Clinical trial NCT03855137
Conditions: Chronic Migraine
Sponsor: Allergan
Start date: 2019-03-11; Completion date: 2022-01-20
Enrollment: 778 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the efficacy, safety and tolerability of atogepant in participants with chronic migraine. This study included a 12-week treatment period.

Detailed description:

Arms: arm 1: Participants received atogepant-matching placebo tablets, orally, twice daily (BID) for 12 weeks in a double-blind (DB) treatment period. arm 2: 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. arm 3: Participants received atogepant 60 mg, orally, once daily (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.
Interventions: intervention 1: Atogepant 30 mg intervention 2: Atogepant 60 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Tablets containing 30 mg atogepant intervention 2: Tablets containing 60 mg atogepant intervention 3: 30 mg/60 mg tablets containing atogepant-matching placebo

Protocol documents:
Prot_000.pdf: 
Allergan Confidential
Protocol 3101-303-002 Amendment 3
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ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information 
which is the property of Allergan
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)
Protocol Number:
3101-303-002
EudraCT Number:
2018-004337-32
Phase:
3
Name of Study Intervention:
Atogepant (AGN-241689)
Sponsor:
Allergan Ltd
Marlow International,
The Parkway, Marlow, 
Buckinghamshire
SL7 1YL United Kingdom
US Agent
Allergan Sales, LLC
2525 DuPont Drive
Irvine, California USA
92612
Emergency Telephone Number(s):
+1-866-438-8820
Serious Adverse Event Reporting 
Fax Number(s):
+1-714-796-9504
(Back Up Fax No.: +1-714-246-5295)
Email:
IR-Clinical-SAE@allergan.com
Allergan Medical Safety Physician
Contact Information:
Refer to the Study Contacts Page
Allergan Signatory:
MS, MD
Vice President, Neuroscience Development
Original Protocol Date:
13 December 2018
Protocol Amendment 1 Date:
08 April 2019
Protocol Amendment 2 Date:
23 September 2019
Protocol Amendment 3 Date:
29 May 2020
NCT03855137


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The following information can be found on FDA Form 1572 and/or study contacts page: Name 
and contact information of the sponsor study personnel and Emergency Telephone Numbers; 
name, address, and statement of qualifications of each investigator; name of each subinvestigator 
working under the supervision of the investigator; name and address of the research facilities to 
be used; name and address of each reviewing IRB; US 21 CFR 312.23 section 6(iii)b.


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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol, GCP, 
and all applicable laws and regulations.

Maintain all information supplied by the sponsor in confidence and, when this information is 
submitted to an IRB, IEC or another group, it will be submitted with a designation that the 
material is confidential.

Ensure that all persons assisting with the trial are adequately informed about the protocol, the 
study intervention(s), and their trial-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Signature
Date


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Table of Contents
Title Page ........................................................................................................................................ 1
Table of Contents ............................................................................................................................ 4
List of Tables................................................................................................................................. 10
List of Figures............................................................................................................................... 10
Protocol Summary .........................................................................................................................11
1.
Background and Clinical Rationale....................................................................................... 20
1.1
Background ...................................................................................................................20
1.2
Overview of Atogepant.................................................................................................21
1.3
Study Rationale.............................................................................................................22
1.4
Rationale for Doses and Dose Regimens Selected .......................................................22
1.5
Benefit/Risk Assessment...............................................................................................22
2.
Study Objectives and Clinical Hypotheses............................................................................ 22
2.1
Study Objectives ...........................................................................................................22
2.2
Clinical Hypotheses ......................................................................................................23
3.
Study Design.......................................................................................................................... 23
3.1
Structure........................................................................................................................23
3.2
Data Safety Monitoring Board......................................................................................25
3.3
Adjudication Committee...............................................................................................25
3.4
End of Study Definition ................................................................................................25
4.
Study Population and Entry Criteria...................................................................................... 25
4.1
Number of Participants .................................................................................................25
4.2
Inclusion Criteria...........................................................................................................26
4.3
Exclusion Criteria .........................................................................................................26
4.4
Permissible and Prohibited Medications/Treatments....................................................30
4.4.1
Permissible Medications/Treatments ................................................................30
4.4.2
Prohibited Medications/Treatments ..................................................................31
4.4.3
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .....................................................................................32
4.4.4
Special Diet or Activities ..................................................................................34
4.5
Screen Failures..............................................................................................................34
5.
Study Interventions................................................................................................................ 34


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5.1
Study Interventions and Formulations ..........................................................................34
5.2
Control Interventions and Formulations .......................................................................34
5.3
Methods for Masking/Blinding.....................................................................................35
5.4
Treatment Allocation Ratio and Stratification..............................................................35
5.5
Method for Assignment to Treatment Groups/Randomization.....................................36
5.6
Study Intervention Regimen and Dosing......................................................................37
5.7
Storage of Study Interventions......................................................................................38
6.
Response Measures and Summary of Data Collection Methods........................................... 38
6.1
Efficacy Measures.........................................................................................................38
6.1.1
Migraine Day ....................................................................................................38
6.1.2
Headache Day ...................................................................................................39
6.1.3
Acute Medication Use Day and Triptan Use Day.............................................40
6.2
Health Outcomes Measures...........................................................................................40
6.2.1
Activity Impairment in Migraine – Diary (AIM-D) .........................................40
6.2.2
Activity Level and Activity Limitation.............................................................40
6.2.3
Patient Satisfaction with Study Medication (PSSM) ........................................41
6.2.4
Headache Impact Test (HIT-6)..........................................................................41
6.2.5
Migraine Disability Assessment (MIDAS).......................................................41
6.2.6
Patient Global Impression of Change (PGIC)...................................................41
6.2.7
Work Productivity and Activity Impairment Questionnaire: Migraine V2.0 
(WPAI:MIGRAINE).........................................................................................41
6.2.8
European Quality of Life – 5 Dimensional (EQ-5D-5L)..................................42
6.2.9
Patient Global Impression – Severity (PGI-S)..................................................42
6.2.10 Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1).....42
6.2.11 Patient-Reported Outcomes Measurement Information System Pain 
Interference – Short Form 6a (PROMIS-PI).....................................................42
6.2.12 Patient Health Questionnaire (PHQ-9) .............................................................43
6.3
Pharmacokinetics Measures..........................................................................................43
6.4
Future Biomedical Research .........................................................................................44
6.5
Safety Measures ............................................................................................................44
6.5.1
Adverse Events..................................................................................................44
6.5.2
Adverse Events of Special Interest ...................................................................44
6.5.3
Clinical Laboratory Determinations..................................................................45
6.5.4
Vital Signs.........................................................................................................46
6.5.5
Physical Examination........................................................................................46
6.5.6
Electrocardiograms ...........................................................................................47


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6.5.7
Columbia-Suicide Severity Rating Scale..........................................................47
6.6
Other Study Supplies ....................................................................................................48
6.7
Summary of Methods of Data Collection .....................................................................48
7.
Statistical Procedures............................................................................................................. 49
7.1
Analysis Populations.....................................................................................................49
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments ..............49
7.2.1
Primary Efficacy Endpoint................................................................................50
7.2.2
Secondary Efficacy Endpoints ..........................................................................50
7.2.3
Additional Efficacy Endpoints..........................................................................51
7.2.3.1
Other Health Outcome Variables........................................................ 53
7.3
Hypothesis and Methods of Analysis............................................................................53
7.3.1
Primary Efficacy Analyses................................................................................53
7.3.1.1
Sensitivity Analyses in Missing Data Handling................................. 54
7.3.1.2
Sensitivity Analysis for Possible Violation of Normality Assumption
............................................................................................................ 55
7.3.2
Secondary Efficacy Analyses............................................................................56
7.3.3
Additional Efficacy Analyses............................................................................57
7.3.4
Safety Analysis..................................................................................................58
7.4
Off-treatment Hypothetical Estimand Framework for EMA........................................58
7.4.1
Treatment Condition of Interest ........................................................................58
7.4.2
Population .........................................................................................................59
7.4.3
Variable .............................................................................................................59
7.4.4
Accounting of Intercurrent Events....................................................................59
7.4.5
Population-Level Summary ..............................................................................59
7.4.6
Off-Treatment Hypothetical Estimand Approach for the Secondary Endpoints60
7.5
Subgroup Analyses .......................................................................................................60
7.5.1
Subgroup Analyses for Evaluating the Consistency of Treatment Effects Across 
Regions and Subpopulations.............................................................................60
7.5.2
Other Subgroup Analyses..................................................................................61
7.6
Sample Size Calculation ...............................................................................................61
7.7
Pharmacokinetics and Exposure-Response Analyses...................................................62
7.8
Interim Analyses ...........................................................................................................62
8.
Study Visit Schedule and Procedures .................................................................................... 62
8.1
Participant Entry Procedures.........................................................................................63
8.1.1
Overview of Entry Procedures..........................................................................63
8.1.2
Informed Consent and Participant Privacy .......................................................63


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8.1.3
Procedure for Duplicate Participant Identification – Verified Clinical Trials...63
8.2
Washout Intervals..........................................................................................................63
8.3
Procedures for Final Study Entry..................................................................................64
8.4
Visits and Associated Procedures .................................................................................64
8.4.1
Visit 1 (Screening/Baseline) Day -35 to Day -28..............................................64
8.4.2
Double-blind Treatment Phase (12 Weeks).......................................................65
8.4.2.1
Visit 2 (Randomization) Day 1 .......................................................... 65
8.4.2.2
Visits 3 to 6 (Weeks 2 to 8) ................................................................ 66
8.4.2.3
Visit 7/Early Termination (Week 12) ................................................. 67
8.4.3
Follow-up Period (4 Weeks) .............................................................................68
8.4.3.1
Visit 8/End of Study (Week 16) ......................................................... 68
8.5
Instructions for the Participants ....................................................................................68
8.6
Unscheduled Visits .......................................................................................................69
8.7
Compliance with Protocol.............................................................................................69
8.8
Early Discontinuation of Participants ...........................................................................70
8.8.1
Participants Who Discontinue Study Intervention Early ..................................70
8.9
Withdrawal Criteria.......................................................................................................72
8.10 Study Termination.........................................................................................................72
9.
Adverse Events ...................................................................................................................... 72
9.1
Definitions.....................................................................................................................72
9.1.1
Adverse Event...................................................................................................72
9.1.2
Serious Adverse Event ......................................................................................73
9.1.3
Intensity.............................................................................................................75
9.1.4
Assessment of Causality ...................................................................................76
9.1.5
Follow-up of Adverse Events and Serious Adverse Events..............................76
9.1.6
Adverse Reactions, Serious Adverse Reactions, and Suspected Unexpected 
Serious Adverse Reactions................................................................................77
9.2
Procedures for Reporting Adverse Events....................................................................77
9.3
Procedures for Reporting a Serious Adverse Event......................................................77
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events....................78
9.4
Exposure to Study Intervention During Pregnancy ......................................................78
9.5
ALT or AST Elevations.................................................................................................79
9.5.1
Potential Hy’s Law Cases .................................................................................80
9.6
Procedures for Unmasking of Study Medication..........................................................81
10. Administrative Items ............................................................................................................. 81


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10.1 Protection of Human Participants .................................................................................81
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ..........................................................................81
10.1.2 Compliance With IRB or IEC Regulations.......................................................82
10.1.3 Compliance With Good Clinical Practice .........................................................82
10.1.4 Compliance With Electronic Records; Electronic Signatures Regulations (US 
21CFR Part 11)..................................................................................................82
10.2 Financial Disclosure......................................................................................................82
10.3 Changes to the Protocol ................................................................................................82
10.4 Data Protection..............................................................................................................83
10.5 Participant Confidentiality ............................................................................................83
10.6 Participant Privacy ........................................................................................................83
10.7 Documentation..............................................................................................................84
10.7.1 Source Documents ............................................................................................84
10.7.2 Case Report Form Completion .........................................................................85
10.7.3 Study Summary.................................................................................................85
10.7.4 Retention of Documentation .............................................................................85
10.8 Labeling, Packaging, and Return or Disposal of Study Interventions/Treatments.......86
10.8.1 Labeling/Packaging...........................................................................................86
10.8.2 Clinical Supply Inventory .................................................................................86
10.8.3 Return or Disposal of Study Medications/Treatments and/or Supplies ............86
10.9 Monitoring by the Sponsor............................................................................................86
10.10 Handling of Biological Specimens ...............................................................................87
10.11 Publications...................................................................................................................87
10.12Coordinating Investigator..............................................................................................87
11. References.............................................................................................................................. 88
12. Attachments........................................................................................................................... 91
12.1 International Classification of Headache Disorders, 3rd Edition...................................91
12.2 Examples of Prohibited Medications ..........................................................................109
12.3 List of Migraine Preventive Medications With Proven Efficacy & Criteria for 
Determining that a Prior Migraine Preventive Medication Has Been Failed .............111
12.3.1 List of Migraine Preventive Medications With Proven Efficacy....................111
12.3.2 Criteria for Determining That a Prior Migraine Preventive Medication has 
Been Failed .....................................................................................................112
12.4 Study Visits Conducted Remotely..............................................................................113


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12.5 Glossary of Abbreviations ..........................................................................................116
12.6 Protocol Amendment 1 Summary...............................................................................119
12.7 Protocol Amendment 2 Summary...............................................................................123
12.8 Protocol Amendment 3 Summary...............................................................................129


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List of Tables
Table 1
Schedule of Visits and Procedures........................................................................ 17
Table 2
Study Interventions ............................................................................................... 37
Table 3
Clinical Laboratory Parameters ............................................................................ 46
Table 4
Statistical Power for Primary and the First Three Secondary Endpoints.............. 62
Table 5
Remote Visits Schedule of Assessments (ie, Schedule of Visits and Procedures)
..............................................................................................................................114
List of Figures
Figure 1
Study Diagram ...................................................................................................... 16
Figure 2
Study Diagram for Estimand Framework............................................................. 71


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Protocol Summary
Study Compounds: Atogepant
Phase: 3
Study Objectives: 
To evaluate the safety and tolerability of atogepant 30 mg twice per day (BID) and 60 mg once daily for the 
prevention of chronic migraine (CM). 
To prospectively test for superiority of atogepant 30 mg BID and 60 mg once daily versus placebo for the prevention 
of CM.
Clinical Hypotheses: In participants with CM, at least one of the following atogepant doses (30 mg BID and 60 mg 
once daily) is superior to placebo as measured by the change from baseline in mean monthly migraine days across 
the 12-week treatment period.
Atogepant has an acceptable safety and tolerability profile in participants with CM.
Study Design
Structure: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study
Duration: The study will consist of a 4-week screening and baseline period, a 12-week double-blind treatment 
period, and a follow-up period of 4 additional weeks, for a total duration of 20 weeks
Study Intervention: Atogepant 30 mg BID and 60 mg once daily tablets
Control: Atogepant-matching placebo
Dosage/Dose Regimen: Atogepant 30 mg BID, atogepant 60 mg once daily, and placebo will be administered for 
12 weeks duration.
Randomization/Stratification: 
Approximately 750 participants will be randomized to 1 of 3 treatment arms in a 1:1:1 ratio as follows:

Placebo (n = 250)

Atogepant 30 mg BID (n = 250)

Atogepant 60 mg once daily (n = 250)
Participants will be stratified by:

Randomization will be stratified by use of acute headache medications during the baseline period (acute 
headache medication overuse Yes or No). Acute headache medication overuse (Yes) will be defined as 
follows: use of triptans on ≥10 days OR use of ergots on ≥10 days OR use of simple analgesics (ie, 
aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], or acetaminophen) on ≥ 15 days, OR use of any 
combination of triptans, ergots or simple analgesics on ≥10 days.


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
Approximately 70% of randomized participants will have taken at least 1 prior migraine prevention 
medication with proven efficacy (see Attachment 12.3)1. Randomization will be stratified based on 
migraine prevention medication exposure (Current Use, Past Use, or Never Used) with proven efficacy. 
Participants with current or past use will be further stratified based on the number of medications failed 
with unique mechanisms of action: “failed 0 medications or failed 1 or more medication(s) with the same 
mechanism of action” or “failed 2 to 4 medications with different mechanisms of action” (see 
Attachment 12.3). Enrollment of participants with current use of a migraine prevention medication will be 
capped at ~15%.
o
Below are examples to illustrate how to implement the stratification based on prior migraine 
prevention medications:

Example 1: Participant has taken metoprolol and propranolol. According to 
Attachment 12.3, these medications both belong to the beta-blocker pharmacologic 
category. This participant should be randomized to the “failed 0 medications or failed 
1 or more medication(s) with the same mechanism of action” stratum.

Example 2: Participant has taken metoprolol, propranolol, and topiramate. According to 
Attachment 12.3, metoprolol and propranolol belong to the beta-blocker pharmacologic 
category and topiramate belongs to the antiepileptic pharmacologic category. This 
participant should be randomized to the “failed 2 to 4 medications with different 
mechanisms of action” stratum.

Example 3: Participant has taken metoprolol and topiramate. According to 
Attachment 12.3, metoprolol belongs to the beta-blocker pharmacologic category and 
topiramate belongs to the antiepileptic category; however, the patient stopped both of 
these medications because of a change in health insurance coverage and therefore did not 
meet the failure definition for either medication. This participant should be randomized to 
the "failed 0 medications or failed 1 or more medication(s) with the same mechanism of 
action" stratum.

Randomization will be stratified by regions (ie, North America, Europe, Japan, China, Other)
Visit Schedule: Participation will begin with a 4-week screening/baseline period. Participants who complete the 
4-week screening/baseline period and meet all entry criteria will be randomized to the double-blind treatment period 
of this study at Visit 2 (Randomization Visit). The double-blind treatment period will last 12 weeks, with a follow-
up period of 4 additional weeks.
There will be 8 scheduled clinic visits: Visit 1 (screening/baseline), Visit 2 (randomization), Visit 3 (Week 2), 
Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7 (Week 12), and Visit 8 (follow-up). The Visit 8 
(follow-up) must be completed for all participants who take at least 1 dose of study medication, except for 
participants rolling over into Study 3101-312-002 (long-term safety extension study in regions excluding Japan and 
China), Study 3101-306-002 (long-term safety extension study in Japan), or Study 3101-311-002 (open-label safety 
extension study in China). For these rollover participants Visit 8 of Study 3101-303-002 is not required, because the 
Follow-up Visit (Visit 8) will be performed after the OL treatment in the respective long-term safety study. For 
participants who screen fail for the long-term safety study, the Follow-up Visit (Visit 8) of Study 3101-303-002 
must be completed. For details, see Table 1, Schedule of Visits and Procedures.
Study Population Characteristics
Number of Participants: Approximately 750 participants will be randomized into this global study (ie, North 
America, Europe, Japan, China, Other).
                                                
1 All French participants must have taken at least 1 prior migraine prevention medication with proven efficacy to be eligible for 
Study 3101-303-002.


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Condition/Disease: Chronic migraine
Key Inclusion Criteria:

Male or female participants age 18 to 80 years, inclusive, at Visit 1

At least a 1-year history of CM consistent with a diagnosis according to the International Classification 
of Headache Disorders, 3rd Edition (ICHD-3, 2018)

Age of the participant at the time of migraine onset < 50 years

Confirmation of headache/migraine headache day frequency as follows:
a.
History of, on average, ≥15 headache days per month in the 3 months prior to Visit 1 in the 
opinion of the investigator AND
b.
≥15 headache days during the 4-week screening/baseline period per the electronic diary 
(eDiary) AND
c.
≥8 days during the 4-week screening/baseline period that qualify as being a migraine day per 
the eDiary
Key Exclusion Criteria:

Has a history of migraine, accompanied by diplopia or decreased level of consciousness, or retinal 
migraine as defined by ICHD-3, 2018

Has a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster 
headache), or painful cranial neuropathy as defined by ICHD-3, 2018

History of an inadequate response to > 4 medications (2 of which have different mechanisms of action) 
prescribed for the prevention of migraine (see Attachment 12.3)

Usage of opioids and/or barbiturates > 4 days/month in the 3 months prior to Visit 1 per investigator’s 
judgment, or during the baseline period (barbiturates are excluded 30 days prior to screening, and for 
the duration of the study)(see Attachment 12.2)

Participants with any clinically significant hematologic, endocrine, cardiovascular, cerebrovascular, 
pulmonary, renal, hepatic, gastrointestinal, or neurologic disease.
Response Measures
Efficacy: Efficacy assessments will be based on information recorded by the participant. An eDiary will be used 
daily at home to collect data on headache frequency, duration, characteristics, and symptoms; acute medication use
and triptan use, which will be collectively applied to define migraine days and headache days per the criteria listed 
in Sections 6.1.1, 6.1.2, and 6.1.3.
Health Outcomes: Activity Impairment in Migraine – Diary (AIM-D); Activity Level and Activity Limitation; 
Patient Satisfaction with Study Medication (PSSM); Headache Impact Test (HIT-6); Migraine Disability 
Assessment (MIDAS); Patient Global Impression of Change (PGIC); Work Productivity and Activity Impairment 
Questionnaire: Migraine V2.0 (WPAI:MIGRAINE); European Quality of Life – 5 Dimensional (EQ-5D-5L); Patient 
Global Impression – Severity (PGI-S); Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1); 
Patient-Reported Outcomes Measurement Information Systems Pain Interference – Short Form 6a (PROMIS-PI); 
and Patient Health Questionnaire (PHQ-9).
Pharmacokinetics: Blood samples will be collected for pharmacokinetic (PK) analysis for participants who consent.
Safety: Adverse events (AEs), clinical laboratory determinations, vital sign measurements, physical examinations, 
electrocardiogram (ECG) parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS)


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General Statistical Methods and Types of Analyses:
All efficacy analyses will be performed using the modified intent-to-treat (mITT) population, which consists of all 
randomized participants who received at least 1 dose of study intervention, had an evaluable baseline period of 
eDiary data and at least 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data
during the double-blind treatment period. All safety analyses will be performed using the safety population, which 
consists of all participants who took at least 1 dose of study intervention. The analysis population for off-treatment 
hypothetical estimand includes all randomized participants who received at least 1 dose of study intervention, had an 
evaluable baseline period of eDiary data and at least 1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 
and 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment. This 
population is used for the primary estimand to support filing in Europe.
For all regulatory submissions, the primary efficacy endpoint will be the same. However, secondary efficacy 
endpoints will differ. 
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in mean monthly migraine days across the 12-week 
treatment period. Baseline is defined as the number of migraine days during the last 28 days prior to the 
randomization date.
The primary comparison between treatment groups will be done by a mixed-effects model for repeated measures 
(MMRM) of the change from baseline. The statistical model will include treatment group, visit, region, acute 
medications during the baseline period (medication overuse Y/N), current and past use of migraine prevention 
medications and the number of medications failed with unique mechanisms of action (Current Use and “failed 0 
medications or failed 1 or more medication(s) with the same mechanism of action”, Current Use and “failed 2 to 4 
medications with different mechanisms of action”, Past Use only and “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action”, Past Use only and “failed 2 to 4 medications with different 
mechanisms of action”, and Never Used), and treatment group by visit interaction as categorical fixed effects. The 
statistical model will also include the baseline score and baseline-by-visit interaction as covariates. An unstructured 
covariance matrix will be used to model the covariance of within-participant repeated measurements. The Kenward-
Roger approximation (Kenward 1997) will be used to estimate the denominator degrees of freedom. The analysis
will be performed based on all postbaseline values using only the observed cases without imputation of missing
values. Pairwise contrasts in the MMRM model will be used to make the pairwise comparisons of each atogepant 
dose to placebo.
Secondary Efficacy Endpoints for all regions, except Europe and Canada:

Change from baseline in mean monthly headache days across the 12-week treatment period

Change from baseline in mean monthly acute medication use days across the 12-week treatment period

At least a 50% reduction in 3-month average of monthly migraine days

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12

Change from baseline in mean monthly Performance of Daily Activities domain score of the AIM-D across 
the 12-week treatment period

Change from baseline in mean monthly Physical Impairment domain score of the AIM-D across the
12-week treatment period 
Secondary Efficacy Endpoints for Europe and Canada:

Change from baseline in mean monthly headache days across the 12-week treatment period

Change from baseline in mean monthly acute medication use days across the 12-week treatment period

At least a 50% reduction in 3-month average of monthly migraine days

Change from baseline in the HIT-6 total score at Week 12

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12


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The secondary endpoints for headache days, acute medication use days, MSQ v2.1 Role Function-Restrictive 
domain score, Performance of Daily Activities domain score of the AIM-D, Physical Impairment domain score of 
the AIM-D, and HIT-6 total score will be analyzed in the same manner as that used to analyze the primary endpoint. 
The secondary endpoint of 50% responders, defined as participants with at least a 50% reduction from baseline in 
the 3-month average of monthly migraine days, will be assessed for each individual. A logistic regression model will 
be used to analyze 50% responders across the 12-week treatment period. This model assumes a binary distribution 
for the response and uses a logit link. The analysis model will include treatment group, region, acute medications 
during the baseline period (medication overuse Y/N), current and past use of migraine prevention medications and 
the number of medications failed with unique mechanisms of action as categorical fixed effects; baseline value will 
be included as a covariate. The analysis will be performed based on all postbaseline values using only the observed 
cases without imputation of missing values. The treatment difference in terms of odds ratio between each atogepant 
dose group and placebo will be estimated and tested from this model. 
A logistic regression model will be used to analyze 50% responders across the 12-week treatment period. This 
model assumes a binary distribution for the response and uses a logit link. The analysis model will include treatment 
group, region, acute medications during the baseline period (medication overuse Y/N), current and past use of
migraine prevention medications and the number of medications failed with unique mechanisms of action as 
categorical fixed effects; baseline value will be included as a covariate. The analysis will be performed based on all
postbaseline values using only the observed cases without imputation of missing values. The treatment difference in 
terms of odds ratio between each atogepant dose group and placebo will be estimated and tested from this model. 
Incidence of treatment emergent adverse events (TEAEs) will be tabulated by primary system organ class (SOC)
and by specific event within each primary SOC. TEAEs will be analyzed after treatment start on Day 1 through the 
end of the study.
Sample Size Calculation: A total sample size of 250 randomized participants per treatment group will provide at 
least 96% power to detect the treatment difference between each of the 2 atogepant doses (assumed equally 
effective) and placebo for the primary efficacy endpoint. This sample size was selected to provide sufficient power 
for the first 3 secondary endpoints. The power calculations are based on the following assumptions: 
1) the treatment difference from placebo will be similar to the average value across the CM prevention studies for 
Botox® (Aurora 2010, Diener 2010) and TEV-48125 (Bigal 2015, Silberstein 2017). In particular, the assumed 
treatment difference from placebo in change from baseline in mean monthly migraine days across the 12-week 
treatment period is -2 days, and the standard deviation is 5.5 days. 
2) the study statistical testing plan controls the overall type I error at 5%. The power calculations of the primary and 
secondary endpoints have taken the multiple comparisons into consideration by testing each dose versus placebo at a 
0.025 significance level, 2-sided. Once the primary endpoint for each dose is significant at 0.025, 2-sided, the 
secondary endpoints will be tested sequentially.


