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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of Atogepant for the Prevention of Chronic Migraine (Progress)

    Summary
    EudraCT number
    		 2018-004337-32
    Trial protocol
    		 FR   CZ   SE   PL   DE   DK   ES   GB   IT  
    Global end of trial date
    20 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2023
    First version publication date
    07 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3101-303-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03855137
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan Limited
    Sponsor organisation address
    Allergan Limited Marlow International The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy, safety and tolerability of atogepant in subjects with chronic migraine.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 28
    Country: Number of subjects enrolled
    Czechia: 117
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Japan: 157
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 214
    Worldwide total number of subjects
    778
    EEA total number of subjects
    238
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    754
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total of 778 subjects were randomised in a 1:1:1 ratio to receive atogepant matching placebo and, 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 a 4 week follow up (FU) period till the end of the study up to approximately 16 weeks.

    Period 1
    Period 1 title
    DB Treatment Period (Day 1 to Week 12)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Arm title
    		 Atogepant 60 mg QD
    Arm description
    		 Subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Investigational medicinal product name
    Atogepant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant tablets administered orally.

    Arm title
    		 Atogepant 30 mg BID
    Arm description
    		 Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Investigational medicinal product name
    Atogepant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant tablets administered orally.

    Number of subjects in period 1
    		Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Started
    259
    262
    257
    Safety Population
    255
    261
    257
    Modified Intent-to-Treat Population
    246
    256
    253
    Off-treatment Hypothetical Estimand
    249
    256
    254
    Completed
    230
    233
    231
    Not completed
    29
    29
    26
         Adverse event
    10
    9
    13
         Non-compliance with study drug
    1
    -
    -
         Lost to follow-up
    -
    3
    1
         Lack of efficacy
    5
    1
    2
         Withdrawal by subject
    8
    14
    7
         Protocol deviation
    5
    2
    3
    Period 2
    Period 2 title
    FU Period (Week 12 to Week 16)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Arm title
    		 Atogepant 60 mg QD
    Arm description
    		 Subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Investigational medicinal product name
    Atogepant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant tablets administered orally.

    Arm title
    		 Atogepant 30 mg BID
    Arm description
    		 Subject sreceived atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant-matching placebo tablets administered orally.

    Investigational medicinal product name
    Atogepant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atogepant tablets administered orally.

    Number of subjects in period 2 [1]
    		Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Started
    169
    169
    179
    Completed
    161
    165
    170
    Not completed
    8
    4
    9
         Protocol deviation
    2
    -
    -
         Reason not specified
    1
    -
    -
         Lost to follow-up
    -
    1
    3
         Withdrawal by subject
    5
    3
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 694 subjects who completed the double-blind treatment period, only 517 subjects continued the follow-up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period.

    Reporting group title
    Atogepant 60 mg QD
    Reporting group description
    		 Subjects 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.

    Reporting group title
    Atogepant 30 mg BID
    Reporting group description
    		 Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.

    Reporting group values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID Total
    Number of subjects
    		 259 262 257 778
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.0 ( 12.43 ) 41.7 ( 12.30 ) 42.6 ( 11.89 ) -
    Gender categorical
    Units: Subjects
        Female
    		 229 226 227 682
        Male
    		 30 36 30 96
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 6 12 31
        Not Hispanic or Latino
    		 246 256 245 747
        Unknown or Not Reported
    		 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 1 3
        Asian
    		 95 93 95 283
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        Black or African American
    		 7 9 8 24
        White
    		 154 157 151 462
        More than one race
    		 1 2 2 5
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period.

    Reporting group title
    Atogepant 60 mg QD
    Reporting group description
    		 Subjects 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.

    Reporting group title
    Atogepant 30 mg BID
    Reporting group description
    		 Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.

    Reporting group title
    Atogepant 60 mg QD
    Reporting group description
    		 Subjects 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.

    Reporting group title
    Atogepant 30 mg BID
    Reporting group description
    		 Subject sreceived atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.

    Primary: Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in mITT Population

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    End point title
    		 Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in mITT Population
    End point description
    Subjects recorded daily duration of migraine in a diary. Migraine day was any calendar day on which the subject experienced a migraine headache. 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 randomisation 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. Modified Intent-to-Treat (mITT) Population=all randomised subjects 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.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    246
    256
    253
    Units: migraine days per month
    median (full range (min-max))
        Baseline
    18.0 (8.0 to 28.0)
    19.0 (9.0 to 28.0)
    18.0 (8.0 to 28.0)
        Change From Baseline at Week 12
    -4.63 (-21.9 to 9.7)
    -7.27 (-22.3 to 12.9)
    -7.13 (-27.0 to 7.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.48
         upper limit
    		 -1.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.547
    Notes
    [1] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [2] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0009 [4]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.89
         upper limit
    		 -0.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.545
    Notes
    [3] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [4] - 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.

