記住我
Migraine is a sometimes severe and often disabling disease that impairs daily activities and physical functioning.1 Symptoms can be aggravated by routine physical movement, such as straining and bending over.2 People with migraine often require bed rest during episodes.3-5 As a consequence, migraine can interfere with physical functioning, as well as leisure and social activities, and can have a profound impact on emotional and cognitive function.1, 6 Measuring the burden of migraine and the benefits of treatment relies on the use of patient-reported outcome (PRO) measures. In clinical trials of treatments for preventing migraine,7-10 outcomes in people with episodic migraine (EM) or chronic migraine (CM) have been assessed using various generic and disease-specific PRO measures, including the Migraine Disability Assessment (MIDAS),11 Headache Impact Test (HIT-6),12 and Work Productivity and Activity Impairment (WPAI) questionnaire.13, 14 However, although the Food and Drug Administration (FDA) provides guidance on PRO development,15 at the time this research began, no PRO measures for migraine-related functional impairment were included in labeling for migraine preventive medications in the United States. Subsequently, two PRO measures were included in labeling: the Migraine Specific Quality of Life Questionnaire, Version 2.1 Role Function-Restrictive (MSQ v2.1 RFR) domain and the Migraine Physical Function Impact Diary (MPFID).16-18 However, the 4-week recall period of the MSQ v2.1 potentially affects the accuracy of the assessments and is subject to recall bias. The MPFID, by contrast, is a daily diary measure, but was still in development and was therefore not available for use.
This paper describes the development and evaluation of the Activity Impairment in Migraine Diary (AIM-D), a new disease-specific PRO measure designed to assess the functional impact of migraine and intended to support labeling for migraine preventive medications. Development of the AIM-D began with a qualitative study to identify the symptom and impact concepts of greatest importance to patients with migraine. Based on findings from this qualitative research, a set of candidate items was developed to assess difficulties in performing daily activities, as well as physical and cognitive impairment due to migraine. Initial development and subsequent refinement of the AIM-D were underpinned by patient input through concept elicitation (CE) and cognitive interviews, input from clinical experts, and FDA recommendations. The psychometric properties of the AIM-D were subsequently evaluated in the context of an observational study in adults with EM or CM. The benefits and limitations of AIM-D as an outcome measure in migraine prevention trials are discussed.
METHODSInstitutional review board approval was obtained for all studies, and written informed consent was obtained from all study participants prior to enrolment. All authors were granted full access to the study data.
Qualitative development of the AIM-DQualitative development of the AIM-D is summarized in Figure 1. Consolidated criteria for reporting qualitative research-required information19 for the qualitative work is provided in Table S1. The AIM-D was developed in accordance with U.S. FDA PRO guidance.15, 20 A targeted literature review was performed to identify existing PRO measures for assessing treatment outcomes in adults with EM or CM.
Qualitative development of the AIM-D
Concepts relevant for the AIM-D were identified through telephone interviews with five clinicians experienced in treating migraine and face-to-face interviews with adults with EM or CM. The interviews with adults with migraine combined CE and cognitive debriefing of PRO measures, which included draft headache diaries and the Functional Impact of Migraine Questionnaire (FIMQ)21 but not the AIM-D. Table S2 shows sample questions from the interview guide used for the interviews with adults with migraine. These interviews were audio-recorded, transcribed, anonymized, and coded using ATLAS.ti (Atlas.ti GmbH, Berlin, Germany). The coding scheme, which had been developed based on the target literature review and the objectives of the study, was updated iteratively to reflect the actual terms participants used to describe concepts and to incorporate new concepts that emerged. This process was complemented by clinical guidance (from R.L. and D.D.). Interviews were continued until new concepts ceased to emerge, an outcome known as concept saturation.22 This was evaluated using saturation grids to determine the adequacy of the sample size and to ensure that no new concepts of interest were likely to be elicited by conducting further interviews. Individual concepts were explored to obtain an in-depth understanding of their meaning by obtaining examples from multiple participants.
In two subsequent in-person advisory meetings with a panel of clinical experts and experts in clinical outcome assessment research, concepts that emerged from these qualitative interviews were used to develop and refine the AIM-D. To minimize recall bias, the AIM-D was developed as a 24-h daily diary. The wording of the draft AIM-D items was informed by the words and phrases patients used to describe their migraine experience and the concepts of migraine impact. Concepts were selected for inclusion based on their importance and relevance to patients and the extent to which they were aligned with the target measurement concepts. Because the focus of the AIM-D was physical impairment (PI) and performance of daily activities (PDAs), other impacts with a different focus, such as interference with relationships and wanting to be alone, were excluded.
Three additional virtual advisory meetings of the expert panel were conducted to finalize the list of AIM-D items and refine the wording of the items and response options. The second and third of these meetings also aimed to gather clinician feedback on the instrument.
The AIM-D was debriefed in three waves of cognitive interviews with adults with EM or CM. Participants were asked to provide feedback on the instructions, items, and response options and suggest any changes they would make. After each wave of cognitive interviews, participant feedback was considered during one or more virtual meetings of the expert panel. During an additional virtual advisory meeting of the expert panel held after the second wave of interviews, it was decided to create separate versions of the AIM-D for use when headache occurred in the previous 24 h and when it did not.
The preliminary AIM-D conceptual framework included items evaluating PI and difficulties with daily activities. In addition, items assessing cognitive functioning, activity level, and activity limitations were developed outside of the conceptual framework for inclusion in the planned psychometric evaluation, on the advice of the expert panel. Based on the importance of cognitive impacts to patients with migraine and a review of the qualitative interview studies, the FDA recommended that further consideration be given to evaluating two of the items on cognition (concentrating and thinking clearly) within the AIM-D. Following further discussion with clinical experts, the conceptual framework was modified to include these two items.
Content analysis and psychometric evaluation in a longitudinal observational studyContent analysis and psychometric evaluation of the AIM-D were then assessed in an observational study. The observational study was approved by an institutional review board (Advarra, Columbia, MD) and was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation E6 guidelines for Good Clinical Practice.
Study designThe observational study was a prospective non-interventional study over 13 weeks (including a 1-week baseline period), conducted at 28 clinical sites in the United States (which included clinical research sites and neurology/pain centers). Participants were treated according to applicable standards of clinical care.
ParticipantsEnrolment ran from March to May 2019. Participants were recruited either directly by the participating clinical sites or through advertising on social media and then referred to one of the clinical sites for confirmation of eligibility. No formal sample size calculation was performed. However, the aim was to include at least 10 participants per AIM-D item for both the EM and CM subpopulations, in accordance with standard practices.23
Eligible participants were English-speaking adults (18–80 years of age) with EM or CM of at least 1 year's duration who met International Classification of Headache Disorders, 3rd edition criteria for migraine with or without aura. The EM group had 4–14 migraine days/month in the previous 3 months, and the CM group had an average of ≥15 headache days/month (with migraine headache on ≥8 days) in the previous 3 months. Participants were recruited who had changed migraine medication or dosing in the 2 weeks prior to enrollment (to facilitate assessment of the AIM-D’s responsiveness) or who had been on stable treatment for at least 12 weeks (to facilitate assessment of reliability). People who had changed migraine medication 2–12 weeks previously were excluded.
Potential participants were excluded if they were participating in a clinical trial; had difficulty distinguishing migraine headache from other headache types; had a history of retinal migraine or migraine accompanied by diplopia or decreased consciousness; had responded inadequately to ≥5 prescription preventive medications for migraine; had used opioids or barbiturates for >4 days/month in the previous 3 months (CM only); had a confounding psychiatric condition, a significant risk of self-harm, dementia, epilepsy, or a significant neurological disorder other than migraine; were also suffering from another pain condition; or had a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia, or painful cranial neuropathy.
AIM-DParticipants completed PRO assessments at home using an eDiary and at the clinical site using an eTablet. They completed the AIM-D daily throughout the study. Each AIM-D item asks respondents to rate level of difficulty on a six-point rating scale ranging from (0) “Not difficult at all” to (5) “I could not do it at all.” Three items (errands, leisure outside the home, and strenuous activities) include a response option allowing respondents to indicate that the activity was not planned. The headache and non-headache versions of the AIM-D include the same sets of items and instruct respondents to answer each question based on the level of difficulty experienced “in the past 24 hours.” However, the headache version instructs respondents to specifically consider the period “during [their] headache.” This is because the impact of migraine on patient functioning on a given day depends on whether or not the patient experiences a headache. This approach also aimed to make the items easier to respond to by anchoring them to a period that is clearly recognizable to respondents. The non-headache version provides a more comprehensive evaluation of functional impairment for days when the respondent does not experience a headache.
In addition to the AIM-D, participants provided daily responses to supplementary items evaluating activity level and activity limitation. Activity level was assessed on a 5-point scale ranging from “No activity – Spent all day lying down” to “Exercised – Brisk walk, running, jogging, biking or other activity for 30 or more minutes,” and activity limitation on a 5-point scale ranging from “Not at all limited – I could do everything” to “Extremely limited.”
Additional PRO measures for psychometric evaluationTo test the psychometric properties of the AIM-D, participants completed additional PRO assessments using the eDiary or eTablet, including a daily headache diary in which participants recorded whether they had experienced a headache (Yes/No). Other PRO assessments were the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L),24, 25 FIMQ,21 HIT-6,12 Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference – Short Form 6a,26, 27 PROMIS Pain Intensity Numeric Rating Scale (NRS),28 MSQ v2.1,29, 30 and MIDAS.11 Participants also completed the Patient Global Impression – Severity (PGI-S), a single-item measure that assesses overall severity of migraine symptoms over the previous 7 days on a 5-point scale ranging from “None” to “Very severe”; and the Patient Global Impression of Change (PGIC), a single-item measure that assesses change in migraine symptoms over time on a 7-point scale ranging from “Very much better” to “Very much worse.” The version of the PGIC used in this study asked participants to rate the change in migraine symptoms since the beginning of the study. Further details on these additional PRO assessments, including their timing, are provided in Tables S3 and S4.
Statistical analysisThis was the primary analysis of these data and was based on a prespecified statistical analysis plan for the psychometric analyses. Analyses were conducted using SAS® version 9.4 or later (SAS Institute Inc., Cary, NC). Data for all enrolled participants were used for the content analysis and internal consistency reliability analysis; the full analysis set (FAS), which comprised participants with AIM-D data for baseline and for at least 1 week from day 1 to week 12 (end of study), was used for other analyses. All statistical tests used a two-sided significance level of 0.05. Descriptive statistics were calculated for demographics and baseline characteristics. For the AIM-D, scores were calculated by summing the individual scores (out of 5) for the non-missing items, dividing the result by the number of non-missing items, and multiplying by the total number of items. For exploratory factor analysis and subsequent psychometric evaluation, raw scores were transformed to a 0–100 scale by dividing them by the maximum possible score and multiplying by 100.
The factor structure of the AIM-D was determined using random draws, with one observation per participant. The item-level analyses used data from one headache day and one non-headache day per participant, drawn at random from day 1 through day 28 using the SAS function “ranuni.” Floor effects were defined as >30% of participants selecting the minimum response and ceiling effects as >30% of participants selecting the maximum response. Item–item and item–total correlations were calculated as Spearman rank-order correlations using data for the same randomly drawn headache day and non-headache day used to assess floor and ceiling effects.
Exploratory factor analysis was conducted to examine the potential factor structure of the AIM-D using data for each participant from four randomly drawn days, each of which could be a headache or non-headache day. Factors with eigenvalues near to or greater than 1 were favored for retention. Root mean square error of approximation (RMSEA; acceptable if <0.07)31 and root mean square of residuals were calculated to evaluate model fit. Confirmatory factor analysis was used to confirm the domain structure of the AIM-D using data from three randomly drawn days (headache or non-headache). Weighted least squares (LS) mean and variance-adjusted maximum likelihood estimation was used to estimate the models. Model fit was assessed by calculating comparative fit index (CFI; acceptable if ≥0.9),32 Tucker–Lewis Index (TLI; acceptable if ≥0.9),32 RMSEA,31 and standardized root mean square residual (SRMR; acceptable if <0.08).33 Factor loadings of ≥0.40 were considered acceptable.34 For each of the factor analyses, data are presented for one random draw.
Internal consistency reliability was separately assessed for headache and non-headache days by calculating Cronbach's alpha using data for a randomly drawn day (headache or non-headache). A value ≥0.7 is considered good internal consistency reliability.23, 35
We compared weekly average scores at baseline with weekly average scores at week 2 and monthly average scores at week 4 for participants who selected the same response for the PGI-S at baseline and week 2 or at baseline and week 4, and for patients who indicated “no change” on the PGIC at week 4. A weekly average AIM-D score was calculated if AIM-D scores were available for ≥4 days within a period of seven consecutive days; monthly average AIM-D scores were calculated if AIM-D scores were available for ≥14 days in the relevant 28-day period. In calculating weekly and monthly AIM-D scores, data for all days in the given period were used (i.e., headache and non-headache days were not distinguished from each other). Data for the pairs of time points were compared by a paired t-test. To assess test–retest reliability, intraclass correlation coefficients (ICCs) were calculated using a random-effects analysis of variance model.36 An ICC of 0.41–0.60 indicates moderate agreement, 0.61–0.80 substantial agreement, and 0.81–1.00 near-perfect agreement.37
To examine the convergent validity of the AIM-D, Spearman's rank-order correlations were calculated between AIM-D scores and scores for other PRO measures using baseline data. A correlation coefficient >0.30 among measures of similar concepts indicates moderate convergent validity and a correlation coefficient >0.50 strong convergent validity.38
Known-groups validity was evaluated by comparing least squares mean AIM-D scores at baseline between different subgroups of participants, grouped according to number of migraine days, MSQ v2.1 RFR score (dichotomized around the median score: <54 vs. ≥54), and HIT-6 score category.39 Analysis of covariance was conducted to assess the significance of the differences in AIM-D scores between participant subgroups, with age and sex included in the models as covariates.
Finally, responsiveness was explored by using regression models to evaluate the associations of changes in monthly AIM-D scores between baseline and month 3 with change in PGI-S score (categorized as worsened, no change, improved), percentage change in number of monthly migraine days (no change or increased, reduced by <30%, reduced by ≥30%), change in activity limitation (worsened, no change, improved), and change in HIT-6 total score (no change or increased, reduced by <2.5 points, reduced by ≥2.5 points). Effect sizes for the magnitude of differences between categories were calculated using Cohen's d.38
RESULTS Qualitative developmentThe targeted literature review identified 17 existing PRO measures that could be used to assess treatment outcomes in adults with EM or CM. Migraine-specific instruments addressing migraine symptoms, impacts, and/or patient satisfaction and with information available on development of the instrument were subjected to an in-depth review. Evaluation of the seven PRO measures included in the in-depth review revealed limitations in content validity and development according to FDA PRO guidance, and indicated that none of the instruments identified adequately measured the proximal impacts of migraine (Table S5).
Demographics and clinical characteristics of the 40 adults with EM (n = 20) or CM (n = 20) who participated in the mixed CE/cognitive interviews are shown in Table S6. Concepts that frequently emerged in these interviews included impacts on ability to concentrate (92.5%), ability to move around (80.0%), social activities (80.0%), leisure activities (75.0%), ability to communicate (65.0%), and household activities (65.0%) (Table S7). Saturation of all impact-related concepts was achieved for both EM and CM. The identified impacts were considered during subsequent development of the AIM-D, whose preliminary conceptual framework comprised two domains of items on PI and difficulties with daily activities, as well as a total score.
The AIM-D was debriefed in three waves of cognitive interviews with a total of 38 adults with EM (n = 18) or CM (n = 20). In addition to the AIM-D items measuring PI and PDAs, items on cognitive functioning (“concentrating,” “thinking clearly,” and “remembering things”), activity level, and activity limitations were developed and debriefed outside of the AIM-D conceptual framework. Demographics and clinical characteristics of the cognitive interview participants are shown in Table S8. Changes to the initial pool of AIM-D items were made based on expert panel review of participant feedback from the interviews. These changes are summarized in Table S9. To reduce redundancy and shorten the instrument, the three items pertaining to the home were consolidated as two items (household activities at home and leisure activities at home) after the first wave of cognitive interviews (n = 11), and daily activities outside the home was removed. Three other items were also removed: moving the head, due to issues in attributing the concept to something other than migraine; moving the body, due to its generic nature and because it was likely captured through another item on walking; and getting around, because participants incorrectly interpreted the item as pertaining to transportation.
Following debriefing of the revised AIM-D in a second wave of cognitive interviews (n = 13), moving the head and moving the body were reinstated based on their clinical relevance. In the third wave of cognitive interviews (n = 14), participants reported that the instructions, response options, and recall period of the headache and non-headache versions of the AIM-D were easily understood and relevant. Eight participants (57.1%) suggested that relevant concepts such as emotional impact or pain were not covered by the AIM-D, but none of these concepts were reported by more than two participants. Because the instructions, items, and response options were interpreted as intended, no changes to the AIM-D were made based on the results of the third wave of cognitive interviews. However, at the recommendation of the FDA and following further discussion with clinical experts, two of the items on cognition (“concentrating” and “thinking clearly”) were added to the preliminary conceptual framework, and the AIM-D was psychometrically evaluated as an 11-item measure (Table S9).
Observational study participantsThe observational study was conducted from March to August 2019. A total of 375 participants provided written informed consent and were enrolled, of whom 316 (186 with EM and 130 with CM) were included in the FAS (Figure 2). Forty-seven participants were excluded from the FAS because they did not have AIM-D data for both baseline and at least one subsequent study week.
Participant disposition. †Participants from two clinical sites were excluded because of data collection problems. ‡Reasons for exclusion were not mutually exclusive. §Change of current treatment, including change of dosing (preventive or acute for episodic migraine; preventive for chronic migraine) within the previous 2 weeks. FAS, full analysis set
The mean (standard deviation [SD]) age of participants was 45.0 (12.8) years (range 18–79) and 86.4% of participants were female (Table 1). Most participants were White (74.7%), not Hispanic or Latino (74.1%), and living with a spouse or partner (78.8%). Participants with EM and CM were well balanced in terms of demographics.