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Figure 1
Study Diagram
BID = twice daily; V = visit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1
Schedule of Visits and Procedures 
Study Period
Screening/
Baseline
(4 weeks)
Double-blind Treatment Period (12 weeks)
Follow-up 
Period 
(4 weeks)
Visit #a
Visit 1
Visit 2 
(Randomization)
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/ETb
Visit 8c
(End of Study)
Day/Week
Week -4
Day 1
Week 2 
(Day 14)
Week 4 
(Day 28)
Week 6 
(Day 42)
Week 8 
(Day 56)
Week 12 
(Day 84)
Week 16
(Day 112)
Visit Windows
Day –35 to 
Day -28
NA
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Obtain Informed Consent and 
participant privacy
X
Obtain Informed Consent for future 
biomedical research (optional)
X
Obtain Informed Consent for PK 
(optional)
X
Obtain VCT consent and perform 
verification (United States and 
Canada only)
X
Access IWRS
X
X
X
X
X
X
X
X
Assess inclusion/exclusion criteria
X
X
Collect demographic information
X
Collect medical history
X
Collect migraine history 
X
Review prior medications including 
migraine prophylactic medication use
X
Perform physical examination
X
X
X
Collect vital sign measurementsd
X
X
X
X
X
X
X
X
Perform ECG
X
X
X
Perform urine pregnancy teste
X
X
X
X
X
X
X
X
Collect start date (first day) of last 
menstrual cycle for women having 
menstrual cycles
X
X
X
X
X
X
X
X
Collect urine drug screen
X
Collect clinical laboratory 
determinationsf
X
X
X
X
X
X
X
X
Collect PK sample (for those 
participating)g
X
X
X
X
X
X


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Study Period
Screening/
Baseline
(4 weeks)
Double-blind Treatment Period (12 weeks)
Follow-up 
Period 
(4 weeks)
Visit #a
Visit 1
Visit 2 
(Randomization)
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/ETb
Visit 8c
(End of Study)
Day/Week
Week -4
Day 1
Week 2 
(Day 14)
Week 4 
(Day 28)
Week 6 
(Day 42)
Week 8 
(Day 56)
Week 12 
(Day 84)
Week 16
(Day 112)
Visit Windows
Day –35 to 
Day -28
NA
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Collect blood for future biomedical 
research (for those participating)
X
Provide eDiary, and eDiary 
instructions and trainingh
X
Participant eDiary data collection 
X
Review of medication compliance
X
X
X
X
X
Review eDiary data (headache 
duration, frequency, characteristics 
and symptoms; acute medication use, 
AIM-D, activity level and activity 
limitation) and compliancei
X
X
X
X
X
X
C-SSRS (eTablet)j
X
X
X
X
X
X
X
X
ASC-12 (eTablet)k,l
X
HIT-6 (eTablet)k,l
X
X
X
X
X
PGIC (eTablet)k,l
X
PGI-S (eTablet)k,l
X
X
X
X
WPAI:MIGRAINE (eTablet)k,l
X
X
X
X
PSSM (eTablet)k,l
X
X
X
EQ-5D-5Lm
X
X
X
X
X
X
X
X
MIDAS (eTablet)k,l
X
X
MSQ v2.1 (eTablet)k,l
X
X
X
X
X
PROMIS-PI (eTablet)k,l
X
X
X
X
PHQ-9 (eTablet)k,l
X
X
Collect eDiary
Xn
Xo
Xp
Dispense study intervention
Xq
X
X
X
X
Adverse events
X
Concomitant medications/concurrent 
procedures
X


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ASC-12 = 12-item Allodynia Symptom Checklist; AIM-D = Activity Impairment in Migraine–Diary; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; eDiary = electronic diary; EQ-5D-5L = European Quality of Life – 5 Dimensional; ET = early termination; eTablet = electronic tablet; 
HIT-6 = Headache Impact Test; INR = international normalized ratio; IWRS = interactive web response system; MIDAS = Migraine Disability Assessment; 
MSQ v2.1 = Migraine Specific Quality of Life Questionnaire, Version 2.1; OL = open-label; PGIC = Patient Global Impression of Change; PGI-S = Patient 
Global Impression – Severity; PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; PRO = patient-reported outcome; PROMIS-PI = Patient-Reported 
Outcomes Measurement Information System Pain Interference – Short Form 6a; PSSM = Patient Satisfaction with Study Medication; VCT = verified clinical 
trial; WPAI:MIGRAINE = Work Productivity and Activity Impairment Questionnaire: Migraine V2.0.
a
Visit 1, Visit 2, and either Visit 3 or Visit 4 must be conducted in office. All other visits, should be conducted in office unless it is necessary to conduct 
remote visits for the safety of participants (eg, COVID-19 or other pandemic): for details please refer to the Remote Visit Schedule of Assessments in 
Attachment 12.4.
b
Effort should be made by site to not schedule Visit 7 earlier than Day 85 to ensure that participants complete the full 12 weeks of treatment and have eDiary 
data through Day 84.
c
All participants who take at least 1 dose of study intervention must complete the follow-up period, except for participants rolling over into 
Study 3101-312-002 (long-term safety extension study in regions excluding Japan and China), participants rolling over into Study 3101-306-002 (long-term 
safety extension study in Japan), or Study 3101-311-002 (open-label safety extension study in China). For these rollover participants the Follow-up Visit will 
be performed after the completion of the OL treatment in the respective long-term safety extension study.
d
Vital sign measurements: height, weight, sitting and standing pulse rate, respiratory rate, sitting and standing blood pressure, and body temperature. Height 
will be measured only at Visit 1.
e
For women of childbearing potential only, a urine pregnancy test will be performed at all visits
f
Clinical laboratory determinations include chemistry, hematology, INR, and urinalysis to be collected for all visits. Samples for serology and the urine drug 
screen will be collected only at screening (Visit 1).
g
PK sample should be collected prior to the first dose at Visit 2. One sample should be collected prior to the morning dose during one of the Visits 3 to 7, and 
the remaining samples should be collected 1 to 10 hours postdose. 
h
Participant should begin using the eDiary as soon as it is dispensed. If it is subsequently determined that the participant has failed entry criteria, the eDiary 
should be returned to the site.
i
Participants must bring the eDiary to visits and review with coordinators.
j
Clinicians will complete on eTablet. The screening/baseline assessment of the C-SSRS will be completed. At all other visits, the ‘Since Last Visit’ C-SSRS 
will be completed. 
k
Participant will complete on eTablet.
l
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol (eg, during Randomization Visit 2, 
some tests will be conducted prior to the PROs for eligibility).
m
EQ-5D-5L will be given on eDiary during 7 days in the baseline period and during specific time periods for Visit 1 to 7, except at Visit 8 (Week 16) where it 
will be administered on an eTablet.
n
eDiary will be collected on Visit 2 for screen failures.
o
Collected at Visit 7/ET only for participants who complete the double-blind treatment period.
p
Collected at Visit 8/Follow-up only for participants who discontinue from the double-blind treatment period.
q
The first dose of study intervention should be taken at the study site.


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1.
Background and Clinical Rationale 
1.1
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25 to 55 years. Approximately one-third of patients with migraines 
have 3 or more migraine headaches per month, and over half report severe impairment or the 
need for bed rest (Lipton 2007). In the United States alone, work loss due to migraine is 
estimated to cost ~ $13 billion annually (Hu 1999). Prevalence is similar in Europe, with 
migraine headache affecting on average 17.6% of women and 8% of men (Stovner 2010). The 
prevalence of migraine in China is 8.9%, with a similar distribution across males and females as
the United States, according to the Guidelines for Prevention and Treatment of Migraine in 
China (Yu 2016). In Japan, the overall prevalence of migraine was reported as 8.4%; 5.8% was 
migraine without aura and 2.6% was migraine with aura (Sakai 1997). Like Western countries, 
migraine is more prevalent among women in Japan; women were observed to have a 5.9-fold 
higher risk of migraine than men (Takeshima 2004). The Global Burden of Disease Survey 2010 
estimated the global prevalence of migraine to be 14.7%, making it the third most common 
disease in the world in both males and females (Vos 2012). Migraine was ranked seventh highest 
among specific causes of disability globally (Steiner 2013).
Migraine is typically characterized by attacks of throbbing, unilateral headache of moderate or 
severe pain intensity, associated with nausea, vomiting, and/or sensitivity to light (photophobia) 
and sound (phonophobia). In about 25% of individuals, the migraine headache is preceded by 
focal neurological dysfunction (aura). Improving diagnosis and optimizing treatments for 
migraine have been recognized as critically important to overcoming current barriers to reduce 
the global burden of migraine.
Because there are no biological markers for migraine, diagnosis is based on clinical history, 
examination, and the exclusion of other headache disorders. Physicians apply clinical criteria to 
guide diagnoses and subsequent treatment. Episodic migraine (EM) is a syndrome diagnosis 
applied to patients with migraine (with or without aura) who have 1 to 14 headache days per 
month. CM is a specific ICHD-3 diagnosis applied to a subset of patients with ≥15 headache 
days per month (Katsarava 2012, Olesen 2006, ICHD-3 2018). Approximately 1.3% of the 
United States population (approximately 3 million people) and 1.3% to 2.4% of the European 
population suffer from CM. CM is recognized as the population suffering most from migraine 
and as a disabling, underdiagnosed, and undertreated disorder (Bigal 2008). Studies have 
established that those suffering from CM have impaired quality of life and that they suffer 
substantial socio-economic burden due to increased medical needs, referral to medical specialists, 


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drug utilization, work absenteeism, and reduced effectiveness at work (Blumenfeld 2011; 
Munakata 2009).
This study will evaluate the efficacy, safety and tolerability of atogepant in participants with CM.
1.2
Overview of Atogepant
Atogepant is a potent, selective oral CGRP receptor antagonist being developed for migraine 
prevention. CGRP is a neuropeptide implicated in the pathophysiology of migraine. CGRP
levels in the cranial venous outflow (ie, external jugular vein) are increased during a migraine
attack and exogenously administered CGRP has been shown to trigger migraine-like headache in 
patients with migraine. The majority (80% to 90%) of trigeminal Aδ fibers that innervate the
dura contain CGRP, suggesting that these fibers may be involved in sterile neurogenic
inflammation and migraine pain transmission. Furthermore, the CGRP receptor is present on 
human meningeal and cerebral blood vessels. These observations suggest that activation of the 
trigeminovascular system, with release of CGRP, may play a key role in migraine pathogenesis
and that inhibition of CGRP may yield a novel therapeutic approach to treating migraine.
The ability of CGRP inhibition to induce pain relief in the acute treatment of migraine was
initially observed with an IV formulation of olcegepant (Olesen 2004) and replicated by Merck
& Co., Inc. with an oral formulation of MK-0974 (telcagepant), a highly selective CGRP
receptor antagonist. In Phase 3 studies, telcagepant was superior to placebo in the primary 
endpoints of 2-hour pain freedom, 2-hour pain relief, and the absence of associated symptoms
(photophobia, phonophobia, and nausea), as well as the key secondary endpoint of 24-hour
sustained pain freedom (Connor 2009). However, serum ALT increases were observed with 
telcagepant. For this reason, the development of these oral CGRP antagonists was stopped.
A Phase 2/3 clinical study (Study CGP-MD-01) was conducted, which compared atogepant 
10 mg once daily, atogepant 30 mg once daily, atogepant 30 mg BID, atogepant 60 mg once 
daily and atogepant 60 mg BID to placebo in EM prevention. Overall, all the atogepant doses 
tested were well tolerated and the AE profile of all atogepant doses did not significantly differ 
from placebo. For the primary efficacy endpoint of change from baseline in mean monthly 
migraine days across the 12-week treatment period, all atogepant doses demonstrated a 
statistically significant reduction compared to placebo in patients with EM.
Additional information on nonclinical pharmacology, toxicology, and PK properties of atogepant 
can be found in the investigator’s brochure.


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1.3
Study Rationale
The purpose of this study is to prospectively assess the safety, tolerability and efficacy of 
atogepant doses 30 mg BID and 60 mg once daily compared with placebo in the prevention of 
CM, in a randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study. This study 
is designed to be a pivotal trial and will be used to support registration applications.
1.4
Rationale for Doses and Dose Regimens Selected 
This study will test 2 doses of atogepant, 30 mg BID and 60 mg once daily, selected based on the 
results from Study CGP-MD-01 in patients with EM. All atogepant doses investigated in 
Study CGP-MD-01 demonstrated good safety and tolerability. Whilst all atogepant doses also 
demonstrated a statistically significant reduction from baseline in mean monthly migraine days 
across the 12-week treatment period compared to placebo, there was no clear dose-response 
relationship. However, there was a suggestion that the BID regimen may provide better efficacy 
than the once-daily regimen. The current study will therefore investigate both atogepant 30 mg 
BID; and the highest once daily dose previously tested, atogepant 60 mg once daily, with a 
12-week treatment period.
1.5
Benefit/Risk Assessment
Based on the currently available data, atogepant has demonstrated efficacy for the prevention of 
episodic migraine; in addition, atogepant has been well tolerated with no safety concerns to date. 
The protocol is designed to ensure that patient safety is assessed adequately throughout the study. 
An independent DSMB will review unblinded safety data throughout the trial and make 
recommendations to the sponsor, including modification or early termination of the trial, if 
emerging data show unexpected and clinically significant adverse effects of treatment. Although 
this is a 12-week placebo-controlled trial, treatment for acute migraine is allowed during the 
study and patients already receiving a migraine prevention medication at screening can continue 
treatment during the study. Overall the assessment of benefit/risk is favorable.
2.
Study Objectives and Clinical Hypotheses 
2.1
Study Objectives
To evaluate the safety and tolerability of atogepant 30 mg BID and atogepant 60 mg once daily 
for the prevention of CM.
To prospectively test for superiority of atogepant (30 mg BID and atogepant 60 mg once daily) 
versus placebo for the prevention of CM.


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2.2
Clinical Hypotheses
In participants with CM, at least one dose of atogepant (30 mg BID and atogepant 60 mg once 
daily) is superior to placebo as measured by the change from baseline in mean monthly migraine
days across the 12-week treatment period.
Atogepant has an acceptable safety profile and is well tolerated in participants with CM.
3.
Study Design
3.1
Structure
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3
study conducted at approximately 140 sites worldwide. 
Approximately 750 participants will be randomized to 1 of 3 treatment arms in a 1:1:1 ratio as 
follows:

Placebo (n = 250)

Atogepant 30 mg BID (n = 250)

Atogepant 60 mg once daily (n = 250)
Participants will be stratified by:

Randomization will be stratified by use of acute headache medications during the 
baseline period (acute headache medication overuse Yes or No). Acute headache 
medication overuse (Yes) will be defined as follows: use of triptans on ≥10 days OR 
use of ergots on ≥10 days OR use of simple analgesics (ie, aspirin, nonsteroidal 
anti-inflammatory drugs [NSAIDs], or acetaminophen) on ≥ 15 days OR use of any 
combination of triptans, ergots or simple analgesics on ≥10 days.

Approximately 70% of randomized participants will have taken at least 1 prior 
migraine prevention medication with proven efficacy (see Attachment 12.3).2
Randomization will be stratified based on migraine prevention medication exposure 
(Current Use, Past Use, or Never Used) with proven efficacy. Participants with 
current or past use will be further stratified based on the number of medications failed 
                                                
2 All French participants must have taken at least 1 prior migraine prevention medication with proven efficacy to be 
eligible for Study 3101-303-002.


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with unique mechanisms of action: “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” or “failed 2 to 4 medications with 
different mechanisms of action” (see Attachment 12.3). Enrollment of participants 
with current use of a migraine prevention medication will be capped at ~15%.
o
Below are examples to illustrate how to implement the stratification based on 
prior migraine prevention medications:

Example 1: Participant has taken metoprolol and propranolol. 
According to Attachment 12.3, these medications both belong to the 
beta-blocker pharmacologic category. This participant should be 
randomized to the “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” stratum.

Example 2: Participant has taken metoprolol, propranolol, and 
topiramate. According to Attachment 12.3, metoprolol and propranolol 
belong to the beta-blocker pharmacologic category and topiramate 
belongs to the antiepileptic pharmacologic category. This participant 
should be randomized to the “failed 2 to 4 medications with different 
mechanisms of action” stratum.

Example 3: Participant has taken metoprolol and topiramate. 
According to Attachment 12.3, metoprolol belongs to the beta-blocker 
pharmacologic category and topiramate belongs to the antiepileptic 
category; however, the patient stopped both of these medications 
because of a change in health insurance coverage and therefore did not 
meet the failure definition for either medication. This participant 
should be randomized to the "failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action" stratum.

Randomization will be stratified by regions (ie, North America, Europe, Japan, China, 
Other)
Participation will begin with a 4-week screening/baseline period. Participants who complete the 
4-week screening/baseline period and meet all entry criteria will be randomized to the 
double-blind treatment period of this study at Visit 2 (Randomization Visit). The double-blind 
treatment period will last 12 weeks, with a follow-up period of 4 additional weeks. 
There will be 8 scheduled clinic visits: Visit 1 (screening/baseline), Visit 2 (randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ ET (Week 12), and 
Visit 8 (follow-up). The Visit 8 (follow-up) must be completed for all participants who take at 
least 1 dose of study medication, except for participants rolling over into Study 3101-312-002 
(long-term safety extension study in regions, excluding Japan and China), Study 3101-306-002 
(long-term safety extension study in Japan), or Study 3101-311-002 (open-label safety extension 
study in China). For these rollover participants Visit 8 of Study 3101-303-002 is not required, 


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because the Follow-up Visit (Visit 8) will be performed after the OL treatment in the respective 
long-term safety study. For participants who screen fail for the long-term safety study, the
Follow-up Visit (Visit 8) of Study 3101-303-002 must be completed. For more details on study 
schedule, please see Table 1, Schedule of Visits and Procedures.
3.2
Data Safety Monitoring Board
An independent DSMB will be established to review unblinded safety data and summary reports, 
identify any safety issues and trends, and make recommendations to the sponsor, including 
modification or ET of the study, if emerging data show unexpected and clinically significant AEs 
of treatment. 
Details of the DSMB memberships, standard operational procedures for data monitoring/review, 
frequency of review, and other pertinent details will be provided in a separate DSMB Charter.
3.3
Adjudication Committee
An Adjudication Charter will be established and will describe the process for the blinded 
surveillance, monitoring, and adjudication by the Clinical Adjudication Committee of events of 
post-treatment elevations of ALT and/or AST ≥ 3 × ULN in the atogepant program. The purpose 
of this committee charter will be to provide a standardized process for the adjudication of data 
associated with these events in order to determine whether the elevation was related to atogepant.
3.4
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study. For 
Russia, end of study is defined as the last Close Out Visit.
4.
Study Population and Entry Criteria
4.1
Number of Participants 
Approximately 750 participants will be randomized at approximately 140 sites worldwide (North 
America, Europe, Japan, China, Other). 


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4.2
Inclusion Criteria
The following are requirements for entry into the study: 
1. Written informed consent and participant privacy information (eg, Written 
Authorization for Use and Release of Health and Research Study Information) 
obtained from the participant prior to initiation of any study-specific procedures
2. Male or female participants ages 18 to 80 years, inclusive, at Visit 1
3. At least a 1-year history of CM consistent with a diagnosis according to the 
ICHD-3, 2018
4. Age of the participant at the time of migraine onset < 50 years
5. Confirmation of headache/migraine headache day frequency as follows:
a.
History of, on average, ≥15 headache days per month in the 3 months prior to 
Visit 1 in the opinion of the investigator AND
b. ≥15 headache days during the 4-week screening/baseline period per the 
electronic diary (eDiary) AND
c.
≥8 days during the 4-week screening/baseline period that qualify as being a 
migraine day per the eDiary
6. Completed at least 20 out of 28 days in the eDiary during baseline period and is able 
to read, understand, and complete the study questionnaires and eDiary per 
investigator’s judgment
7. Participants must be using a medically acceptable and effective method of birth 
control during the course of the entire study, as defined in Section 4.4.3
4.3
Exclusion Criteria
The following are criteria for exclusion from participating in the study:
1. Difficulty distinguishing migraine headaches from tension-type or other headaches
2. Has a history of migraine, accompanied by diplopia or decreased level of 
consciousness, or retinal migraine as defined by ICHD-3, 2018


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3. Has a current diagnosis of new persistent daily headache, trigeminal autonomic 
cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3, 
2018
4. History of an inadequate response to > 4 medications (2 of which have different 
mechanisms of action) prescribed for the prevention of migraine (see
Attachment 12.3)
5. Currently taking more than 1 medication with demonstrated efficacy for the 
prevention of migraine OR participants who are taking 1 migraine prevention 
medication, but in the opinion of the investigator:

the dose has not been stable and/or the medication has not been well-tolerated 
for at least 12 weeks prior to Visit 1

the participant is not willing or able to maintain taking this medication at a 
stable dose and dosage regimen throughout the study

Note: Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, 
Botox®, Xeomin®, Myobloc®, JeuveauTM) into areas of the head, face, or neck 
are excluded 6 months prior to screening and for the duration of the study
6. Requirement for any medication, diet (ie, grapefruit juice), or non-pharmacological 
treatment that is on the list of prohibited concomitant medications or treatments (see 
Section 4.4.2 and Attachment 12.2) that cannot be discontinued or switched to an 
allowable alternative medication or treatment
7. Usage of opioids and/or barbiturates > 4 days/month in the 3 months prior to Visit 1 
per investigator’s judgment, or during the baseline period (barbiturates are excluded 
30 days prior to screening and for the duration of the study) (see Attachment 12.2)
8. Woman is pregnant, planning to become pregnant during the course of the study, or 
currently lactating. Women of childbearing potential must have a negative urine 
pregnancy test at Visit 1 and Visit 2.
9. An ECG with clinically significant abnormalities at screening (Visit 1) as determined 
by the investigator
10. QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 on the final 
central vendor ECG report 


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11. Clinically significant cardiovascular or cerebrovascular disease per the investigator’s 
opinion including, but not limited to:

Clinically significant ischemic heart disease (eg, unstable angina pectoris)

Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial 
fibrillation, second- or third-degree heart block) or risk factors for Torsade de 
Pointes (eg, heart failure, hypokalemia, bradycardia)

Myocardial infarction, transient ischemic attack, or stroke within 6 months 
prior to Visit 1

Heart failure defined as New York Heart Association functional classification 
system, Class III or IV
12. Hypertension as defined by sitting systolic BP > 160 mm Hg or sitting diastolic 
BP > 100 mm Hg at Visits 1 or Visit 2. Vital sign measurements that exceed these 
limits may be repeated only once.
13. Clinically significant laboratory values OR any of the following laboratory values at 
Visit 1:

ALT or AST > 1 × ULN OR

total bilirubin > 1 × ULN (except for participants with a diagnosis of Gilbert’s 
disease) OR

serum albumin < 2.8 g/dL
14. Any clinically significant hematologic, endocrine, cardiovascular, cerebrovascular, 
pulmonary, renal, hepatic, gastrointestinal, or neurologic disease

If there is a history of such a disease, but the condition has been stable for 
more than 1 year prior to Visit 1, and is judged by the investigator as not 
likely to interfere with participation in the study, the participant may be 
included.