    Primary: Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in OTHE Population

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    End point title
    		 Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in OTHE Population
    End point 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=improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. Off-treatment hypothetical estimand population: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.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: migraine days per month
    median (full range (min-max))
        Baseline
    18.0 (8 to 28)
    18.0 (8 to 28)
    19.0 (9 to 28)
        Change From Baseline at Week 12
    -4.65 (-21.9 to 9.7)
    -7.19 (-22.3 to 12.9)
    -7.00 (-27.0 to 7.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0001 [6]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.31
         upper limit
    		 -1.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.547
    Notes
    [5] - 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] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0024 [8]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.72
         upper limit
    		 -0.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.544
    Notes
    [7] - 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.
    [8] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.

    Secondary: Change From Baseline in Migraine Specific Quality of Life (QoL) Questionnaire, Version 2.1 (MSQ v2.1) Role Function-Restrictive Domain Score at Week 12 in OTHE Population

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    End point title
    		 Change From Baseline in Migraine Specific Quality of Life (QoL) Questionnaire, Version 2.1 (MSQ v2.1) Role Function-Restrictive Domain Score at Week 12 in OTHE Population
    End point description
    MSQ v2.1=14-item questionnaire measuring health-related QoL impairments for migraine in past 4 weeks,divided into 3 domains:Role Function Restrictive(question no.1-7,score ranges 7-42)assesses how migraines limits daily social, work-related activities;Role Function Preventive(question no.8-11,score ranges 4-24)assesses how migraine prevent activities;Emotional Function(question no.12-14,score ranges 3-18) assesses emotions.Subjects respond using 6-point scale ranging from none to all time.Raw dimension score=sum of item responses rescaled to 0 to 100,higher scores=better quality of life.Contrast from MMRM was used to obtain average treatment effects across 12-week treatment period.Off-treatment hypothetical estimand population:subjects receiving ≥1 dose of drug, had an evaluable baseline period, ≥1 evaluable postbaseline 4-week period(Weeks 1-4, 5-8, 9-12) of eDiary data, regardless of on study or off study treatment.Subjects analysed=no. of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: score on a scale
        arithmetic mean (standard deviation)
    17.56 ( 21.901 )
    23.72 ( 24.335 )
    25.73 ( 23.137 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    7.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.77
         upper limit
    		 11.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.864
    Notes
    [9] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [10] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0018 [12]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    5.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.15
         upper limit
    		 9.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.848
    Notes
    [11] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [12] - 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.

    Secondary: Change From Baseline in Mean Monthly Acute Medication use Days Across 12-Week Treatment Period in mITT Population

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    End point title
    		 Change From Baseline in Mean Monthly Acute Medication use Days Across 12-Week Treatment Period in mITT Population
    End point description
    An acute medication use day was defined as any day on which a subject 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 randomisation 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. mITT Population included all randomised subjects 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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    246
    256
    253
    Units: acute medication use days per month
        median (full range (min-max))
    -3.57 (-23.7 to 20.7)
    -6.33 (-26.0 to 14.2)
    -6.23 (-26.1 to 7.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.63
         upper limit
    		 -1.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Notes
    [13] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [14] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0009 [16]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.13
         upper limit
    		 -1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.508
    Notes
    [15] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [16] - 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.

    Secondary: Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in mITT Population

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    End point title
    		 Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in mITT Population
    End point description
    Subjects recorded daily total duration of a headache in a diary. A headache day is any calendar day on which the subject 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 randomisation date. Negative change from Baseline indicates improvement. MMRM was used for analysis. mITT Population included all randomised subjects 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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    246
    256
    253
    Units: headache days per month
        median (full range (min-max))
    -4.26 (-23.7 to 6.7)
    -6.71 (-22.3 to 9.0)
    -7.16 (-26.3 to 9.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.38
         upper limit
    		 -1.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.541
    Notes
    [17] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [18] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0009 [20]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.93
         upper limit
    		 -0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.538
    Notes
    [19] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [20] - 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.

    Secondary: Change From Baseline in Mean Monthly Physical Impairment Domain Score of the AIM-D Across 12-Week 12 Treatment Period in mITT Population

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    End point title
    		 Change From Baseline in Mean Monthly Physical Impairment Domain Score of the AIM-D Across 12-Week 12 Treatment Period in mITT Population
    End point description
    AIM-D= 11-item PRO measure that assesses impact of migraine on performance of daily activities and physical impairment 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. Raw physical impairment domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). Baseline is defined as the number of migraine days during last 28 days prior to the randomisation date. A contrast from MMRM was used to obtain average treatment effects across 12-week treatment period. mITT Population=all randomised subjects 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 DB treatment period. Subjects analysed=number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    226
    231
    225
    Units: score on a scale
        arithmetic mean (standard deviation)
    -8.05 ( 10.923 )
    -11.65 ( 12.172 )
    -12.34 ( 12.237 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0003 [22]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.95
         upper limit
    		 -2.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.897
    Notes
    [21] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [22] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0025 [24]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.47
         upper limit
    		 -0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.893
    Notes
    [23] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [24] - 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.

