Understanding the migraine treatment landscape prior to the introduction of calcitonin gene-related peptide inhibitors: Results from the Assessment of TolerabiliTy and Effectiveness in MigrAINe Patients using Preventive Treatment (ATTAIN) study.

BACKGROUND: Calcitonin gene-related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction. OBJECTIVE: To characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US. METHODS: Between March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real-world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns. RESULTS: From the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females (n = 204/234; 87.2%) and white (n = 178/234; 76.1%). The majority (n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% (n = 110/164) of the preventive treatment naïve and 77.1% (n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% (n = 145/164) of the treatment naïve and 88.6% (n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti-inflammatory agents (n = 124/234; 53.0%), acetaminophen-based products (n = 112/234; 47.9%), and triptans (n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate (n = 100/234; 42.7%), tricyclic antidepressants (n = 39/234; 16.7%), beta-blockers (n = 26/234; 11.1%), and onabotulinumtoxinA (n = 24/234; 10.3%). Over the 6-month follow-up period, almost half of patients (n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment (n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses (n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued (n = 52/88; 59.1%), decreased frequency or dose (n = 37/89; 41.6%), and skipped doses (n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued (n = 20/88; 22.7%), decreased frequency or dose (n = 15/89; 16.9%), and skipped doses (n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6-month follow-up period. CONCLUSIONS: Prior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

A Controlled Trial of Erenumab for Episodic Migraine.

BACKGROUND: We tested erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, for the prevention of episodic migraine. METHODS: We randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of migraine days per month. Secondary end points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning). RESULTS: A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P<0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P<0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo. CONCLUSIONS: Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE ClinicalTrials.gov number, NCT02456740 .).

Migraine day frequency in migraine prevention: longitudinal modelling approaches.

BACKGROUND: Health economic models are critical tools to inform reimbursement agencies on health care interventions. Many clinical trials report outcomes using the frequency of an event over a set period of time, for example, the primary efficacy outcome in most clinical trials of migraine prevention is mean change in the frequency of migraine days (MDs) per 28 days (monthly MDs [MMD]) relative to baseline for active treatment versus placebo. Using these cohort-level endpoints in economic models, accounting for variation among patients is challenging. In this analysis, parametric models of change in MMD for migraine preventives were assessed using data from erenumab clinical studies. METHODS: MMD observations from the double-blind phases of two studies of erenumab were used: one in episodic migraine (EM) (NCT02456740) and one in chronic migraine (CM) (NCT02066415). For each trial, two longitudinal regression models were fitted: negative binomial and beta binomial. For a thorough comparison we also present the fitting from the standard multilevel Poisson and the zero inflated negative binomial. RESULTS: Using the erenumab study data, both the negative binomial and beta-binomial models provided unbiased estimates relative to observed trial data with well-fitting distribution at various time points. CONCLUSIONS: This proposed methodology, which has not been previously applied in migraine, has shown that these models may be suitable for estimating MMD frequency. Modelling MMD using negative binomial and beta-binomial distributions can be advantageous because these models can capture intra- and inter-patient variability so that trial observations can be modelled parametrically for the purposes of economic evaluation of migraine prevention. Such models have implications for use in a wide range of disease areas when assessing repeated measured utility values.

Patient Preferences for Preventive Migraine Treatments: A Discrete-Choice Experiment.

OBJECTIVE: To understand treatment preferences of people with migraine and the relative importance of improvements in efficacy and avoiding adverse events (AEs), such as cognition problems or weight gain. BACKGROUND: Current preventive migraine medicines are associated with poor adherence and tolerability. There is an unmet need for effective migraine-specific preventive treatments with fewer AEs. METHODS: In a web-based discrete-choice experiment survey, respondents who self-reported having ≥6 migraine days/month were offered choices between pairs of hypothetical preventive migraine medicines. Six attributes, each with 3 levels, defined the medicines: reduction in headache days per month (10%, 25%, or 50%), frequency of limitations with physical activities (none, 1-category improvement, or 2-category improvement), cognition problems (no problems, thinking problems, or memory problems), weight gain (none, 5% body weight gain, or 10% body weight gain), how the medicine is taken (daily oral pill, once-monthly injection, or twice-monthly injection), and monthly out-of-pocket cost ($5, $60, or $175). The attributes and levels were informed by clinician input, the clinical literature, and 2 focus groups. An experimental design was used to create the pairs of hypothetical medicines for the discrete-choice experiment questions. Random-parameters logit was used to estimate the relative importance of the medicine attributes, and the results were used to predict the percentage of respondents who would select one medicine profile over another and to calculate willingness to pay for changes in attribute levels. RESULTS: The sample included 300 respondents; 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription medicine to prevent migraine in the last 6 months. Respondents reported having, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of AEs, but were willing to trade off efficacy for less-severe AEs. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once-monthly injection or daily pill to twice-monthly injection. Respondents, on average, were willing to pay $84 (95% confidence interval [CI], $64-$103) per month to avoid a 10% weight gain, $59 (95% CI, $42-$76) per month to avoid memory problems, $35 (95% CI, $20-$51) per month to avoid a 5% weight gain, and $32 (95% CI, $18-$46) per month to avoid thinking problems. CONCLUSIONS: A preventive migraine medicine with improved efficacy and AE profile and a favorable mode of administration would be valuable to migraine sufferers. Patients may be willing to trade off efficacy for better AE profiles. Clinicians should work with patients to select treatments that meet each patient's needs.