Participants on dialysis for renal failure are excluded.
15. History of acute hepatitis within 6 months of screening (Visit 1); or chronic hepatitis 
(including nonalcoholic steatohepatitis), or a positive result on anti-hepatitis A IgM 
antibody, hepatitis B surface antigen, anti–hepatitis C antibody, or anti-hepatitis E 
IgM antibody testing


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16. In the opinion of the investigator, confounding psychiatric conditions, dementia, 
epilepsy or significant neurological disorders other than migraine
17. Participant has any other concurrent pain condition that, in the opinion of the 
investigator, may significantly impact the current headache disorder 
(eg, fibromyalgia, facial pain)
18. Significant risk of self-harm based on clinical interview and responses on the C-SSRS, 
or of harm to others in the opinion of the investigator; participants must be excluded 
if they report suicidal ideation with intent, with or without a plan, 
(ie, Type 4 or 5 on the C-SSRS) in the past 6 months or report suicidal behavior in the 
6 months prior to Visit 1 or Visit 2 assessments
19. History of malignancy in the 5 years prior to Visit 1, except for adequately treated 
basal cell or squamous cell skin cancer, or in situ cervical cancer
20. History of any gastrointestinal prior procedures or gastrointestinal conditions 
(eg, diarrhea syndromes, inflammatory bowel disease) that may affect the absorption 
or metabolism of study intervention; participants with prior gastric bariatric 
interventions (eg, Lap Band) which have been reversed are not excluded.
21. At Visit 1, a user of recreational or illicit drugs or has had a history within the past 
year of drug or alcohol abuse or dependence
22. Positive result on the urine drug screen at Visit 1 unless explained by concomitant 
medication use (eg, opioids prescribed for migraine pain)
23. Currently participating or has participated in a study with an investigational 
compound or device within 30 days prior to Visit 1 (this includes studies using 
marketed compounds or devices)
24. Previous exposure to:

atogepant (AGN-241689 or MK8031) OR

injectable monoclonal antibodies blocking the CGRP pathway within the past 
6 months OR

ubrogepant and took more than 3 doses of ubrogepant OR

rimegepant and took more than 3 doses of rimegepant 


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25. History of hypersensitivity or clinically significant adverse reaction to a CGRP 
receptor antagonist or hypersensitivity to any component of the study interventions 
(atogepant or placebo)
26. Employed by or is an immediate family member (parents, spouses, siblings or 
children) of one of the investigators, study staff, or the sponsor
27. Participant has a condition or is in a situation which in the investigator's opinion may 
put the participant at significant risk, may confound the study results, or may interfere 
significantly with participation in the study
28. Any medical or other reasons (eg, unlikely to adhere to the study procedures, keep 
appointments, or is planning to relocate during the study) that, in the investigator’s 
opinion, might indicate that the participant is unsuitable for the study
4.4
Permissible and Prohibited Medications/Treatments
4.4.1
Permissible Medications/Treatments
Medications which are not specifically prohibited in Section 4.4.2 are allowed, with the 
following clarifications and restrictions:
The following medications for the acute treatment of migraine are allowed during the study:

any triptan

any ergot derivative

any opioid

any other form of analgesic (including acetaminophen)

any NSAID agent

any antiemetic agent
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
SSRIs or SNRIs will be permitted provided that treatment is stable for at least 60 days prior to 
screening (Visit 1) and continues without change in dose throughout the study.


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Therapy considered necessary for the participant's welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/treatment is in question, please contact 
the sponsor.
4.4.2
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) 
and throughout the study period: 

Strong and moderate CYP3A4 inhibitors, including but not limited to: systemic (oral/IV) 
itraconazole, ketoconazole, fluconazole; erythromycin, clarithromycin, telithromycin3; 
diltiazem, verapamil; aprepitant, cyclosporine, nefazodone3, cimetidine, quinine, and HIV 
protease inhibitors (see Attachment 12.2)

Strong and moderate CYP3A4 inducers, including but not limited to: barbiturates (eg, 
phenobarbital and primidone), systemic (oral/IV) glucocorticoids, nevirapine, efavirenz, 
pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and St. John’s wort (see 
Attachment 12.2)
Strong OATP1B1 inhibitors (eg, gemfibrozil3, cyclosporine) 

Drugs with narrow therapeutic margins with theoretical potential for CYP drug 
interactions (eg, warfarin)

Medications with demonstrated efficacy for the prevention of migraine (eg, amitriptyline, 
propranolol, topiramate) are prohibited when used for any indication other than migraine 
prevention. See Attachment 12.3.
o
Participants taking one medication with demonstrated efficacy for the prevention 
of migraine may be randomized provided that in the opinion of the investigator:

Dose has been stable and the medication has been well-tolerated for at 
least 12 weeks prior to Visit 1 AND

Participant is willing and able to maintain at a stable dose and dosage 
regimen during the study, which should be assessed to ensure compliance 
at each study visit

Enrollment of participants with current use of a migraine prevention 
medication will be capped at ~15%
                                                
3not approved in Japan


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
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, Botox®, Xeomin®, 
Myobloc®, Jeuveau™) into areas of the head, face, or neck within 6 months prior to 
Visit 1 and throughout the study period

Acupuncture, noninvasive neuromodulation devices (eg, transcutanous supraorbital 
neurostimulator, single pulse transcranial magnetic stimulator, vagus nerve stimulator), 
cranial traction, nociceptive trigeminal inhibition, occipital nerve block treatments, or 
dental splints for headache, within 4 weeks prior to entry into the baseline phase at 
Week – 4 or at any time during the study (including the Week – 4 to Day 1 baseline 
phase)

Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™, 
Emgality™, Ajovy®) within 6 months prior to Visit 1 and throughout the study period

For China, South Korea, Japan, and Taiwan, herbal and traditional medicine is prohibited 
from the time the ICF is signed and for the duration of study participation.

Cannabidiol (CBD) oil, cannabis.
Therapy considered necessary for the participant's welfare may be given at the discretion of the 
investigator. The decision to administer a prohibited medication/treatment is done with the safety 
of the study participant as the primary consideration. The sponsor should be notified about 
administration of prohibited medication/treatment as soon as possible.
4.4.3
Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For purposes of this study, women will be considered of childbearing potential unless they are 
naturally postmenopausal (ie, no menses for 2 years) or permanently sterilized (ie, bilateral tubal 
ligation, bilateral tubal occlusion [eg, Essure® placement4 with HSG confirmation], bilateral 
salpingectomy, bilateral oophorectomy, or hysterectomy). For women of childbearing potential 
who may participate in the study, the following methods of contraception, if properly used, are 
generally considered highly effective:

Combined (estrogen and progestogen containing) hormonal contraception such as oral, 
intravaginal4, or transdermal4 (ie, pill, patch4, vaginal ring4)

Progestogen-only hormonal contraception (with inhibition of ovulation) that are oral, 
injectable4, or implantable4
                                                
4 Contraceptive methods not approved in Japan


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
IUD or IUS

Vasectomized partner (provided that the partner is the sole sexual partner of study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success)

Sexual abstinence, defined as refraining from heterosexual intercourse for the entire 
duration of the study, from Visit 1 through the end of study (Visit 8/Follow-up Visit) 
o
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods) is 
not an acceptable method of contraception. The reliability of sexual abstinence 
should be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Acceptable birth control methods which may not be considered as highly effective:

Progestogen-only oral hormonal contraception (where inhibition of ovulation is not the 
primary mode of action)

Male or women condom with or without spermicide4 (women and male condoms should 
not be used together)

Cap4, diaphragm4, or sponge4 with spermicide

A combination of male condom with either cap4, diaphragm4, or sponge4 with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods
For males who may participate in the study, the following methods of contraception, if properly 
used, are generally considered reliable: post-bilateral vasectomy, barrier contraception, or sexual 
abstinence. Male participants must also refrain from donating sperm during the course of the 
study.
The investigator and each participant will determine the appropriate method of contraception for 
the participant during the participation in the study.
If a woman becomes pregnant during the study, the investigator will notify the sponsor
immediately after the pregnancy is confirmed and the participant will be exited from the study 
after appropriate follow-up. The investigator will (1) notify the participant’s physician that the 
participant was being treated with an investigational drug atogepant, and (2) follow the progress 
of the pregnancy. The investigator must document the outcome of the pregnancy and provide a 
copy of the documentation to the sponsor.


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4.4.4
Special Diet or Activities 
Participants should refrain from consuming grapefruit or grapefruit juice from the time the 
consent form is signed until completion of the study. Participants should also refrain from 
making significant changes to their diet or caffeine intake during the study.
Alcohol intake should be limited to no more than 1 drink per day throughout the study. A drink is 
defined as a 12-ounce (or 355 mL) can/bottle of beer, a 4-ounce (or 118 mL) glass of wine, or 
1 ounce (or 30 mL) of liquor.
4.5
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized to treatment. Rescreening of screen failures is permitted in certain 
situations (ie, failure to adequately screen due to COVID-19), with permission from the sponsor.
However, participants with clinically significant laboratory values at Visit 1 (ie, screening; 
including ALT or AST >1 × the ULN, total bilirubin > 1 × ULN or serum albumin < 2.8 g/dL), or 
those with a positive UDS result at Visit 1 for recreational (including marijuana regardless of 
legality) or illicit drugs or non-disclosed5 concomitant medications are not allowed to be 
rescreened.
5.
Study Interventions 
5.1
Study Interventions and Formulations
Tablets containing atogepant 30 mg (Formulation Number 11280X) or atogepant 60 mg 
(Formulation Number 11281X).
5.2
Control Interventions and Formulations
Tablets containing matching placebo 30 mg (Formulation 011326X) for atogepant 30 mg and 
matching placebo 60 mg for atogepant 60 mg (Formulation 011317X).
                                                
5 For participants in the People’s Republic of China, a positive UDS will result in screen failure regardless of 
disclosed concomitant medications.


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5.3
Methods for Masking/Blinding
A double-dummy design will be used to maintain the blind. All study interventions will be 
provided in identical blister cards to maintain masking of the study.
All participants will be instructed to take their study intervention twice daily (ie, 2 tablets in the 
morning and 2 tablets in the evening) at approximately the same times each day. Participants, 
therefore, will receive either placebo BID, atogepant 30 mg BID, or a morning dose of atogepant 
60 mg with an evening dose of placebo.
5.4
Treatment Allocation Ratio and Stratification
Approximately 750 participants will be randomized to one of three treatment arms in a 1:1:1 
ratio as follows:

Placebo (n = 250)

Atogepant 30 mg BID (n = 250)

Atogepant 60 mg once daily (n = 250)
Participant will be stratified by:

Randomization will be stratified by use of acute headache medications during the 
baseline period (acute headache medication overuse Yes or No). Acute headache 
medication overuse (Yes) will be defined as follows: use of triptans on ≥10 days OR use 
of ergots on ≥10 days OR use of simple analgesics (ie, aspirin, NSAIDs, or 
acetaminophen) on ≥ 15 days OR use of any combination of triptans, ergots, or simple 
analgesics on ≥10 days.

Approximately 70% of randomized participants will have taken at least 1 prior migraine 
prevention medication with proven efficacy (see Attachment 12.3)6. Randomization will 
be stratified based on migraine prevention medication exposure (Current Use, Past Use, 
or Never Used) with proven efficacy. Participants with current or past use will be further 
stratified based on the number of medications failed with unique mechanisms of action: 
“failed 0 medications or failed 1 or more medication(s) with the same mechanism of 
action” or “failed 2 to 4 medications with different mechanisms of action” (see 
Attachment 12.3). Enrollment of participants with current use of a migraine prevention 
medication will be capped at ~15%.
                                                
6 All French participants must have taken at least 1 prior migraine prevention medication with proven efficacy to be 
eligible for Study 3101-303-002.


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o
Below are examples to illustrate how to implement the stratification based on 
prior migraine prevention medications:

Example 1: Participant has taken metoprolol and propranolol. According 
to Attachment 12.3, these medications both belong to the beta-blocker 
pharmacologic category. This participant should be randomized to the 
“failed 0 medications or failed 1 or more medication(s) with the same 
mechanism of action” stratum.

Example 2: Participant has taken metoprolol, propranolol, and topiramate. 
According to Attachment 12.3, metoprolol and propranolol belong to the 
beta-blocker pharmacologic category and topiramate belongs to the 
antiepileptic pharmacologic category. This participant should be 
randomized to the “failed 2 to 4 medications with different mechanisms of 
action” stratum.

Example 3: Participant has taken metoprolol and topiramate. According to 
Attachment 12.3, metoprolol belongs to the beta-blocker pharmacologic 
category and topiramate belongs to the antiepileptic category; however, 
the patient stopped both of these medications because of a change in 
health insurance coverage and therefore did not meet the failure definition 
for either medication. This participant should be randomized to the "failed 
0 medications or failed 1 or more medication(s) with the same mechanism 
of action" stratum.

Randomization will be stratified by regions (ie, North America, Europe, Japan, China, 
Other)
5.5
Method for Assignment to Treatment Groups/Randomization
Prior to initiation of study intervention, each participant who provides informed consent will be 
assigned a participant number that will serve as the participant identification number on all study 
documents.
At the time of randomization (Visit 2), eligible participants will be randomized in a 1:1:1 ratio 
into the following arms: placebo, atogepant 30 mg BID, or atogepant 60 mg once daily.
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, log in information and directions for the IWRS will be provided to 
each site.
Study intervention will be labeled with medication kit numbers. The IWRS system will provide 
the site with the specific medication kit number(s) for each randomized participant at the time of 
randomization. Sites will dispense study intervention according to the IWRS instructions. Sites 


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will also log onto the IWRS at subsequent visits to obtain a kit number for dispensing study 
intervention. Sites will receive the IWRS confirmation notifications for each transaction. All 
notifications are to be maintained with the study source documents.
Study intervention will be dispensed at the study visits summarized in Table 1, Schedule of Visits 
and Procedures. Returned study intervention should not be re-dispensed to the participants.
5.6
Study Intervention Regimen and Dosing
Treatments to be used in this trial are listed in Table 2. Participants who meet all the study entry 
criteria at Visit 2 will be randomized and provided with study intervention to be taken on an 
outpatient basis. Sites will subsequently dispense study intervention to participants at Visits 3, 4, 
5, and 6. Participants will take their first dose of study intervention at the clinic at Visit 2. All 
participants will be instructed to take their study intervention twice daily (2 tablets in the 
morning and 2 tablets in the evening) at approximately the same times each day. Details of PK 
samples with respect to timing of study intervention are provided in Section 6.3. Study 
intervention will be administered orally for 12 weeks, and participants will be followed for 
4 weeks following study completion or discontinuation of study intervention.
Table 2
Study Interventions
Drug/Dose
Study Intervention Product and Matching 
Placebo
Study 
Intervention 
Frequency
Route of 
Administration
Placebo
Placebo 30 mg and Placebo 60 mg
BID
Oral
Atogepant 30 mg 
Atogepant 30 mg and Placebo 60 mg
BID
Oral
Atogepant 60 mg 
AM: Atogepant 60 mg and Placebo 30 mg
BID
Oral
PM:  Placebo 30 mg and Placebo 60 mg
AM = morning dose; BID = twice daily; PM = evening dose.


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5.7
Storage of Study Interventions
The study intervention must be stored at room temperature in a securely locked cabinet. Further 
details regarding the storage of the study intervention are in the Study Reference Manual.
6.
Response Measures and Summary of Data Collection Methods
6.1
Efficacy Measures
Efficacy assessments will be based on information recorded by the participant. An eDiary will be 
used daily at home to collect data on headache frequency, duration, characteristics, and
symptoms; acute medication use and triptan use, which will be collectively applied to define 
migraine days and headache days per the criteria listed in Sections 6.1.1, 6.1.2, and 6.1.3. 
The AIM-D, Activity Level, and Activity Limitation will also be collected daily via an eDiary. 
EQ-5D-5L will also be collected via an eDiary for a period of 1 week in the screening period 
(administered on Study Day 22 through 28 for a total of 7 days after screening), randomization 
(Study Day 1) until Visit 3 (14 consecutive days from randomization), Visit 4 (± 3 days, ie, Study 
Days 25 to 31 from randomization for a total of 7 days), Visit 5 (± 3 days, ie, Study Days 39 to 
45 from randomization for a total of 7 days), Visit 6 (± 3 days, ie, Study Days 53 to 59 from 
randomization for a total of 7 days), and Visit 7 (- 7 days, ie, Study Days 77 to 83 from 
randomization for a total of 7 days). At Visit 8, the EQ-5D-5L will be administered on an eTablet.
Additional health outcome measures, namely, the PSSM scale, HIT-6, MIDAS, PGIC, 
WPAI:MIGRAINE, PGI-S, MSQ v2.1, PROMIS-PI, and PHQ-9 will also be administered on an 
eTablet at specified clinic visits.
6.1.1
Migraine Day
A migraine day is defined as any calendar day on which a headache occurs which meets criteria 
A, B, and C OR meets criteria D and E, as listed below, as per participant eDiary. Calendar days 
begin at midnight and last until 11:59 PM (23:59). 
A. Headache has at least 2 of the following 4 characteristics:
i.
Unilateral location
ii.
Pulsating quality
iii.
Moderate or severe pain intensity
iv.
Aggravated by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs)


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B. At least 1 of the following:
i.
Nausea and/or vomiting 
ii.
Photophobia and phonophobia 
iii.
Typical aura (ie, visual, sensory, or speech/language) accompanying or within
60 minutes before headache begins
C. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, 
migraine-specific medication (ie, triptan or ergot derivative) was used after the start of 
the headache, in which case no minimum duration will be specified
OR
D. Any headache which fulfills 1 criterion from (1) and at least 1 criterion from (2) OR 
fulfills at least 2 criteria from (1) and no criteria from (2).
1) Headache characteristics:
i. Unilateral location
ii. Pulsating quality
iii. Moderate or severe pain intensity
iv. Aggravated by or causing avoidance of routine physical activity 
(eg, walking or climbing stairs)
2) Symptoms:
i. Nausea and/or vomiting
ii. Photophobia and phonophobia
iii. Typical aura (ie, visual, sensory, or speech/language) accompanying or 
within 60 minutes before headache begins
E. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, 
migraine-specific medication (ie, triptan or ergot derivative) was used after the start of 
the headache, in which case no minimum duration will be specified.
6.1.2
Headache Day
A headache day is defined as any calendar day on which headache pain lasting 2 hours or longer 
occurs unless an acute headache medication (eg, ibuprofen, triptan) was used after the start of the 
headache, in which case no minimum duration will be specified. Calendar days begin at midnight 
and last until 11:59 PM (23:59).


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6.1.3
Acute Medication Use Day and Triptan Use Day
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 allowed medications include the 
following categories of drugs: triptans, ergots, opioids, analgesics (including acetaminophen), 
NSAIDs (including aspirin), and antiemetics.
A triptan use day is defined as any day on which a participant reports intake of a triptan to treat a 
migraine per participant diary.
6.2
Health Outcomes Measures
6.2.1
Activity Impairment in Migraine – Diary (AIM-D)
The AIM-D is an 11-item daily diary measure that assesses the impact of migraine and is 
comprised of two domains that evaluate performance of daily activities (7 items) and physical 
impairment (4 items). Participants are asked to rate the level of difficulty experienced in the past 
24 hours with performance of daily activities (ie, 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 (ie, difficulty walking, 
moving body, bending forward, moving head) using the 6-point rating scale: “Not difficult at 
all,” “A little difficult,” “Somewhat difficult,” “Very difficult,” “Extremely difficult,” and 
“I could not do it at all.” Three items include a response of “I did not…,” for example, “I did not 
have errands planned.” The AIM-D was developed as an electronic daily diary with the same set 
of questions administered in headache and non-headache versions. The Headache version is 
administered on days when a participant reports a headache and the Non-Headache version is 
administered on days when a participant does not report having a headache. The AIM-D instructs 
participants to answer each question based on the level of difficulty experienced in the past 
24 hours for both versions, with “during your headache” indicated for the AIM-D Headache 
version. In addition to the two domain scores, a total score using all 11 items can also be 
calculated. Each raw daily domain score, as well as the raw daily total score, are transformed to a 
0-100 scale, with higher scores indicating greater impact of migraine (ie, higher disease burden).
6.2.2
Activity Level and Activity Limitation
Two items based on a 24-hour recall will be administered daily using Headache and 
Non-Headache versions as additional health outcome measures and for evaluation of the AIM-D. 
The first item will be used to assess activity level within the past 24 hours with a 5-level 
response ranging from “No activity – Spent all day lying down” to “Exercised – Brisk walk, 


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running, jogging, biking or other activity for 30 or more minutes.” The second item will be used 
to evaluate activity limitation with a 5-level response ranging from “Not at all limited – I could 
do everything” to “Extremely limited.”
6.2.3
Patient Satisfaction with Study Medication (PSSM)
Overall satisfaction with the study medication for prevention of migraine will be assessed using a 
single item and a 7-point rating scale ranging from extremely satisfied (0) to extremely 
dissatisfied (6). 
6.2.4
Headache Impact Test (HIT-6)
The 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).
6.2.5
Migraine Disability Assessment (MIDAS)
The MIDAS is a 7-item questionnaire designed to quantify headache-related disability over a 
3-month period. The MIDAS score is the sum of missed work or school days, days at work or 
school plus days of household work where productivity was reduced by half or more, missed 
household work days, and missed non-work activity days due to headaches in the last 3 months.
6.2.6
Patient Global Impression of Change (PGIC)
The PGIC is a single item questionnaire used to measure the participant’s impression of overall 
change in migraine since the first dose of study medication. The measure uses a 7-point rating 
scale with responses ranging from “very much better” to “very much worse.”
6.2.7
Work Productivity and Activity Impairment Questionnaire: 
Migraine V2.0 (WPAI:MIGRAINE)
The WPAI:MIGRAINE will be used to assess work productivity specific to migraine. The
measure uses a 1-week recall and contains 6 questions related to work productivity. The WPAI 
measures both presenteeism and absenteeism. The measure yields four scores expressed as 
impairment percentages ranging from 0 to 100%: Percent work time missed, percent impairment 


