Migraine, With or Without Aura
Conditions
Brief summary
This study will evaluate the safety and tolerability of the following doses of atogepant (AGN-241689): 10 mg once daily (QD), 30 mg QD, 30 mg twice daily (BID), 60 mg QD, and 60 mg BID for the prevention of episodic migraine and will characterize the dose/response relationship.
Interventions
DRUGAtogepant
Atogepant capsule.
Placebo-matching atogepant capsule.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Has at least a 1-year history of migraine with or without aura * Age of the patient at the time of migraine onset \< 50 years * History of 4 to 14 migraine days (migraine/probable migraine headache days) per month on average in the 3 months prior to Visit 1 in the Investigator's judgment * Demonstrated compliance with e-diary
Exclusion criteria
* Has a history of migraine accompanied by diplopia or decreased level of consciousness and retinal migraine * Has a current diagnosis of chronic migraine, new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy * Difficulty distinguishing migraine headache from other headaches * Has a history of malignancy in the prior 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer * Has a history of gastric or small intestinal surgery, or has a disease that causes malabsorption * Has a history of hepatitis within previous 6 months * Usage of opioids or barbiturates \> 2 days/month, triptans or ergots ≥ 10 days/month, or simple analgesics (eg, aspirin, non-steroidal anti-inflammatory drugs \[NSAIDs\], acetaminophen) ≥ 15 days/month in the 3 months prior to Visit 1 * Pregnant or nursing females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | Baseline (First 28 Days of Screening/Baseline Period) to Week 12 | Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache qualified by duration and acute symptomatic medication use. The 4-week migraine days was defined as the total number of reported migraine days in diary divided by total number of days with diary records during each 4- week period and multiplied by 28. Each 4-week period was averaged. Negative change from Baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | Baseline (First 28 Days of Screening/Baseline Period) to Week 12 | Participants recorded daily total duration of a headache in a diary. A headache day is any calendar day on which the participant experienced a headache qualified by duration and acute symptomatic medication use. The 4-week (monthly) headache days was defined as the total number of reported headache days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Negative change from Baseline indicates improvement. |
| Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | Baseline (First 28 Days of Screening/Baseline Period) to Week 12 | Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache qualified by duration and acute symptomatic medication use. The 4-week migraine days=total number of reported migraine days in diary divided by total number of days with diary records in each 4-week period multiplied by 28. Each 4-week period was averaged. |
| Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | Baseline (First 28 Days of Screening/Baseline Period) to Week 12 | Participants recorded allowed medication(s) to treat an acute migraine in the daily diary. The 4-week (monthly) acute medication use days was defined as the total number of reported acute medication use days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. A negative change from Baseline indicates improvement. |
Countries
United States
Participant flow
Pre-assignment details
Participants diagnosed with migraine, with or without aura were enrolled in one of 6 treatment arms: placebo, or atogepant 10 mg once daily (QD), 30 mg QD, 60 mg QD, 30 mg twice daily (BID), or 60 mg BID.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-matching atogepant capsules orally twice daily in the morning and in the evening for 12 weeks. | 186 |
| Atogepant 10 mg QD Atogepant 10 mg capsule orally once daily (QD) in the morning and one placebo-matching atogepant capsule orally once daily in the evening for 12 weeks. | 93 |
| Atogepant 30 mg QD Atogepant 30 mg capsule orally once daily in the morning and one placebo-matching atogepant capsule orally once daily in the evening for 12 weeks. | 183 |
| Atogepant 60 mg QD Atogepant 60 mg capsule orally once daily in the morning and one placebo-matching atogepant capsule orally in the evening for 12 weeks. | 186 |
| Atogepant 30 mg BID Atogepant 30 mg capsule orally twice daily (BID); 1 capsule in the morning and 1 capsule in the evening for 12 weeks. | 86 |
| Atogepant 60 mg BID Atogepant 60 mg capsule orally twice daily; 1 capsule in the morning and 1 capsule in the evening for 12 weeks. | 91 |
| Total | 825 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Safety Follow-up Period | Lost to Follow-up | 4 | 0 | 2 | 0 | 1 | 3 |
| Safety Follow-up Period | Withdrawal of Consent | 0 | 1 | 1 | 0 | 0 | 2 |
| Treatment Period | Adverse Event | 5 | 4 | 11 | 6 | 5 | 7 |
| Treatment Period | Lost to Follow-up | 5 | 1 | 11 | 7 | 2 | 3 |
| Treatment Period | Non-compliance with Study Drug | 4 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period | Pregnancy | 0 | 0 | 1 | 1 | 0 | 1 |
| Treatment Period | Protocol Violation | 4 | 3 | 4 | 2 | 3 | 3 |
| Treatment Period | Withdrawal of Consent | 20 | 6 | 9 | 6 | 9 | 6 |
Baseline characteristics
| Characteristic | Placebo | Atogepant 10 mg QD | Atogepant 30 mg QD | Atogepant 60 mg QD | Atogepant 30 mg BID | Atogepant 60 mg BID | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.5 years STANDARD_DEVIATION 11.7 | 39.4 years STANDARD_DEVIATION 12.4 | 41.0 years STANDARD_DEVIATION 13.6 | 40.4 years STANDARD_DEVIATION 11.7 | 38.5 years STANDARD_DEVIATION 11.2 | 39.7 years STANDARD_DEVIATION 11.9 | 40.1 years STANDARD_DEVIATION 12.2 |
| Migraine Days (Migraine/Probable Migraine Headache Days) | 7.81 migraine days per month STANDARD_DEVIATION 2.51 | 7.63 migraine days per month STANDARD_DEVIATION 2.51 | 7.64 migraine days per month STANDARD_DEVIATION 2.37 | 7.74 migraine days per month STANDARD_DEVIATION 2.59 | 7.38 migraine days per month STANDARD_DEVIATION 2.43 | 7.62 migraine days per month STANDARD_DEVIATION 2.56 | 7.67 migraine days per month STANDARD_DEVIATION 2.49 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 45 Participants | 20 Participants | 29 Participants | 44 Participants | 11 Participants | 19 Participants | 168 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 29 Participants | 15 Participants | 32 Participants | 25 Participants | 13 Participants | 13 Participants | 127 Participants |
| Race/Ethnicity, Customized Multiple Races | 0 Participants | 3 Participants | 4 Participants | 4 Participants | 1 Participants | 1 Participants | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 157 Participants | 78 Participants | 151 Participants | 161 Participants | 73 Participants | 78 Participants | 698 Participants |
| Race/Ethnicity, Customized White | 137 Participants | 69 Participants | 145 Participants | 133 Participants | 73 Participants | 71 Participants | 628 Participants |
| Sex: Female, Male Female | 154 Participants | 82 Participants | 166 Participants | 156 Participants | 73 Participants | 83 Participants | 714 Participants |
| Sex: Female, Male Male | 32 Participants | 11 Participants | 17 Participants | 30 Participants | 13 Participants | 8 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 186 | 0 / 93 | 0 / 183 | 0 / 186 | 0 / 86 | 0 / 91 |
| other Total, other adverse events | 36 / 186 | 17 / 93 | 47 / 183 | 52 / 186 | 21 / 86 | 26 / 91 |
| serious Total, serious adverse events | 2 / 186 | 1 / 93 | 2 / 183 | 2 / 186 | 0 / 86 | 0 / 91 |
Outcome results
Primary
Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period
Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache qualified by duration and acute symptomatic medication use. The 4-week migraine days was defined as the total number of reported migraine days in diary divided by total number of days with diary records during each 4- week period and multiplied by 28. Each 4-week period was averaged. Negative change from Baseline indicates improvement.
Time frame: Baseline (First 28 Days of Screening/Baseline Period) to Week 12
Population: MITT Population included all randomized participants who received at least 1 dose of study treatment, had an evaluable baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 9-12) of diary data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -2.85 migraine days per month | Standard Error 0.23 |
| Atogepant 10 mg QD | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -4.00 migraine days per month | Standard Error 0.32 |
| Atogepant 30 mg QD | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -3.76 migraine days per month | Standard Error 0.23 |
| Atogepant 60 mg QD | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -3.55 migraine days per month | Standard Error 0.23 |
| Atogepant 30 mg BID | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -4.23 migraine days per month | Standard Error 0.35 |
| Atogepant 60 mg BID | Change From Baseline in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | -4.14 migraine days per month | Standard Error 0.33 |
p-value: 0.003995% CI: [-1.93, -0.37]MMRM
p-value: 0.005695% CI: [-1.55, -0.27]MMRM
p-value: 0.032595% CI: [-1.35, -0.06]MMRM
p-value: 0.00195% CI: [-2.21, -0.56]MMRM
p-value: 0.001695% CI: [-2.09, -0.49]MMRM
Secondary
Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period
Participants recorded allowed medication(s) to treat an acute migraine in the daily diary. The 4-week (monthly) acute medication use days was defined as the total number of reported acute medication use days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. A negative change from Baseline indicates improvement.
Time frame: Baseline (First 28 Days of Screening/Baseline Period) to Week 12
Population: MITT Population included all randomized participants who received at least 1 dose of study treatment, had an evaluable baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 9-12) of diary data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -2.42 acute medication use days per month | Standard Error 0.21 |
| Atogepant 10 mg QD | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -3.71 acute medication use days per month | Standard Error 0.29 |
| Atogepant 30 mg QD | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -3.86 acute medication use days per month | Standard Error 0.2 |
| Atogepant 60 mg QD | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -3.53 acute medication use days per month | Standard Error 0.21 |
| Atogepant 30 mg BID | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -3.77 acute medication use days per month | Standard Error 0.31 |
| Atogepant 60 mg BID | Change From Baseline in Mean Monthly Acute Medication Use Days Across the 12-Week Treatment Period | -3.64 acute medication use days per month | Standard Error 0.29 |
p-value: 0.000295% CI: [-1.99, -0.6]MMRM
p-value: <0.000195% CI: [-2.01, -0.87]MMRM
p-value: 0.000195% CI: [-1.68, -0.54]MMRM
p-value: 0.000395% CI: [-2.08, -0.62]MMRM
p-value: 0.000795% CI: [-1.93, -0.52]MMRM
Secondary
Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period
Participants recorded daily total duration of a headache in a diary. A headache day is any calendar day on which the participant experienced a headache qualified by duration and acute symptomatic medication use. The 4-week (monthly) headache days was defined as the total number of reported headache days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Negative change from Baseline indicates improvement.
Time frame: Baseline (First 28 Days of Screening/Baseline Period) to Week 12
Population: MITT Population included all randomized participants who received at least 1 dose of study treatment, had an evaluable baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 9-12) of diary data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -2.93 headache days per month | Standard Error 0.25 |
| Atogepant 10 mg QD | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -4.31 headache days per month | Standard Error 0.35 |
| Atogepant 30 mg QD | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -4.17 headache days per month | Standard Error 0.25 |
| Atogepant 60 mg QD | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -3.86 headache days per month | Standard Error 0.25 |
| Atogepant 30 mg BID | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -4.23 headache days per month | Standard Error 0.38 |
| Atogepant 60 mg BID | Change From Baseline in Mean Monthly Headache Days Across the 12-Week Treatment Period | -4.32 headache days per month | Standard Error 0.36 |
p-value: 0.001495% CI: [-2.23, -0.54]MMRM
p-value: 0.000595% CI: [-1.94, -0.55]MMRM
p-value: 0.008795% CI: [-1.64, -0.24]MMRM
p-value: 0.004495% CI: [-2.2, -0.41]MMRM
p-value: 0.001795% CI: [-2.26, -0.53]MMRM
Secondary
Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period
Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache qualified by duration and acute symptomatic medication use. The 4-week migraine days=total number of reported migraine days in diary divided by total number of days with diary records in each 4-week period multiplied by 28. Each 4-week period was averaged.
Time frame: Baseline (First 28 Days of Screening/Baseline Period) to Week 12
Population: MITT Population included all randomized participants who received at least 1 dose of study treatment, had an evaluable baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 9-12) of diary data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 40.4 percentage of participants |
| Atogepant 10 mg QD | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 57.6 percentage of participants |
| Atogepant 30 mg QD | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 53.3 percentage of participants |
| Atogepant 60 mg QD | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 52.0 percentage of participants |
| Atogepant 30 mg BID | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 58.2 percentage of participants |
| Atogepant 60 mg BID | Percentage of Participants With at Least a 50% Reduction in Mean Monthly Migraine Days (Migraine/Probable Migraine Headache Days) Across the 12-Week Treatment Period | 62.1 percentage of participants |
p-value: 0.061795% CI: [0.98, 2.31]GLMM for repeated measures
p-value: 0.036995% CI: [1.02, 2.08]GLMM for repeated measures
p-value: 0.051295% CI: [1, 2.03]GLMM for repeated measures
p-value: 0.011395% CI: [1.15, 2.91]GLMM for repeated measures
p-value: 0.001995% CI: [1.3, 3.18]GLMM for repeated measure