Efficacy, Safety, and Tolerability of Atogepant for the Prevention of Chronic Migraine

• ClinicalTrials.gov Identifier: NCT03855137
• Recruitment Status: Completed
• First Posted: February 26, 2019
• Results First Posted: February 14, 2023
• Last Update Posted: February 14, 2023
• Sponsor: Allergan
• Information provided by (Responsible Party): Allergan

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Chronic Migraine
• Interventions: Drug: Atogepant 30 mg; Drug: Atogepant 60 mg; Drug: Placebo
• Enrollment: 778

Participant Flow

Recruitment Details
Pre-assignment Details	Total of 778 participants were randomized in a 1:1:1 ratio to receive atogepant matching placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for up to 12 weeks in a double-blind (DB) treatment period followed by 4 week follow up (FU) period till end of study up to approximately 16 weeks.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Period Title: DB Treatment Period (Day 1 to Week 12)
Started	259	257	262
Safety Population [1]	255	257	261
Modified Intent-to-Treat (mITT) Population [2]	246	253	256
Off-treatment Hypothetical Estimand Population [3]	249	254	257
Completed	230	231	233
Not Completed	29	26	29
Reason Not Completed
Adverse Event	10	13	9
Lack of Efficacy	5	2	1
Withdrawal by Subject	8	7	14
Lost to Follow-up	0	1	3
Protocol Deviation	5	3	2
Non-compliance With Study Drug	1	0	0
[1] Safety population included all participants who received at least 1 dose of study intervention.; [2] mITT population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind treatment period.; [3] Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.
Period Title: FU Period (Week 12 to Week 16)
Started [1]	169	179	169
Completed [2]	161	170	165
Not Completed	8	9	4
Reason Not Completed
Withdrawal by Subject	5	6	3
Lost to Follow-up	0	3	1
Protocol Deviation	2	0	0
Reason not Specified	1	0	0
[1] Out of 694 participants who completed the DB treatment period, only 517 participants continued the follow-up period.; [2] Participants who completed the DB treatment period and rolled-over to other extension studies 3101-312-002 (NCT04686136), 3101-306-002 (NCT04437433),and 3101-311-002 (NCT04829747) were not required to enter the follow-up period.

Baseline Characteristics

Arm/Group Title		Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD	Total
Arm/Group Description		Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.	Total of all reporting groups
Overall Number of Baseline Participants		259	257	262	778
Baseline Analysis Population Description		Intent-to-treat (ITT) population included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	259 participants	257 participants	262 participants	778 participants
		42.0 (12.43)	42.6 (11.89)	41.7 (12.30)	42.1 (12.20)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	257 participants	262 participants	778 participants
	Female	229 88.4%	227 88.3%	226 86.3%	682 87.7%
	Male	30 11.6%	30 11.7%	36 13.7%	96 12.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	257 participants	262 participants	778 participants
	Hispanic or Latino	13 5.0%	12 4.7%	6 2.3%	31 4.0%
	Not Hispanic or Latino	246 95.0%	245 95.3%	256 97.7%	747 96.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	259 participants	257 participants	262 participants	778 participants
	American Indian or Alaska Native	1 0.4%	1 0.4%	1 0.4%	3 0.4%
	Asian	95 36.7%	95 37.0%	93 35.5%	283 36.4%
	Native Hawaiian or Other Pacific Islander	1 0.4%	0 0.0%	0 0.0%	1 0.1%
	Black or African American	7 2.7%	8 3.1%	9 3.4%	24 3.1%
	White	154 59.5%	151 58.8%	157 59.9%	462 59.4%
	More than one race	1 0.4%	2 0.8%	2 0.8%	5 0.6%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Monthly Migraine Days in mITT Population [1] [2]; Median (Full Range); Unit of measure: Migraine days per month
	Number Analyzed	246 participants	253 participants	256 participants	755 participants
		18.00; (8.0 to 28.0)	18.00; (8.0 to 28.0)	19.00; (9.0 to 28.0)	18.2; (8.0 to 28.0)
		[1] Measure Description: A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (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.; [2] Measure Analysis Population Description: mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind treatment period.
Monthly Migraine Days in Off-Treatment Hypothetical Estimand Population [1] [2]; Median (Full Range); Unit of measure: Migraine days per month
	Number Analyzed	249 participants	254 participants	257 participants	760 participants
		18.0; (8 to 28)	18.0; (8 to 28)	19.0; (9 to 28)	18.3; (8 to 28)
		[1] Measure Description: A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (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.; [2] Measure Analysis Population Description: Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in mITT Population
Description	Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (4-week) migraine days were 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. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. Negative change from Baseline indicates improvement. A contrast from Mixed-effects model for repeated measures (MMRM) was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	246	253	256
Median (Full Range); Unit of Measure: migraine days per month
	-4.63; (-21.9 to 9.7)	-7.13; (-27.0 to 7.7)	-7.27; (-22.3 to 12.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	Mixed Model Repeated Measures (MMRM)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.41
	Confidence Interval	(2-Sided) 95%; -3.48 to -1.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.547
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.82
	Confidence Interval	(2-Sided) 95%; -2.89 to -0.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.545
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