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while working, percent overall work impairment, and percent activity impairment due to 
migraine.
6.2.8
European Quality of Life – 5 Dimensional (EQ-5D-5L)
EQ-5D-5L is a generic instrument for use as a measure of health status. The EQ-5D-5L consists 
of 2 components – the EQ-5D descriptive system and the EQ VAS. The descriptive system 
comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. 
The scoring range of the EQ-5D descriptive system is typically from 0 (dead) to 1 (full health). 
The EQ VAS records the respondent’s self-rated health on a vertical VAS where the endpoints 
are labelled “Best imaginable health state” and “Worst imaginable health state.” The scoring 
range of the EQ VAS is from 0 (worst imaginable health) to 100 (best imaginable health).
6.2.9
Patient Global Impression – Severity (PGI-S)
The PGI-S is a single item questionnaire used to measure the participant’s impression of severity 
in relation to migraine symptoms overall at the time of administration of the measure. The 
measure uses a 5-point rating scale with responses ranging from “none” to “very severe.”
6.2.10
Migraine Specific Quality of Life Questionnaire, Version 2.1
(MSQ v2.1)
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 assesses how migraines limit one’s daily social and work-related activities; 
Role Function Preventive assesses how migraines prevent these activities; and the Emotional 
Function 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.
6.2.11
Patient-Reported Outcomes Measurement Information System Pain 
Interference – Short Form 6a (PROMIS-PI)
The PROMIS-PI measures self-reported interference of pain on relevant aspects of daily life (ie, 
social, cognitive, emotional, physical, recreational) over the past 7 days. A 5-level response scale 


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for all six items ranges from “Not at all” to “Very much.” Scores range from 6 to 30, with higher 
scores indicating greater pain interference.
6.2.12
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is a concise, self-administered, validated, screening and diagnostic tool for mental 
health disorder, which has been field-tested in office practice. The screener is quick and user-
friendly, improves the recognition rate of depression, and facilitates diagnosis and treatment. The 
PHQ-9 consists of the 9 diagnostic criteria for depressive disorders in the past 2 weeks from the 
DSM-IV. Participants are asked to indicate the frequency with which they have been bothered by 
9 symptoms of depressive disorders over the previous 2 weeks, on a 4-point scale: 0 (not at all), 
1 (several days), 2 (more than half the days), and 3 (nearly every day). The total score ranges 
from 0 to 27 (from best to worst). A score of 15 to 19 is considered as moderately severe 
depression and 20 to 27 as severe depression.
6.3
Pharmacokinetics Measures
A blood sample for PK analysis will be collected on site at Visits 2, 3, 4, 5, 6, and 7/ET from 
participants who consent to participate in the PK substudy. Participants can withdraw consent at 
any time and should have no further PK samples collected. Each participant in the PK substudy 
will be asked to provide a total of 6 blood samples (1 per visit); At Visit 2, the sample should be 
collected prior to the initial dose of study intervention taken at the clinic. During 1 of the Visits 3 
to 6, the sample should be collected prior to the morning dose of study intervention (participant
should wait to take the morning dose in the clinic after PK sample collection), and the samples 
collected at the remaining visits should be collected 1 to 10 hours post the morning dose and 
prior to the evening dose. At Visit 7 the sample should be collected 1 to 10 hours post the 
morning dose.
The date and time of collection of each PK sample will be recorded in the eCRF. In addition, for 
each of the PK samples collected (except the Visit 2 sample) the date and time of the 2 doses of 
study intervention prior to the PK sample should be recorded. PK samples will be collected, 
stored (frozen), and shipped according to instructions provided in the Study Reference Manual.
The treatment codes will be provided to the bioanalytical lab using a secure process, ensuring no 
one outside the bioanalytical team is unblinded, to allow only atogepant-treated participant PK 
samples to be analyzed. The bioanalytical method for the determination of individual plasma 
concentrations of atogepant and the performance of the assay during validation and sample 
analysis will be summarized in a separate bioanalytical report, including the results obtained 


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from analysis of the PK samples. The bioanalytical report will be appended to the integrated 
clinical study report. 
6.4
Future Biomedical Research
Blood samples will be collected from all participants who consent to participate in the substudy, 
for the purposes of future biomedical research. The samples will be obtained at the Screening
Visit. All samples will be sent to the designated central laboratory and shipped to a biorepository 
for storage. Please refer to the Central Laboratory Manual for the genetic blood sampling 
procedures, shipping instructions, and contact information. Anonymized samples may be stored 
in the biorepository database for potential analysis under separate protocols for up to 15 years. 
Samples may be stored for a longer time if a regulatory or governmental authority has active 
questions that are being answered. In this special circumstance, samples will be stored until these 
questions have been adequately addressed. The anonymized genetic material from the blood 
samples may also be used for future, unspecified research, not limited to the disease being 
studied in this particular clinical study.
All participants enrolled in the clinical trial will be considered for enrollment in the future 
biomedical research substudy; however, participation is optional and will require a separate ICF. 
A participant who initially consents can withdraw that consent at any time and have his or her 
sample destroyed including any by-products of the sample whenever possible.
6.5
Safety Measures
6.5.1
Adverse Events
Subjective AEs will be collected from the time of consent through the last visit. For all AEs, the 
investigator must provide an assessment of the severity, causal relationship to the investigational 
product, start and stop date, and seriousness of the event (eg, SAE), document all actions taken 
with regard to the investigational product, and detail any other treatment measures taken for the 
AE. For events noted as SAEs, the sponsor must be notified immediately to meet their reporting 
obligations to appropriate regulatory authorities.
6.5.2
Adverse Events of Special Interest
Selected non-serious and SAEs are of special interest and will require immediate reporting, 
recording, and follow-up. The following events will be closely monitored:


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
Treatment-emergent suicidal ideations with intent, with or without a plan, (ie, Type 4 or 5 on 
the C-SSRS) or any suicidal behaviors 

Treatment-emergent elevated ALT or AST lab value that is ≥ 3 × ULN

Potential Hy’s law cases: elevated ALT or AST lab value that is ≥ 3 × ULN and an elevated 
total bilirubin lab value that is ≥ 2 × ULN and, at the same time, an alkaline phosphatase lab 
value that is < 2 × ULN.
Reporting requirements for ALT or AST elevations and potential Hy’s law cases are outlined in 
Sections 9.5 and 9.5.1. Responses to the C-SSRS that meet the above criterion will captured on 
the eTablet and monitored by the sponsor. These AEs or events that are determined to be SAEs 
must be reported appropriately via the designated eCRF and safety forms. 
6.5.3
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at the visits outlined in 
Table 1. Hematology, chemistry, coagulation parameters (INR), and urinalysis will be conducted 
at these visits. Serology and the urine drug screen will be conducted at screening (Visit 1). The 
investigator will assess the clinical significance of any values outside the reference ranges 
provided by the central laboratory. Participants with abnormalities judged to be clinically 
significant laboratory values that meet exclusionary criteria, or positive results on the urine drug 
screen at screening (Visit 1), will be excluded from the study. 
Women of childbearing potential will be required to have a urine pregnancy test at all visits. A 
positive pregnancy test at Visit 1 or Visit 2 will exclude the participant from the study.
Investigators may also perform unscheduled clinical laboratory determinations at any time for 
the purpose of participant safety. 
Participants are not required to fast overnight before coming in for their appointments.
The clinical laboratory parameters to be measured are shown in Table 3.


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Table 3
Clinical Laboratory Parameters
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
lactate dehydrogenase, creatine kinase, total protein, albumin, calcium, phosphorus, uric 
acid, total cholesterol. The estimated glomerular filtration rate will be calculated by the 
central laboratory
Hematology
Hemoglobin; hematocrit; red blood cell count; red blood cell indices (mean corpuscular 
volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); 
white blood cell count including differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils); platelet count
Urinalysis
Urine dipstick for specific gravity, pH, protein, glucose, ketones, bilirubin, and blood; 
microscopic exam including red blood cells/high-power field, white blood cells/high-power 
field, and casts/low-power field
Coagulation
International normalized ratio
Serology
At Visit 1 only: anti-hepatitis A IgM antibody, hepatitis B surface antigen, anti-hepatitis C 
antibody, anti-hepatitis E IgM antibody
Urine Drug Screen
Screening for drugs of abuse (eg, marijuana, cocaine, phencyclidine, amphetamines, 
benzodiazepines, barbiturates, opiates) will be conducted using a urine drug screen at 
Visit 1. UDS positive for recreational (including marijuana regardless of legality) or illicit 
drugs or non-disclosed concomitant medications are not allowed to be repeated. All other 
positive urine drug screens may be repeated with permission from the sponsor; a negative 
result or an explanation of a positive result due to concomitant medication use (eg, opioids 
prescribed for migraine pain) will be required for randomization.
IgM = immunoglobulin M.
Please note: For participants in the People’s Republic of China, a positive UDS will result in screen failure 
regardless of disclosed concomitant medications.
A central laboratory will be used to evaluate all urine and blood samples, which will be collected, 
processed, and stored according to the instructions provided by the laboratory.
6.5.4
Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, body weight, and height (at Visit 1 only), will be performed at 
every visit. Sitting and standing BP and pulse rate will be determined as follows: BP and pulse 
measurements will be performed after the participant sits quietly for 5 minutes, followed by a 
second set of measurements taken after the participant stands for at least 3 minutes (but no longer 
than 10 minutes).
6.5.5
Physical Examination
A complete physical examination will be performed at the visits outlined in Table 1. A 
professionally trained physician or healthcare professional licensed to perform physical 
examinations will examine the participant for any detectable abnormalities of the following body 


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systems: general appearance, neck (including thyroid), head, eyes, ears, nose, and throat, lungs,
heart/cardiovascular, abdomen, neurologic, extremities, back, musculoskeletal, lymphatic, skin,
and other. The neurologic examination should be conducted to detect the presence of any 
significant sensory/motor abnormalities.
6.5.6
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in Table 1. All ECGs should be 
performed after the participant has been supine for at least 5 minutes. All ECGs performed will 
be saved as source documents. ECGs will be transmitted electronically to the central ECG 
laboratory for analysis according to the instructions provided by the laboratory to be centrally 
read by a cardiologist. The overall interpretation of the clinical significance of the ECG will be 
determined by the investigator and recorded in the participant’s eCRF. 
6.5.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and 
behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific 
active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to 
act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active 
suicidal ideation with specific plan and intent). The C-SSRS also captures information about the 
intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons 
for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no 
suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), 
and 4 (actual attempt). More than 1 classification can be selected provided they represent 
separate episodes. For actual attempts only, the actual or potential lethality is classified for the 
initial, most lethal, and most recent attempts. The C-SSRS will be completed at all study visits. 
At screening (Visit 1), the C-SSRS will be completed for history of suicidal ideation and suicidal 
behavior for the participant’s lifetime and 6 months prior to screening. At all other visits, the 
C-SSRS will be completed for ideation and behavior since the previous visit. The C-SSRS will 
be completed on the eTablet by the investigator or designee with current and valid training in 
administering the assessment. A participant should not be released from the study center until the 
results of C-SSRS are reviewed and it is confirmed that the participant is not considered to be at 
risk. Participants who reply with “yes” to questions 4 or 5 in the suicidal ideation section or 
“yes” to any question in the suicidal behavior section of the C-SSRS at Visits 3 through 6 must 
be withdrawn from the study and should receive appropriate follow-up as in routine clinical 
practice, including the ET Visit 7 and the follow-up Visit 8. These participants must continue to 
complete their daily eDiary through Visit 8 follow-up.


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6.6
Other Study Supplies
The following will be provided by the sponsor or a delegate:

All supplies needed for blood and urine sampling (central laboratory analysis, urine, and 
urine dipstick reagent strips)

All supplies needed for on-site urine pregnancy test

All supplies needed for PK and future biomedical research sample collections 

Shipping materials for shipment of laboratory samples to central laboratory

All supplies needed for ECG assessment including ECG machine 

Electronic diaries

Electronic tablet(s)
6.7
Summary of Methods of Data Collection
An IWRS will be used to randomize participants and manage study intervention inventory. All 
visit data (ie, non-diary data) for this study will be collected by either on the eTablet or, if 
conducted remotely (Attachment 12.4), utilizing a web-portal (eg, questionnaires for PROs) or 
eCRFs via an electronic data capture system. Source documents will be used at the sites and may 
include a participant’s medical record, hospital charts, clinic charts, the investigator’s participant
study files, as well as the results of diagnostic tests such as laboratory tests, ECGs, etc. 
A centralized clinical laboratory will be used for the analysis of all blood and urine samples and 
for ECG assessments. Additional information on the collection and handling of samples is 
detailed in the Lab Procedure Manual.
Participants will use an eDiary daily to record the daily total duration of headache, headache 
characteristics, associated symptoms, the worst pain severity, and acute medication use both in 
the screening/baseline period and double-blind treatment period until Visit 7/ET. Training for the 
eDiary will be provided for qualified participants during the Screening/Baseline Visit (Visit 1).


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7.
Statistical Procedures
7.1
Analysis Populations
The ITT population will consist of all randomized participants. All efficacy analyses will be 
performed using the mITT population, consisting of 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 postbaseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data
during the double-blind treatment period. All safety analyses will be performed using the safety 
population, consisting of all participants who received at least 1 dose of study intervention.
The primary efficacy analysis population to support filing in Europe for off-treatment estimand 
(defined in Section 7.4) includes 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
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.
7.2
Collection and Derivation of Primary and Secondary Efficacy 
Assessments
On a daily basis during the 28-day baseline period and throughout the study, participants are to 
record, into an eDiary, information on the daily total duration of headache, headache specific 
characteristics and symptoms, the worst pain severity, and use of any acute medication. 
Participants will be able to report headache data, including absence of headache, for the day of 
the diary report and for the day immediately prior to the day of the diary report, as long as 
information reported is for a time subsequent to the participant’s most recent report. This is 
defined as a 1-day “missing-recall” window.
Following randomization on Day 1, there are 4 visits at 2-week intervals, followed by 2 visits at 
4-week intervals; altogether encompassing a 12-week double-blind treatment phase of the study 
and a 4-week follow-up phase. In practice, there may or may not be exact 2-week or 4-week 
durations between 2 consecutive visits, and the visits might not align with each 28-day period 
recorded in the eDiary (ie, Weeks 1 to 4, 5 to 8, and 9 to 12, corresponding to Days 1 to 28, 
29 to 56, and 57 to 84). Therefore, for data analysis purposes, the number of migraine days 
during the last 28 days prior to the randomization date, will serve as the baseline, and change 
from baseline will be calculated for consecutive 28-day periods beginning with the date of the 
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In order to be randomized, a participant should be in the baseline phase for at least 28 days and 
must report diary data for at least 20 days (including missing recall) during the 28-day baseline 
period. If less than 28 days of baseline data are reported, the number of headache days and other 
such counting variables for baseline will be prorated to standardize the count to a 28-day 
equivalent. Subsequent to treatment start, the number of headache days will be counted in 
successive and non-overlapping 4-week (ie, 28-day) windows. Headaches that continue into a 
subsequent 4-week period will be counted (with recorded severity and duration) as occurring in 
each period.
If any postbaseline diary window for a participant has at least 14, but less than 28 days, of 
reported data, the prorated approach will be used. If a participant reports less than 14 days of 
eDiary data, the participant’s observed counts in that particular 28-day diary window will be set 
to missing for that window. These prorating rules will be applied to all efficacy analyses of diary 
data unless otherwise stated.
7.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in mean monthly migraine days 
across the 12-week treatment period. Baseline is defined as the number of migraine days during 
the last 28 days prior to the randomization date.
7.2.2
Secondary Efficacy Endpoints
The Secondary Efficacy Endpoints for all regions except Europe and Canada:

Change from baseline in mean monthly headache days across the 12-week treatment 
period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

At least a 50% reduction in 3-month average of monthly migraine days

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12

Change from baseline in mean monthly Performance of Daily Activities domain score of 
the AIM-D across the 12-week treatment period.

Change from baseline in mean monthly Physical Impairment domain score of the AIM-D 
across the 12-week treatment period.


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The Secondary Efficacy Endpoints for Europe and Canada:

Change from baseline in mean monthly headache days across the 12-week treatment 
period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

At least a 50% reduction in 3-month average of monthly migraine days

Change from baseline in the HIT-6 total score at Week 12

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12
7.2.3
Additional Efficacy Endpoints
Additional efficacy endpoints for the United States and Europe are provided below. Related 
analysis will be documented in the statistical analysis plan (SAP).

≥ 25%, ≥ 30%, ≥ 50%, ≥ 75%, 100% improvement (decrease) in monthly migraine days 
at Weeks 1 to 4, 5 to 8, and 9 to 12

≥ 25%, ≥ 30%, ≥ 75%, 100% improvement (decrease) in 3-month average of monthly 
migraine days

Change from baseline in monthly migraine days at Weeks 1 to 4, 5 to 8, and 9 to 12

Change from baseline in monthly headache days at Weeks 1 to 4, 5 to 8, and 9 to 12

Change from baseline in monthly cumulative headache hours at Weeks 1 to 4, 5 to 8, 
9 to 12, and average across the 12-week treatment period

Change from baseline in monthly acute medication use days at Weeks 1 to 4, 5 to 8, and 
9 to 12

Change from baseline in monthly triptan use days at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in monthly moderate/severe headache days at Weeks 1 to 4, 5 to 8, 
9 to 12, and average across the 12-week treatment period

Change from baseline in monthly severe headache days at Weeks 1 to 4, 5 to 8, 9 to 12, 
and average across the 12-week treatment period

Change from baseline in weekly migraine days at Weeks 1-4


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
Participant having a migraine day on the day of initial dose and on each day of the 6 days 
post the initial dose.

Change from baseline in the HIT-6 total score at Weeks 4, 8, and 16 (for Europe and 
Canada)

Change from baseline in the HIT-6 total score at Weeks 4, 8, 12, and 16 (for all regions
except Europe and Canada)

At least a 5-point improvement (decrease) from baseline in HIT-6 total score at Weeks 4, 
8, 12, and 16

Participant assessed by the PGIC as “much better” or “very much better” at Week 12

Participant reporting “satisfied” or “extremely satisfied” with study medication for 
migraine prevention at Weeks 4, 8, and 12

Change from baseline in percent work time missed, percent impairment while working, 
percent overall impairment, and percent activity impairment due to migraine at Weeks 4, 
8, and 12 as assessed by the WPAI:MIGRAINE

Change from baseline in the MIDAS total score at Week 12

Change from baseline in MIDAS absenteeism score (Questions 1, 3, and 5) at Week 12

Change from baseline in MIDAS presenteeism score (Questions 2 and 4) at Week 12

Change from baseline in PGI-S score at Weeks 4, 8, and 12

Change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at 
Weeks 4, 8, and 16

Change from baseline in the MSQ v2.1 Role Function-Preventive domain score at 
Weeks 4, 8, 12, and 16

Change from baseline in the MSQ v2.1 Emotional Function domain score at Weeks 4, 8,
12, and 16

Change from baseline in monthly Performance of Daily Activities domain score of the 
AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12

Change from baseline in monthly Physical Impairment domain score of the AIM-D at 
Weeks 1 to 4, 5 to 8, and 9 to 12

Change from baseline in mean monthly Performance of Daily Activities domain score of 
the AIM-D across the 12-week treatment period (for Europe and Canada only)


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
Change from baseline in mean monthly Physical Impairment domain score of the AIM-D 
across the 12-week treatment period (for Europe and Canada only)

Change from baseline in monthly AIM-D total score at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in monthly activity level at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in monthly activity limitation at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in PHQ-9 score at Week 12
7.2.3.1
Other Health Outcome Variables
Other health outcome endpoints are listed below. The related health outcome analyses will be 
documented in the health economics and outcomes research SAP.

Change from baseline in EQ-5D-5L descriptive system index score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 12, and 16

Change from baseline in the EQ-5D-5L VAS score at Weeks 1 to 2, at specified windows 
around Weeks 4, 6, 8, 12, and 16

Change from baseline in PROMIS-PI total score at Weeks 4, 8, and 12
7.3
Hypothesis and Methods of Analysis
For efficacy analyses, data will be analyzed according to participants’ randomization 
assignments, regardless of actual treatment received.
For safety data analyses, the participants will be analyzed according to actual treatment received 
(rather than as randomized).
7.3.1
Primary Efficacy Analyses
The primary efficacy endpoint is the change from baseline in mean monthly migraine days 
across the 12-week treatment period. The primary null hypothesis is that atogepant 30 mg BID 
and 60 mg once daily are each equally effective as placebo in mean change from baseline in 
mean monthly migraine days across the 12-week treatment period. The alternative hypothesis is 
that at least 1 of the 2 doses of atogepant has a greater effect than placebo.


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The primary comparison between treatment groups will be done by an MMRM of the change 
from baseline. The statistical model will include treatment group, visit, region, acute migraine 
medications during the baseline period (medication overuse Y/N), current and past use of 
migraine prevention medications and the number of medications failed with unique mechanisms 
of action (Current Use and “failed 0 medications or failed 1 or more medication(s) with the same 
mechanism of action”, Current Use and “failed 2 to 4 medications with different mechanisms of 
action”, Past Use only and “failed 0 medications or failed 1 or more medication(s) with the same 
mechanism of action”, Past Use only and “failed 2 to 4 medications with different mechanisms 
of action”, and Never Used), and treatment group by visit interaction as categorical fixed effects. 
The statistical model will also include the baseline score and baseline-by-visit interaction as 
covariates. An unstructured covariance matrix will be used to model the covariance of within-
participant repeated measurements. The Kenward-Roger approximation (Kenward 1997) will be 
used to estimate the denominator degrees of freedom. The analysis will be performed based on 
all postbaseline values using only the observed cases without imputation of missing values. 
Pairwise contrasts in the MMRM model will be used to make the pairwise comparisons of each 
atogepant dose to placebo. This is the primary analysis method for the primary efficacy endpoint 
in support of US filing. Only data collected during the double-blind period will be included in 
the analysis. Participants are always analyzed based on the treatment group assigned by 
randomization.
7.3.1.1
Sensitivity Analyses in Missing Data Handling
Multiple sensitivity analyses for missing data handling will be conducted and summarized below. 
Details of the sensitivity analyses will be provided in the SAP.
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
A supportive analysis will be performed on the primary endpoint using an ANCOVA model. The 
response variable for the ANCOVA model is the change from baseline in the calculated average 
monthly migraine days during the 12-week treatment period for each participant. The ANCOVA 
model includes terms for treatment, region, acute medications during the baseline period 
(medication overuse Y/N), current or past use of migraine prevention medications and the
number of medications failed with unique mechanisms of action, and baseline score. The 
treatment difference for atogepant doses versus placebo will be estimated and reported along 
with the corresponding 95% CI and nominal p-value for superiority testing.


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Within-group Imputation Based on Observed Data
Sensitivity analysis will be performed based on imputation using participants from the same 
treatment group with observed data under the missing at random (MAR) assumption. Missing 
data for participants who prematurely discontinued are assumed to copy the profile of 
participants in the same treatment group with observed data.
Copy-Reference Approach
Copy-reference approach will be performed on the primary endpoint to assess the robustness of 
the MMRM analysis to possible violation of the MAR assumption. This sensitivity analysis is 
one type of pattern mixture model (PMM), under which data could be missing not at random 
(MNAR), with repeated analyses combined via the reference based multiple imputation (MI) 
procedure. Participants who discontinued in the Atogepant groups are assumed to have no 
treatment effect after the discontinuation. Participants are assumed to copy the profile of placebo 
arm and missing values are imputed based on the distribution estimated from the placebo group 
under the MAR using copy reference approach.
MMRM Based on Primary Measures Collected During the Double-blind and Follow-up 
Periods
The details for this analysis are provided in Section 7.4. The primary analysis in support of EU 
filing will serve as one sensitivity analysis in support of US filing.
7.3.1.2
Sensitivity Analysis for Possible Violation of Normality Assumption
The normality test is performed on the residuals which are generated by the same MMRM as 
used for the primary efficacy analysis. The residuals are scaled by the inverse Cholesky root of 
its estimated variance-covariance matrix. The Kolmogorov-Smirnov test for normality is applied 
to the de-correlated and scaled residuals and normality test is rejected if p-value from the 
Kolmogorov-Smirnov test is less than 0.01. 
If the normality test is rejected, the sensitivity analysis uses MI in conjunction with robust
regression to assess the robustness of the primary MMRM analysis to the possible violation of 
normality assumption. This method has been described and is referred to as ADAP [R] in 
Mehrotra 2012. The detail of the sensitivity analyses will be provided in the SAP. 


