AimThe TACHIS study (from the ancient Greek adjective "tachýs" meaning rapid) aimed to evaluate eptinezumab effectiveness and tolerability in routine clinical practice, integrating patient-reported outcomes and use of International Headache Society (IHS)-endorsed categories of migraine control by treatment.BackgroundEptinezumab is the only intravenous anti-calcitonin gene related peptide (CGRP) monoclonal antibody (mAb) approved for migraine prevention. While its efficacy has been demonstrated in RCTs, real-world evidence in patients with prior preventive treatment failures is still limited.MethodsTACHIS is a prospective, multicenter, observational study conducted in Italy. Adults with episodic or chronic migraine initiating eptinezumab were followed for 24 weeks. Primary outcomes included change from baseline in monthly migraine days (MMDs) and ≥50% responder rate. Secondary outcomes included changes from baseline in acute medication use, Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) and IHS-defined residual burden categories. Logistic regression identified factors of response status.ResultsA total of 128 patients were included (82% female; 82% chronic migraine). MMDs decreased overall by 5.7 days (95% CI: -7.2 to -4.3) at week 12 and 6.9 (95% CI: -8.5 to -5.2) at week 24 (p < 0.001). A ≥ 50% response was achieved in 43.8% and 48.2% of patients at weeks 12 and 24, respectively. Over 40% of patients achieved optimal or modest migraine control. CGRP targeted therapy-naïve patients experienced significant greater benefit, though non-naïve patients also improved. Female sex and chronic migraine diagnosis were independently associated with response at 12 weeks. Adverse events were infrequent (4.7%) and mild, with no discontinuations due to safety concerns.ConclusionsEptinezumab demonstrated effectiveness and tolerability in a real-world population of patients with migraine and prior preventive treatment failures. The integration of migraine control metrics provides a comprehensive evaluation of therapeutic impact and supports eptinezumab use in routine care.Trial RegistrationThe TACHIS study was preregistered on clinicaltrial.gov, NCT06409845.

Background: Chronic migraine (CM) is a highly disabling and difficult-to-manage condition with a high pharmacological and economic burden. OnabotulinumtoxinA (BTx) was the first treatment specifically approved for CM. The main aim of this study was to assess whether the initiation of BTx is associated with discontinuation of previously prescribed preventive therapies. Methods: This study was a prospective cohort investigation conducted in two headache centers: Carlo Besta (Milan) and Policlinico Campus Bio-Medico (Rome). We included patients with CM and previous oral preventive treatments initiating BTx. We analyzed persistence with preventive therapies over 12 months of follow-up and evaluated the conversion rate from chronic to episodic migraine (EM), along with change in migraine days, symptomatic intake, and HIT-6. Results: A total of 95 patients were included in the main analysis, showing a discontinuation of treatment in 28.4% of patients at 12 months. In the exploratory analysis, a CM to EM conversion rate of 58.9% was achieved at 12 months; meanwhile, HIT-6, migraine days, and symptomatic intake showed a sizeable improvement. Conclusion: Treatment with BTx was associated with a reduction in drug burden at 12 months and a CM to EM conversion rate of almost 60% at 12 months, also contributing to a reduction in the economic burden of the disease.

IntroductionEptinezumab is an intravenous anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) approved for the prevention of episodic and chronic migraine. We aimed to explore the earliest changes in migraine pain intensity and associated symptoms during the first 30 min of eptinezumab infusion in a real-world setting, particularly when an acute migraine attack was ongoing.MethodsThe BE-FREE study is an ongoing Italian observational, multicenter, independent, real-world, and prospective study. We enrolled patients affected with episodic migraine (EM) and chronic migraine (CM) who were experiencing an ongoing migraine attack. Eptinezumab was administered within 1–12 h of the onset of the qualifying migraine attack. Data collected included monthly migraine days (MMDs), headache pain intensity, the number of monthly acute medications, and the use of concomitant or past standard preventive treatments (SPTs). The Numerical Rating Scale (NRS), associated symptoms, and pain freedom (PF) were recorded before infusion (T0) and at intervals of 10 (T10), 20 (T20), and 30 (T30) min during infusion.ResultsWe enrolled 31 patients (87% female), with a mean age of 43.1 years (SD 2.7); of these, 68% had CM. NRS scores significantly reduced at T10 (p = 0.011) and T20 (p = 0.004). Photophobia was less frequent at T10 (p = 0.045), phonophobia at T20 (p = 0.014), and osmophobia at T30 (p = 0.046) compared with T0. PF was reported by 6.5% of patients at T10, 19.4% at T20, 29.0% at T30, and 19.4% at T60, T90, and T120.DiscussionThe BE-FREE study results, representing the first real-world evidence, demonstrate the rapid effect of eptinezumab during the first 30 min of infusion in patients experiencing an ongoing migraine attack.

