Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial

Abstract

Background and objectives: The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine.

Methods: 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 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function-Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment 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 improvements 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.

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.

Figure 1. Participant Disposition

DBTP = double-blind treatment period; mITT = modified intent-to-treat; QD = once daily.

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) 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. 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.

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. *p < 0.05 vs placebo. AIM-D = Activity Impairment in Migraine–Diary; LSMD = least-square mean difference; QD = once daily.

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. (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.