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7.3.2
Secondary Efficacy Analyses 
The secondary efficacy variables are identified in Section 7.2.2.
The secondary endpoints for headache days, acute medication use days, MSQ v2.1 Role 
Function-Restrictive domain score, Performance of Daily Activities domain score of the AIM-D, 
Physical Impairment domain score of the AIM-D, and HIT-6 total score will be analyzed in the 
same manner as that used to analyze the primary endpoint. 
The secondary endpoint of 50% responders, defined as participants with at least a 50% reduction 
from baseline in the 3-month average of monthly migraine days, will be assessed for each 
individual. A logistic regression model will be used to analyze 50% responders across the 
12-week treatment period. This model assumes a binary distribution for the response and uses a 
logit link. The analysis model will include treatment group, region, acute medications during the 
baseline period (medication overuse Y/N), current and past use of migraine prevention 
medications and the number of medications failed with unique mechanisms of action as 
categorical fixed effects; baseline value will be included as a covariate. The analysis will be 
performed based on all postbaseline values using only the observed cases without imputation of 
missing values. The treatment difference in terms of odds ratio between each atogepant dose 
group and placebo will be estimated and tested from this model. 
The overall type I error rate for multiple comparisons across two atogepant doses and the 
primary and secondary efficacy endpoints will be controlled at the 0.05 level using a graphical 
approach (Bretz 2011). The primary endpoint will serve as the gatekeeper for the secondary 
endpoints. A complete graph and details of the graphical multiple comparison procedure will be 
presented in the SAP.
However, for Japan, the Hochberg procedure (Hochberg 1988) will 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. Detailed procedure is provided below.
Let p(1) and p(2) denote the nominal p-values in increasing order from the 2 comparisons of 
atogepant doses versus placebo.
Step 1:
If p(2) is ≤ 0.05, then both the 2 comparisons are considered statistically 
significant at the 2-sided significance level of 0.05 and stop here; otherwise, go to
Step 2.


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Step 2:
If p(1) is ≤ 0.025, then the corresponding comparison for p(1) is considered
statistically significant at the 2-sided significance level of 0.05; otherwise, stop
here.
Adjusted p-values using Hochberg procedure will also be provided. 
7.3.3
Additional Efficacy Analyses
In general, other efficacy analyses are performed at the nominal significance level, without 
adjusting for multiplicity.
Other efficacy variables will be analyzed as follows:

For selected diary variables with a continuous response range, the baseline score will be 
included as a covariate in an MMRM analysis of the change from baseline. These 
analyses will be performed similarly to the primary MMRM, with focus again on the 
pairwise contrasts of each dose group to placebo.

For weekly data analysis purposes, baseline is defined to be the baseline derived in 
monthly basis divided by 4, and change from baseline in the weekly migraine days will 
be calculated for consecutive 7-day periods beginning with Day 1. Subsequent to 
treatment start, the number of headache days will be counted in successive and non-
overlapping 1-week (ie, 7-day) windows. Headaches that continue into a subsequent 
1-week period will be counted (with recorded severity and duration) as occurring in each 
period. If any postbaseline eDiary window for a participant has at least 4, but less than 
7 days, of reported data, the prorated approach will be used. If a participant reports less 
than 4 days of headache data, the participant’s observed counts in that particular 7-day 
eDiary window will be set to missing for that window.

For variables where the data are essentially binary, comparisons between treatment 
groups will be done with logistic regression for variables with only one postbaseline
assessment or using generalized linear mixed model for variables with multiple
postbaseline assessments.
Descriptive statistics will be provided by visit for each efficacy variable by treatment group. 
Analysis of some variables will be limited to descriptive summary statistics. Details will be 
specified in the SAP.


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7.3.4
Safety Analysis
The safety analyses will be performed using the safety population. The safety parameters will 
include AEs, clinical laboratory evaluations, vital sign measurements, ECG parameters, and the 
C-SSRS. For each of the clinical laboratory, vital sign, and ECG parameters, the last non-missing 
safety assessment before the first dose of treatment will be used as the baseline for all analyses of 
that safety parameter.
Continuous variables will be summarized by the number of participants, and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of participants.
7.4
Off-treatment Hypothetical Estimand Framework for EMA
This section defines an estimand, termed as off-treatment hypothetical estimand, which will be 
the primary estimand in support of EU filing and serve as one sensitivity analysis in support of 
US filing.
7.4.1
Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-blind treatment period. 
In addition, permissible and prohibited medications are described below:

Participants are allowed to take acute migraine medications (Section 4.4.1) to keep the 
participants in the study

Medications with demonstrated efficacy for the prevention of migraine (eg, amitriptyline, 
propranolol, topiramate) are prohibited when used for any indication other than migraine 
prevention. See Attachment 12.3
o
Participants taking one medication with demonstrated efficacy for the prevention 
of migraine may be randomized provided that in the opinion of the investigator:

Dose has been stable and the medication has been well-tolerated for at 
least 12 weeks prior to Visit 1, AND

Participant is willing and able to maintain at a stable dose and dosage 
regimen during the study, which should be assessed to ensure compliance 
at each study visit

Enrollment of participants with current use of a migraine prevention 
medication will be capped at ~15%


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7.4.2
Population
The target population is patients suffering from CM satisfying the inclusion and exclusion 
criteria as specified in Section 4.
The analysis population is defined to be 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 postbaseline 4-week period (Weeks 1 to 4, 5 to 8, or 9 to 12) of eDiary data, 
regardless of whether on study intervention or off study intervention. 
7.4.3
Variable
The variable is the same as the primary efficacy endpoint defined in Section 7.2.1, which is the 
change from baseline in the patient’s mean monthly (4-weeks) migraine days across the 12-week 
treatment period as derived from the eDiary data.
7.4.4
Accounting of Intercurrent Events
Intercurrent events and their handling rules are as follows:

Participants who started a new migraine prevention treatment after the first dose of 
double-blind treatment will have their data after the end of the double-blind treatment 
period following the start of the new migraine prophylaxis treatment excluded from the 
analysis.

Participants who discontinue study intervention due to all reasons other than starting a 
new migraine prophylaxis treatment will have their data collected after discontinuation of 
study intervention, and those off-treatment data will be included in the analysis.
Detailed methods and procedures will be documented in the SAP prior to study completion.
7.4.5
Population-Level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between each atogepant group and placebo.
Participants are always analyzed based on their treatment assignment by randomization. To 
obtain the estimate of treatment effect defined in the off-treatment hypothetical estimand, a 
MMRM similar to the primary analysis specified in Section 7.3.1, will be performed on observed
data including both on-treatment and off-treatment monthly migraine days.


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7.4.6
Off-Treatment Hypothetical Estimand Approach for the Secondary 
Endpoints
Continuous secondary endpoints will be handled using the same estimand approach defined 
above for the primary endpoint.
Secondary endpoint of 50% responders will be derived using both on-treatment and off-treatment 
observed data as defined in the primary endpoint above. The population-level summary for this 
endpoint is the odds ratio for each atogepant group relative to placebo.
7.5
Subgroup Analyses
7.5.1
Subgroup Analyses for Evaluating the Consistency of Treatment 
Effects Across Regions and Subpopulations
To estimate the treatment effect on the primary efficacy endpoint for individual regions, the same 
model as that of the primary MMRM model in primary efficacy analysis in Section 7.3.1 will be 
utilized. In addition, the model will include region, region by treatment (2-way interaction) and 
region by treatment by visit (3-way interaction) as categorical fixed effects. An unstructured 
covariance matrix will be used to model the covariance of within participant repeated 
measurements. Pairwise contrasts in the MMRM model will be used to compare each atogepant 
dose to placebo for treatment effect in patients enrolled in each region.
The estimate of the between-group treatment effect (with a 95% CI) for each atogepant dose 
versus placebo for the primary efficacy endpoint for each region and overall treatment effect will 
be plotted in a forest plot to visualize the consistency of treatment effect across regions. 
For key efficacy endpoints, the estimate of the between-group treatment effect (with 95% CI) for 
each atogepant dose versus placebo will be summarized overall and for each region in a table to 
facilitate the comparison. The test of treatment-by-region interaction will be provided as 
recommended in ICH E17 Section 2.2.7 on Examination of Consistency across Regions and 
Subpopulations. 
Additional analyses to fulfill region specific regulatory requirement will be performed as 
appropriate. If models do not converge, descriptive statistics for subgroups will be provided. 
Details will be provided in the SAP.


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7.5.2
Other Subgroup Analyses
A subgroup analysis by exposure to migraine prevention medication, preventive medication 
failures, and acute medication overuse is planned for the following efficacy endpoints:

Change from baseline in mean monthly migraine days across the 12-week treatment 
period

Change from baseline in mean monthly headache days across the 12-week treatment 
period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

At least a 50% reduction in 3-month average of monthly migraine days

At least a 75% reduction in 3-month average of monthly migraine days

A 100% reduction in 3-month average of monthly migraine days
If models do not converge, descriptive statistics for subgroups will be provided. Details will be 
provided in the SAP.
7.6
Sample Size Calculation
A total sample size of 250 participants will be randomized per treatment group and that will 
provide at least 96% power to detect the treatment difference between each of the 2 atogepant 
doses (assumed equally effective) and placebo for the primary efficacy endpoint. The sample size 
of this study was selected to provide sufficient power for the first 3 secondary endpoints as 
shown in Table 4. The power calculations are based on the following assumptions:
1) The treatment difference from placebo will be similar to the average value across the CM 
prevention studies for Botox (Aurora 2010, Diener 2010) and TEV-48125 (Bigal 2015, 
Silberstein 2017). In particular, the assumed treatment difference from placebo in change from 
baseline in mean monthly migraine days across the 12-week treatment period is –2 days, and the 
standard deviation is 5.5 days. Detailed treatment difference and standard deviation assumptions 
are listed in Table 4. 
2) The study statistical testing plan controls the overall type I error at 5%. The power 
calculations of the primary and secondary endpoints have taken the multiple comparisons into 
consideration by testing each dose versus placebo at a 0.025 significance level, 2-sided. Once the 
primary endpoint for each dose is significant at 0.025, 2-sided, the secondary endpoints will be 
tested sequentially. A detailed graphical multiple comparison procedure will be presented in the 
SAP.


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Table 4
Statistical Power for Primary and the First Three Secondary Endpoints
Hypothesis 
Testing
Endpoint
Treatment 
Difference 
from Placebo
Standard 
Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across 
the 12-week treatment period
–2
5.5
96%
Secondary 1
Change from baseline in mean 
monthly headache days across 
the 12-week treatment period
–2
6.0
93% a
Secondary 2
Change from baseline in mean 
monthly acute medication use 
days across the 12-week 
treatment period
–1.8
5.5
92% a
Secondary 3
At least a 50% reduction in mean 
monthly migraine days across 
the 12-week treatment period
33% 
Placebo Rate
49% 
Atogepant 
Rate
92% a
a:
Statistical powers for secondary endpoints are conditional on success of prior endpoints (assuming 
independence among the endpoints) in the sequence for the comparisons of each dose versus placebo 
7.7
Pharmacokinetics and Exposure-Response Analyses
A graphical evaluation of the PK and PD data of atogepant will be performed for the 
identification of possible trends. The PK will be evaluated using the existing population PK 
model, updated with data from this study. Individual predictions of atogepant exposure 
(including but not limited to steady state AUC0-Tau and Cmin) will be evaluated graphically for 
potential relationships with efficacy and/or safety endpoints. If graphical evaluation identifies 
possible trends, exploratory PK/PD analyses will be performed for the evaluation and 
quantification of potential relationships via nonlinear mixed effects modeling. Efficacy endpoints 
to be evaluated will include migraine days and responder rates. A stand-alone pharmacometric 
analysis plan will be written, and the analyses results will be reported separately from the 
integrated clinical study report.
7.8
Interim Analyses
There is no interim analysis planned.
8.
Study Visit Schedule and Procedures
Please see Table 1 for a schematic of the Schedule of Visits and Procedures and Figure 1 for a 
study visit flowchart.


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8.1
Participant Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective participants as defined by the criteria in Sections 4.2 and 4.3 (inclusion/exclusion 
criteria) will be considered for entry into this study.
8.1.2
Informed Consent and Participant Privacy
The study will be discussed with the participant, and a participant wishing to participate must 
give informed consent prior to any study-related procedures or change in treatment. The 
participant must also give authorization (United States only), data protection consent (European 
Union only), and other written documentation in accordance with the relevant country and local 
privacy requirements (where applicable) prior to any study-related procedures or change in 
treatment.
Each participant that provides informed consent and/or assent will be assigned a participant
identification number that will be used on participant documentation throughout the study.
The investigator or qualified designee will explain the PK and future biomedical research
substudy consents to the participant and answer all of his/her questions. Participants will sign 
separate consent forms to participate in the PK substudy and future biomedical research before 
performing any procedure related to the substudies, respectively.
8.1.3
Procedure for Duplicate Participant Identification – Verified Clinical 
Trials
At participating sites, a central vendor will be used to verify participants’ current and past 
research study status in order to mitigate safety concerns associated with duplicate enrollment 
and protocol deviations associated with multiple trial enrollment. Following proper informed 
consent and after issuing a participant number, each participant will be checked in the VCT 
database, indicated in the Schedule of Visits and Procedures (Table 1). Partial identifiers will be 
utilized. Participants who are identified as verification failures by VCT should not be enrolled 
without documented approval from the sponsor.
8.2
Washout Intervals
This study will not include a washout period.


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8.3
Procedures for Final Study Entry
At the Screening and Randomization Visits (Visits 1 and 2), participants must meet all of the 
inclusion criteria and must not meet any of the exclusion criteria. Rescreening of participants 
may be considered with permission from the sponsor. However, participants with clinically 
significant laboratory values at Visit 1 (including ALT or AST >1 × the ULN, total bilirubin 
> 1 × ULN or serum albumin < 2.8 g/dL), or those with a positive result on the Visit 1 urine drug 
screen for recreational (including marijuana regardless of legality) or illicit drugs or non-
disclosed concomitant medications are not allowed to be rescreened. Also, all women of 
childbearing potential must have negative results on the urine pregnancy test at the Screening 
and Randomization Visits (Visits 1 and 2), prior to the first administration of study intervention.
Prior to randomization, confirm that the participant had ≥ 15 headache days per month in the 
3 months prior to Visit 1 in the opinion of the investigator, and ≥15 headache days during the 
4-week screening/baseline period per the eDiary, and ≥ 8 days during the 4-week 
screening/baseline period that qualify as a migraine day per the eDiary (see Section 6.1.1 for 
definition), and completed the eDiary for at least 20 of the 28 days.
See Section 5.5 for the method for assignment to treatment groups/randomization.
8.4
Visits and Associated Procedures
There will be 8 scheduled clinic visits: Visit 1 (screening/baseline), Visit 2 (randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ET (Week 12), and 
Visit 8 (follow-up). For details, please see Table 1, Schedule of Visits and Procedures.
8.4.1
Visit 1 (Screening/Baseline) Day -35 to Day -28

Obtain informed consent and participant privacy.

Obtain informed consent for future biomedical research (optional).

Obtain informed consent for PK substudy (optional).

Obtain VCT consent and perform verification at participating sites (United States and 
Canada only).

Register participant in IWRS.

Assess inclusion/exclusion criteria.

Collect demographic information.


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
Collect medical history.

Collect migraine history (3-month retrospective) and confirm diagnosis.

Review prior medications taken in the past 6 months, and all prior headache medications 
including migraine prophylactic medication use and concomitant medications/procedures.

Assess C-SSRS on eTablet (the ‘Screening/Baseline’ assessment of the C-SSRS will be 
completed).

Collect ASC-12 on eTablet.

Perform physical examination.

Collect vital sign measurements including: height, weight, sitting and standing pulse rate, 
respiratory rate, sitting and standing BP, and body temperature.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Perform and transmit ECG.

Perform urine pregnancy test (for women of childbearing potential only).

Collect urine for drug screen.

Collect clinical laboratory determinations including: chemistry, hematology, INR, 
screening serology, and urinalysis.

Collect blood for future biomedical research (for those participants who consented)

Provide eDiary, along with training and instructions. Participants to bring eDiary to all 
visits.

Review and assess AEs.
8.4.2
Double-blind Treatment Phase (12 Weeks)
8.4.2.1
Visit 2 (Randomization) Day 1

Review eDiary data (participants must bring eDiary to visits).

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements including: weight, sitting and standing pulse rate, 
respiratory rate, sitting and standing BP, and body temperature.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.


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
Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Assess inclusion/exclusion criteria.
If the participant continues to meet study entry criteria, including acceptable results from Visit 1 
clinical laboratory and pregnancy tests and the urine drug screen (see Section 6.5.3) the 
following procedures will be carried out at the randomization visit (Visit 2):

Administer PRO measures including: HIT-6, PGI-S, WPAI:MIGRAINE, MIDAS, 
MSQ v2.1, PROMIS-PI, and PHQ-9.

Update concomitant medications and concurrent procedures (including all prior headache 
medications).

Review and assess AEs.

Randomize the participant in IWRS and obtain the kit number for study intervention.

Collect pretreatment PK sample (for those participants who consented).

Collect pretreatment blood and urine samples for chemistry, hematology, INR, and 
urinalysis.

Dispense study intervention. The first dose of study intervention should be taken at the 
study site.
8.4.2.2
Visits 3 to 6 (Weeks 2 to 8)

Prior to any other test or evaluations, administer PRO measures including: HIT-6, PGI-S, 
WPAI:MIGRAINE, PSSM, MSQ v2.1, and PROMIS-PI at the times outlined on the 
Schedule of Visits and Procedures.

Review eDiary data (participants must bring eDiary to visits).

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements including: weight, sitting and standing pulse rate, 
respiratory rate, sitting and standing BP, and body temperature.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG (Visit 5 [Week 6] only)

Update concomitant medications and concurrent procedures (including all prior headache 
medications).


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
Review and assess AEs.

Collect previous visit study intervention, review participant compliance, and perform 
accountability.

Collect PK sample (for those participants who consented). During 1 of the Visits 3 to 6, 
the sample should be collected prior to the morning dose of investigational product 
(participant should wait to take the morning dose in the clinic after PK sample collection) 
and the samples collected at the remaining visits should be collected 1 to 10 hours post 
the morning dose and prior to the evening dose.

Dispense study intervention.

Collect blood and urine samples for chemistry, hematology, coagulation parameters
(INR), and urinalysis.

Access IWRS and obtain the kit number for study intervention and enter accountability.
8.4.2.3
Visit 7/Early Termination (Week 12)

Prior to any other test or evaluations, administer PRO measures including: HIT-6, PGIC, 
PGI-S, WPAI:MIGRAINE, PSSM, MIDAS, MSQ v2.1, PROMIS-PI, and PHQ-9.

Perform physical examination.

Review eDiary data (participants must bring eDiary to visits).

Collect eDiary from participant, if the participant completed the treatment period 
(eDiary collection will occur at Visit 8 for participants who discontinue study 
intervention early [see Section 8.8.1]).

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements including: weight, sitting and standing pulse rate, 
respiratory rate, sitting and standing BP, and body temperature.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG.

Update concomitant medications and concurrent procedures (including all prior headache 
medications).

Collect previous visit study intervention, review participant compliance, and perform 
accountability.


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
Review and assess AEs.

Access IWRS and enter accountability.

Collect PK sample (for those participants who consented). The PK sample should be 
collected 1 to 10 hours post the morning dose.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.
8.4.3
Follow-up Period (4 Weeks)
8.4.3.1
Visit 8/End of Study (Week 16)

Prior to any other test or evaluations, administer PRO measures including: EQ-5D-5L, 
HIT-6, and MSQ v2.1.

Collect eDiary from participant, if the participant discontinued study intervention early 
[see Section 8.8.1]).

Perform physical examination.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Collect vital sign measurements including: weight, sitting and standing pulse rate, 
respiratory rate, sitting and standing BP, and body temperature.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Perform urine pregnancy test for women of childbearing potential.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Update concomitant medications and concurrent procedures (including all prior headache 
medications).

Review and assess AEs.

Access IWRS to enter study visit.
8.5
Instructions for the Participants
Section 4.4.4 provides diet and activity instructions for participants enrolled in the study.
Participants will be provided with instructions on daily completion of the eDiary. A practice 
session with a hypothetical scenario should be administered to ensure the participant’s 
comprehension of the questions and the information to be entered. In addition, prohibited 


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medications should be reviewed with the participants. Participants will be instructed to bring 
their eDiary to each clinic visit and return their study intervention (used and unused blister 
packs).
Participants should be instructed to take study intervention BID at approximately the same times 
each day (approximately 12 hours between doses). For dosing on Day 1 (Visit 2), the first dose is 
to be taken at the study site, and participants should be advised to take the second dose 
depending on the time of the site visit and the participant’s usual routine. Study intervention may 
be taken with or without food. Water is allowed as desired.
Participants should use appropriate contraceptive measures for the duration of their participation 
in the study (see Section 4.4.3).
8.6
Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to ensure 
the safety and well-being of the participants during the study period. Unscheduled visit eCRFs 
should be completed for each unscheduled visit.
8.7
Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1, and the timing 
of the visits should occur as close as possible to the day specified. At each visit, the participant
will be asked if the participant changed the dose/regimen of any existing concomitant 
medications or initiated the use of any new concomitant medications since the last visit to ensure 
compliance with the protocol. 
Study intervention compliance during any period will be closely monitored by counting the 
number of tablets dispensed and returned. Every effort will be made to collect all unused study 
intervention.


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8.8
Early Discontinuation of Participants
A premature discontinuation will occur when a participant who signed the ICF and has been 
randomized ceases participation in the study, regardless of circumstances, before completion of 
the study. Participants can be prematurely discontinued from the study for one of the following 
reasons:

AE

Lack of efficacy

Lost to follow-up

Non-compliance with study intervention

Other (specify reason)

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Withdrawal by participant
Participants may voluntarily withdraw from the study at any time. Notification of early 
participant discontinuation from the study and the reason for discontinuation will be made to the 
sponsor and will be clearly documented on the appropriate eCRF. All randomized participants 
who prematurely discontinue from the study, regardless of cause, should be seen for final study 
assessments. The final assessments will be defined as completion of the evaluations scheduled 
for Visit 7/ET and Visit 8 (follow-up), 4 weeks post the last dose of study intervention.
8.8.1
Participants Who Discontinue Study Intervention Early
All participants who discontinue study intervention early (defined as prior to Week 12 [Visit7]) 
for reasons other than withdrawal of consent or lost to follow-up should remain in the study for 
the purpose of collecting efficacy data to support the estimand framework for EMA. These 
participants should return to the clinic for ET procedures (Visit 7) and the Follow-up Visit 
(Visit 8) per the Schedule of Visits and Procedures (Table 1). If Visit 8 occurs on or after 
Week 12 (relative to randomization), no Final Study Visit is required (Figure 2, Scenario A). If 
Visit 8 occurs before Week 12 (relative to randomization) participants should return to the clinic 




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8.9
Withdrawal Criteria
Women who become pregnant (Section 9.4) and participants who meet study intervention
discontinuation criteria related to abnormal liver function tests (Section 9.5), and advised not to 
be rechallenged, will be withdrawn from the study and should refrain from taking study 
intervention. The participant should return to the clinic for ET procedures (Visit 7) and the 
Follow-up Visit (Visit 8). Participants who reply with “yes” to questions 4 or 5 in the suicidal 
ideation section or “yes” to any question in the suicidal behavior section of the C-SSRS at Visits 
3 through 6 must be withdrawn from the study and should receive appropriate follow-up as in 
routine clinical practice, including the ET Visit (Visit 7) and the Follow-up Visit (Visit 8).
A participant with a condition and/or a situation that, in the investigator's opinion, may put the 
participant at significant risk, may confound the study results, or may interfere significantly with 
the participant’s participation in the study may be withdrawn from treatment.
8.10
Study Termination
The study may be stopped at his/her study site at any time by the site investigator. The sponsor
may stop the study (and/or the study site) for any reason with appropriate notification.
9.
Adverse Events
AEs occurring during the study will be recorded on an AE CRF. If AEs occur, the first concern 
will be the safety of the study participants.
9.1
Definitions
9.1.1
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical study participant associated 
with the use of study intervention, whether or not considered related to the study intervention. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
intervention. In addition, during the screening period, AEs will be assessed regardless of the 
administration of a pharmaceutical product.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).