ABSTRACT Background The Leeds Dependence Questionnaire (LDQ) is a validated tool for assessing psychological dependence across various substances and has been adapted for use in headache patients. No study has yet explored the effects of preventive anti‐CGRP treatments like atogepant on psychological dependence related to acute migraine medications. Methods We conducted a prospective, real‐world, single‐center study on patients with migraine who were treated with atogepant 60 mg daily for 12 weeks. LDQ scores were assessed at baseline and after 12 weeks. Monthly headache days (MHDs), acute medication use, and presence of psychiatric comorbidities were collected. A linear mixed‐effects model evaluated the effect of treatment over time, adjusting for medication overuse (MO) status and psychiatric comorbidities. Results We included 43 patients (69.8% with chronic migraine, 67.4% with MO). The LDQ total score significantly decreased from 7.95 ± 5.79 to 6.42 ± 5.08 after treatment (mean difference: –1.53, p = 0.032). Significant improvements were seen in three specific LDQ items reflecting loss of control, compulsive use, and psychological distress. No significant correlation was found between the reduction in LDQ score and the change in acute medication use. Mixed‐effects modeling confirmed a significant effect of treatment (p = 0.022), but independent of MO or MOH status or psychiatric comorbidities. Conclusion Preventive treatment with atogepant is associated with a significant reduction in psychological dependence on acute migraine medications, as measured by the LDQ. These findings support the need to assess dependence‐like behavior in clinical migraine care and highlight the potential behavioral benefits of effective preventive treatments.

Background:Pulsatility Index (PI) has been linked to cognitive impairment in patients with lacunar infarcts, but its role in other stroke subtypes remains unclear. We investigated whether PI predicts cognitive outcomes in acute stroke/TIA patients across etiologies. Methods:Patients with TIA or mild ischemic stroke were followed for 12 months, with assessments at T1 (baseline; 48-72 hours from onset), T2 (1 month), T3 (6 months), and T4 (12 months). Cognitive tests were performed at all visits, whereas Middle Cerebral Artery (MCA) and Posterior Cerebral Artery (PCA) PI in the unaffected and affected hemispheres, respectively, was measured at T1 and T3. Results:A total of 124 patients (71% men; median age 66) were enrolled; 69.4% had stroke. MCA/PCA PI remained stable from T1-T3 (p=0.630; p=0.086). MoCA increased significantly from T1-T4 (p<0.001), while MMSE showed a trend (p=0.055). MoCA improvement (T1-T4) was independently associated with MCA PI≤1.1 (p=0.014), MoCA at T1 (p<0.001), and NIHSS at T1 (p=0.037). MMSE change (T1-T4) was associated with MMSE at T1 (p<0.001) and NIHSS at T1 (p=0.042), with a trend for MCA PI≤1.1 at T1 (p=0.073). From T3-T4, MMSE improvement was associated with MCA PI≤1.1 (p=0.004) and MMSE at T3 (p<0.001); MoCA improvement was associated only with MoCA at T3 (p<0.001), with a trend for MCA PI≤1.1 at T3 (p=0.082). Age and diabetes were the main determinants of MCA PI at T1 (p<0.0001), while PCA PI was influenced only by age (p<0.0001). Conclusion:PI is a prognostic marker of cognitive outcome in patients with TIA and mild ischemic stroke.

As awareness of migraine disability is becoming higher, the recognition of the pivotal role of caregivers of people with migraine and their burden is still scarce. We aimed to investigate the factors associated with the distress of informal caregivers of patients affected by high-frequency or chronic migraine with depressive symptoms. All consecutive adult patients with high-frequency or chronic migraine and depressive symptoms were considered, along with their caregivers. Sociodemographic characteristics and the average weekly hours spent together were assessed among patients and their caregivers (dyads). In patients, we evaluated monthly migraine days (MMDs), monthly acute medications (MAMs), pain intensity, migraine-related disability, the composite 4D score on migraine burden, and depressive symptoms (Patient Health Questionnaire-9-PHQ-9). Caregivers filled in the Relative Stress Scale (RSS). The mutuality scale (MS) was also collected in the dyads. 154 dyads (308 participants) were enrolled (patients aged 42.6 years, SD 12.7; 80.5