Longitudinal assessment of utilities in patients with migraine: an analysis of erenumab randomized controlled trials.

BACKGROUND: Cost-effectiveness analyses in patients with migraine require estimates of patients' utility values and how these relate to monthly migraine days (MMDs). This analysis examined four different modelling approaches to assess utility values as a function of MMDs. METHODS: Disease-specific patient-reported outcomes from three erenumab clinical studies (two in episodic migraine [NCT02456740 and NCT02483585] and one in chronic migraine [NCT02066415]) were mapped to the 5-dimension EuroQol questionnaire (EQ-5D) as a function of the Migraine-Specific Quality of Life Questionnaire (MSQ) and the Headache Impact Test (HIT-6™) using published algorithms. The mapped utility values were used to estimate generic, preference-based utility values suitable for use in economic models. Four models were assessed to explain utility values as a function of MMDs: a linear mixed effects model with restricted maximum likelihood (REML), a fractional response model with logit link, a fractional response model with probit link and a beta regression model. RESULTS: All models tested showed very similar fittings. Root mean squared errors were similar in the four models assessed (0.115, 0.114, 0.114 and 0.114, for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model respectively), when mapped from MSQ. Mean absolute errors for the four models tested were also similar when mapped from MSQ (0.085, 0.086, 0.085 and 0.085) and HIT-6 and (0.087, 0.088, 0.088 and 0.089) for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model, respectively. CONCLUSIONS: This analysis describes the assessment of longitudinal approaches in modelling utility values and the four models proposed fitted the observed data well. Mapped utility values for patients treated with erenumab were generally higher than those for individuals treated with placebo with equivalent number of MMDs. Linking patient utility values to MMDs allows utility estimates for different levels of MMD to be predicted, for use in economic evaluations of preventive therapies. TRIAL REGISTRATION: ClinicalTrials.gov numbers of the trials used in this study: STRIVE, NCT02456740 (registered May 14, 2015), ARISE, NCT02483585 (registered June 12, 2015) and NCT02066415 (registered Feb 17, 2014).

Migraine-related disability, impact, and health-related quality of life among patients with episodic migraine receiving preventive treatment with erenumab.

Background We evaluated the effect of erenumab, a fully human monoclonal antibody that inhibits the canonical calcitonin gene-related peptide receptor, on migraine-related disability, impact, and health-related quality of life among patients with episodic migraine. Methods Patients enrolled in a phase 3, 6-month, double-blind, placebo-controlled study of once-monthly erenumab 70 and 140 mg for migraine prevention (STRIVE) used an eDiary during the baseline and double-blind treatment phases to complete validated, specific questionnaires, including the modified (monthly) Migraine Disability Assessment Questionnaire; Headache Impact Test; and Migraine-Specific Quality of Life Questionnaire-role function-restrictive (MSQ-RFR), -role function-preventive (MSQ-RFP), and -emotional function (MSQ-EF). Results A total of 955 patients were randomized to receive erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo (n = 319). Erenumab versus placebo resulted in significantly greater improvements in all patient-reported outcomes; changes from baseline were numerically higher with 140 mg erenumab. Improvements occurred rapidly and were maintained over 6 months of treatment. Between-group differences from placebo over months 4-6 for the 70- and 140-mg dose groups were, respectively, -2.1 and -2.8 for modified (monthly) Migraine Disability Assessment Questionnaire, -2.1 and -2.3 for Headache Impact Test, 5.1 and 6.5 for MSQ-RFR, 4.2 and 5.4 for MSQ-RFP, and 5.2 and 6.7 for MSQ-EF ( p < 0.001 for all). Erenumab also significantly reduced the proportion of patients with severe and very severe migraine-related disability and increased the proportion of patients with clinically meaningful improvements in migraine-related impact and health-related quality of life. Conclusion Erenumab reduced migraine disability and impact and improved patients' health-related quality of life, reinforcing its role as a promising new therapy for migraine prevention.