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d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive intervention in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
The sponsor considers all cancer AEs as SAEs. The sponsor considers any spontaneous abortion 
as an SAE. Elective abortions can be SAEs or AEs depending on the reason for the elective 
abortion (eg, fetal death, still birth, congenital anomalies, ectopic pregnancy, which would make 
the elective abortion an SAE).
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
participant requires hospitalization is not reportable as an SAE.
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the participant’s entry into the 
study. If it has not been documented at the time of the participant’s entry into the study, then it 
should be documented as a SAE and reported to the sponsor.






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additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
9.1.6
Adverse Reactions, Serious Adverse Reactions, and Suspected 
Unexpected Serious Adverse Reactions
For the purposes of expedited reporting within the EU, the sponsor will follow the applicable 
definitions for ARs, SARs, and SUSARs (for example, as outlined in Article 2 [n,o,p] of 
Directive 2001/20/EC, see below). Also, seriousness criteria for AEs/ARs (as would apply to 
SARs and SUSARs) are currently included in the protocol, listed in Section 9.1.2.

Adverse Reaction: all untoward and unintended responses to an investigational medicinal 
product related to any dose administered

Serious Adverse Reaction: an adverse reaction that results in death, is life-threatening, 
requires hospitalisation or prolongation of existing hospitalisation, results in persistent or 
significant disability or incapacity, or is a congenital anomaly or birth defect 
(see Section 9.1.2 for further details pertaining to seriousness criteria)

Suspected Unexpected Serious Adverse Reaction: a serious adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (eg, the 
Investigator’s Brochure).
9.2
Procedures for Reporting Adverse Events
Any AE must be recorded on the appropriate CRF.
All AEs that are drug-related and unexpected (not listed as treatment-related in the current 
investigator's brochure) must be reported to the governing IRB/IEC as required by the IRB/IEC, 
local regulations, and the governing health authorities. Any AE that is marked ‘ongoing’ at the 
exit visit must be followed-up as appropriate.
9.3
Procedures for Reporting a Serious Adverse Event
Any SAE occurring during the study period (beginning with informed consent) until the 
Follow-up Visit (Visit 8) or 30 days after the last dose of study intervention if the Follow-up Visit 
is not done must be immediately reported but no later than 24 hours after learning of an SAE. 


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SAEs must be reported to the sponsor (or agent of the sponsor) as listed on the Study Contacts 
Page and recorded on the SAE form. All participants with an SAE must be followed up and the 
outcomes reported. The investigator must supply the sponsor and the IRB/IEC with any 
additional requested information (eg, autopsy reports and discharge summaries).
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and the sponsor’s policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs from the sponsor will review
and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
9.4
Exposure to Study Intervention During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until the Follow-up Visit (Visit 8) or 30 days 
after the last dose of study intervention if the Follow-up Visit is not done. Study center personnel 
must report every pregnancy on the Pregnancy Form (within 24 hours of learning of the 
pregnancy to the Serious Adverse Event Reporting Fax Number: +1-714-796-9504 [back up fax 
number: +1-714-246-5295], email: IR-Clinical-SAE@allergan.com), even if no AE has occurred. 
The pregnancy must be followed to term and the outcome reported by completing a follow-up 
Pregnancy Form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. Elective abortions can be SAEs 
or AEs depending on the reason for the elective abortion (eg, fetal death, still birth, congenital 
anomalies, ectopic pregnancy, which would make the elective abortion an SAE). For pregnancy 
related SAEs, in addition to the Pregnancy Form, a separate SAE Form must be filed as 
described in Section 9.3 with the appropriate serious criterion (eg, hospitalization) indicated.


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9.5
ALT orAST Elevations
Atreatment-emergent ALT ≥ 3 × ULN and/orAST ≥3 × ULN is considered anAE of special 
interest. Any participant with this laboratory result after study intervention was taken must have 
repeat testing within 48 to 72 hours to confirm the abnormality. For this repeat testing, the 
following laboratory tests must be drawn: hematology and chemistry panels, INR, serum 
acetaminophen level, urine drugs of abuse screen, and blood alcohol level. An extra blood 
serology sample must be collected and sent to the central laboratory for further diagnostic testing, 
at a later date, if needed. In addition, the investigator will perform a complete history and 
examination to evaluate the participant for possible liver disease.
AllAEs of special interest must be reported to the sponsor within 24 hours of the time the 
investigator becomes aware of the event using the abnormal liver function reporting form and the 
AE eCRF. All new elements of history, physical examination, diagnostic testing results, and other 
relevant medical reports are to be reported for eachAE of special interest.
If anALT orAST ≥3 × ULN is confirmed, close medical follow-up is required:
For these participants, the following laboratory tests must be performed: anti-hepatitis A IgM, 
hepatitis B surface antigen, anti-hepatitis B core IgM, hepatitis C antibody, hepatitis C 
quantitative RNA by polymerase chain reaction, anti-hepatitis E IgM, anti-hepatitis E IgG, 
Cytomegalovirus IgM antibody, and Epstein-Barr Virus IgM antibody. The participant must be 
followed clinically and further medical evaluation (for other causes of acute hepatic injury) 
should be done per the judgment of the investigator and in conjunction with medical personnel at
the sponsor. In general, the chemistry panel should be repeated 1 to 2 times per week to follow 
the course ofALT/AST elevation.
Study intervention must be discontinued if any of the following criteria are met:

ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (> 5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN

ALT or AST ≥ 3 × ULN and INR > 1.5

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
The participant may be rechallenged with study intervention only after consultation with the
sponsor medical monitor. For participants who are not rechallenged with study intervention, the 


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participant should be discontinued from the study and complete an ET visit (Visit 7/ET) and 
4-week follow-up visit. Participants should receive appropriate follow-up as per standard of care.
The investigator must contact the sponsor medical monitor to discuss all cases of confirmed 
ALT/AST elevation ≥3 × ULN. All ALT/AST elevations must be followed until ALT and 
AST return to < 1.5 × ULN and there is full clinical resolution.
9.5.1
Potential Hy’s Law Cases
Sites must report every participant who meets the following potential Hy’s law criteria if this 
occurs within the time the participant signs the ICF until 30 days after the last dose of 
investigational product:

ALT or AST ≥ 3 × ULN AND

Total bilirubin ≥ 2 × ULN AND

Alkaline phosphatase < 2 × ULN
Study site personnel must report every participant who meets these criteria. Typically, all 
3 analytes will be obtained from the same sample, but they may come from multiple samples 
taken within a 24-hour period. This requirement applies from the time the participant signs the 
ICF for the study until 30 days after the final protocol-defined study visit or the last known dose 
of study intervention (if the final visit does not occur).
A laboratory alert for possible Hy’s law cases will be in place and must notify investigators and 
the sponsor immediately when the above criteria have been met. A possible Hy’s law case must 
be faxed to the sponsor on an abnormal liver function reporting form as soon as possible (within 
24 hours of learning of the possible Hy’s law case) to the fax number on the form or the SAE fax 
number, even if noAE has occurred. If the event is serious, please complete the SAE form. The 
eCRF for possible Hy’s law cases must be completed within 7 calendar days. Every effort to 
determine the cause of the liver enzyme abnormalities must be made, and close monitoring 
should be initiated in conjunction with the medical monitor and medical safety physician and in 
accordance with the FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009. The participant should return to the study site and be evaluated as 
soon as possible, preferably within 48 hours from the time the investigator becomes aware of the 
abnormal results. This evaluation should include laboratory tests, detailed history, and physical 
assessment.


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9.6
Procedures for Unmasking of Study Medication
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor medical monitor prior to unblinding 
a participant’s study intervention assignment unless this could delay emergency treatment of the 
participant. If a participant’s study intervention assignment is unblinded, the sponsor medical 
monitor must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation.
10.
Administrative Items
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines (eg, the ICH Guideline on GCP) and applicable regulations in relevant countries.
10.1
Protection of Human Participants
10.1.1
Compliance With Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each participant prior to any study-related 
activities or procedures in the study, and/or from the participant's legally authorized 
representative.
The following process will be followed:

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
HIPAA requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.


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
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.2
Compliance With IRB or IEC Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) or 
applicable IEC regulations. The investigator must obtain approval from a properly constituted 
IRB/IEC prior to initiating the study and re-approval or review at least annually. The sponsor is 
to be notified immediately if the responsible IRB/IEC has been disqualified or if proceedings 
leading to disqualification have begun. Copies of all IRB/IEC correspondence with the 
investigator should be provided to the sponsor.
10.1.3
Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
10.1.4
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature.
10.2
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.3
Changes to the Protocol
The investigator must not implement any deviation from or changes of the protocol without 
approval by the sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC (and the appropriate regulatory agency, if required by national law) of a protocol 
amendment, except where necessary to eliminate immediate hazards to study participants, or 


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when the changes involve only logistical or administrative aspects of the study (eg, change in 
monitors, change of telephone numbers).
10.4
Data Protection
Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.5
Participant Confidentiality
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study intervention may ultimately be marketed, but the participant’s 
name will not be disclosed in these documents. The participant's name may be disclosed to the 
sponsor of the study, or the governing health authorities or the FDA if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information.
10.6
Participant Privacy
Written authorization (United States sites only), data protection consent (European sites only), 
and other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each participant prior to enrollment into the study, 
and/or from the participant's legally authorized representative in accordance with the applicable 
privacy requirements (eg, HIPAA, European Union Data Protection Directive 95/46/EC [“EU 
Directive”]).
In accordance with HIPAA requirements, additional purposes of this study may include
publishing of anonymous participant data from the study.


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10.7
Documentation
10.7.1
Source Documents
Source documents may include a participant's medical records, hospital charts, clinic charts, the 
investigator's participant study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and ECGs. The investigator's copy of the CRFs serves as part of the 
investigator's record of a participant's study-related data.
The following information should be entered into the participant's medical record:

Participant’s name

Participant’s contact information

The date that the participant entered the study, participant number, and study intervention 
kit numbers

The study title and/or the protocol number of the study and the name of the sponsor

A statement that informed consent was obtained (including the date). A statement that 
written authorization (United States sites only), data protection consent (European Union
sites only), or other country and local participant privacy required documentation for this 
study has been obtained (including the date)

Dates of all participant visits

Participants medical history

Information regarding participant’s diagnosis of migraine headache

All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications should be recorded.)

Occurrence and status of any AEs

The date the participant exited the study, and a notation as to whether the participant
completed the study or reason for discontinuation.

The results of laboratory tests performed by the site (eg, results of urine pregnancy tests).

Key study variables


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Source documentation practices must follow Section 4.0 of ICH E6, GCP: Consolidated 
Guidance, and ALCOA (ie, records must be Attributable, Legible, Contemporaneous, Original 
and Accurate).
10.7.2
Case Report Form Completion
The investigator is responsible for ensuring that data are properly recorded on each participant's 
eCRFs and related documents. An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that the observations 
and findings are recorded on the eCRFs correctly and completely. The eCRFs are to be submitted 
to the sponsor in a timely manner at the completion of the study, or as otherwise specified by the 
sponsor and will be maintained in a central data repository.
10.7.3
Study Summary
An investigator's summary will be provided to the sponsor within a short time after the 
completion of the study, or as designated by the sponsor. A summary is also to be provided to the 
responsible IRB/IEC.
10.7.4
Retention of Documentation
All study related correspondence, participant records, consent forms, participant privacy 
documentation, records of the distribution and use of all study interventions, source documents, 
and copies of eCRFs should be maintained on file.
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study intervention. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirement(s) or if needed by the 
sponsor.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
The sponsor requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person.


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10.8
Labeling, Packaging, and Return or Disposal of Study 
Interventions/Treatments
10.8.1
Labeling/Packaging
Study intervention will be supplied in blister cards and will be labeled with the protocol number, 
storage information, warning language, and instructions to take the tablets as directed. The card 
will also include the medication number. Immediately before dispensing the blister card, the 
investigator or designee will write the participant number and date dispensed on the blister card.
10.8.2
Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units 
received from the sponsor, dispensed or administered to the participants, the number of units 
returned to the investigator by the participant (if applicable), and the number of units returned to 
the sponsor during and at the completion of the study. A detailed inventory must be completed 
for the study medication. The study intervention must be dispensed or administered only by an 
appropriately qualified person to participants in the study. The medication is to be used in 
accordance with the protocol for participants who are under the direct supervision of an 
investigator.
10.8.3
Return or Disposal of Study Medications/Treatments and/or Supplies
All clinical study interventions/treatments and/or supplies will be returned to the sponsor or
designee for destruction.
10.9
Monitoring by the Sponsor
A representative of the sponsor will monitor the study on a periodic basis. The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.
Authorized representatives of the sponsor or regulatory authority representatives will conduct 
on-site visits to review, audit, and copy study-related documents. These representatives will meet 
with the investigator(s) and appropriate staff at mutually convenient times to discuss study-
related data and questions.


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10.10 Handling of Biological Specimens
Urine pregnancy test kits will be provided by the central lab; all urine pregnancy testing will be 
administered on site according to instructions in the central lab manual.
Samples of blood and urine for evaluation of hematology, blood chemistry, urinalysis, urine drug 
screen, INR, and serology will be analyzed at a centralized clinical laboratory with certification 
from a recognized accreditation agency (eg, College of American Pathology or Clinical 
Laboratory Improvement Amendments certification). All samples for future biomedical research
will be sent to the designated central laboratory and shipped to a biorepository for storage.
PK samples obtained from participants in the PK substudy will be stored at the centralized 
clinical laboratory until ready for PK analyses by the sponsor’s Pharmacokinetics and Drug 
Distribution department using a validated method. This laboratory meets GLP requirements.
All samples will be returned to the sponsor or sponsor’s designee for destruction. The sponsor
shall have full ownership rights to any biological specimens/samples derived from the study. For 
additional details regarding handling of biological specimens, please refer to the Study Reference 
Manual.
10.11 Publications
The sponsor has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between multiple investigators and sites and the sponsor personnel. 
Authorship will be established prior to the writing of the manuscript. As this study involves 
multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with the sponsor.
10.12 Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the clinical study 
report.


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11.
References
Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, et al; PREEMPT 1 
Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results 
from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. 
Cephalalgia. 2010 Jul;30(7):793-803.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, 
and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 
2015;14:1081-1090.
Bigal M, Rapoport A, Sheftell F, Tepper D, and Tepper S. Memantine in the preventive treatment 
of refractory migraine. Headache. 2008;48:1337-1342.
Blumenfeld A, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, et al. Disability, HRQoL 
and resource use among chronic and episodic migraineurs: results from the International Burden 
of Migraine Study (IBMS). Cephalalgia. 2011 Feb;31(3):301-315
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biometrical Journal. 53 (2011) 6, 894-913.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled
trial of telcagepant for the acute treatment of migraine. Neurology. 2009 Sep 22;73(12):970-977.
Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, et al; PREEMPT 2 
Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results 
from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. 
Cephalalgia. 2010 Jul;30(7):804-814.
Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guidelines on the drug 
treatment of migraine – revised report of an EFNS task force. Eur J Neurol.
2009 Sep;16(9):968-981.
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika.
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Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in 
migraine. Expert Rev Clin Pharmacol. 2014;7:191-201.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United 
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Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the Differences Between Episodic 
Migraine and Chronic Migraine. Curr Pain Headache Rep. 2012:16:86-92.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-997. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data using 
multiple imputation in conjunction with robust regression. Biometrics. 2012;68(4):1250-1259. 
Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MF, Tierce J, et al. Economic burden of 
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broader concept of chronic migraine. Cephalalgia, 2006;26:742-746.
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Sakai F, Igarashi H. Prevalence of Migraine in Japan: a nationwide survey. Cephalalgia 
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Schürks M, Diener HC, Goadsby P. Update on the Prophylaxis of Migraine. Current Treatment 
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Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. 
Fremanezumab for the Preventive Treatment of Chronic Migraine, N Engl J Med 
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Headache Pain. 2010:11;289-299.
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door-to-door survey of migraine in Japan: the Daisen study. Headache 2004;44:8-19.
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Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
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12.
Attachments
12.1
International Classification of Headache Disorders, 3rd Edition 


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1.
Migraine
1.1
Migraine without aura
1.2
Migraine with aura
1.2.1
Migraine with typical aura
1.2.1.1
Typical aura with headache
1.2.1.2
Typical aura without headache
1.2.2
Migraine with brainstem aura
1.2.3
Hemiplegic migraine
1.2.3.1
Familial hemiplegic migraine
(FHM)
1.2.3.1.1
Familial hemiplegic migraine 
type 1 (FHM1)
1.2.3.1.2
Familial hemiplegic migraine 
type 2 (FHM2)
1.2.3.1.3
Familial hemiplegic migraine 
type 3 (FHM3)
1.2.3.1.4
Familial hemiplegic migraine, 
other loci
1.2.3.2
Sporadic hemiplegic migraine
(SHM)
1.2.4
Retinal migraine
1.3
Chronic migraine
1.4
Complications of migraine
1.4.1
Status migrainosus
1.4.2
Persistent aura without infarction
1.4.3
Migrainous infarction
1.4.4
Migraine aura-triggered seizure
1.5
Probable migraine
1.5.1
Probable migraine without aura
1.5.2
Probable migraine with aura
1.6
Episodic syndromes that may be associated
with migraine
1.6.1
Recurrent gastrointestinal disturbance
1.6.1.1
Cyclical vomiting syndrome
1.6.1.2
Abdominal migraine
1.6.2
Benign paroxysmal vertigo
1.6.3
Benign paroxysmal torticollis
Coded elsewhere:
Migraine-like headache secondary to another 
disorder (symptomatic migraine) is coded as a 
secondary head- ache attributed to that disorder.
General comment
Primary or secondary headache or both? Three 
rules apply to migraine-like headache, 
according to circumstances.
1. When 
a 
new 
headache 
with 
the 
characteristics of migraine occurs for the 
ﬁrst time in close temporal relation to 
another disorder known to cause head-
ache, or fulﬁls other criteria for causation 
by that disorder, the new headache is 
coded as a secondary headache attributed
to the causative disorder.
2. When
pre-existing
migraine
becomes
chronic in close temporal relation to such a 
causative disorder, both the initial migraine 
diagnosis and the secondary diagnosis should 
be given. 8.2 Medication-overuse head- ache is a 
particularly important example of this: both the 
migraine diagnosis (episodic or chronic) and the 
diagnosis 8.2 Medication-overuse headache should
be given when medication overuse is present.
3. When pre-existing migraine is made signiﬁcantly 
worse (usually meaning a twofold or greater
increase in frequency and/or severity) in close 
temporal relation to such a causative disorder, both 
the initial migraine diagnosis and the secondary 
headache diagnosis should be given, provided that 
there is good evidence that the disorder can cause
headache.
Introduction
Migraine is a common disabling primary headache dis-
order. Many epidemiological studies have documented its 
high prevalence and socio-economic and personal impacts. 
In the Global Burden of Disease Study 2010 (GBD2010), 
it was ranked as the third most prevalent disorder in the 
world. In GBD2015, it was ranked the third-highest cause 
of disability worldwide in both males and females under 
the age of 50 years.
Migraine has two major types: 1.1 Migraine without 
aura is a clinical syndrome characterized by headache 
with speciﬁc features and associated symptoms; 1.2
Migraine with aura is primarily characterized by the 
transient focal neurological symptoms that usually 
precede or sometimes accompany the headache. Some 
patients also experience a prodromal phase, occurring 
hours or days before the headache, and/or a postdromal 
phase following headache resolution. Prodromal and 
postdromal symptoms include hyperactivity, hypoactivity, 
depression, cravings for particular foods, repetitive 
yawning, fatigue and neck stiﬀness and/or pain.
When a patient fulﬁls criteria for more than one type, 
subtype or subform of migraine, all should be diagnosed 
and coded. For example, a patient who has frequent 
attacks with aura but also some attacks without aura 
should be coded as 1.2 Migraine with aura and 1.1
Migraine without aura. However, since the diagnostic 
criteria for 1.3 Chronic migraine subsume attacks of all 
types, subtypes or subforms, additional coding is 
unnecessary for episodic subtypes of migraine.
1.1
Migraine without aura
Previously used terms: Common migraine; hemicrania 
simplex
Description: Recurrent headache disorder manifesting 
in attacks lasting 4–72 hours Typical characteristics of 
the headache are unilateral location, pulsating quality, 
moderate or severe intensity, aggravation by routine 
physical activity and association with nausea and/or 
photophobia and phonophobia.


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Diagnostic criteria:
A.
At least ﬁve attacks1 fulﬁlling criteria B–D
B.
Headache attacks lasting 4–72 hours 
(when 
untreated 
or 
unsuccessfully
treated)2,3
C.
Headache has at least two of the following 
four characteristics:
1.
unilateral location
2.
pulsating quality
3.
moderate or severe pain intensity
4.
aggravation by or causing avoidance of 
routine physical activity (eg,walking or
climbing stairs)
D.
During headache at least one of the following:
1.
nausea and/or vomiting
2.
photophobia and phonophobia
E.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. One or a few migraine attacks may be difficult to 
distinguish 
from 
symptomatic 
migraine-like 
attacks. Furthermore, the nature of a single or a 
few attacks may be difficult to understand. 
Therefore, at least ﬁve attacks are required. 
Individuals who otherwise meet criteria for 1.1 
Migraine without aura but have had fewer than 
ﬁve attacks should be coded 1.5.1 Probable 
migraine without aura.
2. When the patient falls asleep during a migraine 
attack and wakes up without it, duration of the 
attack is reckoned until the time of awakening.
3. In children and adolescents (aged under 18 years), 
attacks may last 2–72 hours (the evidence for 
untreated durations of less than two hours in 
children has not been substantiated).
Comments: 
Migraine 
headache 
in 
children 
and
adolescents (aged under 18 years) is more often bilateral
than is the case in adults; unilateral pain usually emerges
in late adolescence or early adult life. Migraine headache 
is usually frontotemporal. Occipital headache in 
children is rare and calls for diagnostic caution. A subset 
of otherwise typical patients have facial location of pain,
which is called ‘facial migraine’ in the literature; there is
no evidence that these patients form a separate subgroup 
of migraine patients. Prodromal symptoms may begin 
hours or a day or two before the other symptoms of a
migraine attack with- out aura. They include various 
combinations of fatigue, diﬃculty in concentrating, neck 
stiﬀness, sensitivity to light and/or sound, nausea, blurred 
vision, yawning and pallor. Postdromal symptoms, most
commonly
feeling tired or weary, difficulty with concentration and
neck stiffness, may follow resolution of the headache,
persisting for up to 48 hours; these are less well studied.
Migraine attacks can be associated with cranial 
autonomic symptoms and symptoms of cutaneous 
allodynia.
In young children, photophobia and phonophobia 
may be inferred from their behaviour.
A minority (<10%) of women have attacks of 
migraine in association with the majority of their 
menstrual cycles; most such attacks are without aura. 
Attacks during menstruation tend to be longer and 
accompanied by more severe nausea than attacks out-
side the menstrual cycle. ICHD-3 offers criteria for 
A1.1.1 Pure menstrual migraine without aura, A1.1.2 
Menstrually related migraine without aura and A1.1.3 
Non-menstrual migraine without aura, but in the 
Appendix because of uncertainty over whether they 
should be regarded as separate entities. Criteria are also 
offered for A1.2.0.1 Pure menstrual migraine with aura, 
A1.2.0.2 Menstrually related migraine with aura and 
A1.2.0.3 
Non-menstrual 
migraine 
with 
aura 
to 
encourage better characterization of these uncommon 
subforms if they are separate entities.
Very frequent migraine attacks are distinguished as 1.3 
Chronic migraine. When there is associatedmedication
overuse, both of the diagnoses 1.3 Chronic migraine and
8.2 Medication-overuse headache should be applied. 1.1 
Migraine without aura is the disease most prone to
accelerate with frequent use of symptomatic medication.
Regional cerebral blood ﬂow imaging shows no
changes suggestive of cortical spreading depression
(CSD) during attacks of 1.1 Migraine without aura,
although blood ﬂow changes in the brainstem may 
occur, as may cortical changes secondary topain
activation. This contrasts with the pathognomonic
spreading oligaemiaof1.2Migrainewithaura.Whilethe
bulkofthe literature suggests that CSD does not occur in
1.1 Migraine without aura, some recent studies disagree.
Furthermore, it has been suggested that glial waves or
other cortical phenomena may be involved in 1.1
Migraine without aura. The messenger molecules nitric
oxide (NO), serotonin (5-hydroxytryptamine;5-HT) and
calcitonin gene-related peptide (CGRP) are involved.
While the disease was previously regarded as primarily 
vascular, the importance of sensitization of pain path-
ways, and the possibility that attacks may originate in the
central nervous system, have gainedincreasing attention
over the last decades. At the same time, the circuitry of 
migraine pain, the trigeminovascular system, and several
aspects of its neurotransmission peripherally and in the
trigeminal nucleus caudalis, central mesencephalic grey
and thalamus, have been recognized. Highly receptor-
speciﬁc acute medications including 5-HT1B/D receptor
agonists (triptans), 5-HT1F receptor agonists and CGRP
receptor antagonists have demonstrated efficacy in the