    Secondary: Percentage of Subjects With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in mITT Population

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    End point title
    		 Percentage of Subjects With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in mITT Population
    End point description
    Data is reported for 50% responders averaged at each 4-week period. 50% responders are subjects with at least a 50 percent reduction from baseline in monthly migraine days. Subjects recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the subject experienced a migraine headache. The monthly (4-week) migraine days were 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. mITT Population included all randomised subjects 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.
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    246
    256
    253
    Units: percentage of subjects
        number (not applicable)
    26.0
    41.0
    42.7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0003 [26]
    Method
    		 Logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 3.14
    Notes
    [25] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [26] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0009 [28]
    Method
    		 Logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.38
         upper limit
    		 3
    Notes
    [27] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [28] - 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.

    Secondary: Change From Baseline in the Headache Impact Test (HIT-6) Total Score at Week 12 in Off-treatment Hypothetical Estimand (OTHE) Population

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    End point title
    		 Change From Baseline in the Headache Impact Test (HIT-6) Total Score at Week 12 in Off-treatment Hypothetical Estimand (OTHE) Population
    End point description
    HIT-6 is a 6-question assessment used to measure the impact headaches have on a subject’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 subject’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). Off-treatment hypothetical estimand population:subjects receiving ≥1 dose of drug, had an evaluable baseline period, ≥1 evaluable postbaseline 4-week period(Weeks 1-4, 5-8, 9-12) of eDiary data, regardless of on study or off study treatment.MMRM was used for the analyses.
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: score on a scale
        arithmetic mean (standard deviation)
    -5.18 ( 6.682 )
    -7.97 ( 8.209 )
    -8.97 ( 8.475 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [29]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.67
         upper limit
    		 -1.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.697
    Notes
    [29] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [30]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.02
         upper limit
    		 -1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.69
    Notes
    [30] - 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.

    Secondary: Change From Baseline in Mean Monthly Performance of Daily Activities Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population

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    End point 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
    End point description
    AIM-D= 11-item patient-reported outcome(PRO) measure assessing impact of migraine on performance of daily activities and physical impairment using 6-point rating scale where 0=not difficult at all,1=a little difficult,2=somewhat difficult,3=very difficult,4=extremely difficult, and5=I could not do it at all. Raw performance of daily activities domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). Baseline=number of migraine days during last 28 days prior to randomisation date.Contrast from MMRM was used to obtain average treatment effects across 12-week treatment period.mITT Population=all randomised subjects receiving at least 1 dose of study intervention,had an evaluable baseline period of eDiary data,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 double-blind treatment period.Subjects analysed=number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    226
    231
    225
    Units: score on a scale
        arithmetic mean (standard deviation)
    -9.80 ( 11.311 )
    -13.90 ( 12.625 )
    -14.56 ( 13.042 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.0003 [32]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.75
         upper limit
    		 -2.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.968
    Notes
    [31] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [32] - 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 title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.0009 [34]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.27
         upper limit
    		 -1.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.963
    Notes
    [33] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    [34] - 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.

    Secondary: Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in OTHE Population

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    End point title
    		 Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in OTHE Population
    End point description
    Participants recorded daily total duration of a headache in a diary. Headache day: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.Monthly (4-week) headache days: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 multiplied by 28. Each 4-week period was averaged. Baseline:the number of headache days during last 28 days prior to the randomization date. Negative change from Baseline=improvement.A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. OTHE population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: headache days per month
        median (full range (min-max))
    -4.33 (-23.7 to 6.7)
    -6.59 (-22.3 to 9.0)
    -7.04 (-26.3 to 9.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.0002 [36]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 -1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.539
    Notes
    [35] - 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.
    [36] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.0024 [38]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 -0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.536
    Notes
    [37] - 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.
    [38] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.

    Secondary: Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in OTHE

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    End point title
    		 Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in OTHE
    End point 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. OTHE population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: acute medication use days per month
        median (full range (min-max))
    -3.56 (-23.7 to 20.7)
    -6.00 (-26.0 to 14.2)
    -6.21 (-26.1 to 7.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.0002 [40]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.52
         upper limit
    		 -1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.507
    Notes
    [39] - 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.
    [40] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.0024 [42]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 -1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.505
    Notes
    [41] - 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.
    [42] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.

