McGinley, James S.

Abstract Objectives To capture patients' perspectives on migraine‐related cognitive symptoms during pre‐headache, headache, post‐headache, and interictal periods. Background Migraine‐related cognitive symptoms are reported by people with migraine both during and between attacks. Associated with disability, they are increasingly viewed as a priority target for treatment. The Migraine Clinical Outcome Assessment System (MiCOAS) project is focused on developing a patient‐centered core set of outcome measures for the evaluation of migraine treatments. The project focuses on incorporating the experience of people living with migraine and the outcomes most meaningful to them. This includes an examination of the presence and functional impact of migraine‐related cognitive symptoms and their perceived impact on quality of life and disability. Methods Forty individuals with self‐reported medically diagnosed migraine were recruited via iterative purposeful sampling for semi‐structured qualitative interviews conducted using audio‐only web conferencing. Thematic content analysis was performed to identify key concepts around migraine‐related cognitive symptoms. Recruitment continued until concept saturation was achieved. Results Participants described symptoms consistent with migraine‐related deficits in language/speech, sustained attention, executive function, and memory that manifest during pre‐headache (36/40 [90%] reported ≥1 cognitive feature), headache (35/40 [88%] reported ≥1 cognitive feature), post‐headache (27/40 [68%] reported ≥1 cognitive feature), and interictal periods (13/40 [33%] reported ≥1 cognitive feature). Among participants reporting cognitive symptoms during pre‐headache, 32/40 (81%) endorsed 2–5 cognitive symptoms. Findings were similar during the headache phase. Participants reported language/speech problems consistent with, for example, impairments in receptive language, expressive language, and articulation. Issues with sustained attention included fogginess, confusion/disorientation, and trouble with concentration/focus. Deficits in executive function included difficulty processing information and reduced capacity for planning and decision‐making. Memory issues were reported across all phases of the migraine attack. Conclusions This patient‐level qualitative study suggests that cognitive symptoms are common for persons with migraine, particularly in the pre‐headache and headache phases. These findings highlight the importance of assessing and ameliorating these cognitive problems.

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.

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 Background/Objective To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain‐related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient‐reported outcome measures (PROMs, general health and migraine/headache‐specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter‐rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine‐associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain‐related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one‐third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial‐to‐trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2‐hour post‐treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi‐item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain‐related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient‐centered and statistically robust could improve the conduct of individual trials, facilitate cross‐trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

Abstract Background Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method A systematic literature review, following a pre‐specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine‐specific outcome, 39.6% (106/268) examined ≥1 headache‐specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache‐related patient‐reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non‐headache‐specific PROM. Furthermore, the definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed across publications. Conclusion Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross‐trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.