off effect toward the end of the dosing interval. Although wearing off was not specifically assessed in RCTs of eptinezumab, Alssadi et al. reported this phenomenon in 36.1% of patients treated with CGRP mAbs in a real-world cohort (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Similarly, approximately one-quarter of responders in our cohort reported a decline in therapeutic effect that consistently occurred during the last two weeks before reinfusion (data not presented because they are declarative and not supported by any quantitative analysis of prospective headache diary).\u003c/p\u003e \u003cp\u003eAt the three assessment time points, the 30% responder rates (M3: 48.7%, M6: 56.1%, M12: 63%) and the 75% responder rates (M3: 10.9%, M6: 15.4%, M12: 23.2%) increased in the same proportions as the 50% responder rates. The effectiveness of eptinezumab was confirmed by significant changes in the values of all PRO measures at all assessment time points compared with baseline, demonstrating improvements in functional impact (HIT-6), emotional impact (HADS-A and HADS-D), interictal burden (MIBS-4), and consequently quality of life (EQ-5D index and EQ-5D VAS).\u003c/p\u003e \u003cp\u003eThis reduction in the number of migraine days and in the burden of migraine resulted in a clinically relevant Patient Global Impression of Change, with 41.9%, 54.8%, and 74.4% of patients in the overall population reporting that they were \u0026lsquo;much improved\u0026rsquo; or \u0026lsquo;very much improved\u0026rsquo; at M3, M6, and M12, respectively.\u003c/p\u003e \u003cp\u003eGiven its large sample size, our study allowed us to compare the effectiveness of eptinezumab in high-frequency EM (all patients included in our study experienced at least 8 migraine days per month) and CM. Overall, effectiveness appeared similar in both groups except at M12, where 50% and 75% responder rates were significantly higher in patients with CM than in those with high frequency EM (50% response: 53.8% vs 34.5%, p\u0026thinsp;=\u0026thinsp;0.025 and 75% response: 30% vs 13.8%, p\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e \u003cp\u003eSuch improved effectiveness in CM had not been demonstrated in a subgroup analysis of the DELIVER study, which instead showed higher responder rates for patients with high-frequency EM than for those with CM, although no statistical comparison between groups was performed and this subgroup analysis was limited to weeks 1\u0026ndash;12 and weeks 13\u0026ndash;24 (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe effectiveness of eptinezumab in CM was further reflected by significant rates of conversion from CM to EM, as illustrated by the evolution of the CM/EM ratio: 60.9%/39.1% at baseline, 35%/65% at M3, 32.2%/67.8% at M6, and 20.3%/79.7% at M12. Similarly, the proportion of patients with MO decreased from 75.8% at baseline to 31.6% at 12 months.\u003c/p\u003e \u003cp\u003eThe safety and tolerability of eptinezumab were good in our cohort. Allergic AEs were expected, as hypersensitivity reactions were reported in 23 (1.1%) patients among a pooled population of 2,076 patients with migraine treated with eptinezumab across 5 RCTs (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). With 5/302 patients experiencing a hypersensitivity reaction, the proportion of patients who experienced this type of adverse event in our cohort (1.6%) was comparable to that observed in controlled trials. In one patient, severe urticaria led to permanent discontinuation of eptinezumab treatment. In remaining patients, eptinezumab treatment was continued using a desensitization protocol previously developed and published by our group (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe primary strength of this study is its large sample size, making it currently the largest real-world study of eptinezumab in terms of patient number. A second major strength is that the study was conducted in accordance with the International Headache Society guidelines for real-world evidence studies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), with Data Quality that may be considered Level 1 owing to the use of a structured data collection method, validated assessment measures and validated PRO instruments.\u003c/p\u003e \u003cp\u003eThis study also has several limitations. First, its single-center design may call into question the generalizability of the findings to the broader French population. Another weakness is the use of a paper headache diary rather than an electronic diary, as recommended by the International Headache Society (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Similarly, our study may be criticized for assessing MHDs and MMDs only during the last 4 weeks of the three-month period between two eptinezumab infusions. This methodological choice was deliberate, given the low rate of adherence to headache diary completion among migraine sufferers, even those with frequent attacks (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFinally, it is important to note that our study focused solely on the 100 mg dose of eptinezumab. Due to financial constraints, escalation to the 300 mg dose was not possible. Consequently, we have no data to determine what proportion of non-responders to 100 mg would respond to 300 mg, or whether higher dosing could be a way to limit the wearing-off effect observed in some patients.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who had previously failed non-migraine specific treatments and are na\u0026iuml;ve to CGRP mAbs. For the international migraine community, these findings, which are consistent with those obtained with other CGRP mAbs, further support the clinical value of this innovative class of migraine therapies. More specifically for the French migraine community, these results give us hope that the ongoing negotiations will yield favorable outcomes, potentially leading to easier treatment access, particularly for patients with the most severe forms of migraine.