Abstract Background Iron overload promotes atherosclerosis in mice and causes vascular dysfunction in humans with Hemochromatosis. However, data are controversial on whether systemic iron availability within physiological limits affects the pathogenesis of atherosclerosis. We, therefore, performed an individual participant data (IPD) meta-analysis and studied the association between serum iron biomarkers with common carotid intima-media thickness (CC-IMT); in addition, since sex influences iron metabolism and vascular diseases, we studied if there are sex-specific differences. Methods We pooled the IPD and analysed the data on adults (age≥18y) by orthogonal approaches: machine learning (ML) and a single-stage meta-analysis. For ML, we tuned a gradient-boosted tree regression model (XGBoost) and subsequently, we interpreted the features using variable importance. For the single-stage metaanalysis, we examined the association between iron biomarkers and CC-IMT using spline-based linear mixed models, accounting for sex interactions and study-specific effects. To confirm robustness, we repeated analyses on imputed data using multivariable regression adjusted for key covariates identified through machine learning. Further, subgroup analyses were performed in children and adolescents (age<18y). In addition, to evaluate causality, we used UK Biobank data to examine associations between the hemochromatosis (HFE) genotypes (C282Y/H63D) and mean CC-IMT in ~ 42,500 participants with carotid ultrasound data, using sex-stratified linear regression (adjusted for age, assessment centre, and genetic principal components). Results We included IPD from 21 studies (N = 10,807). The application of the ML model showed moderate predictive performance and identified iron biomarkers (transferrin, ferritin, transferrin saturation, and iron) as key features for IMT prediction. Multivariable analyses showed non-linear sex-specific relationships for ferritin and transferrin with CC-IMT, both only among females at specific ranges. Ferritin showed a significant positive association [Ferritin > 233 ng/mL: β = 0.04, 95% CI (0.002, 0.08), p = 0.037], while transferrin showed negative associations at specific ranges [ Transferrrin 231–263 mg/dL: β=-0.21, 95% CI (-0.43, 0.003), p = 0.054; Transferrrin > 263 mg/dL: β=-0.73, 95% CI (-1.48, 0.01), p = 0.05]; No significant associations were found between CC-IMT in those with HFE genotypes in either sex in the UK Biobank. Conclusion Our observational data show that iron biomarkers - ferritin and transferrin are non-linearly associated with CC-IMT specifically in females, while a significant causal association between the HFE genotype and CC-IMT could not be demonstrated in the UK Biobank data. We conclude that our observational findings may reflect residual confounding, reverse causation, or other non-causal mechanisms rather than a direct causal relationship. Other No financial support was received for this meta-analysis. The protocol for this study is registered in the PROSPERO database ( CRD42020155429; https://www.crd.york.ac.uk/ ).

BACKGROUND:Migraine's economic burden is mostly due to reduced work productivity, which is underestimated by commonly used patient-reported outcome measures (PROMs). In this prospective, multicentric, real-world study, we used the HEADWORK questionnaire (HWq), a disease-specific work-related PROM, to assess the impact of anti-calcitonin gene receptor peptide (anti-CGRP) monoclonal antibodies (mAbs) on work-related limitations. METHODS:Migraine patients eligible for treatment with anti-CGRP mAbs were enrolled from three headache centers: IRCCS C.Besta, Mondino Foundation and Policlinico Campus Bio-Medico. Migraine days per month (MMDs), monthly acute medications (MAMs), and HWq were collected every 3 months up to 12 months of follow-up. A GLM design was used to address change in HWq scales' score (primary endpoint), MAMs and MMDs; we also tested whether change in HWq differed across responders' group and defined minimum clinically important difference (MCID) for HWq. RESULTS:Out of 175 patients (130 females, mean age 48.9 ± 8.8) 152 completed the study. Among them: 37 (24.3%) were non-responders, 69 (45.4%) were responders, and 46 (30.3%) were super-responders. A reduction in all endpoints was observed since the first 3 months of treatment and maintained up to 12-month follow-up. Time*group interaction showed a superior effect, both in HWq scales and MAMs, with super-responders achieving the best outcome. CONCLUSIONS:A significant reduction in MMDs and MAMs and an improvement in both HWq scales in patients under mAbs treatment was found from the 3-month follow-up onwards. The positive impact on work-related disability should be taken into consideration in planning cost-effectiveness evaluations and drug policy strategy.