Direct and Indirect Healthcare Resource Utilization and Costs Among Migraine Patients in the United States.

OBJECTIVE: The goal of this analysis was to provide a contemporary estimate of the burden of migraine, incorporating both direct and indirect costs, by comparing the costs of migraine patients to a matched group of patients without migraine in a large, nationally representative sample of commercially insured patients in the United States. BACKGROUND: Previous studies have shown that the economic burden of migraine in the United States is substantial for payers, patients, and employers. Despite the availability of multiple acute and preventive pharmacological treatment options and a relatively stable migraine prevalence in the United States, there has been a documented increase in migraine-related healthcare resource and pharmacy use. Given the frequently disabling nature of migraine and its high prevalence, especially during peak productive years, and the lack of recent estimates of the burden of migraine, there is a need to update the existing literature with more current data. METHODS: This retrospective, observational cohort study identified migraine patients in the Truven Health Market Scan Research Databases between January 2008 and June 2013. Adult patients had 12 months of continuous enrollment before (baseline period) and after (follow-up period) the day they received migraine diagnoses and/or medications (index) and no diagnosis of HIV or malignancy during the study period. The patients with migraine were matched 1:1 to a group of patients without migraine on demographic variables and index date. Direct healthcare utilization and costs and indirect (absenteeism, short-term disability, and long-term disability) costs were assessed during the 12-month follow-up period and differences between patients with vs without migraine were assessed. Two additional multivariable logistic regression analyses were conducted. First, an analysis was conducted comparing the odds of having a short-term disability claim between patients with and without migraine after controlling for patient demographic and clinical characteristics. A second analysis, conducted among the migraine patients only, compared the odds of having a short-term disability claim between (1) patients treated with acute or preventive migraine medications only during the baseline period and patients with no migraine treatment during baseline and (2) patients treated with both acute and preventive migraine medications during the baseline period and patients with no migraine treatment during baseline, after controlling for patient demographic and clinical characteristics. RESULTS: Migraine patients had total annual direct plus indirect costs that were $8924 (in 2014 United States dollars) higher than those of demographically similar individuals without evidence of migraine. Migraine patients' mean annual direct all-cause healthcare costs were $6575 higher than those of matched patients without migraine ($11,010 [standard deviation = $19,663] vs $4436 [standard deviation=$13,081]; P < .01). Total mean annual indirect costs were $2350 higher in the migraine cohort than in the matched no migraine patients ($11,294 vs $8945. Migraine patients were 2.0 times more likely as their nonmigraine counterparts to use opioids (45.5% vs 21.9%; P < .01) and among patients with opioid prescriptions, migraine patients had 1.8 times the number of opioid prescriptions per patient than did those without migraine (4.9 [standard deviation = 6.9] vs 2.7 [standard deviation = 4.0]; P < .01). After adjusting for baseline demographic and clinical characteristics, migraine patients treated with either acute or preventive migraine medications (odds ratio = 0.81 [95% confidence interval = 0.72-0.91]; P < .01) or both acute and preventive migraine medications during the baseline period (odds ratio = 0.93 [95% confidence interval = 0.89-0.98]; P < .01) were significantly less likely to have short-term disability claims than untreated patients during the follow-up period (Migraine patients with either acute or preventive medications only: 7290/45,632 [16.0%]; with both acute and preventive medications: 3085/14,941 [20.6%]; untreated patients: 1604/11,169 [14.4%] had a short-term disability claim.) However, overall, migraine patients had 1.94 times the odds of having a short-term disability claim than their matched counterparts (95% confidence interval = 1.83-2.05; P < .01; migraine patients: 11,979/71,742 [16.7%]; nonmigraine patients: 4801/71,742 [6.7%] had a short-term disability claim). CONCLUSIONS: Results from this real-world assessment of the economic burden of migraine suggest that migraine imposes a substantial direct and indirect cost burden in the United States. Compared to matched nonmigraine patients, migraine patients were more likely to have work loss and longer periods of work loss, leading to significantly higher indirect costs. Migraine patients also had higher levels of healthcare utilization, despite the relatively stable prevalence of migraine and the available acute and preventive treatment options for migraine management.

Improving Medical Communication in Migraine Management: A Modified Delphi Study to Develop a Digital Migraine Tracker.