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthic approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l’Informatique et des Libertés; CNIL; CIL register no. 278, dated 11/09/2017). \u0026nbsp;Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailable data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe material used for this work are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFRS has no conflict of interest.\u003c/p\u003e\n\u003cp\u003eFR had no conflict of interest.\u003c/p\u003e\n\u003cp\u003eJT had no conflict of interest.\u003c/p\u003e\n\u003cp\u003eLMM received personal fees for consultancy activities from: Abbvie/Allergan, Amgen, Eli Lilly, IPSEN, Lundbeck, Medtronic, Novartis, Orion Pharma, Perfood, Pfizer, Reckitt-Benckiser, Savia, Bioelectronics, Teva, UPSA. .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by FHU InovPain\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFRS and LMM conceived the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJT and MLM collected the data\u003c/p\u003e\n\u003cp\u003eFR performed statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFRS and LMM drafted the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors revised and approved the final manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2021 Nervous System Disorders Collaborators. 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PMID: 17212676\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Migraine, eptinezumab, migraine prevention, real-world evidence, anti-CGRP monoclonal antibody-naive, chronic migraine, episodic migraine","lastPublishedDoi":"10.21203/rs.3.rs-9588176/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9588176/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e. Randomized clinical trials have demonstrated the efficacy and safety of eptinezumab. The aim of this study was to evaluate the effectiveness and safety of eptinezumab in a real-world setting among patients with difficult-to-treat migraine in France.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e. This is a one year-prospective real-word study including all consecutive adult patients from the FHU InovPain registry who received intravenous eptinezumab 100 mg.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e. Three hundred and two patients (83.8% female / mean age of 48.0 ± 13.9 years) were included. Patients had at least 8 monthly migraine days, had failed at least 3 previous prophylactic treatments across amitryptiline, betablockers, botulinum toxin, candesartan, and topiramate and were CGRP monoclonal antibodies naïve. Among them, 184 patients (60.9%) had chronic migraine and 118 (39.1%) had episodic migraine, whereas 229 patients (75.8%) presented a medication overuse. Regarding the primary endpoint, 50% responder rate at M3, M6, and M12 was 35.4% (107/302), 39.0% (96/246), and 45.7% (63/138), respectively. ≥30% responder rate at M3, M6, and M12 was 48.7% (147/302), 56.1% (138/246), and 63.0% (87/138), respectively. ≥75% responder rates at M3, M6, and M12 was 10.9% (33/302), 15.4% (38/246), and 23.2% (32/138), respectively. The effectiveness of eptinezumab was confirmed by significant changes in the values of all PRO measures at all assessment time points compared with baseline, demonstrating improvement in functional impact (HIT-6), emotional impact (HADS-A and HADS-D), interictal burden (MIBS-4), and quality of life (EQ-5D index and EQ-5D VAS). According to PGIC, the proportions of patients reporting being “much improved” or “very much improved” were 41.9% at M3, 54.8% at M6 and 74.4% at M12. Overall, effectiveness appeared similar in episodic migraine and chronic migraine except at M12, where rates of 50% and 75% response were significantly higher in the chronic migraine (50% response: 53.8% vs 34.5%, p = 0.025; 75% response: 30% vs 13.8%, p = 0.026). Adverse events were uncommon and mostly mild, transient, and self-limited with few expected hypersensitivity reactions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e. This French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who and have failed non-specific preventive migraine treatments and are naïve to CGRP monoclonal antibodies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number: \u003c/strong\u003enot applicable.\u003c/p\u003e","manuscriptTitle":"Twelve-months prospective real-world assessment of effectiveness and safety of eptinezumab in migraine patients difficult-to-treat and naïve to CGRP monoclonal antibodies: results of the French FHU INOVPAIN Registry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 17:59:03","doi":"10.21203/rs.3.rs-9588176/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-06T14:45:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291704398482419532685976509164240645957","date":"2026-05-06T11:13:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T13:31:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-05T09:21:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T09:20:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2026-05-01T16:51:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"95dc4738-dd6c-4eea-9252-ccc03d52d819","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-06T14:45:18+00:00","index":15,"fulltext":""},{"type":"reviewerAgreed","content":"291704398482419532685976509164240645957","date":"2026-05-06T11:13:34+00:00","index":14,"fulltext":""},{"type":"reviewersInvited","content":"8","date":"2026-05-05T13:31:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-05T09:21:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T09:20:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2026-05-01T16:51:55+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T17:59:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 17:59:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9588176","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9588176","identity":"rs-9588176","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}