Migraine and sleep share a bidirectional relationship: sleep disruption can trigger migraine attacks, while migraine impairs sleep continuity and quality. Calcitonin gene-related peptide (CGRP), central to migraine pathophysiology, also contributes to sleep regulation through hypothalamic and brainstem circuits that control arousal and circadian rhythms. This overlap raises the question of whether pharmacological inhibition of CGRP with monoclonal antibodies (mAbs) or gepants could affect sleep. This scoping review summarizes evidence on anti-CGRP therapies and their impact on sleep quality, efficacy, and tolerability. Although results are inconsistent across instruments, emerging data suggest that anti-CGRP mAbs and gepants, particularly erenumab, galcanezumab, and atogepant, can improve subjective sleep quality and objective measures such as sleep efficiency in some cases. Evidence for fremanezumab and eptinezumab remains scarce, whereas large-scale pharmacovigilance datasets indicate low rates of insomnia, somnolence, or abnormal dreams. Overall, current findings suggest that CGRP inhibition impacts the sleep system, but the mechanisms of this interaction remain partly understood, representing a promising area for mechanistic exploration and clinical application. Future studies with standardized sleep endpoints are needed to distinguish direct neuropharmacological effects from indirect benefits mediated by improvement in migraine burden.

AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc analysis of the STAR study, a prospective, Italian, multicenter study evaluating atogepant 60 mg for migraine prevention. Data were collected at baseline (T0) and after the first 12 weeks (T3) of treatment. Patients were grouped by administration timing (morning vs. evening) and by administration with or without food. Changes in monthly headache days (MHDs), monthly migraine days (MMDs), and Migraine Disability Assessment (MIDAS) were measured. Tolerability was evaluated via adverse events (AEs). Linear mixed-effects models (LMMs) were used.ResultsEighty-one patients (86% females, mean age 50.8 ± 13.7 years) were included. At T3, MMDs decreased from 16.6 to 9.7 (p < 0.001) and MHDs from 19.8 to 11.9 (p < 0.001); 60% of patients achieved ≥50% reduction in MMDs. AEs occurred in 34 (42%) participants. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. Fifty-seven out of 81 participants (70.4%) took atogepant with food. No significant differences in MMDs, MHDs, or AEs emerged between morning and evening users. Evening users had higher baseline MIDAS scores (estimated marginal means [EMMs]: 69.9 vs. 39.9, p = 0.034) that showed a greater reduction compared to morning users (F(1,63) = 6.29, p = 0.015), reaching similar final scores after 12 weeks (EMMs: 25.1 vs. 23.8). No difference in atogepant effectiveness and tolerability according to intake with or without food, except for a reduction in MHDs for patients who took atogepant without food (EMMs from 21.3 to 9.9 vs with food: EMMs from 18.4 to 12.7; F(1,79) = 8.553, p = 0.005).ConclusionsAtogepant significantly reduced migraine burden over 12 weeks in a real-world setting. Overall, the timing of atogepant administration did not affect its effectiveness or tolerability. However, a greater reduction in MIDAS scores was observed among evening users. Whether this reflects a pharmacological advantage or a ceiling effect remains unclear. Taking atogepant without food was associated with a significantly greater reduction in MHDs, whereas changes in MMDs and MIDAS scores did not differ between groups. Long-term and dedicated studies are needed to evaluate and confirm these findings.Trial RegistrationThe main study (STAR) was preregistered on clinicaltrial.gov, NCT06414044.

BackgroundThe improved prevention of migraine, driven by the introduction of calcitonin gene-related peptide (CGRP)-targeted therapies, has prompted the International Headache Society (IHS) to propose new goals in migraine management. This study aimed to evaluate the safety and effectiveness of atogepant for migraine prevention over 24 weeks, in accordance with the IHS-defined goals.MethodsThis is a multicenter, prospective, observational, real-world study on patients starting atogepant 60 mg for migraine prevention. We describe efficacy and safety outcomes at weeks 9-12 (T3) and 21-24 (T6) relative to baseline (T0) from the initiation of atogepant treatment. We also report the proportion of patients achieving migraine freedom, optimal, modest or insufficient control according to the IHS position paper categories.ResultsOne hundred twenty-eight (n = 128) patients (63 (49.2%) with chronic migraine, 115 (89.9%) female, aged 48.3 ± 13.3 years) from 17 centers were analyzed. Monthly migraine days decreased from 16.5 ± 8.5 at T0 to 8.0 ± 8.4 at T3 (p < 0.001 vs. T0) and 8.6 ± 9.2 at T6 (p < 0001 vs. T0, p = 0.265 compared to T3). Overall, 64.8% of patients were responders (at least 50% reduction in monthly migraine days from T0) at T3 and 61.7% at T6; 81.9% of responders at T3 maintained the responder status at T6, while 24.4% of patients among non-responders at T3 became responders at T6. At T3 and T6, 39.1% of the entire cohort achieved at least optimal migraine control (20.6% in chronic migraine and 56.9% in episodic migraine).ConclusionsThe STAR study demonstrates, in a real-world setting, the safety and the sustained effectiveness of atogepant 60 mg over 24 weeks and indicates that more than one-third of treated patients can achieve at least optimal disease control, with markedly better outcomes in episodic than in chronic migraine.Trial RegistrationThe study was preregistered on clinicaltrial.gov, NCT06414044.

