The impacts of migraine on functioning: Results from two qualitative studies of people living with migraine.

OBJECTIVE: To describe the impact of migraine on functioning based on comprehensive data collection, analysis, and reporting of patients' experiences. BACKGROUND: Qualitative research conducted to understand patients' perspectives on living with migraine has often focused on narrow topics or specific groups of patients or has been selectively reported. METHODS: Qualitative interviews with 71 participants were conducted during two concept elicitation studies as part of the Migraine Clinical Outcome Assessment System (MiCOAS) project, an FDA grant-funded program designed to develop a core set of patient-centered outcome measures for migraine clinical trials. Participants self-reported being diagnosed with migraine by a healthcare professional and participated in semi-structured qualitative interviews about their experiences with the symptoms and impacts of migraine. Interview transcripts were coded to identify and define concepts, which were then grouped into broad domains based on conceptual similarities. RESULTS: A total of 66 concepts were identified: 12 for physical functioning, 16 for cognitive functioning, 10 for social role functioning, 19 for emotional and psychological functioning, and 9 related to migraine management. Participants described a complex and varied relationship between migraine attack symptoms and impacts on functioning. Impacts from migraine were further influenced by numerous contextual factors, such as people's individual social environments and the level of day-to-day demand for functioning they face. CONCLUSION: Findings showed that migraine impacted individual functioning in multiple ways and the nature of these impacts was dependent on social-contextual factors. The results are being used in the development of core measures designed to improve our understanding of the burden of migraine and the efficacy of migraine therapies. The results also offer new insights and raise new questions about migraine experience that can be used to guide future research.

Longitudinal assessment of comorbidities and co-occurring conditions in adolescents with migraine: A secondary analysis of the National Longitudinal Study of Adolescent to Adult Health (Add Health).

OBJECTIVE: To investigate the links between adolescent migraine and comorbid and co-occurring conditions using a large, nationally representative longitudinal study. BACKGROUND: Comorbidities and co-occurring conditions play an important role in the clinical treatment of individuals with migraine. Research in this area has focused largely on the adult population using cross-sectional data, but less is known about adolescents and how conditions may co-occur over time from a broader developmental perspective. The goals of this manuscript were to empirically evaluate the associations between adolescent migraine and several linked conditions and explore the relative timings of onset of these conditions from adolescence to adulthood. METHODS: Data came from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a school-based study of the health-related behaviors and conditions of adolescents. The present study examined data from Wave 1 (W1, study years: 1994-1995), Wave 4 (W4, study years: 2008-2009), and Wave 5 (W5, study years: 2016-2018). Analyses and visual plots were used to evaluate potential links between parent-reported adolescent migraine status (PR-AdMig) at W1 and 15 medical conditions identified based on self-reported medical diagnoses (SR-MDs) at W4 and W5. Based on prior literature in adults, we identified 11 conditions predicted to be associated with PR-AdMig and four conditions predicted not to be associated with PR-AdMig. The analyses were exploratory and post hoc. RESULTS: The total sample size pooling over all analyses was n = 13,786, but the wave-specific sample sizes differed due to missing data (W4 analyses, n = 12,692; W5 analyses, n = 10,340); 7243/13,786 (unweighted: 52.5%; weighted: 50.5%) of participants were female, 7640/13,786 (unweighted: 55.4%; weighted: 68.6%) were White, and 1580/13,786 (unweighted: 11.5%; weighted: 12.0%) had PR-AdMig. The average ages were 15.8 years at W1, 28.7 years at W4, and 37.8 years at W5. Findings showed that PR-AdMig was associated with anxiety/panic disorder (W4: PR-AdMig vs. Control weighted %: 17.1% vs. 12.6%, unadjusted odds ratio [OR] = 1.43, 95% confidence interval [CI] 1.18-1.74, p = 0.0003; W5: 31.6% vs. 22.4%, OR = 1.60, 95% CI 1.28-2.02, p < 0.0001), asthma/chronic bronchitis/emphysema (W4: 20.0% vs. 14.7%, OR = 1.45, 95% CI 1.20-1.76, p < 0.001; W5: 21.0% vs. 14.6%, OR = 1.55, 95% CI 1.25-1.94, p < 0.001), attention deficit hyperactivity disorder (W4: 8.3% vs. 5.4%, OR = 1.58, 95% CI 1.18-2.10, p = 0.002), depression (W4: 23.7% vs. 15.4%, OR = 1.71, 95% CI 1.43-2.04, p < 0.0001; W5: 33.8% vs. 25.1%, OR = 1.53, 95% CI 1.22-1.90, p < 0.001), epilepsy/seizure disorder (W4: 2.2% vs. 1.2%, OR = 1.84, 95% CI 1.23-2.76, p = 0.004), migraine (W4: 38.8% vs. 11.9%, OR = 4.7, 95% CI 4.1-5.5, p < 0.001), post-traumatic stress disorder (W4: 4.1% vs. 2.8%, OR = 1.45, 95% CI 1.01-2.08, p = 0.042; W5: 11.3% vs. 7.1%, OR = 1.67, 95% CI 1.27-2.20, p < 0.001), and sleep apnea (W5: 11.0% vs. 7.6%, OR = 1.51, 95% CI 1.15-1.98, p = 0.003). Among theoretically unlinked conditions, only hepatitis C at W4 was shown to have a relationship with adolescent onset migraine (0.7% vs. 0.2%, OR = 3.63, 95% CI 1.32-10.0, p = 0.013). Visual plots suggested that the retrospective, self-report timing of onset of specific subsets of co-occurring conditions tended to group together over time. CONCLUSIONS: Consistent with the existing headache literature, results showed that adolescent migraine was associated with other medical and psychological conditions and visual plots suggested that there may be developmental patterns in the occurrence of migraine with other related conditions.

