Ashina, Messoud

Background Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. Methods In this 52-week, multicenter, randomized, open-label trial, adults with 4–14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. Results Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16–31.87) at week 12 and 34.70 (95% confidence interval = 32.74–36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. Conclusion Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact. Trial Registration: NCT03700320

Abstract Objective Assess the long‐term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. Background Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. Methods This 52‐week open‐label extension study followed a 12‐week double‐blind placebo‐controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once‐monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. Results Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was −9.3 (95% confidence interval: −10.4, −8.1 days) in the medication overuse subgroup versus −9.3 (−10.1, −8.5 days) in the non‐medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine‐specific medication, the mean change in monthly migraine‐specific medication days at Week 52 was −7.4 (−8.3, −6.4 days) in the medication overuse subgroup versus −5.4 (−6.1, −4.7 days) in the non–medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non‐overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. Conclusion Long‐term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., “common data elements”), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache.

Abstract Objective To assess the utility of the novel patient‐identified (PI) most bothersome symptom (MBS) measure from PROMISE‐2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. Background Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI‐MBS could improve clinical decision‐making. Methods In PROMISE‐2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses ( n = 1072). PI‐MBS was an exploratory outcome requiring each patient to self‐report their MBS in response to an open‐ended question. At baseline and week 12, patients rated overall improvement in PI‐MBS. The relationships among PI‐MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6‐item Headache Impact Test total, EuroQol 5‐dimensions 5‐levels visual analog scale, and 36‐item Short‐Form Health Survey component scores were assessed. Results Treatment groups had similar baseline characteristics and reported a total of 23 unique PI‐MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI‐MBS at week 12 correlated with changes in MMDs ( ρ = −0.49; p < 0.0001) and other patient‐reported outcomes. Controlling for changes in MMDs, PI‐MBS improvement predicted other patient‐reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI‐MBS were 0.31 ( p < 0.0001 vs. placebo) and 0.54 ( p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. Conclusions Improvement in PI‐MBS at week 12 was associated with improvement in other patient‐reported outcome measures, and PI‐MBS may be an important patient‐centered measure of treatment benefits in patients with chronic migraine.

Abstract Objective To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background Current guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

Abstract Background Erenumab is a human anti‐calcitonin gene‐related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. Methods This is a post hoc analysis of a 12‐week, randomized, double‐blind, placebo‐controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). Results Among the erenumab 140 mg group ( n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group ( n = 188). Conclusion A majority of erenumab‐treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

Background Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine. Methods An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine. Results Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created. Conclusions Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.

AbstractBackground and purposeAlthough erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long‐term therapy.MethodsThis study was an open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially received open‐label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine‐specific medication (AMSM) days, and health‐related quality of life.ResultsOf 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open‐label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was −5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was −4.4 (0.3) days at the end of 5 years. Patient‐reported outcomes indicated stable improvements in disability, headache impact, and migraine‐specific quality of life. Exposure‐adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient‐years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient‐years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure.ConclusionsTreatment with erenumab was associated with reductions in migraine frequency and improvements in health‐related quality of life that were maintained for at least 5 years. No new safety signals were observed.