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acute treatment of migraine attacks. Because of their 
high receptor-speciﬁcity, their mechanisms of action
pro- vide new insight into migraine mechanisms. It is 
now clear that 1.1 Migraine without aura is a
neurobiological disorder, while clinical as well as basic
neuroscience
stu-
dies continue to advance our 
knowledge of migraine mechanisms.
1.2
Migraine with aura
Previously used terms: Classic or classical migraine; 
ophthalmic, hemiparaesthetic, hemiplegic or aphasic 
migraine; migraine accompagne´ e; complicated migraine.
Description: Recurrent attacks, lasting minutes, of 
unilateral fully reversible visual, sensory or other 
central nervous system symptoms that usually develop 
gradually and are usually followed by headache and 
associated migraine symptoms.
Diagnostic criteria:
A.
At least two attacks fulﬁlling criteria B and C
B.
One or more of the following fully reversible 
aura symptoms:
1.
visual
2.
sensory
3.
speech and/or language
4.
motor
5.
brainstem
6.
retinal
C.
At least three of the following six
characteristics:
1.
at least one aura symptom spreads gradually 
over 5 minutes
2.
two or more aura symptomsoccur in
succession
3.
each individual aura symptom lasts 5–60 
minutes1
4.
at least one aura symptom is unilateral2
5.
at least one aura symptom is positive3
6.
the aura is accompanied, or followed within 
60 minutes, by headache
D.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. When, for example, three symptoms occur during 
an aura, the acceptable maximal duration is 3 x 60 
minutes. Motor symptoms may last up to 72
hours.
2. Aphasia is always regarded as a unilateral 
symptom; dysarthria may or may notbe.
3. Scintillations and pins and needles are positive 
symptoms of aura.
Comments: Many patients who have migraine attacks with 
aura also have attacks without aura; they should be coded 
as both 1.2 Migraine with aura and 1.1 Migraine without
aura.
Field testing has compared the diagnostic criteria for 1.2 
Migraine with aura in the main body of ICHD-3 beta with 
those for A1.2 Migraine with aura in the Appendix. The 
latter performed better in distinguishing migraine with aura 
from transient ischaemic attacks. These are now adopted in 
ICHD-3, which no longer has Appendix criteria for this
disorder.
The aura is the complex of neurological symptoms that 
occurs usually before the headache of 1.2 Migraine with 
aura, but it may begin after the headache phase has 
commenced or continue into the headache phase.
Visual aura is the most common type of aura, occur-
ring in over 90% of patients with 1.2 Migraine with aura, 
at least in some attacks. It often presents as a fortiﬁcation 
spectrum: a zigzag ﬁgure near the point of ﬁxation that 
may gradually spread right or left and assume a laterally 
convex shape with an angulated scintillating edge, leaving 
absolute or variable degrees of relative scotoma in its wake. 
In other cases, scotoma without positive phenomena may 
occur; this is often perceived as being of acute onset but, on 
scrutiny, usually enlarges gradually. In children and 
adolescents, less typical bilateral visual symptoms occur 
that may represent an aura. A visual aura rating scale with 
high speciﬁcity and sensitivity has been developed and
validated.
Next in frequency are sensory disturbances, in the form 
of pins and needles moving slowly from the point of origin
and aﬀecting a greater or smaller part of one side of the body,
face and/or tongue. Numbness may occur in its wake, but 
numbness may also be the only symptom.
Less frequent are speech disturbances, usually aphasic 
but often hard to categorize.
Systematic studies have demonstrated that many 
patients with visual aura occasionally have symptoms in 
the extremities and/or speech symptoms. Conversely, 
patients with symptoms in the extremities and/or speech or 
language symptoms almost always also experience visual 
aura symptoms at least during some attacks. A distinction 
between migraine with visual aura, migraine with 
hemiparaesthetic aura and migraine with speech and/or 
language aura is probably artiﬁcial, and therefore not
recognized in this classiﬁcation: they are all coded as 1.2.1 
Migraine with typical aura.
When aura symptoms are multiple, they usually follow 
one another in succession, beginning with visual, then 
sensory, then aphasic; but the reverse and other orders have 
been noted. The accepted duration for most aura symptoms 
is one hour, but motor symptoms are often longer lasting.
Patients with aura symptoms arising from the brain- stem
are coded as 1.2.2 Migraine with brainstem aura, but


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they almost always have additional typical aura symptoms. 
When the aura includes motor weakness, the dis- order 
should be coded as 1.2.3 Hemiplegic migraine or one of its 
subforms. 1.2.3 Hemiplegic migraine is classiﬁed as a 
separate subtype because of genetic and pathophysiological
differences from 1.2.1 Migraine with typical aura. Patients 
with 1.2.3 Hemiplegic migraine often have brainstem 
symptoms in addition.
Patients often ﬁnd it hard to describe their aura
symptoms, in which case they should be instructed to time 
and record them prospectively. The clinical picture then 
becomes clearer. Common mistakes are incorrect reports of 
lateralization, of sudden rather than gradual onset and of 
monocular rather than homonymous visual disturbances, as 
well as of duration of aura and mistaking sensory loss for 
weakness. After an initial consultation, use of an aura diary
may clarify the diagnosis.
Migraine aura is sometimes associated with a head-
ache that does not fulﬁll criteria for 1.1 Migraine without 
aura, but this is still regarded as a migraine headache 
because of its relation to the aura. In other cases, migraine 
aura may occur without headache.
Before or simultaneously with the onset of aura 
symptoms, regional cerebral blood ﬂow is decreased in the 
cortex corresponding to the clinically affected area and 
often over a wider area. Blood ﬂow reduction usually starts 
posteriorly and spreads anteriorly, and is usually above the 
ischaemic threshold. After one to several hours, gradual 
transition into hyperaemia occurs in the same region. 
Cortical spreading depression of Lea˜ o is the likely
underlying mechanism.
The previously deﬁned syndromes, migraine with 
prolonged aura and migraine with acute-onset aura, have 
been abandoned. It is not rare for aura to last more than one 
hour but, in most such cases, patients have at least two of 
the other characteristics of criterion
C. Even when most of a patient’s attacks do not fulﬁl 
criterion C, it is usual that other attacks fulﬁl criteria for 
one of the recognized subtypes or subforms of 1.2 
Migraine with aura, and this should be the diagnosis. The 
few other cases should be coded to 1.5.2 Probable migraine 
with aura, specifying the atypical feature (pro- longed aura or 
acute-onset aura) in parenthesis. The diagnosis is usually 
evident after a careful history alone, although there are rare 
secondary mimics including carotid dissection, arteriovenous 
malformation and seizure.
Prodromal symptoms may begin hours or a day or two 
before the other symptoms of a migraine attack with aura. 
They include various combinations of fatigue, difﬁculty in
concentrating, neck stiﬀness, sensitivity to light and/or 
sound, nausea, blurred vision, yawning and pallor. The 
term ‘prodrome’, which has replaced ‘pre- monitory phase’ 
or ‘premonitory symptoms’, does not include aura. 
Postdromal symptoms, most commonly feeling tired or 
weary, difficulty with concentration and
neck stiffness, may follow resolution of the headache, 
persisting for up to 48 hours; these are less well studied.
1.2.1 Migraine with typical aura
Description: Migraine with aura, in which aura 
consists 
of 
visual 
and/or 
sensory 
and/or 
speech/language symptoms, but no motor weakness, 
and is characterized by gradual development, duration 
of each symptom no longer than one hour, a mix of 
positive 
and 
negative 
features 
and 
complete 
reversibility
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura with both of the following:
1.
fully reversible visual, sensory and/or 
speech/ language symptoms
2.
no motor, brainstem or retinal symptoms.
1.2.1.1 Typical aura with headache
Description: Migraine with typical aura in which aura 
is accompanied or followed within 60 minutes by 
head- ache with or without migraine characteristics.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine with 
typical aura and criterion B below
B.
Headache, with or without migraine
characteristics, accompanies or follows the aura
within 60 minutes.
1.2.1.2 Typical aura without headache
Description: Migraine with typical aura in which aura is 
neither accompanied nor followed by headache of any sort.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine with 
typical aura and criterion B below
B.
No headache accompanies or follows the aura 
within 60 minutes.
Comments: In some patients, a typical aura is always 
followed by migraine headache, but many patients 
have, in addition, attacks with aura followed by a less 
distinct headache or even without headache. A number 
of patients have, exclusively, 1.2.1.2 Typical aura 
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In the absence of headache fulﬁlling criteria for 1.1 
Migraine without aura, the precise diagnosis of aura and 
its distinction from mimics that may signal serious dis-
ease (eg,transient ischaemic attack) becomes more 
difﬁcult and often requires investigation. When aura 
occurs for the ﬁrst time after age 40, when symptoms 
are exclusively negative (eg,hemianopia) or when aura 
is prolonged or very short, other causes, particularly 
transient ischaemic attacks, should be ruled out.
1.2.2 Migraine with brainstem aura
Previously used terms: Basilar artery migraine; basilar 
migraine; basilar-type migraine.
Description: Migraine with aura symptoms clearly 
originating from the brainstem, but no motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura with both of the following:
1.
at least two of the following fully reversible 
brainstem symptoms:
a.
dysarthria1
b.
vertigo2
c.
tinnitus
d.
hypacusis3
e.
diplopia4
f.
ataxia not attributable to sensory
deﬁcit
g.
decreased level of consciousness (GCS 
≤13)5
2.
no motor6 or retinal symptoms.
Notes:
1. Dysarthria should be distinguished from aphasia.
2. Vertigo does not embrace and should be 
distinguished from dizziness.
3. This criterion is not fulﬁlled by sensations of ear 
fullness.
4. Diplopia does not embrace (or exclude) blurred 
vision.
5. The Glasgow Coma Scale (GCS) score may have 
been assessed during admission; alternatively, 
deficits clearly described by the patient allow GCS 
estimation.
6. When motor symptoms are present, code as 1.2.3
Hemiplegic migraine.
Comments: Originally the terms basilar artery 
migraine or basilar migraine were used but, since 
involvement of the basilar artery is unlikely, the term 
migraine with brainstem aura is preferred.
There are typical aura symptoms in addition to the 
brainstem symptoms during most attacks. Many 
patients who have attacks with brainstem aura also 
report other attacks with typical aura and should be 
coded for both 1.2.1 Migraine with typical aura
and 1.2.2 Migraine with brainstem aura.
Many of the symptoms listed under criterion B1 
may occur with anxiety and hyperventilation, and are 
therefore subject to misinterpretation.
1.2.3 Hemiplegic1 migraine
Description: Migraine
with
aura
including
motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura consisting of both of the following:
1.
fully reversible motor weakness2
2.
fully reversible visual, sensory and/or 
speech/ language symptoms.
Notes:
1. The term plegic means paralysis in most languages, 
but most attacks are characterized by motor 
weakness.
2. Motor symptoms generally last less than 72 hours 
but, in some patients, motor weakness may persist 
for weeks.
Comment: It may be difficult to distinguish weakness 
from sensory loss.
1.2.3.1 Familial hemiplegic migraine (FHM)
Description: Migraine with aura including motor 
weak- ness, and at least one ﬁrst- or second-degree 
relativehas migraine aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 Hemiplegic 
migraine
B.
At least one ﬁrst- or second-degree relative has 
had 
attacks 
fulﬁlling 
criteria 
for 
1.2.3 
Hemiplegic migraine.
Comments: New genetic data have allowed a more
precise deﬁnition of 1.2.3.1 Familial hemiplegic 
migraine than was previously possible. Speciﬁc 
genetic subforms have been identiﬁed: in FHM1 there 
are mutations in the


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CACNA1A gene (coding for a
calcium
channel) on 
chromosome 19; in FHM2 there are mutations in the 
ATP1A2 gene (coding for a K/Na-ATPase) on chromo-
some 1; and in FHM3 there are mutations in the SCN1A 
gene (coding for a sodium channel) on chromosome 2. 
There may be other loci not yet identiﬁed. When genetic 
testing is done, the genetic subform (if discovered) should be
speciﬁed at the ﬁfth digit.
It has been shown that 1.2.3.1 Familial hemiplegic 
migraine very often presents with brainstem symptoms in 
addition to the typical aura symptoms, and that headache 
almost always occurs. Rarely, during FHM attacks, 
disturbances of consciousness (sometimes including coma), 
confusion, fever and cerebrospinal ﬂuid (CSF) pleocytosis 
can occur.
1.2.3.1Familialhemiplegicmigrainemaybemistaken for 
epilepsy and treated (unsuccessfully) as such. FHM attacks 
can be triggered by (mild) head trauma. In approximately 
50% of FHM families, chronic progressive cerebellar 
ataxia occurs independently of the migraine attacks.
1.2.3.1.1 Familial hemiplegic migraine type 1 (FHM1)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the CACNA1A gene has been 
demonstrated.
1.2.3.1.2 Familial hemiplegic migraine type 2 (FHM2)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the ATP1A2 gene has been 
demonstrated.
1.2.3.1.3 Familial hemiplegic migraine type 3 (FHM3)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the SCN1A gene has been 
demonstrated.
1.2.3.1.4 Familial hemiplegic migraine, other loci
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
Genetic testing has demonstrated no mutation
on the CACNA1A, ATP1A2 or SCN1A genes.
1.2.3.2 Sporadic hemiplegic migraine (SHM)
Description: Migraine with aura including motor 
weak- ness, and no ﬁrst- or second-degree relative has 
migraine aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 Hemiplegic 
migraine
B.
No ﬁrst- or second-degree relative fulﬁls criteria 
for 1.2.3 Hemiplegic migraine.
Comments: Epidemiological studies have shown that 
sporadic cases occur with approximately the same 
prevalence as familial cases.
The attacks in 1.2.3.2 Sporadic hemiplegic 
migraine have the same clinical characteristics as 
those in 1.2.3.1 Familial hemiplegic migraine. Some
apparently sporadic cases have known FHM mutations 
and, in some, a ﬁrst- or second-degree relative later 
develops hemiplegic migraine,
thus
completing
fulﬁlment of the criteria for
1.2.3.1 Familial hemiplegic migraine and requiring a 
change of diagnosis.
Sporadic cases usually require neuroimaging and 
other tests to rule out other causes. A lumbar puncture 
may be necessary to rule out 7.3.5 Syndrome of 
transient headache and neurological deﬁcits with
cerebrospinal ﬂuid lymphocytosis (HaNDL).
1.2.4 Retinal migraine
Description: Repeated attacks of monocular visual 
disturbance, including scintillations, scotomata or 
blindness, associated with migraine headache.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura characterized by both of the following:
1.
fully reversible, monocular, positive and/or 
negative visual phenomena (eg,scintillations, 
scotomata or blindness) conﬁrmed during 
an attack
by
either
or
both
of
the
following:
a.
clinical visual ﬁeld examination
b.
the patient’s drawing of a monocular 
ﬁeld defect (made after clear
instruction)
2.
at least two of the following:
a.
spreading gradually over ≥ 5 minutes
b.
symptoms last 5–60 minutes


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c.
accompanied, or followed within 60 
minutes, by headache
C.
Not better accounted for by another ICHD-3 
diagnosis, and other causes of amaurosis fugax 
have been excluded.
Comments: 
Some 
patients 
who 
complain 
of 
monocular visual disturbance in fact have hemianopia. 
Some cases without headache have been reported, but 
migraine as the underlying aetiology cannot be 
ascertained.
1.2.4 Retinal migraine is an extremely rare cause 
of transient monocular visual loss. Cases of permanent 
monocular visual loss associated with migraine have 
been 
described. 
Appropriate 
investigations 
are 
required to exclude other causes of transient 
monocular blindness.
1.3
Chronic migraine
Description: Headache occurring on 15 or more 
days/ month for more than three months, which, on 
at least eight days/month, has the features of migraine
headache.
Diagnostic criteria:
A.
Headache (migraine-like or tension-type-like1) 
on 15 days/month for >3 months, and fulﬁlling
criteria B and C
B.
Occurring in a patient who has had at least ﬁve 
attacks fulﬁlling criteria B–D for 1.1 Migraine
with- out aura and/or criteria B and C for 1.2 
Migraine with aura
C.
On 8 days/month for >3 months, fulﬁlling any of 
the following2:
1.
criteria C and D for 1.1 Migraine without
aura
2.
criteria B and C for 1.2 Migraine with aura
3.
believed by the patient to be migraine at 
onset and relieved by a triptan or ergot
derivative
D.
Not better accounted for by another ICHD-3 
diagnosis.3–5
Notes:
1. The reason for singling out 1.3 Chronic migraine
from types of episodic migraine is that it is 
impossible to distinguish the individual episodes 
of headache in patients with such frequent or 
continuous headaches. In fact, the characteristics 
of the headache may change not only from day to 
day but even within the same day. Such patients 
are extremely diﬃcult to keep medication-free in 
order to observe the natural history of the 
headache. In this situation, attacks with and those 
without aura are both counted, as are both 
migraine-like and tension-type-like headaches (but 
not secondary headaches).
2. Characterization 
of 
frequently 
recurring 
headache generally requires a headache diary to
record information on pain and associated 
symptoms day by day for at least one month.
3. Because tension-type-like headache is within the 
diagnostic criteria for 1.3 Chronic migraine, this 
diagnosis excludes the diagnosis of 2. Tension-
type headache or its types.
4. 4.10 New daily persistent headache may have
features suggestive of 1.3 Chronic migraine. The
latter disorder evolves over time from 1.1 Migraine
without aura and/ or 1.2 Migraine with aura; 
therefore, when these criteria A–C are fulﬁlled by 
headache that, unambiguously, is daily and 
unremitting from <24 hours after its ﬁrst onset,
code as 4.10 New daily persistent head- ache.
When the manner of onset is not remembered or is
otherwise uncertain, code as 1.3 Chronic migraine.
5. The most common cause of symptoms suggestive
of chronic migraine is medication overuse, as
deﬁned under 8.2 Medication-overuse headache.
Around 50% of patients apparently with 1.3 
Chronic migraine revert to an episodic migraine 
type after drug withdrawal; such patients are in a 
sense wrongly diagnosed as 1.3 Chronic migraine. 
Equally, many patients apparently overusing 
medication do not improve after drug withdrawal; 
the diagnosis of 8.2 Medication-overuse headache 
may be inappropriate for these (assuming that 
chronicity induced by drug overuse is always 
reversible). For these reasons, and because of the 
general rule to apply all relevant diagnoses, 
patients meeting criteria for 1.3 Chronic migraine 
and for 8.2 Medication-overuse headache should 
be coded for both. After drug withdrawal, 
migraine will either revert to an episodic type or 
remain chronic and should be re-diagnosed 
accordingly; in the latter case, the diagnosis of 8.2 
Medication-overuse headache may be rescinded.
1.4
Complications of migraine
Comment: Code separately for both the migraine type, 
subtype or subform and for the complication.
1.4.1 Status migrainosus
Description: A debilitating migraine attack lasting for 
more than 72 hours.
Diagnostic criteria:
A.
A headache attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.1 Migraine without 
aura and/or 1.2 Migraine with aura, and typical 
of previous attacks except for its duration and
severity


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C.
Both of the following characteristics:
1.
unremitting for >72 hours1
2.
pain
and/or
associated
symptoms
are debilitating2
D.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. Remissions of up to 12 hours due to medication or 
sleep are accepted.
2. Milder cases, not meeting criterion C2, are
coded
1.5.1 Probable migraine without aura.
Comment: Headache with the features of 1.4.1 Status 
migrainosus may often be caused by medication overuse. 
When headache in these circumstances meets the criteria for 
8.2 Medication-overuse headache, code for this dis- order 
and the relevant type or subtype of migraine but not for 
1.4.1 Status migrainosus. When overuse of medication is of 
shorter duration than three months, code for the appropriate 
migraine type or subtype(s) only.
1.4.2 Persistent aura without infarction
Description: Aura symptoms persisting for one week 
or more without evidence of infarction on 
neuroimaging.
Diagnostic criteria:
A.
Aura fulﬁlling criterion B
B.
Occurring in a patient with 1.2 Migraine with
aura and typical of previous auras except that 
one or more aura symptoms persists for 1 week
C.
Neuroimaging shows no evidence of infarction
D.
Not better accounted for by another ICHD-3 
diagnosis.
Comments: Persistent aura symptoms are rare but well 
documented. They are often bilateral and may last for 
months or years. The one-week minimum in criterion 
B is based on the opinion of experts and should be 
formally studied.
Diagnostic 
work-up 
must 
distinguish 
1.4.2
Persistent 
aura 
without 
infarction 
from 1.4.3 
Migrainous infarction and exclude symptomatic aura 
due to cerebral infarction of other causes. Attacks with
prolonged aura lasting less than one week and not 
fulﬁlling criteria for 1.2.1 Migraine with typical aura 
are coded 1.5.2 Probable migraine with aura.
1.4.3 Migrainous infarction
Description: One or more migraine aura symptoms 
occurring in association with an ischaemic brain
lesion in the appropriate territory demonstrated by 
neuroimaging, with onset during the course of a 
typical migraine with aura attack.
Diagnostic criteria:
A.
A migraine attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.2 Migraine with 
aura and typical of previous attacks except that 
one or more aura symptoms persists for >60
minutes1
C.
Neuroimaging demonstrates ischaemic 
infarction in a relevant area
D.
Not better accounted for by another ICHD-3 
diagnosis.
Note:
1. There may be additional symptoms attributable to
the infarction.
Comments: Ischaemic stroke in a migraine sufferer 
may be categorized as cerebral infarction of other 
cause coexisting with 1. Migraine, cerebral infarction 
of other cause presenting with symptoms resembling 
1.2 Migraine with aura, or cerebral infarction 
occurring during the course of a typical attack of 1.2 
Migraine with aura. Only the last fulﬁls criteria for 
1.4.3 Migrainous infarction.
1.4.3 Migrainous infarction mostly occurs in the
posterior circulation and in younger women.
A twofold increased risk of ischaemic stroke in 
patients with 1.2 Migraine with aura has been 
demonstrated in several population-based studies. 
However, it should be noted that these infarctions are 
not migrainous infarctions. The mechanisms of the 
increased risk of ischaemic stroke in migraine 
sufferers remain unclear; likewise, the relationship 
between increased risk and frequency of aura and the 
nature of aura symptoms denoting the increase in risk 
are unknown. Most studies have shown a lack of 
association between 1.1 Migraine without aura and 
ischaemic stroke.
1.4.4 Migraine aura-triggered seizure
Description: A seizure triggered by an attack of 
migraine with aura.
Diagnostic criteria:
A.
A seizure fulﬁlling diagnostic criteria for one 
type of epileptic attack, and criterion B below
B.
Occurring in a patient with 1.2 Migraine with
aura, and during or within one hour after an 
attack of migraine with aura


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C.
Not better accounted for by another ICHD-3 
diagnosis.
Comment: Migraine and epilepsy are prototypical 
examples of paroxysmal brain disorders. While
migraine-like headaches are quite frequently seen in 
the epileptic post-ictal period, sometimes a seizure
occurs during or following a migraine attack. This 
phenomenon, sometimes referred to as migralepsy, is 
a rare event, originally described in patients with 1.2 
Migraine with aura. Evidence of an association with 
1.1 Migraine without aura is lacking.
1.5
Probable migraine
Previously used term: Migrainous disorder.
Coded elsewhere: Migraine-like headache secondary 
to another disorder (symptomatic migraine) is coded 
according to that disorder.
Description: Migraine-like attacks missing one of the 
features required to fulﬁl all criteria for a type or sub-
type of migraine coded above, and not fulﬁlling 
criteria for another headache disorder.
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–D
for
1.1 Migraine without aura, or all but one of
criteria A–C for 1.2 Migraine with aura
B.
Not fulﬁlling ICHD-3 criteria for any other 
head- ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
Comment: In making a headache diagnosis, attacks 
that fulﬁl criteria for both 2. Tension-type headache 
and 1.5 Probable migraine are coded as the former in 
accordance with the general rule that a deﬁnite 
diagnosis always trumps a probable diagnosis. 
However, in patients who already have a migraine 
diagnosis, and where the issue is to count the number 
of attacks they are having (eg, as an outcome measure 
in a drug trial), attacks fulﬁlling criteria for 1.5 
Probable migraine should be counted as migraine. 
The reason for this is that mild migraine attacks, or 
attacks treated early, often do not achieve all 
characteristics necessary for a migraine attack 
diagnosis but nevertheless respond to speciﬁc 
migraine treatments.
1.5.1 Probable migraine without aura Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–D for
1.1 Migraine without aura
B.
Not fulﬁlling ICHD-3 criteria for any other 
head- ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
1.5.2 Probable migraine with aura
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–C for 1.2
Migraine with aura or any of its subtypes
B.
Not fulﬁlling ICHD-3 criteria for any other 
head- ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
1.6
Episodic syndromes that may be 
associated with migraine
Previously 
used 
terms: 
Childhood 
periodic 
syndromes; periodic syndromes of childhood.
Comments: This group of disorders occurs in patients 
who also have 1.1 Migraine without aura or 1.2 
Migraine with aura, or who have an increased 
likelihood to develop either of these disorders. 
Although historically noted to occur in childhood,
they may also occur in adults.
Additional conditions that may also occur in these 
patients include episodes of motion sickness and 
periodic sleep disorders including sleep walking, sleep 
talking, night terrors and bruxism.
1.6.1 Recurrent gastrointestinal disturbance
Previously used terms: Chronic abdominal pain; 
functional abdominal pain; functional dyspepsia; 
irritable bowel syndrome; functional abdominal pain 
syndrome.
Description: Recurrent episodic attacks of abdominal 
pain and/or discomfort, nausea and/or vomiting, 
occurring infrequently, chronically or at predictable 
intervals, that may be associated with migraine.