OBJECTIVE: This study aimed to identify the essential content and amount of information to be collected from people with migraine via a patient-facing smartphone-based migraine tracker for them to share with clinicians during live discussions to assist in optimizing migraine management. The proposed tracker is intended for use in non-interventional research to evaluate disease burden in episodic migraine and chronic migraine patients as assessed by demographic and clinical characteristics and health resource utilization in an integrated delivery network setting. The proposed tracker is not intended for commercial purposes. BACKGROUND: Epidemiological studies suggest migraine is underdiagnosed and undertreated. Studies of patient-clinician interactions suggest that effective medical communication may help address these issues. METHODS: Four migraine practice leaders, an epidemiologist with extensive migraine experience, and a measurement expert took part in a modified Delphi panel process to identify data elements that could be collected from people with migraine through a smartphone-based migraine tracker. Importantly, the proposed tracker would not be intended to replace the patient-clinician encounter but to support the encounter through enabling the patient to document migraine symptoms and experiences in a timely and accurate manner for sharing with a clinician as part of a broader face-to-face discussion. The panel reviewed questions derived from the existing migraine diaries in the public domain, those used in clinical trials, and patient-centric surveys assessing the impact of migraine on physical function and other related concepts. Key considerations included identification of the most clinically useful data elements for a shared communication tool for people with migraine under the care of a clinician. The panel also identified numerous functionality requirements for such a tool and provided recommendations on the most effective way to present results to a clinician. RESULTS: The expert panel opined that people with migraine may value the ability to capture a relatively broad range of information for their own migraine-tracking purposes, while clinicians will likely find greater value in a small set of data relevant to the management of migraine. The panel identified the 3 most essential concepts in categories of data for a clinician, for which they coined the term "The 3 Fs": Frequency of days with headache; Frequency of acute medication usage; and Functional impairment. Information on the frequency of days with headache was felt to combine with the information on the frequency of acute medication usage to provide essential insights into current migraine management strategy and its outcomes, and to assist considerations of preventive measures. Functional impairment was treated as an effective surrogate for headache severity and was assessed based on the following: degree of difficulty in performing activities of daily living, impact on absenteeism (taking leave from work or cancelling/avoiding other activities) and presenteeism (performing work or other daily activities, with reduced productivity/capability), and amount of rest required as a result of a migraine attack. The modified Delphi panel process resulted in the selection of 13 questions in 8 categories to elicit sufficient and meaningful data comprising headache occurrence, symptoms, daily/preventive and as-needed/acute medication usage, triggers, ability to concentrate, and functional impairment. The panel also agreed that the tracker should generate 2 distinct reports: one for people with migraine that would include a wider range of data about symptoms and perceived triggers, and a targeted report for the clinician that would place prime emphasis on the 3 Fs for aggregating the results of each headache occurrence and the trend over time. CONCLUSIONS: A system that easily captures critical data elements about migraine, with specific feedback displays for patients to share with clinicians during live discussions, may offer some benefit to people with migraine and their clinicians by facilitating more objective communication and optimizing management. The tracker's output may enable people with migraine to track a wide range of data for their own purposes, allowing them to better understand their condition, while a synthesized view of the selected data may support more informed clinical decision-making for the clinician and individualized, evidence-based discussion with the patient. As a result, this shared decision-making tool may enable patients to more accurately convey essential migraine information during live patient-clinician discussions to drive improved management and patient outcomes.

Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary.

OBJECTIVE: The objective of this study was to evaluate the measurement properties of the Migraine Physical Function Impact Diary (MPFID), a novel patient-reported outcome (PRO) measure for assessing the impact of migraine on physical functioning. METHODS: In a prospective, observational study, adults with episodic migraine (EM) or chronic migraine (CM) used an eDiary to complete the MPFID (assessing daily impacts of migraine on physical function) and a headache diary (capturing migraine days, migraine pain intensity, and migraine interference) each day, and other PRO instruments related to migraine. Item-level evaluation, item response theory (IRT), and exploratory factor analysis (EFA) methods were applied to identify domains, select final MPFID items, and develop scoring procedures. Psychometric properties of the final 13-item MPFID were evaluated using confirmatory factor analysis and tests of reliability (Cronbach's α for internal consistency and intra-class correlation [ICC] for test-retest) and validity (convergent and known-groups). RESULTS: The study enrolled 569 adults with chronic or episodic migraine, mean (SD) age 39.9 (12.0) years and 87.2% female. Item-level analyses based on interim data informed selection of a set of 13 items for the MPFID, through evaluation of floor/ceiling effects, item-to-item correlations, factor loadings, and IRT-based fit/misfit statistics. Two domain scores (EA: Impact on Everyday Activities; PI: Physical Impairment) and a global item score for impact on everyday activities were identified. EA and PI domains exhibited high internal consistency (α = 0.97; α = 0.93) and good test-retest reliability among stable subjects (ICCs = 0.74 and 0.77). Convergent validity was demonstrated by moderate correlations (r = ±0.50-0.68; P < .0001) between MPFID domain scores and number of migraine days, headache days, bed days, and other migraine-related PRO instruments. EA and PI scores differentiated between groups who varied by number of migraine days, migraine interference levels, migraine pain intensity, and median split groups of scores based on other PROs instruments (P < .05). CONCLUSIONS: The MPFID has robust psychometric properties (ie, reliability and validity). Findings supported two distinct domains about the impact of migraine on physical functioning: Impact on Everyday Activities and Physical Impairment. Both domain scores showed evidence of excellent reliability and construct validity in assessing the impacts of migraine on physical functioning.