Priority acute and preventive migraine treatment benefits: Results of the Migraine Clinical Outcome Assessment System (MiCOAS) qualitative study of people living with migraine.

BACKGROUND: There is renewed emphasis on including patients in determining, defining, and prioritizing outcomes for migraine treatment. OBJECTIVES: To obtain insights directly from people living with migraine on their priorities for treatment. METHODS: A total of 40 qualitative interviews were conducted as part of the Migraine Clinical Outcome Assessment System project, a United States Food and Drug Administration grant-funded program to develop a core set of patient-centered outcome measures for migraine clinical trials. Interviews included a structured exercise in which participants rank-ordered pre-defined lists of potential benefits for acute and preventive migraine therapy. The 40 study participants who reported being diagnosed with migraine by a clinician ranked the benefits and explained their rationale. RESULTS: Study participants consistently ranked either pain relief or absence of pain as their top priority for acute treatment. Relief/absence of other migraine symptoms and improved functioning were also prioritized. For preventive treatment, participants prioritized reductions in migraine frequency, symptom severity, and attack duration. Few differences were found between participants with episodic migraine and those with chronic migraine. However, participants with chronic migraine ranked "increased predictability of attacks" much higher than those with episodic migraine. Participants' rankings were influenced by prior expectations and experiences of migraine treatments, which caused many participants to deprioritize desired benefits as unrealistic. Participants also identified several additional priorities, including limited side-effects and reliable treatment efficacy in both acute and preventive treatments. CONCLUSION: The results showed the participants prioritized treatment benefits aligned with existing core clinical outcomes used in migraine research, but also valued benefits that are not typically assessed, such as predictability. Participants also deprioritized important benefits when they believed treatment was unlikely to deliver those outcomes.

Patient-reported experiences with migraine-related cognitive symptoms: Results of the MiCOAS qualitative study.

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.

Measuring headache day severity using multiple features in daily diary designs.

OBJECTIVE: Though migraine is thought of as a symptom complex, symptoms are typically assessed one at a time. For use in clinical research, we developed a composite measure of headache day severity by combining eight well-known symptoms captured in daily diaries. SUBJECTS AND METHODS: Data came from adults with a self-reported diagnosis of migraine (n = 4380) who provided daily diary information assessed using a novel digital platform. Nine observed features theoretically linked to headache day severity were analyzed using latent variable modeling to create a psychometrically robust headache day severity score. Logistic regression was used to assess the cross-sectional relationships of headache day severity scores against an array of clinically-relevant outcomes. RESULTS: Participants were largely females (90%), approaching middle age (mean age of 37.3) and living in the United States (49%) or United Kingdom (23%). Findings supported a single latent headache day severity construct based on eight observed headache features. Headache day severity scores were associated with an increased odds of physician visits (Odds ratio[95% CI]: 1.71[1.32-2.21]), emergency department visits (4.12[2.23-7.60]), missed school/work (2.90[2.56-3.29]), missed household work (3.37[3.06-3.72]), and missed other activities (3.29[2.97-3.64]) (p < .0001 for all). CONCLUSIONS: Modern measurement techniques support a single headache day severity construct that reflects migraine is a symptom complex. The headache day severity scores were associated with external validators and initial visualizations showed how headache day severity scores can be applied broadly in clinical practice and research.

