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(2021)Objective
Atogepant - To determine whether oral atogepant (10mg, 30mg, or 60mg once daily) was more effective than placebo for the preventive treatment of episodic migraine over 12 weeks
Study Summary
• All three doses of atogepant significantly reduced migraine days compared to placebo (10mg: -1.2 days, 30mg: -1.4 days, 60mg: -1.7 days; all P<0.001)
• 56-61% of atogepant-treated patients achieved ≥50% reduction in migraine days vs 29% with placebo
• Well tolerated with most common adverse events being constipation (7%) and nausea (5%)
• 56-61% of atogepant-treated patients achieved ≥50% reduction in migraine days vs 29% with placebo
• Well tolerated with most common adverse events being constipation (7%) and nausea (5%)
Intervention
Oral atogepant (CGRP receptor antagonist) administered once daily at doses of 10mg, 30mg, or 60mg
Inclusion Criteria
Adults 18-80 years with 4-14 migraine days per month, ≥1-year history of migraine with/without aura per ICHD-3, migraine onset before age 50
Study Design
Arms: Four arms: Placebo, Atogepant 10mg once daily, Atogepant 30mg once daily, Atogepant 60mg once daily
Patients per Arm: 214-223 in efficacy analysis per arm (873 total); 221-231 in safety analysis per arm (902 total)
Outcome
• Primary: All atogepant doses superior to placebo for reducing migraine days (difference -1.2 to -1.7 days, all P<0.001)
• ≥50% responder rate: 56-61% atogepant vs 29% placebo
• Constipation most common AE (7% atogepant vs 0.5% placebo)
• ≥50% responder rate: 56-61% atogepant vs 29% placebo
• Constipation most common AE (7% atogepant vs 0.5% placebo)
Bottom Line
Oral atogepant once daily at all three tested doses (10mg, 30mg, 60mg) was significantly more effective than placebo in reducing migraine days over 12 weeks in adults with episodic migraine, with a favorable safety profile. The 60mg dose showed the greatest efficacy, reducing migraine days by 1.7 days more than placebo, with 61% of patients achieving ≥50% reduction in migraine days. Constipation and nausea were the most common adverse events.
Major Points
- First phase 3 trial of atogepant, an oral CGRP receptor antagonist, for migraine prevention
- 2270 participants screened, 910 randomized, 873 included in efficacy analysis (modified ITT)
- Multicenter (128 sites), double-blind, parallel-group, placebo-controlled trial in United States
- Primary endpoint met for all three doses: mean change from baseline in migraine days per month was -3.7 (10mg), -3.9 (30mg), -4.2 (60mg) vs -2.5 (placebo)
- Differences from placebo: 10mg -1.2 days (95% CI -1.8 to -0.6, P<0.001); 30mg -1.4 days (95% CI -1.9 to -0.8, P<0.001); 60mg -1.7 days (95% CI -2.3 to -1.2, P<0.001)
- Dose-response relationship observed, with 60mg dose showing greatest efficacy
- ≥50% responder rates: 55.6% (10mg), 58.7% (30mg), 60.8% (60mg) vs 29.0% (placebo); all P<0.001
- All secondary endpoints favored atogepant over placebo except AIM-D Performance of Daily Activities and Physical Impairment scores for 10mg dose
- Significant reductions in headache days (difference -1.4 to -1.7 days, all P<0.001) and acute medication use (difference -1.3 to -1.5 days, all P<0.001)
- Improvement in quality of life: MSQ Role Function-Restrictive domain improved by 9.9-10.8 points more than placebo (all P<0.001)
- Efficacy observed within first 4 weeks and maintained throughout 12-week treatment period
- Overall adverse event rates similar across groups (52.2-53.7% atogepant vs 56.8% placebo)
- Most common AEs: constipation (6.9-7.7% atogepant vs 0.5% placebo), nausea (4.4-6.1% atogepant vs 1.8% placebo), upper respiratory tract infection (3.9-5.7% atogepant vs 4.5% placebo)
- No serious constipation cases; no serious liver events; no cases meeting Hy's law criteria
- Two serious AEs in 10mg group (asthma, optic neuritis), two in placebo group; none in 30mg or 60mg groups
- Similar discontinuation rates due to adverse events across groups (1.8-4.1%)
- Trial completion rate: 88.5% overall; 86.9-90.5% across groups
- Population: mean age 41.6 years, 88.8% female, 83.4% White, mean BMI 30.6
- Baseline mean migraine days: 7.5-7.9 per month; headache days: 8.4-9.0 per month
- 70.3% had previously used preventive treatment; 99.3% currently using acute medications