Real-world studies have explored potential predictors of response to anti-calcitonin gene related peptide (CGRP) monoclonal antibodies (mAbs), though results have remained inconsistent. Machine learning (ML) algorithms are becoming increasingly relevant in migraine research, offering a data-driven approach to identifying predictors of response to preventive treatments. To maximize their potential, a clinically applicable and user-oriented framework is needed to promote the use of these algorithms in research and, eventually, as supportive tools in clinical practice. This prospective cohort study included adults with migraine treated with anti-CGRP mAbs (anti-ligand and receptor) at two headache centers. Responders were defined as patients achieving ≥ 50

Migraine is often associated with impaired sleep quality, including insomnia, fragmented sleep, and circadian rhythm disturbances. These factors can exacerbate migraine severity and chronification. Calcitonin gene-related peptide (CGRP), a key player in migraine pathophysiology, also influences sleep regulation. While CGRP monoclonal antibodies have shown mixed effects on sleep, no study to date has evaluated the impact of gepants on sleep quality. This study assessed whether atogepant, recently approved for migraine prevention, affects sleep quality and sleep-related adverse events in real-world settings. We conducted a prospective, observational, open-label, single-center study. All received atogepant 60 mg/day up to 12 weeks. Adults (≥ 18 years) with migraine (with/without aura or chronic migraine) experiencing ≥ 4 monthly migraine days were enrolled. Inclusion required ≥ 1 month of headache diaries and stable preventive or sleep treatments for ≥ 3 months. Patients were accepted regardless of prior preventive failures. Exclusion criteria were unstable treatments, recent sleep-impacting disease, and pregnancy. Sleep quality was assessed using five validated questionnaires (Pittsburgh Sleep Quality Index [PSQI], Athens Insomnia Scale [AIS], Bergen, Epworth Sleepiness Scale [ESS], Insomnia Severity Index [ISI]) at baseline and at follow-up. Migraine frequency, disability (Migraine Disability Assessment [MIDAS], Headache Impact Test [HIT-6]), allodynia (Allodynia Symptom Checklist [ASC-12]), acute medication use, and adverse events (AEs) were also recorded. Pre–post differences were assessed with Wilcoxon and McNemar’s tests, while linear mixed-effects models were applied to evaluate the impact of clinical factors (response status, psychiatric comorbidities, prior anti-CGRP failures) on PSQI outcomes, with model fit estimated via REML and pseudo-R2. The study population included 43 participants (93.0

PURPOSE:To understand the role of enlarged Perivascular Spaces (PVSs) in a population with young middle age stroke and to identify predictors of PVSs enlargment using clinical and imaging data. MATERIALS/METHODS:Retrospective revision of demographics, clinical and MRI data, of 163 patients, with MRI confirmed stroke. Ischemic area and WMH were semi-automatically segmented on DWI images and FLAIR images. Severity of PVS was evaluated on T2-weighted images according to the Potter scale. To identify potential predictors of the extent of PVSs, an exploratory backward stepwise ordinal regression model was developed, including all measured variables. RESULTS:With the extent of PVSs at Basal Ganglia as the dependent variable, the logarithm of WMH demonstrated a significant positive association with the outcome. ESUS exhibited a positive relationship, underscoring its potential role as a predictor of the outcome. In PVSs in Mid Brain, dyslipidemia displayed a significant negative effect, signifying a reduced likelihood of the outcome in its presence. Hypertension emerged as a statistically significant and notably positive predictor of PVSs. CONCLUSION:Significant associations between PVSs, WMH volume, and vascular features suggest their potential as vascular health indicators. These findings underscore the potentiality of PVSs as a biomarker for further investigation in stroke research. However, given the cross-sectional nature of our data, the relationship between PVS alterations and stroke requires further longitudinal studies to clarify their role and temporal association and eventually refining diagnostic and therapeutic approaches and mitigating stroke risks for younger stroke populations.