What do people want to know about "Growing Up with Migraine"? Results of a preference survey of people with lived experience to guide future research.

In recent years, emphasis has been placed on conducting headache research that is patient-centered to more explicitly incorporate the input of people who live with headache diseases. The Growing Up with Migraine Study was developed with this intention using a two-step process: 1. develop and administer a survey to identify research areas that matter most to people with adolescent migraine and/or their caregivers and 2. use the survey results to guide future secondary data analyses. This brief report summarizes the survey results from 373 individuals impacted by adolescent migraine. Findings suggested that people with history of adolescent migraine and/or their caregivers are most interested in research about migraine comorbidities and effects on psychological/social/emotional health, along with health-related outcomes and family-related topics. Future quantitative studies are planned that will explore these patient-identified priorities through secondary data analysis of an existing dataset.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

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.

Impact of the COVID-19 pandemic on people living with migraine: Results of the MiCOAS qualitative study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis that has had a range of impacts on people living with migraine. METHODS: Qualitative interviews performed as part of the Migraine Clinical Outcome Assessment System project, a multi-stage Food and Drug Administration-grant funded program to develop a patient-centered core set of outcome measures for use in migraine clinical trials, offered an opportunity to explore the experience of living with migraine during the pandemic as well as to examine whether migraine treatment priorities, symptoms, and associated disability changed due to the pandemic. Semi-structured interviews were conducted in the United States between the summer and fall of 2020 with 40 individuals with self-reported, medically diagnosed migraine who self-reported that they had not tested positive for or been diagnosed with COVID-19. RESULTS: Seventy percent (n = 28) of the sample reported ≥1 pandemic-related impact on their life with migraine. Fourteen participants reported both positive and negative impacts, twelve reported negative impacts only, and two reported positive impacts only. Among those reporting ≥1 pandemic-related impact, nine participants (32%) reported more frequent and five (17%) reported less frequent migraine attacks. Other negative impacts included interrupted medical care (n = 9; 32%), and greater stress (n = 13; 46%). The most frequent positive impact reported was greater access to health care (n = 8; 29%). Ictal and interictal symptoms were not noted to change due to the pandemic, but some respondents reported less disability due to increased flexibility of schedules and reduced expectations. Treatment priorities did not change due to the pandemic. CONCLUSION: The global COVID-19 pandemic has resulted in both negative and positive impacts for people living with migraine. Lessons to be considered when moving into a post-pandemic world include benefits of and satisfaction with telehealth and the benefits and importance of healthy lifestyle habits and flexibility such as improved sleep, reduced stress, and fewer social expectations.

Using validity theory and psychometrics to evaluate and support expanded uses of existing scales.

BACKGROUND: Scale development is a complex activity requiring significant investments of time and money to produce evidence of a scale's ability to produce reliable scores and valid inferences. With increasing use of clinical outcome assessments (COAs) in medical product development, evidentiary expectations of regulatory bodies to support inferences are a key consideration. The goal of this paper is to demonstrate how existing methods in measurement science can be used to identify and fill evidence gaps when considering re-purposing an existing scale for a new use case (e.g., new patient population, altering the recall period), rather than creating a new COA tool. METHODS: We briefly review select validity theory and psychometric concepts, linking them to the nomenclature in the COA/regulated space. Four examples (two in-text and two in online supplemental materials) of modifications are presented to demonstrate these ideas in practice for quality of life (QOL)-related measures. RESULTS: Each example highlights the initial process of evaluating the desired validity claims, identifying gaps in evidence to support these claims, and determining how such gaps could be filled, often without having to develop a new measure. CONCLUSIONS: If an existing scale, with minimal modification or additional evidence, can be shown to be fit for a new purpose, considerable effort can be saved and research waste avoided. In many cases, a new instrument is simply unnecessary. Far better to recycle an "old" scale for a new use-with sufficient evidence that it is fit for that purpose-than to "buy" a new one.