    Secondary: Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in OTHE

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    End point title
    		 Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in OTHE
    End point 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. OTHE population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Number of subjects analysed
    249
    257
    254
    Units: percentage of participants
        number (not applicable)
    26.5
    40.1
    42.1
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Atogepant 30 mg BID
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.0006 [44]
    Method
    		 Logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.38
         upper limit
    		 2.98
    Notes
    [43] - 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.
    [44] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atogepant 60 mg QD
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.0024 [46]
    Method
    		 Logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 2.79
    Notes
    [45] - 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.
    [46] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to end of study (Up to approximately 16 weeks)
    Adverse event reporting additional description
    Safety population included all participants who received at least 1 dose of study intervention and was used for serious adverse events and non-serious adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period.

    Reporting group title
    Atogepant 60 mg QD
    Reporting group description
    		 Subjects 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.

    Reporting group title
    Atogepant 30 mg BID
    Reporting group description
    		 Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.

    Serious adverse events
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 255 (1.18%)
    7 / 261 (2.68%)
    4 / 257 (1.56%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BENIGN OVARIAN TUMOUR
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 261 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 261 (0.00%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL CORD NEOPLASM
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HIP FRACTURE
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPICONDYLITIS
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 261 (0.00%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VACCINATION COMPLICATION
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    NASAL SEPTUM DEVIATION
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    SUICIDE ATTEMPT
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 261 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    SPINAL PAIN
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 261 (0.38%)
    0 / 257 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 261 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 261 (0.00%)
    1 / 257 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Atogepant 60 mg QD Atogepant 30 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 255 (6.27%)
    46 / 261 (17.62%)
    44 / 257 (17.12%)
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    9 / 255 (3.53%)
    25 / 261 (9.58%)
    20 / 257 (7.78%)
         occurrences all number
    9
    27
    21
    CONSTIPATION
         subjects affected / exposed
    8 / 255 (3.14%)
    26 / 261 (9.96%)
    28 / 257 (10.89%)
         occurrences all number
    8
    26
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2019
    The following changes were implemented with Amendment 1: Added instructions for study conducted in China and Canada. Clarified primary and secondary endpoints for China, and Canada. Clarified prohibited medications. Updated laboratory parameters. Updated the subgroup analyses. Corrected the study diagram for the estimand framework. Updated the definition of failed migraine preventive medication.
    23 Sep 2019
    The following changes were implemented with Amendment 2: Added instructions for study conducted in Japan. Added instruction regarding Visit 8 (follow-up) for subjects in Japan and China who may rollover to a regional, long-term, extension, safety study. Clarified secondary efficacy endpoints for Europe and Canada, and for all other regions except Europe and Canada. Updated description of the AIM-D health outcomes measure and endpoints. Described the Hochberg procedure to be used to control the overall Type I error rate at a 0.05 level (2-sided) for multiple comparisons of 2 atogepant doses with placebo for the primary efficacy endpoint, only for the analysis in Japan. Described weekly data analysis procedures for other efficacy analyses. Described planned subgroup analyses to evaluate consistency of treatment across regions and subpopulations. Updated description of safety analysis. Clarified criteria for sexual abstinence to be considered as a highly effective contraceptive method. Added a benefit/risk assessment. Added definition of the end of the study. Clarified exclusion criterion based on hypersensitivity to study interventions. Clarified the instructions regarding prohibited medication/treatments. Clarified instructions for the subjects. Clarified instructions regarding assessment of causality of adverse events. Added definition of adverse reaction, serious adverse reaction, and suspected unexpected serious adverse reaction. Clarified instruction regarding changes to the protocol.
    29 May 2020
    The following changes were implemented with Amendment 3: Updated the requirements by French authorities. Updated the enrollment criteria based on data review of recent migraine prevention studies. Clarified the randomization and stratification process to include region. Clarified participation in Visit 8/EOS for rollover subjects, by region and respective long-term safety extension study, and added information to allow for subjects to roll over to the respective open-label (OL) long-term extension study. Adapted description of regions for consistency with stratification. Clarified the description of the ITT and mITT population, and the analysis population for off-treatment hypothetical estimand for the primary efficacy analysis to support filing in Europe.Clarified primary endpoint and added the statistical model term ‘region’ to the MMRM model for primary analysis. Clarified the AIM-D related secondary endpoint, based on psychometric evidence of the AIM-D consisting of 2 domains, performance of daily activities and physical impairment. Clarified secondary endpoints and statistical analysis model for secondary analysis. Outlined conduct of study when remote visits are necessary due to COVID-19. Updated the Close Out Visit to comply with Russian requirement. Updated the masking/blinding and dosage schedule. Updated the additional efficacy endpoints.Clarified that 50% responder will be assessed for each individual.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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