PROGRESS
Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial
Clinical Question
Is atogepant effective for preventive treatment of chronic migraine in patients with and without acute medication overuse?
Bottom Line
Atogepant (30 mg BID or 60 mg QD) is effective for preventive treatment of chronic migraine in patients with and without acute medication overuse, reducing MMDs, MHDs, acute medication use days, and the proportion of patients meeting medication overuse criteria, with improvements in patient-reported outcomes.
Major Points
- Atogepant 30 mg BID reduced MMDs vs placebo by -2.7 days (95% CI -4.0 to -1.4) in patients with acute medication overuse
- Atogepant 60 mg QD reduced MMDs vs placebo by -1.9 days (95% CI -3.2 to -0.6) in patients with acute medication overuse
- Mean MHDs reduced by LSMD -2.8 (30mg BID) and -2.1 (60mg QD) vs placebo in overuse subgroup
- Mean acute medication use days reduced by LSMD -2.8 (30mg BID) and -2.6 (60mg QD) vs placebo in overuse subgroup
- ≥50% MMD reduction: 44.7% (30mg BID, OR 2.5) and 41.8% (60mg QD, OR 2.3) vs 24.9% placebo in overuse subgroup
- 52.1%-61.9% of atogepant-treated participants no longer met medication overuse criteria over 12 weeks
- Similar efficacy and improvements in PROs (HIT-6, MSQv2.1, AIM-D) seen in subgroup without acute medication overuse
- Class II evidence that atogepant reduces MMDs, MHDs, and acute medication use days regardless of medication overuse status
Design
Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (subgroup analysis)
Randomization: 1
Blinding: Double-blind
Allocation: 1:1:1 to placebo, atogepant 30 mg BID, or atogepant 60 mg QD
Enrollment Period: March 11, 2019 to January 20, 2022
Follow-up Duration: 12-week double-blind treatment period plus 4-week follow-up
Centers: 142
Countries: Multiple - North America, Europe, East Asia
Sample Size: 778
Analyzed: 755
Analysis: Modified intent-to-treat (mITT); MMRM for continuous endpoints; logistic regression for binary endpoints
Power Calculation: Sample size determination previously described in primary PROGRESS publication
Registration: ClinicalTrials.gov NCT03855137
Inclusion Criteria
- Adults aged 18-80 years
- ≥1-year history of chronic migraine per ICHD-3 criteria
- Migraine onset at younger than 50 years
- ≥15 headache days per month for ≥3 months before baseline visit
- ≥15 headache days including ≥8 migraine days during 4-week baseline period (per eDiary)
- Completed eDiary for ≥20 days of 28-day baseline period
Exclusion Criteria
- Clinically significant laboratory values
- Positive urine drug screen at visit 1 (unless explained by concomitant medication)
- Did not meet baseline headache/migraine day criteria
Arms
| Field | Control | Atogepant 30 mg BID | Atogepant 60 mg QD |
|---|---|---|---|
| N | 246 | 253 | 256 |
| Intervention | Placebo | Atogepant 30 mg orally twice daily | Atogepant 60 mg orally once daily |
| Duration | 12 weeks | 12 weeks | 12 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period (subgroup analysis by acute medication overuse status) | Primary | Placebo (acute medication overuse subgroup) | Atogepant 30 mg BID and 60 mg QD | With acute medication overuse: LSMD -2.7 days (30 mg BID) and -1.9 days (60 mg QD) vs placebo. Without overuse: LSMD -1.7 days (30 mg BID) and -1.6 days (60 mg QD) vs placebo | |
| Change from baseline in mean MHDs across 12 weeks (acute medication overuse subgroup) | Secondary | LSMD -2.8 days (30 mg BID) and -2.1 days (60 mg QD) vs placebo | |||
| Change from baseline in mean monthly acute medication use days across 12 weeks (overuse subgroup) | Secondary | LSMD -2.8 days (30 mg BID) and -2.6 days (60 mg QD) vs placebo | |||
| ≥50% reduction in mean MMDs across 12 weeks (acute medication overuse subgroup) | Secondary | 24.9% (42/169) placebo | 44.7% (72/161) atogepant 30 mg BID; 41.8% (71/170) atogepant 60 mg QD | 2.5 (30 mg BID); 2.3 (60 mg QD) | |
| ≥50% reduction in mean MMDs across 12 weeks (subgroup without acute medication overuse) | Secondary | 39.1% (36/92) atogepant 30 mg BID; 39.5% (34/86) atogepant 60 mg QD | 1.7 (30 mg BID); 1.7 (60 mg QD) | ||
| Reduction in proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks | Secondary | 52.1%-61.9% reduction | |||
| Patient-reported outcomes (HIT-6, MSQv2.1 RFR/RFP/EF domains, AIM-D PDA/PI domains) | Secondary | Improved with atogepant in both subgroups |
Subgroup Analysis
Prespecified subgroup analysis by acute medication overuse status at baseline (overuse: 66.2% of mITT; without overuse: 33.8%). Treatment effects on MMDs, MHDs, acute medication days, ≥50% responder rates, and PROs were similar in both subgroups, demonstrating efficacy regardless of baseline medication overuse status.
Criticisms
- Subgroup analyses other than primary/secondary endpoints were not controlled for type I error
- Analyses not powered to compare the two atogepant dosing regimens directly
- 12-week treatment duration limits assessment of longer-term efficacy and safety
- Industry-sponsored trial (AbbVie) with multiple authors employed by sponsor
- Class II evidence (not Class I) per AAN classification
Funding
AbbVie funded the trial and Article Processing Charge
Based on: PROGRESS (Neurology, 2024)
Authors: Goadsby PJ, Friedman DI, Holle-Lee D, ..., Trugman JM
Citation: Neurology 2024;103:e209584
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