Headache complexity (number of symptom features) differentiates post-traumatic from non-traumatic headaches.

BACKGROUND: Post-traumatic headaches are a common sequela of mild traumatic brain injury (concussion). It is unclear whether or how these headaches differ phenotypically from primary headaches. OBJECTIVE: Determine whether there is an overarching unobserved latent trait that drives the expression of observed features of post-traumatic headache and other headaches. METHODS: Data from this post-hoc analysis come from the Warrior Strong Cohort Study conducted from 2010 through 2015. Approximately 25,000 soldiers were screened for concussion history at routine post-deployment health assessments. A random sample was invited to participate, enrolling 1567. Twelve observed headache phenotypic features were used to measure "headache complexity", the latent trait of clinical interest, using single factor confirmatory factor analysis. We compared headache complexity between groups and determined whether headache complexity predicted accessing medical care for headache. RESULTS: Of 1094 soldiers with headaches, 198 were classified as having post-traumatic headache. These headaches were compared to those in the other soldiers (647 without concussion history and 249 with concussion history). Soldiers with post-traumatic headache had greater endorsement of all 12 headache features compared to the soldiers with non-concussive headaches. The confirmatory factor analysis showed good model fit (χ2 (51) = 95.59, p = 0.0002, RMSEA = 0.03, comparative fit index = 0.99, and Tucker-Lewis index = 0.99), providing empirical support for the headache complexity construct. Soldier groups differed in their mean headache complexity level (p < 0.001) such that post-traumatic headache soldiers had greater headache complexity compared to non-concussed soldiers (standardized mean difference = 0.91, 95% confidence interval: 0.72-1.09, p < 0.001 and to concussed soldiers with coincidental headaches standardized mean difference = 0.75, 95% confidence interval: 0.53-0.96, p < 0.001). Increasing headache complexity predicted medical encounters for headache (odds ratio = 1.87, 95% confidence interval: 1.49-2.35, p < 0.001) and migraine (odds ratio = 3.74, 95% confidence interval: 2.33-5.98, p < 0.001) during the year following deployment.Conclusions and relevance: The current study provided support for a single latent trait, characterized by observed headache symptoms, that differentiates between concussive and non-concussive headaches and predicts use of medical care for headache. The single trait confirmatory factor analysis suggests that post-traumatic headaches differ from non-concussive headaches by severity more than kind, based on the symptoms assessed.ClinicalTrials.gov identifier NCT01847040.

Between and within-woman differences in the association between menstruation and migraine days.

OBJECTIVE: To investigate between and within-woman differences in the association between menstruation and migraine days. BACKGROUND: Prior diary studies have shown that at the population level, aggregating across individuals, the odds of migraine increase during the perimenstrual window (from day -2 to day +3, where +1 is the first day of bleeding). These studies have been neither long nor large enough to assess the association between migraine and menses from an individual perspective. Consequently, existing research on menstrual-related migraine has largely overlooked between and within-woman variation that is critical for progressing clinical understanding and practice. METHODS: Intensive longitudinal data for the current study were collected in a digital platform (N1-Headache® ) that tracks individual migraine-related factors daily. Participants for the current study were actively menstruating adult (18+ years old) women who used the platform. Two variables were of primary interest, migraine day (no/yes) and menstrual status (inside or outside the 5-day perimenstrual window). RESULTS: The sample consisted of 203 women with a mean age of 35.6 (SD = 8.7) years. At baseline, the women reported an average of 30.6 (SD = 23.6) headache days over the last 3 months. Analyses were based on a total of 53,302 days (median of 150 per person), 18,520 of which were migraine days (median of 44 per person), and a total of 2,126 menstrual cycles (median of 7 per person). Results showed that the 5-day perimenstrual window was associated with a 34% increase in odds of a migraine day compared to other days (OR = 1.34, 95% CI: 1.23-1.45, p < 0.0001). Importantly, there was between and within-woman variability in the association between menses and migraine days (between-woman variability: p = 0.002; within-woman [between-cycles] variability: p < 0.0001). Exploration of these individual differences demonstrated that relationship between menses and migraine days varied more within-person across cycles than between women. DISCUSSION: This study supports previous research and demonstrates that the odds of migraine days are elevated from day -2 to day +3 of the menstrual cycle. We also show that the effect of menses on migraine days varies more within-woman than between-women. This work provides an initial foundation for better understanding menstrual-related migraine from the perspective of the individual patient.

