Tassorelli, Cristina

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 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.

Background Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist for the preventive treatment of migraine. Methods In the double-blind, phase 3 ADVANCE trial, participants with 4–14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1–4, and proportion of participants with a migraine on each day during the first week. Results We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1–4, mean change from baseline in mean monthly migraine days ranged from −3.1 to −3.9 across atogepant doses vs −1.6 for placebo ( p < 0.0001). For weeks 5–8 and 9–12, reductions in mean monthly migraine days ranged from −3.7 to −4.2 for atogepant vs −2.9 for placebo ( p ≤ 0.012) and −4.2 to −4.4 for atogepant vs −3.0 for placebo ( p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from −0.77 to −1.03 for atogepant vs −0.29 with placebo ( p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo ( p ≤ 0.0071). Conclusion Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period. Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059

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.

Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately.

The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medicine led to second and third editions in 2000 and 2012, respectively. The current, fourth edition of the Guidelines retains the structure and much content from previous editions. However, it also incorporates evidence from clinical trials published after the third edition as well as feedback from meetings with regulators, pharmaceutical and device manufacturers, and patient associations. Its final form reflects the collective expertise and judgement of the Committee. These updated recommendations and commentary are intended to meet the Society's continuing objective of providing a contemporary, standardized, and evidence-based approach to the conduct and reporting of randomised controlled trials for the acute treatment of migraine attacks.

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents.