RESEARCH ARTICLE OPEN ACCESS Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial Richard B. Lipton, MD, Patricia Pozo-Rosich, MD, PhD, Andrew M. Blumenfeld, MD, Ye Li, PhD, Correspondence Lawrence Severt, MD, PhD, Jonathan T. Stokes, MBA, Lela Creutz, PhD, Pranav Gandhi, PhD, and Dr. Lipton David Dodick, MD richard.lipton@ einsteinmed.edu ® Neurology 2023;100:e764-e777. doi:10.1212/WNL.0000000000201568 Abstract RELATED ARTICLE Background and Objectives Editorial The oral calcitonin gene–related peptide receptor antagonist atogepant is indicated for the Migraine—Not Just a preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes Numbers Game: Aim to Improve Quality of Life with atogepant in adults with migraine. Page 357 Methods MORE ONLINE In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4–14 migraine days per month received atogepant (10, 30, or 60 Class of Evidence mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine- Criteria for rating Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function–Restrictive (RFR) do- therapeutic and diagnostic main at week 12 and mean monthly Activity Impairment in Migraine–Diary (AIM-D) Performance studies of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment NPub.org/coe period. Exploratory endpoints included change in MSQ Role Function–Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)–6 scores. Results Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: −2.54; p = 0.0003; PI: −1.99; and p = 0.0011) and 60 mg groups (PDA: −3.32; p < 0.0001; PI: −2.46; p < 0.0001), but not for the 10 mg group (PDA: −1.19; p = 0.086; PI: −1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal im- provements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. Discussion Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention. From the Albert Einstein College of Medicine and the Montefiore Headache Center (R.B.L.), Bronx, NY; Headache Unit, Neurology Department (P.P.-R.), Vall d’Hebron University Hospital, Barcelona; Headache Research Group, VHIR (P.P.-R.), Universitat Autonoma of Barcelona, Barcelona, Spain; Headache Center of Southern California (A.M.B.), Carlsbad, CA; AbbVie (Y.L., L.S., J.T.S., P.G.), Madison, NJ; Peloton Advantage LLC, an OPEN Health Company (L.C.), Parsippany, NJ; and Department of Neurology (D.W.D.), Mayo Clinic, Scottsdale, AZ. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by AbbVie. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. e764 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Glossary AIM-D = Activity Impairment in Migraine–Diary; CGRP = calcitonin gene–related peptide; CM = chronic migraine; eDiary = electronic diary; EF = Emotional Function; EM = episodic migraine; eTablet = electronic tablet; HA = headache (day); HIT-6 = Headache Impact Test–6; FDA = Food and Drug Administration; HRQoL = health-related quality of life; ICHD-3 = International Classification of Headache Disorders, third edition; LSMD = least-square mean difference; mAb = monoclonal antibody; MID = minimally important difference; mITT = modified intent-to-treat; MHD = monthly headache day; MMD = monthly migraine days; MMRM = mixed models for repeated measure; MSQ v2.1 = Migraine-Specific Quality- of-Life Questionnaire version 2.1; nHA = nonheadache (day); PDA = performance of daily activities; PI = physical impairment; PRO = patient-reported outcome; QD = once daily; RFP = Role Function–Preventive; RFR = Role Function–Restrictive. Trial Registration Information ClinicalTrials.gov NCT03777059. Submitted: December 13, 2018; First patient enrolled: December 14, 2018. clinicaltrials. gov/ct2/show/NCT03777059. Classification of Evidence This study provides Class II evidence that daily atogepant is associated with improvements in health-related quality-of-life measures in patients with 4–14 migraine days per month. Migraine, a highly prevalent neurologic disease defined by re- (HIT)–6 score. The primary research question was the effect of current attacks of headache pain and associated symptoms daily atogepant on health-related qualify-of-life measures among (e.g., aura, photophobia, nausea, and allodynia), is a leading patients with 4–14 migraine days per month. cause of disease burden.1-5 Migraine reduces the performance of daily activities, participation in social/leisure activities, physical/emotional functioning, and health-related quality of Methods life (HRQoL), both during and between attacks.6-11 Preventive migraine treatments aim to reduce the frequency, intensity, and Trial Design duration of attacks and should reduce activity limitations and Detailed methods of the ADVANCE trial have been published.18 improve HRQoL.12,13 Assessing the effect of migraine on This multicenter, randomized, double-blind, placebo-controlled, HRQoL using patient-reported outcome (PRO) measures is parallel-group phase 3 trial was conducted from December 14, important when evaluating preventive treatments.12-15 2018, to June 19, 2020, at 136 sites in the United States. Partici- pants were randomized to receive placebo and atogepant (10, 30, Atogepant is a recently approved oral, small-molecule, calcitonin or 60 mg) once daily (QD) at a 1:1:1:1 ratio. Randomization was gene–related peptide (CGRP) receptor antagonist (gepant)16,17 stratified by previous exposure to a migraine prevention medica- that demonstrated efficacy, safety, and tolerability for preventive tion with proven efficacy. The randomization sequence was treatment of migraine in phase 2/316 and phase 3 (ADVANCE) generated by an automated interactive web response system. trials in people with 4–14 monthly migraine days (MMDs).18 In Blinding was maintained by providing treatments in identical the ADVANCE trial, 10, 30, and 60 mg of atogepant once daily blister cards and masking treatment assignment from participants significantly reduced MMDs across the 12-week treatment pe- and site and sponsor personnel. The study included a 4-week riod (primary endpoint) compared with placebo. In this study, baseline period, 12-week double-blind treatment period, and we emphasized results from PROs that were selected as alpha- 4-week safety follow-up period. Participants were instructed to controlled secondary endpoints in the ADVANCE trial, in ac- take study treatment once daily, orally, at approximately the same cordance with the US Food and Drug Administration (FDA) time each day. regulatory guidance.19 These endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire ver- Participants sion 2.1 (MSQ v2.1) Role Function–Restrictive (RFR) domain Eligible participants were adults aged 18–80 years with 4–14 score at week 12 and mean monthly Activity Impairment in MMDs in the 3 months before screening and 4–14 migraine Migraine–Diary (AIM-D) Performance of Daily Activities days recorded in an electronic diary (eDiary) during the 28-day (PDA) and Physical Impairment (PI) domain scores across the baseline run-in period. Additional inclusion criteria required 12-week treatment period. We also presented results from pre- ≥1-year history of migraine with or without aura consistent specified exploratory analyses of the MSQ v2.1 RFR and AIM-D with a diagnosis according to the International Classification of PDA and PI domains at other time points and other MSQ v2.1 Headache Disorders, third edition (ICHD-3)2 and migraine onset domains, total AIM-D score, and the Headache Impact Test before 50 years of age. Participants were excluded if they had a Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e765 current diagnosis of chronic migraine (CM), new persistent daily psychometrically sound 11-item daily diary measure that assesses headache, trigeminal autonomic cephalalgia (e.g., cluster head- the effect of migraine.24 The AIM-D has 2 domains: PDA (7 ache), or painful cranial neuropathy as defined by ICHD-32; ≥15 items) and PI (4 items). Validation studies for the AIM-D have monthly headache days (MHDs) on average across 3 months been published.24 Participants were asked to rate the level of before visit 1 or during the 28-day baseline period; a history of difficulty experienced in the past 24 hours with PDA (i.e., difficulty inadequate response to >4 medications (2 with different mech- with household chores, errands, leisure activities at home, leisure anisms of action) prescribed for preventive migraine treatment; or social activities outside the home, strenuous physical activities, use of opioids >2 days per month, triptans or ergots ≥10 days per concentrating, and thinking clearly) and PI (i.e., difficulty walking, month, or simple analgesics (e.g., aspirin, nonsteroidal anti- moving body, bending forward, and moving head) using a 6-point inflammatory drugs, and acetaminophen) ≥15 days per month ordinal response scale ranging from “not difficult at all” to “I could during the 3 months before screening or baseline period; or the not do it at all.” Three items also include response options of “I did use of barbiturates >2 days per month in the 3 months before not…” (e.g., “I did not have errands planned.”). The AIM-D was screening or any use within 30 days of screening. developed with similar questions and content for headache (HA) day and nonheadache (nHA) day items; the only difference is the Outcome Measures instruction provided to the patient with “during your headache” Migraine-Specific Quality-of-Life Questionnaire indicated for the HA day version. Version 2.1 Participants completed the MSQ v2.1 through electronic tablet For both HA and nHA days, the daily AIM-D PDA domain score (eTablet) at study sites at baseline (treatment day 1) and at weeks required availability of ≥4 item scores per day; otherwise, the 4, 8, and 12. The MSQ v2.1, a 14-item questionnaire designed to domain score was considered missing. A raw daily AIM-D PDA measure migraine-specific HRQoL over the past 4 weeks, has 3 score was calculated based on summation of scores for individual domains.20,21 The 7-item MSQ v2.1 RFR domain measures the items 1–5, 10, and 11. Each of the 7 items had scores of 0–5, so degree to which migraine limits the performance of daily social that raw domain scores were 0–35. If the response category “I did and work-related activities. The 4-item MSQ v2.1 Role not have errands, leisure or social, strenuous activities planned” Function–Preventive (RFP) domain measures the degree to (items 2, 4, and 5) was selected, the response was considered which migraine interrupts or prevents the performance of daily missing. The raw daily AIM-D PDA score was the sum of social and work-related activities. The 3-item Emotional Function nonmissing item scores divided by the number of nonmissing (EF) domain assesses emotions associated with migraine. All items, given >50% of items have responses, and then multiplied MSQ v2.1 items use a 6-point ordinal scale with response options by 7. Raw daily scores were transformed to a 0–100 daily domain ranging from “none of the time” to “all of the time.” Raw domain score by multiplying by 100 and dividing by the highest possible scores were computed as a sum of item responses and rescaled to raw score (35). Higher scores indicate greater difficulty in per- a 0–100 scale, based on the developer’s scoring scheme, where forming daily activities. A similar approach was used for com- higher scores indicate better daily functioning (i.e., lesser effect of puting the raw daily score for the AIM-D PI domain and required migraine) and positive changes in scores reflect improvement in that ≥2 item scores were available; if not, the domain score was quality of life. The MSQ v2.1 has been shown to be reliable, valid, considered missing. The raw daily AIM-D PI score (range: and sensitive to changes in migraine with treatment.20-22 The 0–20) was the sum of scores for individual items 6–9. between-group minimally important difference (MID) for the MSQ-RFR is 3.2 points, MSQ-RFP is 4.6 points, and MSQ-EF is For both HA and nHA days, the daily total raw score (range: 7.5 points.23 The meaningful within-group change for responder 0–55) was the sum of scores for individual items 1–11, if ≥6 analyses is 5.0 points for the MSQ-RFR, 5.0–7.9 points for MSQ- items had nonmissing responses. When the response category “I RFP, and 8.0–10.6 points for MSQ-EF.18,23 Change from baseline did not have errands, leisure or social, strenuous activities plan- in MSQ-v2.1 RFR domain score at week 12 was a prespecified ned” (items 2, 4, and 5) was selected, the response was con- alpha-controlled secondary efficacy endpoint. Changes from sidered missing. The daily total raw score was transformed to a baseline in the MSQ-v2.1 RFR domain score at weeks 4 and 8 and 0–100 scale by multiplying by 100 and dividing by the highest MSQ-v2.1 RFP and -EF domain scores at weeks 4, 8, and 12 were possible raw score (55), with higher scores indicating worse prespecified exploratory endpoints. activity impairment. Monthly AIM-D PDA and PI domain and total scores were the average of daily scores, calculated by Per COVID-19–related protocol amendments, the MSQ v2.1 summing nonmissing daily scores (HA and nHA days com- and HIT-6 at visit 7/week 12 were collected remotely by bined) and dividing by the number of nonmissing daily scores, eTablet starting on 4/20/2020, according to the remote visit provided there were ≥14 nonmissing daily scores (HA and nHA procedure. A total of 10 participants (1.1%) missed ≥1 PRO days combined) in the corresponding 28-day period; otherwise, assessment at week 12 because of COVID-19. the monthly total score was set to missing. Activity Impairment in Migraine–Diary Changes from baseline in the mean monthly AIM-D PDA do- Participants completed the AIM-D in eDiaries once daily main score and the mean monthly PI domain score across the throughout the entire study, including during the 4-week baseline 12-week treatment period were prespecified alpha-controlled period. The AIM-D is a novel, rigorously developed, and secondary efficacy endpoints and have been previously e766 Neurology | Volume 100, Number 8 | February 21, 2023 Neurology.org/N reported.18 Changes from baseline in monthly PDA and PI models that included treatment group, visit, previous exposure to a domain scores of the AIM-D at weeks 1–4, 5–8, and 9–12 and in preventive migraine medication (yes/no), and treatment group by monthly AIM-D total score at weeks 1–4, 5–8, 9–12 and average visit as categorical fixed effects; and baseline score and baseline-by- across the 12-week treatment period were prespecified explor- visit interaction as covariates. Binary exploratory endpoints atory efficacy endpoints. (i.e., percentage of participants with ≥5-point improvement [de- crease] from baseline in HIT-6 total score) were analyzed using a Headache Impact Test–6 generalized linear mixed model that included treatment group, Participants completed the HIT-6 on an eTablet at study sites at visit, previous exposure (yes/no) to a preventive migraine medi- baseline (day 1 of treatment) and at weeks 4, 8, and 12. The HIT-6 cation, and treatment group–by-visit interaction as categorical fixed is a 6-item assessment used to measure the effect of headaches on effects; baseline value and baseline-by-visit interaction as covariates; normal daily life and ability to function on the job, at school, at and participants as random effects. Post hoc exploratory analyses of home, and in social situations in the past 4 weeks.25,26 Responses the proportions of participants reaching the within-group MID for are based on frequency using a 5-point verbal response scale each MSQ v2.1 domain used a similar generalized linear mixed ranging from “never” to “always.” The HIT-6 total score is the sum model. p Values from the tests between each atogepant dose group of all responses, each of which is assigned a score ranging from 6 and the placebo group are reported. Except for secondary efficacy points (never) to 13 points (always). HIT-6 total scores range endpoints, all analyses were performed at the nominal significance from 36–78 and are interpreted as little or no effect (score ≤49), level, without adjusting for multiplicity. some effect (50–55), substantial effect (56–59), and severe effect (60–78) due to headache, with higher scores indicating greater Standard Protocol Approvals, Registrations, effect and lower scores indicating improvement.27 The HIT-6 has and Participant Consents been validated in people with episodic migraine (EM)28 and in All participating sites obtained approval from a local or central those with CM.28-30 The between-group MID for HIT-6 in people Institutional Review Board. The trial was conducted accord- with EM is −1.5 points,31 and the within-patient MID for re- ing to Good Clinical Practice and the Declaration of Helsinki. sponder analyses is a score reduction of 5.0 points.28,31-33 Changes Participants provided written informed consent before en- from baseline in HIT-6 total score at weeks 4, 8, and 12 and rollment. The study is registered with ClinicalTrials.gov percentages of participants with ≥5-point reduction in HIT-6 (NCT03777059). The study protocol and statistical analysis (responders) at weeks 4, 8, and 12 were prespecified exploratory plan have been published.18 endpoints. Data Availability Statistical Analysis Clinical trial data can be requested by any qualified researchers All analyses were conducted on participants in the modified who engage in rigorous, independent scientific research and will intent-to-treat (mITT) population with available data for each be provided following review and approval of a research proposal outcome measure and time point. The mITT population in- and Statistical Analysis Plan and execution of a Data Sharing cluded all participants who received ≥1 dose of study drug, who Agreement. Data requests can be submitted at any time, and data had an evaluable baseline period of eDiary data, and who had will be accessible for 12 months, with possible extensions con- ≥1 evaluable postbaseline 4-week period of eDiary data during sidered. For more information on the process, or to submit a the double-blind treatment period. Descriptive comparisons request, visit the following link: abbvie.com/our-science/clinical- between the atogepant and placebo groups were reported as trials/clinical-trials-data-and-information-sharing/data-and-in- differences in change from baseline and corresponding odds formation-sharing-with-qualified-researchers.html. ratios. Secondary endpoints of change from baseline in MSQ v2.1 RFR domain score at week 12 and changes from baseline in mean monthly AIM-D domain scores across the 12-week Results treatment period were analyzed using mixed models for re- Participants and Baseline Characteristics peated measures (MMRMs) that included the treatment Of 910 participants randomized, 902 took ≥1 dose of trial treat- group, visit, previous exposure to a migraine prevention med- ment (safety population), and 873 were included in the mITT ication (yes/no), and treatment group by visit as categorical population (placebo, n = 214; atogepant [10 mg], n = 214; ato- fixed effects and baseline score and baseline-by-visit interaction gepant [30 mg], n = 223; and atogepant [60 mg], n = 222; as covariates. The overall type I error rate for multiple com- Figure 1). Demographic and baseline characteristics are summa- parisons across the 3 atogepant doses and the secondary effi- rized in Table 1. In the mITT population, the mean (SD) age was cacy endpoints was controlled at the 0.05 level using a graphical 41.7 (12.3) years. Most participants were female (89%) and White approach with weighted-Bonferroni test procedure.34 Within (84%). Participants had a mean (SD) of 7.6 (2.4) MMDs and 8.7 each dose, testing started from the primary endpoint, followed (2.6) MHDs during the baseline period. by testing of the secondary endpoints in a prespecified order.18 Migraine-Specific Quality-of-Life Continuous exploratory endpoints (i.e., changes from baseline in Questionnaire Version 2.1 MSQ v2.1 domain scores, mean monthly AIM-D domain and total MSQ v2.1 domain scores at baseline were similar among scores, and HIT-6 total scores) were analyzed using MMRM treatment groups and were reflective of substantial to Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e767 Figure 1 Participant Disposition DBTP = double-blind treatment period; mITT = modified intent-to-treat; QD = once daily. moderate effect on daily social and work-related activities with a Activity Impairment in Migraine–Diary mean MSQ-RFR score of 46, mean MSQ-RFP score of 61, and At baseline, the mean AIM-D domain scores were similar substantial emotional effect of migraine with a mean MSQ-EF among groups and reflected modest impairment in PDA (mean score of 53 (Table 1). As previously reported,18 the change scores: 15–17) and PI (mean scores: 11–13; Table 1). As from baseline in the MSQ-v2.1 RFR domain score at week 12 previously reported,18 changes from baseline in mean monthly (secondary endpoint) demonstrated statistically significant and AIM-D PDA and PI scores across the entire 12-week double- clinically meaningful (between-group difference exceeded MID blind treatment period (secondary endpoints) showed statis- of 3.2 points) improvements in the effect of migraine on daily tically significant improvement with atogepant (30 and 60 mg) social and work-related activities in all atogepant groups com- compared with placebo (p ≤ 0.002 after multiplicity adjust- pared with placebo (p < 0.0001 for all comparisons after ment); the 10 mg group did not show statistically significant multiplicity adjustment; Figure 2). improvement compared with placebo (PDA, p = 0.086; PI, p = 0.074; Figure 3). Analysis of exploratory MSQ v2.1 endpoints demonstrated nominally greater (p ≤ 0.02) improvements in all atogepant Analysis of exploratory AIM-D endpoints demonstrated groups compared with placebo in MSQ-v2.1 RFR, MSQ-v2.1- nominally greater improvements in mean monthly AIM-D RFP, and MSQ-v2.1-EF scores on the least-square mean dif- PDA and PI domain scores and total scores vs placebo in all ference (LSMD) scores from the earliest time point assessed atogepant groups over the first month of treatment (weeks (week 4) and throughout the 12-week double-blind treatment 1–4, p ≤ 0.012) and for the 30 and 60 mg atogepant groups at period (Figure 2). The LSMD between each atogepant group weeks 5–8 (p ≤ 0.040) and 9–12 (p ≤ 0.009; Figure 3). Im- vs placebo in MSQ-v2.1 RFR, MSQ-v2.1-RFP, and MSQ-v2.1- provements in AIM-D scores increased with atogepant dose, EF scores achieved the between-group MID at all doses and with the largest improvements in AIM-D PDA, PI, and total time points evaluated, except for the EF domain in the 10 mg scores consistently observed with 60 mg of atogepant at each group at week 4 (Figure 2). Nominally greater proportions of time point (Figure 3). participants in the atogepant groups than placebo had im- provements in MSQ v2.1 scores that exceeded the established Headache Impact Test–6 within-group MID (reflective of clinically meaningful im- The mean baseline HIT-6 total scores were similar among provement) for all 3 domains of the MSQ v2.1 at weeks 4, 8, treatment groups and reflective of a severe effect of headaches and 12 (p ≤ 0.04), except for the RFP and EF domains at week (HIT-6 total score >60; Table 1). All atogepant groups had 4 in the 10 mg group (Table 2). nominal improvement (p ≤ 0.006) vs placebo in HIT-6 total e768 Neurology | Volume 100, Number 8 | February 21, 2023 Neurology.org/N Table 1 Demographics and Baseline Characteristics (Modified Intent-to-Treat Population) Atogepant Placebo (n = 214) 10 mg QD (n = 214) 30 mg QD (n = 223) 60 mg QD (n = 222) Total (N = 873) Age, y 40.3 (12.9) 41.5 (12.0) 42.2 (11.7) 42.8 (12.3) 41.7 (12.3) Female, n (%) 190 (88.8) 193 (90.2) 199 (89.2) 191 (86.0) 773 (88.5) Race, n (%) White 188 (87.9) 176 (82.2) 181 (81.2) 184 (82.9) 729 (83.5) Black or African American 22 (10.3) 32 (15.0) 37 (16.6) 27 (12.2) 118 (13.5) Asian 2 (0.9) 2 (0.9) 1 (0.4) 7 (3.2) 12 (1.4) Other or unknown 2 (0.9) 4 (1.9) 4 (1.8) 4 (1.8) 14 (1.6) Ethnicity, non-Hispanic, n (%) 192 (89.7) 193 (90.2) 205 (91.9) 209 (94.1) 799 (91.5) MMDs 7.5 (2.4) 7.5 (2.5) 7.9 (2.3) 7.8 (2.3) 7.6 (2.4) MHDs 8.4 (2.6) 8.4 (2.8) 8.8 (2.6) 9.0 (2.6) 8.7 (2.6) Monthly acute medication use days 6.5 (3.2) 6.6 (3.0) 6.7 (3.0) 6.9 (3.2) 6.7 (3.1) MSQ v2.1 n = 213 n = 212 n = 222 n = 222 n = 869 Role Function–Restrictive 46.8 (19.7) 44.9 (21.4) 44.0 (19.6) 46.8 (20.4) 45.6 (20.3) Role Function–Preventive 63.0 (21.9) 60.9 (23.4) 57.6 (24.0) 61.1 (24.2) 60.6 (23.4) Emotional Function 54.0 (26.1) 53.5 (28.3) 49.9 (27.0) 53.3 (29.4) 52.6 (27.8) AIM-D n = 188 n = 191 n = 188 n = 192 n = 759 Performance of Daily Activities 15.2 (8.3) 15.5 (8.9) 16.9 (8.0) 15.9 (8.3) 15.9 (8.4) Physical Impairment 11.2 (8.1) 11.7 (8.5) 13.0 (8.0) 11.6 (7.9) 11.9 (8.1) Total score 13.6 (7.9) 14.0 (8.4) 15.4 (7.7) 14.2 (7.9) 14.3 (8.0) HIT-6 total score n = 213 n = 212 n = 223 n = 222 n = 870 64.5 (4.6) 64.2 (5.3) 64.3 (4.7) 63.8 (5.5) 64.2 (5.0) Abbreviations: AIM-D = Activity Impairment in Migraine–Diary; HIT-6 = Headache Impact Test–6; MHD = monthly headache day; MMD = monthly migraine day; MSQ v2.1 = Migraine-Specific Quality-of-Life Questionnaire version 2.1; QD = once daily. Data represent mean (SD) unless otherwise indicated. score at the earliest time point assessed (week 4) and (i.e., improvements) in other alpha-controlled secondary ef- throughout the double-blind treatment period (exploratory ficacy endpoints (e.g., AIM-D PI and PDA across 12 weeks of endpoints; Figure 4A). The LSMD in change from baseline for treatment) for the 30 and 60 mg doses. Although atogepant atogepant vs placebo exceeded the between-group MID (1.5 (10 mg) produced reductions on these outcomes, the differ- points) in all atogepant groups at weeks 4, 8, and 12. Greater ences were not uniformly significant. proportions of atogepant-treated participants vs placebo- treated participants were HIT-6 responders (≥5-point im- provement from baseline) with all atogepant doses at all time Discussion points (p ≤ 0.03), with the exception of 30 mg of atogepant at week 4 (p = 0.07; Figure 4B). Atogepant is a daily oral CGRP receptor antagonist for the preventive treatment of migraine. The ADVANCE trial com- Classification of Evidence pared 3 doses of atogepant with placebo for the preventive This study provides Class II evidence that daily atogepant is treatment of migraine in participants with 4–14 MMDs. A associated with improvements in health-related quality-of-life previous publication reported significant reductions in MMDs measures in patients with 4–14 migraine days per month. with corresponding significant increases in 50% responder rates, Further, it was associated with HRQoL improvement in the low discontinuation rates, and evidence of safety and tolerability RFR domain of the MSQ v2.1 at week 12, a prespecified for all 3 doses of atogepant vs placebo.18 In addition to de- alpha-controlled secondary efficacy endpoint, for all 3 doses. creasing MMDs, reducing the effect of migraine on functioning In addition, atogepant is associated with reductions in daily activities and improving overall HRQoL are important Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e769 Figure 2 Change in MSQ v2.1 Scores LS mean changes from baseline in MSQ v2.1 (A) RFR, (B) RFP, and (C) EF scores at weeks 4, 8, and 12. The LSMD for each atogepant group vs placebo was at least the between-group minimally important difference for each domain (MSQ-RFR: 3.2; MSQ-RFP: 4.6, and MSQ-EF: 7.5)23 at each time point evaluated, with the exception of the EF domain at week 4 in the 10 mg group. Data for change from baseline MSQ v2.1 RFR at week 12 have been previously published.18 EF = Emotional Function; LSM = least-square mean; LSMD = least-square mean difference; MSQ v2.1 = Migraine-Specific Quality-of-Life Questionnaire version 2.1; QD = once daily; RFP = Role Function-Preventive; RFR = Role Function-Restrictive. e770 Neurology | Volume 100, Number 8 | February 21, 2023 Neurology.org/N Table 2 Migraine-Specific Quality-of-Life Questionnaire Version 2.1 Responder Rates Atogepant 10 mg Atogepant 30 mg Atogepant 60 mg Placebo (N = 214) QD (N = 214) QD (N = 223) QD (N = 222) Role Function–Restrictive domain (≥5-point improvement from baseline) Week 4, n/N (%)a 135/205 (65.9) 159/208 (76.4) 177/217 (81.6) 179/217 (82.5) Odds ratio vs placebo (95% CI)b 1.63 (1.03, 2.59) 2.22 (1.38, 3.57) 2.54 (1.57, 4.11) p Value 0.036 0.001 <0.001 a Week 8, n/N (%) 146/202 (72.3) 162/187 (86.6) 179/208 (86.1) 178/206 (86.4) b a Odds ratio vs placebo (95% CI) 2.44 (1.43, 4.18) 2.36 (1.40, 3.96) 2.43 (1.45, 4.07) p Value 0.001 0.001 <0.001 a Week 12, n/N (%) 141/198 (71.2) 158/186 (84.9) 178/203 (87.7) 172/201 (85.6) b Odds ratio vs placebo (95% CI) 2.22 (1.33, 3.69) 2.79 (1.66, 4.71) 2.44 (1.47, 4.03) p Value 0.002 <0.001 <0.001 Role Function–Preventive domain (≥5-point improvement from baseline) Week 4, n/N (%)a 133/205 (64.9) 154/208 (74.0) 178/217 (82.0) 171/217 (78.8) Odds ratio vs placebo (95% CI)b 1.49 (0.95, 2.33) 2.33 (1.45, 3.75) 2.00 (1.26, 3.16) p Value 0.082 <0.001 0.003 a Week 8, n/N (%) 141/202 (69.8) 158/187 (84.5) 168/208 (80.8) 168/206 (81.6) b Odds ratio vs placebo (95% CI) 2.35 (1.39, 3.98) 1.66 (1.02, 2.70) 1.75 (1.08, 2.84) p Value 0.002 0.041 0.024 Week 12, n/N (%)a 140/198 (70.7) 153/186 (82.3) 170/203 (83.7) 169/201 (84.1) b Odds ratio vs placebo (95% CI) 1.85 (1.10, 3.08) 2.04 (1.22, 3.42) 2.05 (1.23, 3.41) p Value 0.019 0.007 0.006 Emotional Function domain (≥8-point improvement from baseline) Week 4, n/N (%)a 110/205 (53.7) 130/208 (62.5) 142/217 (65.4) 144/217 (66.4) b Odds ratio vs placebo (95% CI) 1.49 (0.97, 2.30) 1.56 (1.01, 2.40) 1.80 (1.17, 2.78) p Value 0.069 0.043 0.008 a Week 8, n/N (%) 109/202 (54.0) 137/187 (73.3) 149/208 (71.6) 138/206 (67.0) b Odds ratio vs placebo (95% CI) 2.42 (1.51, 3.88) 2.15 (1.36, 3.39) 1.85 (1.18, 2.91) p Value <0.001 0.001 0.007 Week 12, n/N (%)a 112/198 (56.6) 129/186 (69.4) 148/203 (72.9) 137/201 (68.2) b Odds ratio vs placebo (95% CI) 1.69 (1.07, 2.67) 1.92 (1.22, 3.03) 1.70 (1.09, 2.67) p Value 0.025 0.005 0.020 Abbreviation: QD = once daily. a Percentages are relative to the number of participants available for analysis at a specific time point in the modified intent-to-treat population. b Analyses are based on a generalized linear mixed model for repeated measures. The model includes baseline as a covariate, previous exposure to migraine prevention medications (Y/N), treatment group and visit (month) as fixed factors, and treatment group–by-visit and baseline-by-visit as interaction terms. Participants are included as random effects with unstructured covariance matrix in the model. goals of migraine treatment from the perspectives of the patient, impairment, and overall effect of headaches. Atogepant (30 and their family, employers, and payers.12,35,36 Our results demon- 60 mg) was associated with significant improvements in key strated significant improvements in PROs that assessed func- alpha-controlled secondary endpoints (MSQ v2.1 RFR and tioning in daily social and work-related activities and AIM-D PDA and PI) over the 12-week treatment period; for the performance of daily activities, emotional effect, physical 10 mg dose, differences were statistically significant for MSQ Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e771 Figure 3 Change in AIM-D Scores LS mean changes from baseline in average monthly AIM-D (A) Performance of Daily Activities, (B) Physical Impairment, and (C) Total Score. Data for Performance of Daily Activities and Physical Impairment across the 12-week treatment period (months 1–3; secondary endpoint) have been previously published.18 *p < 0.05 vs placebo. AIM-D = Activity Impairment in Migraine–Diary; LSMD = least-square mean difference; QD = once daily. e772 Neurology | Volume 100, Number 8 | February 21, 2023 Neurology.org/N Figure 4 Change in HIT-6 Score (A) Mean changes from baseline in HIT-6 total score. The between-group MID for HIT-6 is 1.5 points.31 (B) Percentage of participants with ≥5-point improvement (responders) from baseline in HIT-6 total score. *p < 0.05 vs placebo. HIT-6 = Headache Impact Test–6; LSMD = least-square mean difference; QD = once daily. v2.1 RFR but not for AIM-D among the alpha-controlled end- For the MSQ v2.1, change in the RFR domain from baseline points. Atogepant was also associated with nominal improve- to week 12 was a key secondary endpoint, and earlier time ments in a series of exploratory endpoints as early as week 4. points for the RFR domain and all time points for the RFP and Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e773 EF domains were exploratory endpoints. At week 12, each of headache effect vs placebo at first assessment (week 4) and the 3 atogepant groups demonstrated statistically significant throughout the double-blind treatment period. The HIT-6 and clinically meaningful improvement compared with placebo responder rate (proportion of individuals ≥5-point improve- in the effect of migraine on daily social and work-related ac- ment) at week 12 was 63%–65% across atogepant dose groups tivities as measured by the MSQ v2.1 RFR domain. In addition, compared with 52% with placebo. all 3 doses of atogepant achieved nominal improvements rel- ative to placebo for all 3 MSQ v2.1 domains at weeks 4 and 8. Previous studies have demonstrated that preventive migraine All atogepant groups achieved the between-group MID vs treatments from various drug classes, including oral preventives placebo for the mean improvement in each MSQ v2.1 domain and injectable CGRP-targeted monoclonal antibodies (mAbs), as early as week 4 and throughout the double-blind treatment improved HRQoL and functioning and reduced headache ef- period, except for the EF domain in the 10 mg group at week 4. fect and disability in people with EM.39-43 Multiple placebo- The proportion of individuals with clinically meaningful im- controlled clinical trials of CGRP-targeted mAbs in participants provements (i.e., responders with score improvement exceed- with EM demonstrated significant and clinically meaningful ing the within-group MID) in the MSQ v2.1 at week 12 was improvements in the MSQ v2.1 RFR, RFP, and EF domains 85%–88% with atogepant 10–60 mg (vs 71% placebo) for the and in HIT-6 scores with mAbs vs placebo for up to 6 months MSQ-RFR; 82%–84% (vs 71% placebo) for the MSQ-RFP; of treatment.41-46 Methodological differences limit cross-study and 68%–73% (vs 57% placebo) for the MSQ-EF. comparisons. However, all CGRP-targeted treatments were associated with improvements in MSQ v2.1 domains and HIT- The AIM-D, a novel migraine-specific PRO, provides a daily 6 total scores. This is the first randomized controlled trial to diary-based assessment of performance of daily activities and assess treatment benefits using AIM-D. reduction of physical impairment related to migraine. The 1-day recall period and daily diary format of the AIM-D are intended to This trial has strengths and limitations. This rigorously minimize the bias that influences measures with longer recall designed double-blind placebo-controlled trial used established intervals. The other validated daily diary PRO for migraine, the validated PRO instruments that measure changes in functional Migraine Physical Function Impact Diary,37 was not available ability, activity impairment, and headache effect over time. The when study was planned, as exemplified by the 4-week recall trial was not powered for key secondary endpoints, including interval of the MSQ v2.1 and the 3-month recall interval of the the change from baseline in MSQ v2.1 RFR at week 12 and Migraine Disability Assessment Scale.15,38 Both the MSQ v2.1 AIM-D PDA and PI across the 12-week treatment period, al- and the AIM-D contribute valuable information regarding the though these were prespecified alpha-controlled secondary effect of migraine on functioning and performance of daily ac- efficacy endpoints. The MSQ v2.1 RFR measure has been in- tivities and therefore provide a more complete evaluation of cluded in the US labeling for migraine preventives; however, migraine burden and treatment benefits. In particular, the AIM- the HIT-6 has not.47 The National Institute of Neurological D’s assessment of difficulty in performance of daily activities and Disorders and Stroke highly recommends both the MSQ v2.1 physical impairment provides complimentary measurement to and HIT-6 for headache studies.48 The MSQ v2.1 and HIT-6 the MSQ v2.1 RFR domain’s evaluation of the frequency of have 4-week recall periods, raising recall bias as a potential migraine effect on daily social and work activities. The AIM-D limitation. There are other recall-based PROs, which were not PDA and PI domains and total score demonstrated good internal included or available during the study, including the Migraine consistency reliability, test-retest reliability, construct validity, Functional Impact Questionnaire.49 By contrast, as a daily di- known-groups validity, and responsiveness. In the ADVANCE ary, the AIM-D has a same-day recall period. The AIM-D, trial, changes from baseline in mean monthly AIM-D PDA and which was specifically constructed based on FDA guidance for PI domain scores across the 12-week treatment period were PRO development19 for use in clinical trials of migraine alpha-controlled secondary endpoints, and PDA and PI domain treatments, provides some unique insights into the effects of scores at monthly time points and AIM-D total scores were atogepant on migraine-related activity impairment. The lack of exploratory endpoints. Atogepant (30 and 60 mg) demonstrated statistically significant changes in AIM-D scores in the 10 mg statistically significant improvements from baseline compared dose group is surprising, considering the significant changes with placebo in mean monthly AIM-D PDA and PI scores across with MSQ v2.1 and HIT-6. AIM-D scores are averaged across the 12-week treatment period; the 10 mg group also showed the month for HA and nHA days. In an EM study, by definition, improvement in both domains, but the mean change was not participants do not have headaches on most days, truncating significantly different from placebo. The 30 and 60 mg atogepant the potential range of AIM-D scores and creating a potential for groups had numerically greater improvements than the placebo floor effects. The baseline AIM-D total score for the overall group in exploratory endpoints of AIM-D PDA, PI, and total population was 14.3 (range: 13.6–15.4), on a scale with a scores across weeks 1–4 that were maintained through the end of maximum value of 100. In addition, the benefits of atogepant the trial. might be greater on HA days than on nHA days. Combining HA days and nHA days may generate an AIM-D metric that is Changes from baseline in HIT-6 total score (exploratory less sensitive than an HA day measure, particularly for a lower endpoint) showed that each atogepant dose was associated dose of a preventive treatment. The AIM-D has not been with nominal and clinically meaningful reductions in compared directly with other diary data or scales. Finally, the e774 Neurology | Volume 100, Number 8 | February 21, 2023 Neurology.org/N duration of follow-up was only 12 weeks; some PRO outcomes Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, may continue to improve beyond 12 weeks, so longer studies Theranica, and Zoscano; has received funding for speaking from could be helpful.50 Future work should separately score HA and AbbVie, Allergan, Amgen, Biohaven, Lundbeck, Lilly, and Teva; nHA days to distinguish the benefits of atogepant on ictal and has served as a consultant for AbbVie, Alder, Allergan, Amgen, interictal burden. Only participants with 4–14 MMDs were Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica; re- included in the ADVANCE trial, but a phase 3 atogepant trial in ceived grant support from Allergan and Amgen; and is a con- people with CM is ongoing (NCT03855137). tributing author for AbbVie, Allergan, Amgen, Biohaven, Lily, Novartis, and Teva. J. Stokes and P. Gandhi are employees of In conclusion, atogepant demonstrated significant and clini- AbbVie and may hold AbbVie stock. Y. Li and L. Severt were cally meaningful improvements in functioning in daily social employees of AbbVie during this study and may hold AbbVie and work-related activities and performance of daily activities stock. L. Creutz declares no disclosures relevant to the manu- and reductions in emotional effect, physical impairment, and script. D.W. Dodick reports the following conflicts: consulting: overall effect of headaches. Improvements were observed at Amgen, Atria, Cerecin, Cooltech, Ctrl M, Allergan, Biohaven, the earliest assessment point (4 weeks) and throughout the GSK, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, 12-week double-blind treatment period for the 30 and 60 mg WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosci- doses. In addition, atogepant (10 mg), the lowest dose ences, and Revance; honoraria: Teva (speaking), Amgen assessed, improved MSQ v2.1 domain and HIT-6 scores. The (speaking), Eli Lilly (speaking), Lundbeck (speaking), Vector early onset of improved functioning is important to patients Psychometric Group, Clinical Care Solutions, CME Outfitters, and payers.35,36 Together, these results reinforce the benefi- Curry Rockefeller Group, DeepBench, Global Access Meetings, cial effects of atogepant as a promising new treatment for the KLJ Associates, Academy for Continued Healthcare Learning, prevention of migraine. Majallin LLC, Medlogix Communications, Synapse, MJH Lifesciences, Miller Medical Communications, WebMD Acknowledgment Health/Medscape, Wolters Kluwer, Oxford University Press, Writing and editorial assistance was provided to the authors by Cambridge University Press. Research Support: Department of Peloton Advantage, LLC, an OPEN Health company, Parsip- Defense, NIH, Henry Jackson Foundation, Sperling Founda- pany, NJ, and was funded by AbbVie. The opinions expressed in tion, American Migraine Foundation, Patient-Centered Out- this article are those of the authors. The authors received no comes Research Institute (PCORI). Stock Options/ honorarium/fee or other form of financial support related to the Shareholder/Patents/Board of Directors: Ctrl M (options), development of this article. Aural analytics (options), ExSano (options), Palion (options), Healint (options), Theranica (options), Second Opinion/ Study Funding Mobile Health (options), Epien (options/board), Nocira (op- Allergan, now AbbVie, sponsored the study; contributed tions), Matterhorn (shares/board), Ontologics (shares/board), to the design; and participated in the analysis and in- King-Devick Technologies (options/board), Precon Health terpretation of data and in writing, reviewing, and approval (options/board), AYYA Biosciences (options), Axon Thera- of the final version. No honoraria or payments were made peutics (options/board), Cephalgia Group (options/board), for authorship. and Atria Health (options/employee). National Center for Biotechnology Information (2022). PubChem Patent Summary Disclosure for WO-2011123456-A1. Retrieved February 17, 2022 from R.B. Lipton has received research support from the NIH, the pubchem.ncbi.nlm.nih.gov/patent/WO-2011123456-A1 (Bot- FDA, and the National Headache Foundation. He serves as a ulinum toxin dosage regimen for chronic migraine prophylaxis). consultant and advisory board member and has received hon- Go to Neurology.org/N for full disclosures. oraria or research support from AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories (Promius), electroCore, Eli Publication History Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Teva, Received by Neurology September 1, 2021. Accepted in final form Vector, and Vedanta Research. He receives royalties from September 28, 2022. Submitted and externally peer reviewed. The Wolff’s Headache, 8th edition (Oxford University Press, 2009), handling editor was Rebecca Burch, MD. and Informa. He holds stock/options in Biohaven, Manistee, and Ctrl M. P. Pozo-Rosich reports the following conflicts within the past 18 months: consulting: AbbVie, Eli Lilly, Lundbeck, Medscape, Novartis, and Teva; research grants: Appendix Authors EraNet Neuron, FEDER RISC3CAT, la Caixa foundation, Name Location Contribution Instituto Investigación Carlos III, AbbVie, Novartis, and Teva; and has received funding for clinical trials from AbbVie, Amgen, Richard B. Albert Einstein College of Designed and Lipton, MD Medicine, Bronx, NY conceptualized study; Eli Lilly, Lundbeck, Novartis, and Teva. She is the founder of analyzed and interpreted the midolordecabeza.org. She does not own stocks in any phar- data; and drafted and revised the article for maceutical company. A.M. Blumenfeld has served on advisory intellectual content boards for AbbVie, Aeon, Alder, Allergan, Amgen, Axsome, Continued Neurology.org/N Neurology | Volume 100, Number 8 | February 21, 2023 e775 12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59(1): Appendix (continued) 1-18. doi:10.1111/head.13456. 13. Diener HC, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Name Location Contribution Society for controlled trials of preventive treatment of migraine attacks in episodic migraine in adults. Cephalalgia. 2020;40(10):1026-1044. doi:10.1177/0333102420941839. Patricia Headache Unit, Neurology Revised the article for 14. Management of migraine (with or without aura). National Institute for Health and Care Pozo-Rosich, Department, Vall d’Hebron intellectual content Excellence, 2021. pathways.nice.org.uk/pathways/headaches/management-of-mi- MD, PhD University Hospital, graine-with-or-without-aura. Accessed February 10, 2021. Barcelona; Headache 15. McGinley JS, Houts CR, Nishida TK, et al. Systematic review of outcomes and Research Group, VHIR, endpoints in preventive migraine clinical trials. Headache. 2021;61(2):253-262. doi: Departamento de Medicina, 10.1111/head.14069. Universitat Autonoma of 16. Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally Barcelona, Spain administered atogepant for the prevention of episodic migraine in adults: a double- blind, randomised phase 2b/3 trial. Lancet Neurol. 2020;19(9):727-737. doi:10.1016/ Andrew M. Headache Center of Revised the article for s1474-4422(20)30234-9. Blumenfeld, Southern California, intellectual content 17. Qulipta (atogepant) tablets [package insert]. AbbVie, 2021. MD Carlsbad 18. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706. doi:10.1056/nejmoa2035908. Ye Li, PhD* AbbVie, Madison, NJ Revised the article for 19. 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