2. Primary Outcome

Title	Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in Off-Treatment Hypothetical Estimand Population
Description	Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (4-week) migraine days were 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. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. Negative change from Baseline indicates improvement. A contrast from Mixed-effects model for repeated measures (MMRM) was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	249	254	257
Median (Full Range); Unit of Measure: migraine days per month
	-4.65; (-21.9 to 9.7)	-7.00; (-27.0 to 7.7)	-7.19; (-22.3 to 12.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.24
	Confidence Interval	(2-Sided) 95%; -3.31 to -1.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.547
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	MMRM
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.66
	Confidence Interval	(2-Sided) 95%; -2.72 to -0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.544
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

3. Secondary Outcome

Title	Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in mITT Population
Description	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 pain lasting 2 hours or longer unless an acute headache medication was used after the start of the headache. The monthly (4-week) headache days were 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. Baseline is defined as the number of headache days during the last 28 days prior to the randomization date. Negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	246	253	256
Median (Full Range); Unit of Measure: headache days per month
	-4.26; (-23.7 to 6.7)	-7.16; (-26.3 to 9.0)	-6.71; (-22.3 to 9.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.32
	Confidence Interval	(2-Sided) 95%; -3.38 to -1.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.541
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.87
	Confidence Interval	(2-Sided) 95%; -2.93 to -0.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.538
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

4. Secondary Outcome

Title	Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in Off-Treatment Hypothetical Estimand Population
Description	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 pain lasting 2 hours or longer unless an acute headache medication was used after the start of the headache. The monthly (4-week) headache days were 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. Baseline is defined as the number of headache days during the last 28 days prior to the randomization date. Negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	249	254	257
Median (Full Range); Unit of Measure: headache days per month
	-4.33; (-23.7 to 6.7)	-7.04; (-26.3 to 9.0)	-6.59; (-22.3 to 9.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.14
	Confidence Interval	(2-Sided) 95%; -3.20 to -1.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.539
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.72
	Confidence Interval	(2-Sided) 95%; -2.78 to -0.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.536
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

5. Secondary Outcome

Title	Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in mITT Population
Description	An acute medication use day is defined as any day on which a participant reports, per eDiary, the intake of allowed medication(s) to treat an acute migraine. The monthly (4-week) acute medication use days were 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. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. A negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	246	253	256
Median (Full Range); Unit of Measure: acute medication use days per month
	-3.57; (-23.7 to 20.7)	-6.23; (-26.1 to 7.4)	-6.33; (-26.0 to 14.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.63
	Confidence Interval	(2-Sided) 95%; -3.63 to -1.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.510
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.13
	Confidence Interval	(2-Sided) 95%; -3.13 to -1.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.508
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

6. Secondary Outcome

Title	Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in Off-treatment Hypothetical Estimand Population
Description	An acute medication use day is defined as any day on which a participant reports, per eDiary, the intake of allowed medication(s) to treat an acute migraine. The monthly (4-week) acute medication use days were 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. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. A negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	249	254	257
Median (Full Range); Unit of Measure: acute medication use days per month
	-3.56; (-23.7 to 20.7)	-6.21; (-26.1 to 7.4)	-6.00; (-26.0 to 14.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.52
	Confidence Interval	(2-Sided) 95%; -3.52 to -1.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.507
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.09
	Confidence Interval	(2-Sided) 95%; -3.09 to -1.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.505
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in mITT Population
Description	Data is reported for 50% responders averaged at each 4-week period. 50% responders are participants with at least a 50 percent reduction from baseline in 3-month average of monthly migraine days. Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (4-week) migraine days is equal to 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. The values are rounded off to the first decimal value.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	246	253	256
Measure Type: Number; Unit of Measure: percentage of participants
	26.0	42.7	41.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	Logistic regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.13
	Confidence Interval	(2-Sided) 95%; 1.45 to 3.14
	Estimation Comments	Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	Logistic regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.04
	Confidence Interval	(2-Sided) 95%; 1.38 to 3.00
	Estimation Comments	Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors.