Systematic review of outcomes and endpoints in acute migraine clinical trials.

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.

Systematic review of outcomes and endpoints in preventive migraine clinical trials.

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.

Reliability and validity of the 6-item Headache Impact Test in chronic migraine from the PROMISE-2 study.

PURPOSE: We examined the reliability and validity of the 6-item Headache Impact Test (HIT-6) specifically on patients with chronic migraine (CM) from the PROMISE-2 clinical trial. METHODS: The conceptual framework of HIT-6 was evaluated using baseline data from the PROMISE-2 study (NCT02974153; N = 1072). A unidimensional graded response model within the item response theory (IRT) framework was used to evaluate model fit and item characteristics. Using baseline and week 12 data, convergent and discriminant validity of the HIT-6 was evaluated by correlation coefficients. Sensitivity to change was assessed by evaluating correlations between HIT-6 scores and change scores for other established reference measures. All examined correlations were specified a priori with respect to direction and magnitude. Known-groups analyses were anchored using Patient Global Impression of Change and monthly headache days at week 12. RESULTS: A unidimensional model fit the data well, supporting that the 6 items measure a single construct. All item slopes and thresholds were within acceptable ranges. In both the validity and sensitivity to change analyses, all observed correlations conformed to directional expectations, and most conformed to magnitude expectations. Known-groups analyses demonstrated that the HIT-6 total score can distinguish between clinically meaningful CM subgroups. CONCLUSION: The HIT-6 was successfully calibrated using IRT with data from PROMISE-2. Results from these analyses were generally consistent with previous literature and provided supportive evidence that the HIT-6 is well suited for measuring the impact of headache and migraine in the CM population.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Determining Thresholds for Meaningful Change for the Headache Impact Test (HIT-6) Total and Item-Specific Scores in Chronic Migraine.

OBJECTIVE: The objective of the analyses described here was to develop thresholds defining clinically meaningful response on the total and item scores of the 6-item short-form Headache Impact Test (HIT-6) in a population of patients with chronic migraine (CM). BACKGROUND: The HIT-6 is a short, easily understood, and useful measure of the impact of headache on daily life. Though widely used, limited literature supports a threshold value for clinically meaningful response within individuals over time for the HIT-6 total score and for the item scores, especially in the CM population. METHODS: PROMISE-2 is a randomized, double-blind, multicenter study comparing intravenous eptinezumab 100 and 300 mg with placebo for the preventive treatment of CM. Responder definitions for HIT-6 total and items scores using data from PROMISE-2 study were calculated via distribution-based and anchor-based methods. Distribution-based methods included half of the baseline standard deviation and baseline standard error of measurement. The change from baseline to week 12 in HIT-6 scores was assessed using the following anchors: patient global impression of change, reduction in migraine frequency, and change in EuroQol 5 dimensions 5 levels visual analog scale. Values from the literature and PROMISE-2 analyses were plotted against the cumulative distribution function of change values (baseline to week 12) and used to triangulate to empirically support clinically meaningful change definitions for the HIT-6 total and item scores in patients with CM. RESULTS: From the literature, 5 articles provided 7 candidate values for a responder threshold for the HIT-6 total score. From distribution- and anchor-based methods, 5 candidate values were derived from PROMISE-2 data. Using the median of all candidate values, a HIT-6 total score responder definition estimate of -6 (ie, ≥6-point improvement in the total score) appears most appropriate for discriminating between individuals with CM who have experienced meaningful change over time and those who have not. For item-level analyses using anchor-based methods, the responder definition for items 1-3 ("severe pain," "limits daily activities," and "lie down") was a 1-category improvement in response (eg, from Sometimes to Rarely); for items 4-6 ("too tired," "felt fed up or irritated," and "limits concentration"), a 2-category improvement in response (eg, from Always to Sometimes) was clinically meaningful. CONCLUSIONS: Using a multifaceted, statistically-based approach, the recommended responder definition for the HIT-6 total score in the CM population is a ≥6-point decrease, consistent with previous literature. Anchor-based item-level responder thresholds were defined as a decrease of 1 or 2 categories, depending on the item. These CM-specific values will provide researchers and clinicians a means to interpret clinically meaningful change in the HIT-6 total and item scores and may facilitate the measurement of treatment benefits in specific functional domains of the HIT-6.