Development and exploration of the content validity of a patient-reported outcome measure to evaluate the impact of migraine- the migraine physical function impact diary (MPFID).

BACKGROUND: Adults with migraine experience substantial reductions in quality of life during and in-between migraine attacks. Clinical and regulatory guidelines encourage the inclusion of patient reported outcomes for the evaluation of benefits of interventions for migraine. METHODS: The conceptual framework and items for a new patient-reported outcome (PRO) instrument, the Migraine Physical Function Impact Diary (MPFID), were developed using scientific methods recommended to ensure content validity of PRO instruments. The MPFID was developed to measure the impact of migraine on physical functioning based on themes raised in concept elicitation (CE) interviews (conducted previously) with adults with migraine. Cognitive interviews were conducted with adults with migraine to further explore content validity. The instrument was modified following an interim analysis of a first round of cognitive interviews, to assess comprehensiveness and clarity of items, instructions, and response options. Refinements were subsequently tested in additional cognitive interviews. RESULTS: The conceptual framework included impacts on physical functioning experienced by most adults with migraine and deemed clinically relevant for measuring the outcome of an intervention for migraine. Concepts in the framework included the impact of migraine on physical impairments (acts) and ability to complete day-to-day activities and perform everyday activities (tasks). MPFID items were generated to evaluate functioning over the past 24 h and to collect data daily, to capture experiences on days with migraine as well as the days in-between migraines. Items asked about needing to rest or lie down; ability to get out of bed, stand up, bend over, walk, perform household chores, do tasks outside the home, keep routines or schedules, get ready for the day, do activities that require concentration or clear thinking; difficulty moving head and body, doing activities requiring physical effort; avoiding interacting with others. Initial modifications based on the first round of cognitive interviews (n = 8) included clarifying instructions, updating three items to enhance specificity and clarity, and revising one item to include gender-neutral language. The second round of interviews (n = 9) confirmed acceptability of revisions and supported content validity. CONCLUSIONS: The results provide qualitative evidence supporting the content validity of the MPFID for evaluating outcomes of interventions for migraine.

Measuring the impact of migraine for evaluating outcomes of preventive treatments for migraine headaches.

BACKGROUND: Migraine is characterized by headache with symptoms such as intense pain, nausea, vomiting, photophobia, and phonophobia that significantly impact individuals' lives. The objective of this study was to develop a strategy to measure outcomes from the patients' perspectives for use in evaluating preventive treatments for migraine. METHODS: This study used a multi-stage process. The first stage included concept identification research through literature review, patient-reported outcome (PRO) instrument content review, and clinician interviews, and resulted in a list of concepts relevant to understand the migraine experience. These results informed the design of the subsequent concept elicitation stage that involved qualitative interviews of adults with migraine to understand their experiences. Information from these two stages was used to develop a conceptual disease model (CDM) of the migraine experience. This CDM was used to identify concepts of interest (COI) to evaluate patient-relevant outcomes for assessing treatment benefit of migraine prophylactics. In the final stage, existing PRO instruments were reviewed to assess coverage of concepts related to the selected COI. RESULTS: Nine articles from 563 screened abstracts underwent full review to identify migraine-relevant concepts. This concept identification and subsequent concept elicitation interviews (N = 32; 21 episodic migraine; 11 chronic migraine) indicated that people with migraine experience difficulties during and between migraine attacks with considerable day-to-day variability in the impact on movement, ability to perform every day and social activities, and emotion. The CDM organized concepts as proximal to and more distal from disease-defining migraine symptoms, and was used to identify impact on physical function as the key COI. The item level review of PRO instruments revealed that none of the existing PRO instruments were suitable to collect data on impact of migraine on physical functioning, to evaluate treatment benefit. CONCLUSIONS: The impact of migraine includes impairments in functioning during and between migraine attacks that vary considerably on a daily basis. There is a need for novel PRO instruments that reflect patients' migraine experience to assess treatment benefit of migraine prophylactics. These instruments must evaluate the concepts identified and be able to capture the variability of patients' experience.

Measurement properties of the flu-like symptom index from the hepatitis physical symptom severity diary.