8. Secondary Outcome

Title	Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in Off-Treatment Hypothetical Estimand Population
Description	Data is reported for 50% responders averaged at each 4-week period. 50% responders are participants with at least a 50 percent reduction from baseline in 3-month average of monthly migraine days. Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (4-week) migraine days is equal to 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. The values are rounded off to the first decimal value.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	249	254	257
Measure Type: Number; Unit of Measure: percentage of participants
	26.5	42.1	40.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	Logistic regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.03
	Confidence Interval	(2-Sided) 95%; 1.38 to 2.98
	Estimation Comments	Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	Logistic regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.90
	Confidence Interval	(2-Sided) 95%; 1.29 to 2.79
	Estimation Comments	Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors.

9. Secondary Outcome

Title	Change From Baseline in Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1) Role Function-Restrictive Domain Score at Week 12 in Off-Treatment Hypothetical Estimand Population
Description	The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality of life impairments attributed to migraine in the past 4 weeks. It is divided into 3 domains: Role Function Restrictive (question numbers 1-7, score ranges 7 to 42) assesses how migraines limit one's daily social and work-related activities; Role Function Preventive (question numbers 8-11, score ranges 4 to 24) assesses how migraines prevent these activities; and the Emotional Function (question numbers 12-14, score ranges 3 to 18) domain assesses the emotions associated with migraines. Participants respond to items using a 6-point scale ranging from none of the time to all of the time. Raw dimension scores are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores indicate better quality of life. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	At Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment. Overall number analyzed are the number of participants with data available for analyses.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	225	229	236
Mean (Standard Deviation); Unit of Measure: score on a scale
	17.56 (21.901)	25.73 (23.137)	23.72 (24.335)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	7.43
	Confidence Interval	(2-Sided) 95%; 3.77 to 11.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.864
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	5.78
	Confidence Interval	(2-Sided) 95%; 2.15 to 9.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.848
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

10. Secondary Outcome

Title	Change From Baseline in Mean Monthly Performance of Daily Activities Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population
Description	The AIM-D is a 11-item patient-reported outcome (PRO) measure that assesses the impact of migraine on the performance of daily activities which include, 7 items: difficulty with household chores, errands, leisure activities at home, leisure or social activities outside the home, strenuous physical activities, concentrating, and thinking clearly and physical impairment; 4 items: difficulty walking, moving body, bending forward, moving head using a 6-point rating scale where 0=not difficult at all, 1=a little difficult, 2=somewhat difficult, 3=very difficult, 4=extremely difficult, and 5=I could not do it at all. The raw performance of daily activities domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period. Overall number analyzed are the number of participants with data available for analyses.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	226	225	231
Mean (Standard Deviation); Unit of Measure: score on a scale
	-9.80 (11.311)	-14.56 (13.042)	-13.90 (12.625)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.85
	Confidence Interval	(2-Sided) 95%; -6.75 to -2.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.968
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.38
	Confidence Interval	(2-Sided) 95%; -5.27 to -1.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.963
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

11. Secondary Outcome

Title	Change From Baseline in Mean Monthly Physical Impairment Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population
Description	The AIM-D is a 11-item PRO measure that assesses the impact of migraine on the performance of daily activities which includes 7 items: difficulty with household chores, errands, leisure activities at home, leisure or social activities outside the home, strenuous physical activities, concentrating, and thinking clearly and physical impairment; 4 items: difficulty walking, moving body, bending forward, moving head using a 6-point rating scale where 0=not difficult at all, 1=a little difficult, 2=somewhat difficult, 3=very difficult, 4=extremely difficult, and 5=I could not do it at all. The raw physical impairment domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT Population included all randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period. Overall number analyzed are the number of participants with data available for analyses.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	226	225	231
Mean (Standard Deviation); Unit of Measure: score on a scale
	-8.05 (10.923)	-12.34 (12.237)	-11.65 (12.172)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.19
	Confidence Interval	(2-Sided) 95%; -5.95 to -2.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.897
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0025
	Comments	Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.71
	Confidence Interval	(2-Sided) 95%; -4.47 to -0.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.893
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

12. Secondary Outcome

Title	Change From Baseline in the Headache Impact Test (HIT-6) Total Score at Week 12 in Off-Treatment Hypothetical Estimand Population
Description	HIT-6 is a 6-question assessment used to measure the impact headaches have on a participant's ability to function on the job, at school, at home, and in social situations. It assesses the effect that headaches have on normal daily life and the participant's ability to function. Responses are based on frequency using a 5-point scale ranging from "never" to "always." The HIT-6 total score, which ranges from 36 to 78, is the sum of the responses - each of which is assigned a score ranging from 6 points (never) to 13 points (always). MMRM was used for the analyses.
Time Frame	At Week 12

Outcome Measure Data

Analysis Population Description

Off-treatment hypothetical estimand population included all randomized participants who received ≥ 1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥ 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment. Overall number analyzed are the number of participants with data available for analyses.