Content Validity of HIT-6 as a Measure of Headache Impact in People With Migraine: A Narrative Review.

BACKGROUND: The short-form Headache Impact Test (HIT-6) is a widely used patient-reported outcome measure that assesses the negative effects of headaches on normal activity. It was developed using the general headache population and prior to the establishment of the now well-accepted FDA patient-reported guidance. OBJECTIVE: The objective of this narrative review was to examine existing qualitative research in patients with migraine and headache, providing insight into the relevance and meaningfulness of HIT-6 items to the lives of migraine patients. METHODS: Articles were identified through database searches (National Library of Medicine and Google Scholar) and review of reference lists of candidate articles. RESULTS: A total of 3227 articles were identified through database and hand searching. Of these, 12 contained patient- or expert-generated qualitative information regarding headache patients' experience (8 specific to migraine [episodic and chronic] patients and 4 citing general headache patients). The combined publications described a total of 283 patient interviews. Overarching themes and specific information were identified that provide support of the relevance of content for each HIT-6 item to migraine patients' lives. Identified effects of headaches on patients with migraine included limitations in daily activities, needing to lie down during headaches, feeling tired, being irritated by headaches, difficulty concentrating, and the experience of pain. Further, previous research specific to the HIT-6 indicated that patients understood the instructions, items, and response scales as intended by the instrument authors. CONCLUSIONS: This narrative literature review demonstrates qualitative research support for the relevance of the items of the HIT-6 in migraine patients, supporting its ongoing use in clinical migraine research and practice.

Growth Curves for Headache Research: A Multilevel Modeling Perspective.

OBJECTIVE: To introduce growth curve modeling for longitudinal headache research. BACKGROUND: Longitudinal data play an important role in the study of headache-related outcomes by allowing researchers to test hypotheses about change over time. However, headache researchers are often unfamiliar with the flexibility and power that growth curves can offer in analyzing longitudinal data. The goals of this paper are to introduce growth curve models within the multilevel modeling framework for analyzing longitudinal headache-related data and to show how these models can be applied in practice. METHODS: Longitudinal data for the empirical example came from publicly available data from Wave I to Wave IV of the National Longitudinal Study of Adolescent to Adult Health. In total, 5608 individuals were included in the study and multilevel models were fit to examine, for individuals with and without adolescent migraine, longitudinal changes in depression from age 13 to 27 years old. RESULTS: Findings showed that individuals varied in their longitudinal depression trajectories. A cubic time trend best approximated the data with depression increasing through adolescence, decreasing during young adulthood, and then beginning to increase again in adulthood. Further, results also indicated that individuals with adolescent migraine had higher levels of depression throughout the age span compared those without adolescent migraine, but the shape of change did not differ across the groups. CONCLUSION: Growth curve models offer a flexible alternative to traditional statistical methods and can rigorously evaluate a wide array of headache-related hypotheses.

Evaluating Mean Level and Within-Person Consistency in Migraine Pain Intensity and Migraine-Related Disability for AVP-825 vs Oral Sumatriptan: Results from the COMPASS Study, A Randomized Trial.