TABLE 1. Demographics and baseline characteristics Total sample (N = 316) Episodic migraine (N = 186) Chronic migraine (N = 130) Demographics Age, years Mean (SD) 45.0 (12.8) 43.9 (12.8) 46.7 (12.7) Range 18–79 18–79 21–75 Sex, n (%) Female 273 (86.4) 160 (86.0) 113 (86.9) Race, n (%)a American Indian/Alaskan Native 4 (1.3) 3 (1.6) 1 (0.8) Asian 22 (7.0) 14 (7.5) 8 (6.2) Black or African American 58 (18.4) 33 (17.7) 25 (19.2) Native Hawaiian/Pacific Islander 0 0 0 White 236 (74.7) 141 (75.8) 95 (73.1) Other 5 (1.6) 2 (1.1) 3 (2.3) Ethnicity, n (%) Hispanic or Latino 82 (25.9) 54 (29.0) 28 (21.5) Not Hispanic or Latino 234 (74.1) 132 (71.0) 102 (78.5) Living/domestic situation, n (%) Living alone 64 (20.3) 40 (21.5) 24 (18.5) Living with spouse or partner 249 (78.8) 145 (78.0) 104 (80.0) Other 3 (0.9) 1 (0.5) 2 (1.5) Clinical characteristics b Diagnosis, n (%) Migraine without aura 241 (76.3) 143 (76.9) 98 (75.4) Migraine with aura 143 (45.3) 81 (43.5) 62 (47.7) Years since diagnosis of migraine Mean (SD) 16.5 (13.6) 15.7 (13.0) 17.7 (14.4) Range 1.2–58.0 1.2–55.0 1.3–58.0 History of 4–14 migraine days/month, n (%) 186 (100.0) 0 Average number of migraine days/month,c n (%) 4–5 days 67 (36.0) 6–7 days 51 (27.4) 8–9 days 26 (14.0) 10–14 days 42 (22.6) History of 15 or more headache days/month, n (%) 0 130 (100.0) Preventive medication for migraine ever prescribed, n (%) None 143 (45.3) 123 (66.1) 20 (15.4) Baseline PRO assessments d HIT-6 total score Mean (SD) 62.4 (6.0) 61.7 (6.0) 63.4 (5.9) PROMIS Pain Interference total score Mean (SD) 60.8 (8.1) 59.7 (8.8) 62.4 (6.9) PROMIS Pain Intensity NRS Mean (SD) 5.9 (2.3) 5.6 (2.4) 6.2 (2.0) MSQ v2.1 Role Function-Restrictive Mean (SD) 51.7 (23.6) 55.0 (23.6) 47.1 (23.0) Role Function-Preventive Mean (SD) 64.4 (24.6) 66.2 (24.0) 61.8 (25.2) Emotional Function Mean (SD) 62.2 (30.2) 65.8 (29.6) 57.1 (30.5) MIDAS Mean (SD) 71.8 (85.4) 66.6 (91.7) 79.4 (75.0) Missing, n 5 2 3 EQ-5D-5L Utility score Mean (SD) 0.86 (0.11) 0.88 (0.10) 0.82 (0.11) Missing, n 48 28 20 VAS Mean (SD) 79.2 (13.6) 81.7 (12.0) 75.6 (15.0) Missing, n 48 28 20 FIMQ Mean (SD) 46.6 (19.1) 43.0 (18.1) 51.6 (19.6) AIM-De PDA domain Mean (SD) 20.5 (17.7) 15.7 (14.0) 27.3 (20.1) PI domain Mean (SD) 14.5 (15.0) 11.0 (11.7) 19.5 (17.5) AIM-D total score Mean (SD) 18.1 (16.3) 13.8 (12.8) 24.3 (18.6) Abbreviations: AIM-D, Activity Impairment in Migraine Diary; EQ-5D-5L, EuroQoL 5 Dimensions 5 Levels; FIMQ, Functional Impact of Migraine Questionnaire; HIT-6, Headache Impact Test; MIDAS, Migraine Disability Assessment; MSQ v2.1, Migraine Specific Quality of Life Questionnaire, Version 2.1; NRS, Numeric Rating Scale; PDA, performance of daily activities; PI, physical impairment; PRO, patient-reported outcome; PROMIS, Patient-Reported Outcomes Measurement Information System; SD, standard deviation; VAS, Visual Analog Scale.The mean time since diagnosis of migraine was 16.5 (13.6) years (range 14 months to 58 years) (Table 1). The most frequently used preventive treatment for migraine was topiramate (26.9% for CM, 13.4% for EM). Two-thirds (66.1%) of participants with EM and 15.4% of participants with CM were not taking a preventive treatment for migraine. Sumatriptan (21.8% overall) was the most frequently used acute treatment for migraine.
Mean (SD) HIT-6 total score at baseline was 62.4 (6.0) (Table 1), indicating a substantial impact on participants' ability to function. Similarly, the mean (SD) PROMIS Pain Interference total score of 60.8 (8.1), which is approximately 1 SD above the US population norm of 50,
留言 (0)