PURPOSE: Chronic Hepatitis C (CHC) Virus infection is a serious health issue in the US. Standard treatment involves peginterferon alpha and ribavirin, often associated with adverse side effects including flu-like symptoms. These adverse effects are common reasons for the discontinuation of treatment and therefore represent a major obstacle in the effective treatment of CHC. METHODS: The Hepatitis Physical Symptom Severity Diary, a newly developed patient-reported outcome measure for assessing physical symptoms in CHC patients, was recently developed. It contains four questions addressing flu-like symptoms [the Flu-Like Symptom Index (FLSI)]. Measurement properties of the FLSI in CHC patients were assessed using data from two randomized clinical trials. RESULTS: Exploratory factor analysis using data from baseline and the last visit while on treatment supported a single-factor solution for the FLSI. Internal reliability and test-retest reliability are acceptable (Cronbach's alpha range 0.73-0.81; intraclass correlation coefficient range 0.85-0.97), and correspondence to several similar constructs was acceptable. The FLSI score was higher among those with investigator-reported flu-like symptoms (mean = 4.1) versus those without (1.4), although not statistically significant (p = 0.12). Responsiveness of the FLSI was moderate, as measured by standardized effect sizes and response means, and the minimum important difference (MID) was estimated at 2.5-3.0 points. CONCLUSIONS: While additional research should be conducted to evaluate validity with more closely related constructs and to utilize anchor-based methods for estimating the MID, data suggest that the FLSI has acceptable measurement properties and can be an effective tool in assessing flu-like symptoms in CHC patients.

Incidence and cost of treatment-emergent comorbid events in insured patients with chronic hepatitis C virus infection: a retrospective cohort study.

BACKGROUND: Treatment-emergent comorbid events (TECs) are common In patients initiating treatment with pegylated interferon alpha (PEG-IFN-alfa) and ribavirin for chronic hepatitis C virus (HCV) infection. The purpose of this study was to estimate the incidence and incremental cost of these events. METHODS: In a retrospective cohort analysis of healthcare claims, we studied patients with HCV who were newly treated with PEG-IFN-alfa/ribavirin between 2006 and 2008. TECs were defined by new medical/pharmacy claims for predefined conditions in the 12 months after treatment initiation. The net incremental cost of the TECs was the difference between baseline and follow-up costs for these comorbidities and their treatment, excluding PEG-IFN-alfa/ribavirin costs. RESULTS: Of 3,795 newly treated patients, 1,269 (mean age 50.2, 36.2% female) met the selection criteria. New TECs were common, with 61.6% of patients having ≥1 event. Anemia was identified in 29.2% of patients, fatigue in 16.4%, depression in 11.5%, and neutropenia in 11.0%. The mean incremental cost for the predefined TEC in the postindex period was $6,377 ($2,782 for medical and $3,595 for pharmacy claims). CONCLUSIONS: In an insured US cohort with chronic HCV infection, TECs with PEG-IFN-alfa/ribavirin were common and increased costs by approximately $6,000 per treated patient. This estimate may be conservative because it excludes indirect costs. Costs might increase with new regimens that include a protease inhibitor because additional TECs may be expected. Better-tolerated therapies that reduce the financial burden on the healthcare system and improve patient experience are needed.

Patient-reported experiences during and following treatment with belantamab mafodotin for relapsed/refractory multiple myeloma in the DREAMM-2 study.

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) are likely to be living with persistent symptoms, especially bone pain and fatigue, and experiencing restrictions in their physical and social functioning, which reduce health-related quality of life. Methods: This qualitative interview study evaluated patients' perspectives about living with RRMM and their treatment with belantamab mafodotin, using interviews embedded in the Phase II DREAMM-2 trial (NCT03525678) with belantamab mafodotin. Patients consented to participate in up to 2 recorded telephone interviews (at treatment cycle 4 [C4] and at end of treatment [EOT]) comprising open-ended questions. Results: A total of 142 interviews were conducted with 111 unique patients. At C4, common symptoms included neuropathy, fatigue, and bone or joint pain. Improvements in symptom severity were reported by patients who responded to belantamab mafodotin. Symptoms associated with visual impairment, eye irritation, and eye pain reported during the trial were reported to be at- or near-resolution by the EOT interview. Regarding impacts of underlying MM, patients most commonly expressed concerns about changes in daily performance and lifestyle for both responders (67.5% of all impact expressions) and non-responders (63.2%). Overall, interview participants reported being satisfied with belantamab mafodotin treatment. Discussion: This qualitative patient interview study provides valuable insight into patients' symptomatic experience with belantamab mafodotin for their RRMM treatment and may help healthcare providers better anticipate their patients' real-world experience and needs when prescribing this novel agent in the clinic.