BACKGROUND: Consistency of response across multiple attacks is typically measured as the proportion of study participants who achieve a categorical endpoint over a specified number of attacks (ie, 2-hour pain-free response in 2 of 3 attacks). We applied a novel analytic approach for measuring consistency of response in the acute treatment of episodic migraine using data from the COMPASS study. METHODS: The COMPASS study (NCT01667679) was a multiple attack crossover study which compared AVP-825, a Breath Powered® intranasal delivery system for low-dose sumatriptan powder (22 mg), with 100-mg oral sumatriptan tablets in the acute treatment of migraine. Participants were 18-65 years old, met ICHD-2 criteria for migraine with or without aura, and had migraine for ≥1 year prior to screening. They were instructed to treat up to 5 migraine attacks with each treatment and recorded migraine pain intensity and disability data at pre-dose and 10, 15, 30, 45, 60, 90, and 120 minutes post-dose for each attack. We explored the mean level and within-person variability (WPV; a measure of consistency) in migraine pain intensity and migraine-related disability across multiple attacks after treatment with AVP-825 (22 mg) vs oral sumatriptan (100 mg) using location scale mixed-effects models (LSMEMs). LSMEMs controlled for pre-dose pain/disability, demographics, treatment sequence, and treatment period. RESULTS: The mean age was 40 and the sample was 84.6% women. Participants (N = 259) treated an average of 6.8 attacks each during the course of the study. Attacks treated with AVP-825 showed significantly lower mean pain intensity and mean disability from 10 to 90 minutes post-dose (effect sizes ranged from -0.09 to -0.29 and P values ranged from P < .0001 to P = .01). WPV was significantly greater at 10-15 minutes (WPV ratios ranged from 1.20 to 1.58 and P values ranged from P < .0001 to P = .04) but significantly reduced from 45 to 120 minutes for attacks treated with AVP-825 compared to oral sumatriptan (WPV ratios ranged from 0.67 to 0.81 and P values ranged from P < .0001 to P = .03). CONCLUSIONS: LSMEMs demonstrate that treatment with AVP-825 is associated with lower average migraine pain intensity and disability from 10 to 90 minutes and greater within-person consistency across multiple migraine attacks (reduced WPV) from 45 to 120 minutes post-dose compared to oral sumatriptan. These findings may reflect the more rapid and consistent absorption of sumatriptan using AVP-825. Increased WPV with AVP-825 in the first 15 minutes likely reflects the earlier onset of treatment effects with the device compared to oral sumatriptan. LSMEMs show promise as a novel approach for assessing and comparing consistency of treatment response in migraine trials.

AVP-825 (Sumatriptan Nasal Powder) Reduces Nausea Compared to Sumatriptan Tablets: Results of the COMPASS Randomized Clinical Trial.

BACKGROUND: Migraine-related nausea is associated with significant disability, increased burden of disease, and personal distress. Nausea can lead to delays or avoidance of initiating oral migraine treatment, sometimes resulting in treatment failures and poor outcomes. Nausea is often a symptom of migraine, but nausea may also be a consequence of treatment (ie, treatment emergent nausea [TEN]). Relieving nausea and minimizing TEN are important goals in acute migraine therapy. METHODS: We analyzed data from the COMPASS study, a randomized, double blind, double-dummy, comparative efficacy study that contrasted two active treatments, AVP-825 (breath-powered intranasal delivery of powdered sumatriptan 22 mg) and oral sumatriptan tablets (100 mg). Three-level logistic multilevel models were used to examine longitudinal changes in nausea from three distinct perspectives across multiple attacks. Model 1 (Overall Nausea) examined longitudinal change in nausea from pre-dose through 120 minutes post-dose for the entire sample, independent of baseline nausea. Model 2 examined TEN from 10 minutes through 120 minutes post-dose in attacks free of nausea at baseline to investigate whether or not nausea developed following treatment. Model 3 examined Nausea Relief from 10 minutes through 120 minutes post-dose in eligible attacks with nausea at baseline to examine whether or not nausea was relieved over the first 2 hours post-dose. Models tested for differences in rate of change in nausea over time and odds of nausea at specific time-points. RESULTS: Longitudinal nausea trajectories differed for AVP-825 and oral sumatriptan in the Overall Nausea model (Model 1) and TEN model (Model 2), but were more comparable across treatments for the Nausea Relief (Model 3). More specifically, in the Overall Nausea model (Model 1), an individual treating an attack with AVP-825 had a significantly faster decrease in nausea through the first 60 minutes post-dose and reduced odds of nausea at each time-point from 30 minutes through 120 minutes post-dose compared to oral sumatriptan. In Model 2, an individual's risk for TEN increased at a significantly faster rate through the first 45 minutes post-dose when treating an attack with oral sumatriptan, with significantly greater odds of experiencing TEN at 45, 60, and 90 minutes post-dose compared to AVP-825. The Nausea Relief model (Model 3) showed similar rates of change in nausea over time for the two treatments, but there was a constant difference in nausea level leading to reduced odds of nausea when treating with AVP-825 compared to oral sumatriptan. CONCLUSIONS: All three longitudinal models showed that AVP-825 had more favorable nausea outcomes compared to oral sumatriptan. AVP-825 treatment led to more rapid early reductions in Overall Nausea rates during the first hour, reduced odds of nausea from 30 minutes to 2 hours following treatment and reduced risk of TEN compared to oral sumatriptan. These results highlight the importance of separately assessing TEN and Nausea Relief in acute treatment trials of migraine.