Study Design
- Study Type
- Phase 3, multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- Blinding
- Double-blind; participants, site personnel, and trial sponsor personnel were unaware of trial-group assignments. Atogepant and placebo tablets were identical in appearance. Sealed code-break envelopes provided but never opened during study
- Sample Size
- 910
- Follow-up
- 12-week double-blind treatment period with 4-week safety follow-up (total 16 weeks from randomization). Eight scheduled clinic visits (screening, randomization, weeks 2, 4, 6, 8, 12, and week 16 follow-up)
- Centers
- 128
Primary Outcome
Definition: Change from baseline in mean number of migraine days per month across the 12-week treatment period (average of month 1, month 2, and month 3) as recorded in electronic diaries
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Mean baseline 7.5 days; change -2.5±0.2 days | 10mg: Mean baseline 7.5 days, change -3.7±0.2 days; 30mg: Mean baseline 7.9 days, change -3.9±0.2 days; 60mg: Mean baseline 7.8 days, change -4.2±0.2 days | - | 10mg: P<0.001; 30mg: P<0.001; 60mg: P<0.001 (adjusted for multiple comparisons) |
Limitations & Criticisms
- 12-week treatment duration not adequate to assess long-term safety and side effects of atogepant; longer trials needed (52-week safety trial results pending)
- Study limited to participants with 4-14 migraine days per month; excluded those with ≥15 headache days per month (chronic migraine), so results cannot be generalized to this population
- Excluded participants with clinically significant coexisting conditions, limiting generalizability to real-world populations
- Excluded participants taking triptans/ergots on ≥10 days per month or simple analgesics on ≥15 days per month, excluding potential medication overuse headache patients
- Excluded participants who did not respond to >4 preventive treatments, limiting assessment in treatment-resistant patients
- Safety of atogepant in pregnant women not evaluated
- High screen failure rate: only 910 of 2270 screened (40%) were randomized
- 11.5% discontinuation rate overall (22 of 222 in placebo, 29 of 221 in 10mg, 23 of 228 in 30mg, 31 of 231 in 60mg groups)
- Most common reason for discontinuation was withdrawal of consent (3.8%), but reasons for withdrawal not detailed
- Modified intention-to-treat population used rather than full intention-to-treat (37 randomized participants excluded from efficacy analyses)
- Missing data handled by missing-at-random assumption in general linear model; potential for bias if assumption violated (though sensitivity analyses supported robustness)
- Protocol modified during COVID-19 pandemic to allow remote visits for up to 8 weeks; potential impact on data quality
- Some participants (8% of randomized, 12% of completers) provided only telephone/email data for some assessments rather than full diary data
- Exploratory time-course analysis not powered for definitive conclusions; described as exploratory only
- 10mg dose did not show significant differences from placebo for AIM-D Performance of Daily Activities and Physical Impairment scores, suggesting possible floor dose
- No direct comparison with other approved migraine preventives (e.g., CGRP monoclonal antibodies, topiramate, propranolol)
- No assessment of patient preference between oral daily medication vs injectable monthly/quarterly options
- Constipation rate 7% across atogepant doses vs 0.5% placebo; while no serious cases, may limit tolerability in clinical practice
- Association between CGRP blockade and decreased GI motility noted; long-term implications unknown
- Adherence assessed by tablet counts and interviews but electronic monitoring not used
- Population predominantly female (88.8%) and White (83.4%); generalizability to other demographic groups uncertain
- Mean BMI 30.6 indicates overweight/obese population; generalizability to normal weight individuals uncertain
- Trial conducted only in United States; international generalizability uncertain
- No evaluation of atogepant effect on migraine-associated symptoms beyond those captured in diary (e.g., allodynia)
- No assessment of medication overuse headache development or rebound after discontinuation beyond 4-week safety follow-up
Citation
N Engl J Med 2021;385:695-706