Arm/Group Title	Placebo	Atogepant 30 mg BID	Atogepant 60 mg QD
Arm/Group Description:	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.	Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.	Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
Overall Number of Participants Analyzed	225	229	236
Mean (Standard Deviation); Unit of Measure: score on a scale
	-5.18 (6.682)	-8.97 (8.475)	-7.97 (8.209)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 30 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.30
	Confidence Interval	(2-Sided) 95%; -4.67 to -1.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.697
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atogepant 60 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.66
	Confidence Interval	(2-Sided) 95%; -4.02 to -1.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.690
	Estimation Comments	MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates.

Adverse Events

Time Frame	From first dose of study drug up to end of study (Up to approximately 16 weeks)
Adverse Event Reporting Description	All-Cause Mortality is reported for all randomized participants. Safety population included all participants who received at least 1 dose of study intervention and was used for serious adverse events and other adverse events.
Arm/Group Title	Placebo		Atogepant 30 mg BID		Atogepant 60 mg QD
Arm/Group Description	Participants received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.		Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.		Participants received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period.
All-Cause Mortality
	Placebo		Atogepant 30 mg BID		Atogepant 60 mg QD
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/259 (0.00%)		0/257 (0.00%)		0/262 (0.00%)
Serious Adverse Events
	Placebo		Atogepant 30 mg BID		Atogepant 60 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/255 (1.18%)		4/257 (1.56%)		7/261 (2.68%)
Hepatobiliary disorders
CHOLELITHIASIS † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
Infections and infestations
ANAL ABSCESS † 1	0/255 (0.00%)	0	1/257 (0.39%)	1	0/261 (0.00%)	0
COVID-19 † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
COVID-19 PNEUMONIA † 1	0/255 (0.00%)	0	1/257 (0.39%)	1	0/261 (0.00%)	0
Injury, poisoning and procedural complications
EPICONDYLITIS † 1	1/255 (0.39%)	1	0/257 (0.00%)	0	0/261 (0.00%)	0
FALL † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
HIP FRACTURE † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
ROAD TRAFFIC ACCIDENT † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
VACCINATION COMPLICATION † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
Musculoskeletal and connective tissue disorders
SPINAL PAIN † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BENIGN OVARIAN TUMOUR † 1	0/255 (0.00%)	0	1/257 (0.39%)	1	0/261 (0.00%)	0
PLASMA CELL MYELOMA † 1	1/255 (0.39%)	1	0/257 (0.00%)	0	0/261 (0.00%)	0
SPINAL CORD NEOPLASM † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
Psychiatric disorders
SUICIDE ATTEMPT † 1	1/255 (0.39%)	1	1/257 (0.39%)	1	0/261 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
NASAL SEPTUM DEVIATION † 1	0/255 (0.00%)	0	0/257 (0.00%)	0	1/261 (0.38%)	1
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Atogepant 30 mg BID		Atogepant 60 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/255 (6.27%)		44/257 (17.12%)		46/261 (17.62%)
Gastrointestinal disorders
CONSTIPATION † 1	8/255 (3.14%)	8	28/257 (10.89%)	28	26/261 (9.96%)	26
NAUSEA † 1	9/255 (3.53%)	9	20/257 (7.78%)	21	25/261 (9.58%)	27
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.

Results Point of Contact

• Name/Title: Global Medical Services
• Organization: AbbVie
• Phone: 800-633-9110
• EMail: abbvieclinicaltrials@abbvie.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Boinpally R, McNamee B, Yao L, Butler M, McGeeney D, Borbridge L, Periclou A. A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1099-1107. doi: 10.1002/cpdd.940. Epub 2021 May 4.

Min KC, Kraft WK, Bondiskey P, Colon-Gonzalez F, Liu W, Xu J, Panebianco D, Mixson L, Dockendorf MF, Matthews CZ, Boinpally R. Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults. Clin Transl Sci. 2021 Mar;14(2):599-605. doi: 10.1111/cts.12917. Epub 2020 Nov 24.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT03855137
• Obsolete Identifiers: NCT04961671
• Other Study ID Numbers: 3101-303-002; 2018-004337-32 ( EudraCT Number )
• First Submitted: February 25, 2019
• First Posted: February 26, 2019
• Results First Submitted: January 18, 2023
• Results First Posted: February 14, 2023
• Last Update Posted: February 14, 2023