BackgroundFocusing on calcitonin gene-related peptide (CGRP) as a specific target has changed and improved migraine management. After the positive results of monoclonal antibodies directed to the CGRP pathway (anti-CGRP mAbs), randomized controlled trials also demonstrated the efficacy of gepants in migraine prevention. The present study aimed to assess the effectiveness of atogepant in preventing migraine after a 12-week treatment in clinical practice.MethodsAdult patients with a clinical indication for atogepant 60 mg daily were screened for participation in this multicentric prospective observational cohort study. At baseline (T0) and after 12 weeks (T3) since the first atogepant administration, monthly migraine days (MMDs), monthly headache days (MHDs) and monthly acute medications (MAMs) were assessed. The co-primary endpoints were the changes in MMDs from T0 to T3 and the percentage of T3 Responders (those with a reduction of MMDs ≥50%, i.e. 50% response rate (RR)). At T0 and T3, we also collected the Headache Impact Test (HIT-6), the Migraine Disability Assessment (MIDAS) questionnaire, the Migraine Treatment Optimization Questionnaire-6 (mTOQ-6), the Migraine-Specific Quality-of-Life Questionnaire (MSQ), the 12-item Allodynia Symptom Checklist (ASC-12) and the Migraine Interictal Burden Scale (MIBS-4).ResultsOne hundred and six patients (56/106 (52.8%) with chronic migraine (CM), 93/106 (87.7%) female, aged 50.6 ± 13.2 years) from 10 Italian centers completed the 12-week observation since the first atogepant tablet intake. From baseline to T3, a reduction of 6.9 MMDs (SD 9.7; p < 0.001) was achieved in the whole group and, specifically, of -4.9 (SD 6.6; p < 0.001) in episodic migraine (EM) and of -8.6 (SD 11.7; p < 0.001) in CM patients. Overall, 60/106 (56.6%) of patients were Responders (60.0% in the EM and 46.4% in the CM group). Non-Responders previously experienced more ineffective treatments than Responders with anti-CGRP mAbs (65.2% vs. 43.3%, respectively, p = 0.031) and with onabotulinumtoxinA (56.5% vs. 28.3%, p = 0.005), and presented more medication overuse at baseline (55.7% vs. 44.3%, p = 0.003). However, no baseline characteristics were significantly associated with the Responder status in the multiple regression analysis. For T0 to T3, MAMs, MIDAS, ASC-12 and mTOQ-6 reduced (p ≤ 0.001 consistently), and MSQ role-function restriction increased (p = 0.026), whereas HIT-6 and MIBS-4 did not change. Only seven subjects (7/106, 6.6%) dropped out of atogepant treatment: four for lack of effectiveness and three for adverse events or poor tolerability.ConclusionsThe STAR study demonstrates the effectiveness and tolerability of atogepant 60 mg at 12 weeks in a real-world setting. Previous ineffective anti-CGRP mAbs were not a relevant prognostic factor.Trial RegistrationThe study was preregistered on clinicaltrial.gov, NCT06414044.

