Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial

Abstract

Background and objectives: Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse.

Methods: This subgroup analysis of the phase 3, 12-week, randomized, double-blind, placebo-controlled PROGRESS trial evaluated adults with a ≥1-year history of CM, ≥15 monthly headache days (MHDs), and ≥8 monthly migraine days (MMDs) during the 4-week baseline period. Participants were randomized (1:1:1) to placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks and were analyzed by acute medication overuse status (triptans/ergots for ≥10 days per month, simple analgesics for ≥15 days per month, or combinations of triptans/ergots/simple analgesics for ≥10 days per month). Outcomes included change from baseline in mean MMDs, MHDs, and monthly acute medication use days; ≥50% reduction in mean MMDs across 12 weeks; and patient-reported outcome (PRO) measures.

Results: Of 755 participants in the modified intent-to-treat population, 500 (66.2%) met baseline acute medication overuse criteria (placebo, n = 169 [68.7%]; atogepant 30 mg BID, n = 161 [63.6%]; atogepant 60 mg QD, n = 170 [66.4%]). The least squares mean difference (LSMD) (95% CI) from placebo in MMDs was -2.7 (-4.0 to -1.4) with atogepant 30 mg BID and -1.9 (-3.2 to -0.6) with atogepant 60 mg QD. Mean MHDs (LSMD [95% CI] -2.8 [-4.0 to -1.5] and -2.1 [-3.3 to -0.8]) and mean acute medication use days (LSMD [95% CI] -2.8 [-4.1 to -1.6] and -2.6 [-3.9 to -1.3]) were reduced and a higher proportion of participants achieved ≥50% reduction in MMDs (odds ratio [95% CI] 2.5 [1.5-4.0] and 2.3 [1.4-3.7]) with atogepant 30 mg BID and atogepant 60 mg QD. There was a 52.1%-61.9% reduction in the proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks. Atogepant improved PRO measures. Similar results were observed in the subgroup without acute medication overuse.

Discussion: Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs.

Trial registration information: ClinicalTrials.gov NCT03855137. Submitted: February 25, 2019; first patient enrolled: March 11, 2019. clinicaltrials.gov/ct2/show/NCT03855137.

Classification of evidence: This study provides Class II evidence that atogepant reduces mean MMDs, MHDs, and monthly acute medication use days in adult patients with or without medication overuse.

Figure 1. Participant Disposition

Safety analyses were conducted in all participants who received ≥1 dose of study intervention, according to treatment received. The modified intent-to-treat population included all randomized participants who received ≥1 dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had ≥1 evaluable postbaseline 4-week period of eDiary data during the double-blind treatment period. Of 1,489 participants screened for eligibility, 778 were randomized to a study intervention. 658 participants were excluded because of screen failures. The most common reasons for screen failure included the following: not meeting a history, on average, of ≥15 headache days per month in the 3 months before visit 1, ≥15 headache days during the 4-week baseline period, and ≥8 migraine days during the 4-week baseline period; having clinically significant laboratory values; and positive result on the urine drug screen at visit 1, unless explained by concomitant medication use (e.g., opioids prescribed for migraine pain). AMO = acute medication overuse. Used with permission from Elsevier Science & Technology Journals, from Pozo-Rosich et al.; permission conveyed through Copyright Clearance Center, Inc.

Figure 2. Participants Meeting Criteria for Acute Medication Overuse at Baseline, During the Three 4-Week Intervals, and at Weeks 1–12 (A) and Participants Meeting Criteria for Acute Medication Overuse by Medication Type (B) (Modified Intent-to-Treat Population)

In (A), at baseline and during the three 4-week intervals, acute medication overuse was defined as use of triptans for ≥10 days; use of ergots for ≥10 days; use of simple analgesics (i.e., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], or acetaminophen) for ≥15 days; or use of any combination of triptans, ergots, or simple analgesics for ≥10 days. At weeks 1–12, acute medication overuse was defined as use of triptans for ≥30 days; use of ergots for ≥30 days; use of simple analgesics for ≥45 days; or use of any combination of triptans, ergots, or simple analgesics for ≥30 days. In (B), at baseline, triptan overuse was defined as use of triptans for ≥10 days, regardless of use of other medications. Simple analgesic overuse was defined as use of simple analgesics for ≥15 days, regardless of use of other medications. Combination overuse was defined as use of any combination of triptans, ergots, or simple analgesics for ≥10 days. At weeks 1–12, triptan overuse was defined as use of triptans for ≥30 days, regardless of use of other medications. Simple analgesic overuse was defined as use of simple analgesics for ≥45 days, regardless of use of other medications. Combination acute medication overuse was defined as use of any combination of triptans, ergots, or simple analgesics for ≥30 days. The week 1–12 analyses were restricted to participants who completed the double-blind treatment period. Combination headache medications such as Excedrin Migraine (acetaminophen, aspirin, and caffeine) were categorized as simple analgesics for these analyses. Ergot overuse (ergot use for ≥10 days, regardless of use of other medications) was also evaluated but was not included in the figure because of ≤3 participants per treatment arm meeting criteria for ergot overuse. *p-value for the interaction between the treatment visit and atogepant 30 mg BID compared with placebo. ^†p-value for the interaction between the treatment visit and atogepant 60 mg QD compared with placebo.