A toolbox of different approaches to analyze and present PRO-CTCAE data in oncology studies.

BACKGROUND: The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is used to assess symptomatic adverse events in oncology trials. Currently, no standard for PRO-CTCAE analysis exists. METHODS: Key methods of descriptive analysis and longitudinal modeling using PRO-CTCAE data from an oncology clinical trial, DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2), a phase II trial of belantamab mafodotin in multiple myeloma (NCT03525678), were explored. Descriptive methods included maximum postbaseline ratings, mean change over time, ratings above a predefined cutoff, line graphs, and stacked bar charts to illustrate patient-reported adverse events at one timepoint or dynamics over time. Analysis methods involving modeling over time included toxicity over time (ToxT) (repeated measurement model, time-to-event, area under the curve analyses), generalized estimating equations (GEE), and ordinal log-linear models (OLLMs). RESULTS: Visualizations of PRO-CTCAE data highlighted different aspects of the data. Selection of the appropriate visualization will depend on the audience and message to be conveyed. Consistent results were obtained by all modeling approaches; no difference was found between dose groups of the DREAMM-2 study in any PRO-CTCAE item by the ToxT approach or the more sophisticated GEE and OLLM methods. Interpretation of GEE results was the most challenging. OLLM supported the interval nature of the PRO-CTCAE response scale in the DREAMM-2 study. All modeling approaches account for multiple testing (driven by the number of items). CONCLUSIONS: Descriptive analyses and longitudinal modeling approaches are complementary approaches to presenting PRO-CTCAE data. In modeling, the ToxT approach may be a good compromise compared with more sophisticated analyses.

Assessing the treatment pattern, health care resource utilisation, and economic burden of multiple myeloma in France using the Système National des Données de Santé (SNDS) database: a retrospective cohort study.

BACKGROUND: Real-world data on health care resource utilisation (HCRU) and costs for French patients with multiple myeloma (MM) are limited due to the quickly evolving MM treatment landscape. This retrospective, national-level study quantified the MM economic burden in France. METHODS: The study included patients with newly diagnosed MM from the Système National des Données de Santé coverage claims database between 2013 and 2018 who received active treatment within 30 days of diagnosis. HCRU included hospitalisations, drugs, consultations, procedures, tests, devices, transport, and sick leave. Costs were annualized to 2019 prices. Drug treatments, reported by line of therapy (LOT), were algorithmically defined using drug regimen, duration of therapy, and gaps between treatments. Analyses were stratified by stem cell transplantation status and LOT. RESULTS: Among 6413 eligible patients, 6229 (97.1%) received ≥ 1 identifiable LOT; most received 1 (39.8%) or 2 LOT (27.5%) during follow-up. Average annual hospitalisation was 6.3 episodes/patient/year (median duration: 11.6 days). The average annual cost/patient was €58.3 K. Key cost drivers were treatment (€28.2 K; 39.5% of total HCRU within one year of MM diagnosis) and hospitalisations (€22.2 K; 48.6% of total HCRU costs in first year). Monthly treatment-related costs increased from LOT1 (€2.447 K) and LOT5 + (€7.026 K); only 9% of patients received LOT5 + . At LOT4 + , 37 distinct regimens were identified. Hospitalisation costs were higher in patients with stem cell transplantation than total population, particularly in the first year. CONCLUSIONS: This study showed a high economic burden of MM in France (€72.37 K/patient/year in the first year) and the diversity of regimens used in late-line treatments.

Patient-Reported Outcomes With Belantamab Mafodotin Treatment in Patients With Triple-Class Refractory Multiple Myeloma.

In the randomized phase II DREAMM-2 study, single-agent belantamab mafodotin demonstrated deep and durable responses and a manageable safety profile in triple-class refractory relapsed/refractory multiple myeloma (RRMM). We present patient-reported outcomes (PROs) from this study for patients treated with the approved dose of belantamab mafodotin (2.5 mg/kg q3w). Disease and treatment-related symptoms, health-related quality of life (HRQOL), functioning, and patient-reported ocular changes were assessed using questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life questionnaires EORTC-QLQ-C30 and EORTC-QLQ-MY20, Ocular Surface Disease Index [OSDI], and the National Eye Institute Visual Functioning Questionnaire 25 [NEI VFQ-25]) at baseline, during treatment (every 3 or 6 weeks), and at the end of treatment (EOT). Eye examinations were conducted at baseline, prior to each treatment cycle, and at EOT. Patients reported ocular symptoms in the OSDI and NEI VFQ-25 questionnaires, with the median time to worst severity of 45 to 64 days depending on symptoms considered. Some limitations in driving and reading were reported. Ocular symptoms were improved and median time to recovery was 23.5 to 44.0 days. EORTC-QLQ-C30 data suggest core MM symptoms (including fatigue and pain), overall HRQOL, and patient functioning were maintained while patients continued belantamab mafodotin treatment, even if meaningful worsening of vision-related symptoms occurred. These PRO results, together with the clinical efficacy of belantamab mafodotin, support its use in patients with RRMM and further evaluation of its use at earlier lines of therapy.

Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis.

BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) require several lines of therapy, with typically shorter remission duration with each additional line. RESEARCH DESIGN AND METHODS: The cost-effectiveness of belantamab mafodotin (belamaf; DREAMM-2; NCT03525678) was compared with selinexor plus dexamethasone (SEL+DEX; STORM Part 2; NCT02336815) among patients with RRMM who have received at least four prior therapies. The base case used a US commercial payer's perspective over a 10-year time horizon. Efficacy data were based on parametric survival analysis of DREAMM-2 and matching-adjusted indirect treatment comparison between DREAMM-2 and STORM Part 2, which assessed relative treatment effects between belamaf and SEL+DEX. Cost inputs included drug treatment, concomitant medications, adverse event management, subsequent treatments, and disease management. RESULTS: Belamaf decreased total treatment costs per patient by $14,267 and increased patient life years by 0.74 and quality-adjusted life years (QALYs) by 0.49 versus SEL+DEX. Patients receiving belamaf accrued 0.12 fewer progression-free life years versus patients on SEL+DEX. CONCLUSIONS: From a US commercial payer's perspective, belamaf had lower costs, and increased QALYs and life-year gain, compared with SEL+DEX. Belamaf is therefore likely to be a cost-effective treatment option for patients with RRMM who have received four or more prior lines of therapy.

Care of asthma patients in relation to guidelines.

Clinical asthma care may have to change to be brought in line with Expert Panel Report 3 (EPR3) guidelines, which recommend increased intensity of therapy (steps) to treat uncontrolled asthma. This study determined if asthma therapy steps can be identified using claims data and if patients have appropriate step-up in therapy if their disease is not controlled. A cohort study was performed using an administrative claims database and involving patients 12-64 years old with uncontrolled asthma events (either impairment or risk). Patients were assigned to a preindex step (6 months before the index date) and postindex steps (1 year after the index date). The primary study outcome was a change in therapy steps. We used logistic regression to identify variables predictive of an increase in step. Our algorithm for assigning steps appeared internally valid; patients identified as being at higher steps saw more specialists and had higher levels of asthma risk. Among 14,781 patients for which a step-up option existed, 12.4-41.3% had a step-up in therapy after an uncontrolled asthma event. For all steps, high-risk patients had higher odds of having a step-up in therapy than low-risk patients. The odds ratio for appropriate therapy increased with increasing baseline step: from 1.50 for step 2 versus step 1, to 11.41 for step 5 versus step 1. Steps can be assigned using claims data. Bringing care in line with EPR3 guidelines will require significant changes from current practice but will improve quality by reducing use of oral corticosteroids and increasing use of inhaled steroids.

Poor disease control among insured users of high-dose combination therapy for asthma.

Adherence to asthma treatment may not completely prevent exacerbations. Clinical trial results indicate that many highly adherent asthma patients still have symptoms. Little is known about the level of control achieved by adherent patients outside clinical trials. This study was designed to evaluate the extent of asthma control among insured patients who were highly adherent to combination controller therapy. We used an administrative claims database for this cohort study of patients aged 12-64 years. Patients were newly treated with fluticasone, 500 micrograms/salmeterol, 50 micrograms, between January 1, 2003 and June 30, 2004. Patients were stratified according to adherence levels: low (<50%), moderate (50-74%), and high (> or =75%). We compared rates of poor control. A logistic regression model was used to control for baseline differences. Among 3357 patients, the mean age was 40.5 +/- 13.6 years, and 64.1% were women. Sixty-one percent had low adherence, 20% had moderate adherence, and 19% had high adherence. Highly adherent patients were older, and more used fluticasone, 250 micrograms/salmeterol, 50 micrograms, during the preindex period than the other groups. Even after starting high-dose fluticasone/salmeterol, many patients with low, moderate, and high adherence had indicators of poor symptom control (28.9% [587/2030], 30.6% [209/682], and 30.7% [198/645], respectively). Patients who were highly adherent and used additional controller medications had rates of poor control that ranged from 23.1 to 31.2%. After adjusting for age, gender, and baseline characteristics, results were similar. Many patients continue to have poor asthma control despite being adherent to high-dose combination therapy or using additional controller medications.