INTRODUCTION Different measures are currently used to evaluate migraine frequency and disability, but a single measure may only partially represent the burden of migraine. A composite measure that includes the most relevant parameters, obtained through a statistically weighted approach, would better assess migraine severity and treatment efficacy. OBJECTIVES This study aimed to develop a composite "four dimensions (4D) migraine scale" by selecting four commonly used endpoints: monthly migraine days (MMDs), number of monthly acute medications (MAMs), attack pain intensity (Numerical Rating Score, NRS), and Migraine Disability Assessment (MIDAS) Score. METHODS For each parameter, specific levels were chosen to cover the entire empirical range of each scale. To estimate utilities and develop the 4D migraine scale, a series of pairwise choice tasks were generated using Lighthouse Studio, a Conjoint Analysis platform. In these tasks, respondents (patients and clinicians) were presented with two hypothetical migraine patient profiles, described by scale parameters, and asked to identify the patient in better health. The design of the Discrete Choice Experiment (DCE) aimed for orthogonality and balance, meaning attribute levels should vary independently and occur equally often. However, a perfectly orthogonal and balanced design was not feasible due to the generation of unrealistic combinations, such as a patient with one monthly migraine day (MMD=1) taking more than 14 symptomatic medications or having a MIDAS score ≥ 16 points. To address this, expert clinicians identified and prohibited certain implausible combinations. Although prohibitions hinder a perfectly orthogonal and balanced design, statistical procedures were applied to adjust for these discrepancies. The sample size was determined using Orme’s formula, n≥500∗b/(a∗c). With two alternatives (a=2), the largest attribute having seven levels (MAMs, b=7), and 12 choice tasks (c=12), a minimum sample size of 146 was calculated. Furthermore, simulations using Lighthouse Studio software estimated that the standard errors of the effects for each level, with 300 respondents, were consistently below the recommended threshold of 0.05. For statistical analysis, discrete choices from patients and clinicians were used to estimate the utilities attributed to each attribute level. This estimation was performed using the Hierarchical Bayes algorithm within Lighthouse Studio. Positive utility values were indicated by values above a reference line of 0, while negative utility (disutility) was indicated by values less than 0. These utility measures were then regressed against the levels of each scale to identify polynomial models that best interpolated the relationship between scores and utility. A log-transformation was applied to MIDAS utilities to account for its lognormal distribution and mitigate outlier bias. Polynomial models were applied within a General Estimating Equations framework, treating each respondent as a "cluster" with an "unstructured" working correlation matrix. Finally, an overall composite score, weighted by utility, was computed and standardized to a 0-100 scale, representing a range from a patient without migraine to a patient with the most severe migraine condition. RESULTS The relative weight of each level per parameter was rated by 197 migraine patients and 118 headache experts using Conjoint Analysis. A substantial agreement was found between clinicians and patients regarding the relative importance (RI) of each parameter. MMDs was identified as the most important attribute for both categories (RI: 34% for clinicians, 32% for patients), while PAIN-NRS was the least important (RI: 14% for clinicians, 13% for patients). MIDAS was marginally more important than MAMs for patients (29% vs. 26%), while for clinicians, their relevance was almost equal (26% and 27%). The strong agreement between clinicians and patients was also confirmed in terms of the utility assigned to each level. Polynomial models were developed to estimate the utilities for each scale: Utility_MMD = 68.48 - 11.52 * MMD + 0.582 * MMD2 - 0.011 * MMD3 Utility_MAMs = 43.57 - 1.96 * MAMs Utility_MIDAS = 51.43 - 4.836 * (loge(MIDAS + 1)) Utility_NRS = 28.85 - 11.33 * NRS + 1.916 * NRS2 - 0.144 * NRS3 A composite raw 4D score was calculated as: 4D score raw = -(Utility_MMD + Utility_MAMs + Utility_MIDAS + Utility_NRS) / 4 and finally a more intuitive and clinically relevant score ranging from 0 to 100 (0 = no migraine, 100 = most severe migraine) was derived using: 4D score = 100 * (4D score raw + 48.1) / 110.7 The 4D score was applied to a sample of 205 migraine patients treated with galcanezumab. It demonstrated sensitivity to changes, effectively summarizing the treatment's effect with a larger effect size compared to single parameters (eta-squared = 0.685). The 4D score also showed concurrent validity with the Head Impact Test HIT-6, an external patient-reported outcome measure. CONCLUSION This composite score, based on the preference weights of both clinicians and patients, can serve as a valuable Patient-Reported Outcome to comprehensively quantify migraine burden and treatment efficacy. The study highlights the importance of a multi-dimensional approach to migraine assessment, as single measures often fail to capture the full complexity of the condition and treatment response. The 4D score was applied to a sample of 205 migraine patients treated with galcanezumab. It demonstrated sensitivity to changes, effectively summarizing the treatment's effect with a larger effect size compared to single parameters (eta-squared = 0.685). The 4D score also showed concurrent validity with the Head Impact Test HIT-6, an external patient-reported outcome measure. CONCLUSION This composite score, based on the preference weights of both clinicians and patients, can serve as a valuable Patient-Reported Outcome to comprehensively quantify migraine burden and treatment efficacy. The study highlights the importance of a multi-dimensional approach to migraine assessment, as single measures often fail to capture the full complexity of the condition and treatment response.

BackgroundThe management and role of standard preventive treatments (SPTs) in patients co-treated with monoclonal antibodies (mAbs) directed towards calcitonin gene-related peptide (CGRP) has been poorly investigated. The present study aimed to prospectively compare the clinical profile of patients co-treated with SPTs and anti-CGRP mAbs with patients with anti-CGRP mAb monotherapy and to assess the possible SPT influence on their outcome. The SPT withdrawal or a new SPT prescription during the 12-month treatment period with anti-CGRP mAbs and their possible relation with comorbidities were also evaluated.MethodsOur Italian multicentric, prospective observational cohort study enrolled patients with migraine receiving the first prescription of subcutaneous anti-CGRP mAbs. Only patients who completed the annual cycle of therapy were included in the analyses. At baseline, the population was divided into two groups: with (SPT+ patients) or without concomitant SPTs (SPT- patients). At baseline (T0), T6 (after six months of therapy) and T12 (at the end of the one-year treatment period), we collected migraine clinical data (monthly migraine days (MMDs) and/or the pain intensity, by a numerical rating scale (NRS)); disability (Migraine Disability Assessment (MIDAS) score); and the type and the presence of SPTs at baseline, the beginning of a new SPT or its withdrawal. The primary endpoint was to compare the clinical outcome (variation of MMDs at T6) of baseline SPT+ patients with that of baseline SPT- patients. Secondary endpoints were: (i) to describe the percentage of concomitant SPTs from T0 to T12 in the SPT+ group; (ii) to investigate the factors (i.e. comorbidities, demographics, migraine burden), if any, influencing the persistence of concomitant SPTs from T0 to T12; (iii) to evaluate whether baseline SPT presence influences pain intensity (NRS) and disability (MIDAS) at T0, T6 and T12.ResultsWe enrolled 599 patients who started a new treatment with anti-CGRP mAbs. The analysis was conducted on 555 patients who started galcanezumab (260; 46.8%), erenumab 140 mg (167; 30.0%) or fremanezumab (128; 23.1%). Patients with baseline concomitant SPTs presented lower T0 MMDs than SPT+ patients (18.6 ± 7.8 vs. 20.3 ± 7.2; p = 0.007) and a lower MMD reduction from T0 to T6 (-10.4 ± 7.2 vs -12.4 ± 7.4, p = 0.007), reaching similar MMD numbers at T6 (p = 0.984). Baseline SPTs were not associated with MMD 50% response rate at T6 (odds ratio = 0.779, 95% confidence interval = 0.534-1.138; p = 0.205). Moreover, the changes in MIDAS score (p = 0.919) and NRS (p = 0.664) from T0 to T6 and T6 to T12 did not differ according to baseline concomitant SPTs. During the 12-month treatment period, anti-CGRP mAbs SPT+ patients progressively decreased from 35.0% at baseline to 28.8% at T6 and to 19.6% at T12. A comorbid condition, although neither MMD 50% response rate nor T12 MMDs, influenced the use of concomitant SPTs at T12 (odds ratio = 3.132, 95% confidence interval = 1.981-4.954; p < 0.001). The introduction of a new SPT during 12-month mAb therapy occurred only in seven subjects. Overall, 13% of patients reported at least one adverse event.ConclusionsOur study confirms that concomitant SPTs at baseline do not influence the clinical outcome of CGRP mAbs after six months of treatment. A progressive withdrawal of SPTs during 12-month anti-CGRP therapy was observed, dissimilar among preventive classes, with persistence of SPTs at T12, mainly in patients with comorbid conditions.

BackgroundDifferent parameters are currently used to evaluate migraine frequency and disability. We aimed to formulate a composite scale including the most relevant clinical measures to better evaluate the burden of migraine.MethodsTo create the composite four dimensions 4D migraine scale, we selected the most commonly used outcome measures: monthly migraine days (MMDs), number of monthly acute medications (MAMs), pain intensity (by Numerical Rating Score, NRS) and Migraine Disability Assessment (MIDAS) Score. Each parameter was categorized in different levels: five for MMDs, seven for MAMs, five for NRS and six for MIDAS to cover the entire empirical range of each variable. First, the relative weight of each level per parameter was rated by 197 migraine patients and 118 headache experts using Conjoint Analysis. Secondly, we applied the 4D migraine score to a sample of patients treated with galcanezumab. We assessed its concurrent validity for the scale's single parameters and the Head Impact Test HIT-6, an external patient-reported outcome measure.ResultsThere was a substantial agreement between clinicians and patients about the weight of each parameter in terms of Relative Importance (RI). For both categories, MMDs were the most relevant attribute (RI: 34% for clinicians, 32% for patients) and pain intensity NRS the least important (RI: 14% vs 13%). Though marginally, MIDAS was more important than MAMs for patients (29% vs. 26%), while for clinicians the relevance of these two attributes was almost equal (26% and 27%). In terms of the utility assigned to each level, strong agreement was confirmed between clinicians and patients. According to the utilities implicitly attributed by participants to the chosen representative levels of the four parameters, four different statistical models were derived, allowing to compute utilities from all possible values of MMDs, MAMs, NRS and MIDAS and finally a unique 4D migraine score for every possible patient, ranging from 0 (without migraine) to 100 (with the most severe migraine). The 4D score was valid in terms of sensitivity to changes and showed concurrent validity with respect to HIT-6.ConclusionThe 4D migraine scale, based on the preference weights of both clinicians and patients, could be useful to fully quantify the migraine burden and the efficacy of a treatment.