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Diagnostic criteria:
A.
At least ﬁve attacks with distinct episodes of 
abdominal pain and/or discomfort and/or nausea 
and/or vomiting
B.
Normal
gastrointestinal
examination
and evaluation
C.
Not attributed to another disorder.
1.6.1.1 Cyclic vomiting syndrome
Description: Recurrent episodic attacks of intense 
nausea and vomiting, usually stereotypical in the 
individual and with predictable timing of episodes. 
Attacks may be associated with pallor and lethargy. 
There is complete resolution of symptoms between
attacks.
Diagnostic criteria:
A.
At least ﬁve attacks of intense nausea and 
vomiting, fulﬁlling criteria B and C
B.
Stereotypical in the individual patient and recur-
ring with predictable periodicity
C.
All of the following:
1.
nausea and vomiting occur at least four 
times per hour
2.
attacks last for ≥ 1 hour, up to 10 days
3.
attacks occur ≥ 1 week apart
D.
Complete freedom from symptoms between 
attacks
E.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination do 
not show signs of gastrointestinal disease.
Comments: 1.6.1.1 Cyclic vomiting syndrome is 
typically a self-limiting episodic condition occurring 
in child- hood, with periods of complete normality 
between episodes. The cyclic nature is the hallmark, 
and attacks are predictable.
This disorder was ﬁrst included as a childhood 
periodic syndrome in ICHD-II. The clinical features 
of this syndrome resemble those found in association 
with migraine headaches, and multiple threads of 
research over the last years have suggested that 1.6.1.1 
Cyclic vomiting syndrome is a condition related to 
migraine.
1.6.1.2 Abdominal migraine
Description: An idiopathic disorder seen mainly in 
children as recurrent attacks of moderate to severe 
midline
abdominal pain, associated with vasomotor symptoms, 
nausea and vomiting, lasting 2–72 hours and with 
normality between episodes. Headache does not occur 
during these episodes.
Diagnostic criteria:
A.
At least ﬁve attacks of abdominal pain, fulﬁlling 
criteria B–D
B.
Pain has at least two of the following three 
characteristics:
1.
midline location, periumbilical or poorly 
localized
2.
dull or ‘just sore’ quality
3.
moderate or severe intensity
C.
At least two of the following four associated 
symptoms or signs:
1.
anorexia
2.
nausea
3.
vomiting
4.
pallor
D.
Attacks last 2–72 hours when untreated or
unsuccessfully treated
E.
Complete freedom from symptoms between 
attacks
F.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination do 
not show signs of gastrointestinal or renal disease, 
or such disease has been ruled out by appropriate 
investigations.
Comments: Pain of 1.6.1.2 Abdominal migraine is 
severe enough to interfere with normal daily activities.
In young children, the presence of headache is 
often overlooked. A careful history of presence or 
absence of headache must be taken and, when 
headache or head pain during attacks is identiﬁed, a 
diagnosis of 1.1 Migraine without aura should be 
considered.
Children may ﬁnd it difficult to distinguish 
anorexia from nausea. Pallor is often accompanied by 
dark shadows under the eyes. In a few patients, 
ﬂushing is the predominant vasomotor phenomenon.
Most children with abdominal migraine will 
develop migraine headache later in life.
1.6.2 Benign paroxysmal vertigo
Description: A disorder characterized by recurrent 
brief attacks of vertigo, occurring without warning and 
resolving spontaneously, in otherwise healthy children.


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Diagnostic criteria:
A.
At least ﬁve attacks fulﬁlling criteria B and C
B.
Vertigo1 occurring without warning, maximal at 
onset and resolving spontaneously after minutes
to hours without loss of consciousness
C.
At least one of the following ﬁve associated 
symptoms or signs:
1.
nystagmus
2.
ataxia
3.
vomiting
4.
pallor
5.
fearfulness
D.
Normal neurological examination and 
audiometric and vestibular functions between
attacks
E.
Not attributed to another disorder.2
Notes:
1. Young children with vertigo may not be able to 
describe 
vertiginous 
symptoms. 
Parental 
observation of episodic periods of unsteadiness 
may be interpreted as vertigo in young children.
2. In particular, posterior fossa tumours, seizures and 
vestibular disorders have been excluded.
Comment: The relationship between 1.6.2 Benign
paroxysmal vertigo and A1.6.6 Vestibular migraine 
(see Appendix) needs to be further examined.
1.6.3 Benign paroxysmal torticollis
Description: Recurrent episodes of head tilt to one 
side, perhaps with slight rotation, which remit 
spontaneously. The condition occurs in infants and 
small children, with onset in the ﬁrst year.
Diagnostic criteria:
A.
Recurrent attacks1 in a young child, fulﬁlling 
criteria B and C
B.
Tilt of the head to either side, with or without 
slight rotation, remitting spontaneously after 
minutes to days
C.
At least one of the following ﬁve associated 
symptoms or signs:
1.
pallor
2.
irritability
3.
malaise
4.
vomiting
5.
ataxia2
D.
Normal neurological examination between
attacks
E.
Not attributed to another disorder.3
Notes:
1. Attacks tend to recur monthly.
2. Ataxia is more likely in older children within the 
affected age group.
3. The 
differential 
diagnosis 
includes 
gastro-
oesophageal reﬂux, idiopathic torsional dystonia 
and com-
plex partial seizure, but particular 
attention must be paid to the posterior fossa and 
craniocervical 
junction 
where 
congenital 
or 
acquired lesions may pro- duce torticollis.
Comments: The child’s head can be returned to the 
neutral position during attacks: some resistance may 
be encountered but can be overcome.
These observations need further validation by patient 
diaries, structured interviews and longitudinal data
collection.
1.6.3 Benign paroxysmal torticollis may evolve into
1.6.2 Benign paroxysmal vertigo or 1.2 Migraine with 
aura (particularly 1.2.2 Migraine with brainstem 
aura) or cease without further symptoms.
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mutations in the Na,K-ATPase gene ATP1A2 
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Eur J Hum Genet 2006; 14: 555–560.


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1.2.4 Retinal migraine
Carroll D. Retinal migraine. Headache 1970; 10: 9–13.
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1.3 Chronic migraine
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Bigal ME and Lipton RB. Concepts and mechanisms of 
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Silberstein SD, Lipton RB and Sliwinski M. 
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1.4.1 Status migrainosus
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1.4.2 Persistent aura without infarction
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166–170.
Bento MS and Esperanca P. Migraine with prolonged 
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1.4.3 Migrainous infarction
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Bousser 
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Conard 
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Family Planning and Reproductive Health Care 
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more frequent than migraine induced ischemic
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Rothrock JF, Walicke P, Swenson MR, et al.
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cortical energy metabolism in migrainous stroke: 
A 31P-MR spectroscopy study. Stroke 2009; 40: 
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Tietjen GE. The relationship of migraine and stroke.
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and stroke in young women. Cephalalgia 2000; 
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Vollbracht S, Robbins MS and Kister I. Classiﬁcation 
challenge in migrainous infarction. Headache 
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Wolf ME, Szabo K, Griebe M, et al. Clinical and MRI 
characteristics of acute migrainous infarction. 
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1.4.4 Migraine aura-triggered seizure
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Migralepsy, 
hemicrania 
epileptica, 
postictal 
headache and ‘‘ictal epileptic headache’’:
a
proposal 
for 
terminology 
and 
classiﬁcation 
revision. J Headache Pain 2011; 12: 289–294.
Davies PT and Panayiotopoulos CP.
Migraine 
triggered seizures and epilepsy triggered headache
and migraine attacks: a need for re-assessment. J 
Headache Pain 2011; 12: 287–288.
Friedenberg S and Dodick DW. Migraine-associated 
seizure: a case of reversible MRI abnormalities
and persistent nondominant hemisphere syndrome. 
Headache 2000; 40: 487–490.
Maggioni F, Mampreso E, Ruﬀatti S, et al. 
Migralepsy: is the current deﬁnition too narrow? 
Headache 2008; 48: 1129–1132.
Marks DA and Ehrenberg BL. Migraine-related 
seizures in adults with epilepsy, with EEG 
correlation. Neurology 1993; 43: 2476–2483.
Merlino G, Valente MR, D’Anna S, et al. Seizures
with prolonged EEG abnormalities during an
attack of migraine without aura. Headache 2007;
47: 919–922.
Parisi 
P 
and 
Kasteleijn-Nolst 
Trenite` 
DGA. 
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revision
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deﬁnition.
Epilepsia 2010; 51: 932–933.
Rogawski 
MA. 
Common 
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mechanisms in migraine and epilepsy. Arch 
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Sances G, Guaschino E, Perucca P, et al. Migralepsy: 
a call for revision of the deﬁnition. Epilepsia 2009;
50: 2487–2496.
Ter Berg HW. Migraine-associated seizure: a case of 
reversible MRI abnormalities and persistent non-
dominant hemisphere syndrome. Headache 2001; 
41: 326–328.
Velioglu SK and Ozmenoglu M. Migraine-related 
seizures in an epileptic population. Cephalalgia 
1999; 19: 797–801.
Verrotti A, Coppola G, Di Fonzo A, et al. Should 
‘‘migralepsy’’ be considered an obsolete concept?
A multicenter retrospective clinical/EEG study and 
review of the literature. Epilepsy Behav 2011; 21: 
52–59.
1.5 Probable migraine
Granella F, Alessandro RD, Manzoni GC, et al. 
International Headache Society classiﬁcation: 
inter- observer reliability in the diagnosis of 
primary head- aches. Cephalalgia 1994; 14: 16–20.
Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis of 
migraine: empirical analysis of a large clinical 
sample of atypical migraine (IHS 1.7) patients and 
proposed revision of the IHS criteria. Cephalalgia 
2001, 21: 584–595.
Rasmussen
BK,
Jensen
R
and
Olesen
J.
A
population- based analysis of the diagnostic 
criteria of the International Headache Society.
Cephalalgia 1991; 11: 129–134.
Russell MB and Olesen J. Migrainous disorder and its 
relation to migraine without aura and migraine 
with aura. A genetic epidemiological study. 
Cephalalgia 1996; 16: 431–435.
1.6.1 Recurrent gastrointestinal 
disturbance
Abu-Arafeh I and Russel G. Prevalence and clinical 
features of abdominal migraine compared with
those of migraine headache. Arch Dis Child 1995; 
72: 413–417.
Al-Twaijri WA and Shevell MI. Pediatric migraine 
equivalents: occurrence and clinical features in 
prac- tice. Pediatr Neurol 2002; 26: 365–368.
Dignan F, Abu-Arafeh I and Russell G. The prognosis 
of childhood abdominal migraine. Arch Dis Child 
2001; 84: 415–418.
Drossman DA and Dumitrascu DL. Rome III: new 
standard for functional gastrointestinal disorders. J 
Gastrointestin Liver Dis 2006; 15: 237–241.
Farquar HA. Abdominal migraine in children. BMJ
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Fleisher DR. Cyclic vomiting syndrome and migraine.
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Haan J, Kors EE and Ferrari MD. Familial cyclic 
vomiting syndrome. Cephalalgia 2002; 22: 552–
554.
Li BU. Cyclic vomiting syndrome: age-old syn- drome 
and new insights. Semin Pediatr Neurol 2001; 8:
13–21.
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Hepatology, and Nutrition consensus statement on 
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syndrome. J Pediatr Gastroenterol Nutr 2008; 47: 
379–393.
Rashed H, Abell TL, Familoni BO, et al. Autonomic 
function in cyclic vomiting syndrome and classic 
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Russell G, Abu-Arafeh I and Symon DN. Abdominal 
migraine: evidence for existence and treatment 
options. Paediatr Drugs 2002; 4: 1–8.
Thiessen PN. Recurrent abdominal pain. Pediatr Rev
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Welch KM. Scientiﬁc basis of migraine: speculation 
on the relationship to cyclic vomiting. Dig Dis Sci
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1.6.2 Benign paroxysmal vertigo
Drigo P, Carli G and Laverda AM. Benign 
paroxysmal vertigo of childhood. Brain Dev 
2001; 23: 38–41.
Dunn DW and Snyder CH. Benign paroxysmal
vertigo of childhood. Am J Dis Child 1976; 
130: 1099–1100.
Fenichel GM. Migraine as a cause of benign
paroxysmal vertigo of childhood. J Pediatr 
1967; 71: 114–115.
1.6.3 Benign paroxysmal torticollis
Drigo P, Carli G and Laverda AM. Benign 
paroxysmal torticollis of infancy. Brain Dev 
2000; 22: 169–172. 
Giffin NJ, Benton S and Goadsby PJ. Benign 
paroxysmal torticollis of infancy: four new 
cases and linkage to CACNA1A mutation. 
Dev Med Child Neurol 2002; 44: 490–493.
Rosman NP, Douglass LM, Sharif UM, et al. The 
neurology of benign paroxysmal torticollis of 
infancy: report of 10 new cases and review of 
the literature. J Child Neurol 2009; 24: 
155–160.


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12.2
Examples of Prohibited Medications
The following medications are prohibited 30 days prior to screening and throughout the study 
period:
Strong OATP1B1 inhibitors, eg, gemfibrozil (Lopid™)*, cyclosporine
Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Anti-Depressants/ 
Anti-Anxiety
Barbiturates 

Amobarbital (Amytal™)

Aprobarbital (Alurate™)*

Butalbital (Fiorinal™, Fioricet™)*

Butabarbital (Busodium™, 
Butisol™)*

Mephobarbital (Mebaral™)*

Pentobarbital (Nembutal™)

Phenobarbital (Luminal™, 
Solfoton™)

Secobarbital (Seconal™)
Nefazodone (Serzone™)*
Anti-Seizure
Carbamazepine (Atretol™, Carbatrol™, 
Epitol™, Equetro™, Tegretol™)
Oxcarbazepine (Trileptal™)*
Phenytoin (Dilantin™, Phenytek™)
Primidone (Myidone™, Mysoline™)
Diabetes 
Pioglitazone (Actos™)
Troglitazone (Rezulin™, Resulin™)*
Antiemetic
Aprepitant (Emend™)
Anti-Hypertension
Diltiazem (Cardizem™)
Verapamil (Calan™, Calan SR™)
Glucocorticoid 
(Systemic)
Betamethasone (Celestone™)
Dexamethasone (Baycadron™, DexPak™)
Hydrocortisone (Cortef™)
Methylprednisolone (Medrol™)
Prednisolone (Prelone™)
Prednisone (Deltasone™)
Triamcinolone (Kenalog™)
Antibiotics
Rifabutin (Mycobutin™) 
Rifampicin/Rifampin (Rifadin™, Rifater™, 
Rimactane™) 
Erythromycin (Benzamycin™, EryTab™)
Clarithromycin (Biaxin™)
Telithromycin (Ketek™)
Anti-Fungal
Fluconazole (Diflucan™, Trican™)
Itraconazole (Sporanox™)
Ketoconazole (Nizoral™)
Anti-HIV
Efavirenz (Stocrin™, Sustiva™) 
Nevirapine (Viramune™) 
Indinavir (Crixivan™)
Nelfinavir (Viracept™) 
Ritonavir (Norvir™)
Saquinavir (Fortovase™, Invirase™)
Immune 
Suppressant
Cyclosporine - Oral/IV only (Neoral™, 
Sandimmune™)
Others
St. John’s wort 
Enzalutamide (Xtandi™)
Modafinil (Provigil™)
Armodafinil (Nuvigil™)*
Buprenorphine (Cizol™, Subutex™, 
Suboxone™)
Quinine


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Drugs with narrow therapeutic margins 
with potential for CYP drug interactions
Warfarin (Coumadin™)
Digoxin (Digitek™, Lanoxin™, Digox™)
Cisapride (Prepulsid™, Propulsid™)*
Pimozide (Orap™)
Non-pharmacologic headache 
interventions:
Acupuncture
Non-invasive neuromodulation devices (eg, transcutaneous 
supraorbital neurostimulator single pulse transcranial magnetic 
stimulator vagus nerve stimulator)
Cranial traction
Nociceptive trigeminal inhibition
Occipital nerve block treatments
Dental splints for headache
*not approved in Japan
The following treatments are prohibited 6 months prior to screening and throughout the 
study period:

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, Botox®, Xeomin®, 
Myobloc®, JeuveauTM) into areas of the head, face, or neck

Injectable monoclonal antibodies blocking the CGRP pathway (eg, AimovigTM, 
EmgalityTM, Ajovy®)


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12.3
List of Migraine Preventive Medications With Proven Efficacy & 
Criteria for Determining that a Prior Migraine Preventive Medication 
Has Been Failed
12.3.1
List of Migraine Preventive Medications With Proven Efficacy
Below is a list of migraine preventive medications considered effective or probably effective 
sorted by mechanism of action. Of note, topiramate and valproic acid derivatives are considered 
separate categories. A history of inadequate response (based on inadequate efficacy or inadequate 
tolerability) to more than 4 of these medications (2 of which have different mechanisms of 
action) will exclude the participant from the study.
Pharmacologic Category
Drug Name (all regions unless otherwise noted)
Antiepileptic
Valproic acid, sodium valproate, divalproex sodium
Topiramate
Tricyclic antidepressant
Amitriptyline
Nortriptyline
Beta-blockers
Metoprolol
Bisoprolol
Atenolol
Nadolol
Propranolol
Timolol
Calcium channel blocker
Flunarizine
Lomerizine (Japan)
Verapamil (Japan)
Angiotensin receptor blocker (ARB)
Candesartan
Angiotensin-converting enzyme (ACE) inhibitor
Lisinopril
Serotonin-norepinephrine reuptake inhibitor (SNRI)
Desvenlafaxine
Venlafaxine
Miscellaneous
Oxetorone (Europe), pizotifen (Japan, Taiwan, Korea, 
Australia, and Europe)
Source: Evers 2009, Hoffmann 2014, Schürks 2008, Silberstein 2012, Steiner 2007.


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12.3.2
Criteria for Determining That a Prior Migraine Preventive 
Medication has Been Failed 
The criteria below should be used to determine how to stratify each participant based on the 
number of prior migraine preventive medications failed with unique mechanisms of action. 
Failure of a migraine preventive medication can be assessed on the basis of tolerability or 
efficacy and is based on investigator judgment.

For efficacy, investigators must consider:
o
Failure is defined as no meaningful reduction in frequency of migraine days after 
an adequate trial of at least 2 months at generally accepted therapeutic doses, per 
investigator judgement and participant interview.
o
Medications must have been started within the past 7 years.
o
Note the following for participants who are currently taking a stable dose of one 
of the migraine prevention medications listed and meet the efficacy criteria:

If the participant meets all study entry criteria, this participant is eligible to 
be randomized provided that the participant agrees to continue to take this 
migraine preventive medication for the duration of the study.

This medication should be considered as one of the failed drugs for the 
prevention of migraine.

Enrollment of participants with current use of a migraine prevention 
medication will be capped at ~15%.

For tolerability, investigators should consider:
o
Failure is defined as discontinuation of a drug treatment due to adverse effects. 
o
In assessing failure of a migraine preventive drug on the basis of inadequate 
tolerability, the entire medical history can be considered. For example, a 
participant who tried and discontinued topiramate 10 years ago for cognitive 
clouding should be considered to have failed this treatment.


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12.4
Study Visits Conducted Remotely
Remote study visits, conducted virtually or by phone, are permitted if the Investigator determines 
there to be a public health risk due to viral infection (eg, COVID-19) to the participant or site 
staff. During remote study visits, the Remote Visit Schedule of Assessments (Table 5) should be 
followed. Remote visits may be conducted between Visit 3 – Visit 8 but participants must attend 
in office assessments at Visit 3 or Visit 4 to ensure laboratory samples are obtained within the 
first 4-weeks of treatments and remote visits should not be performed for greater than 8 weeks.
Missed in-person safety assessments (ie, clinical laboratory samples, vital signs and ECGs) 
should be collected at the next in-person visit. Patient reported outcomes collected on the eTablet 
during in-office visits, will be collected using a web-based portal during remote visits, if 
available.


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Table 5
Remote Visits Schedule of Assessments (ie, Schedule of Visits and Procedures)
Study Period
Screening/
Baseline
(4 weeks)
Double-blind Treatment Period (12 weeks)
Follow-up 
Period 
(4 weeks)
Visit #
Visit 1a
Visit 2a
(Randomization)
Visit 3a
Visit 4a
Visit 5
Visit 6
Visit 7/ET
Visit 8
(End of Study)
Day/Week
Week -4
Day 1
Week 2 
(Day 14)
Week 4 
(Day 28)
Week 6 
(Day 42)
Week 8 
(Day 56)
Week 12 
(Day 84)
Week 16
(Day 112)
Visit Windows
Day –35 to 
Day -28
NA
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Dispense study intervention
(ie, atogepant)b
X
X
X
X
X
Review of atogepant compliance
X
X
X
X
X
Participant eDiary Data Collectionc
X
Review eDiary data and compliance
X
X
X
X
X
X
Perform urine pregnancy testb,d
X
X
X
X
X
X
X
X
C-SSRS (eTablet or web portal)
X
X
X
X
X
X
X
X
HIT-6 (web portal)e
X
X
X
X
X
PGIC (web portal)e
X
PGI-S (web portal)e
X
X
X
X
WPAI:MIGRAINE (web portal)e
X
X
X
X
PSSM (web portal)e
X
X
X
EQ-5D-5L f
X
X
X
X
X
X
X
X
MIDAS (web portal)e
X
X
MSQ v2.1 (web portal)e
X
X
X
X
X
PROMIS-PI (web portal)e
X
X
X
X
PHQ-9 (web portal)e
X
X
Adverse events
X
Concomitant medications/concurrent 
procedures
X


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AIM-D = Activity Impairment in Migraine–Diary; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; eDiary = electronic diary; 
EQ-5D-5L = European Quality of Life – 5 Dimensional; ET = early termination; eTablet = electronic tablet; HIT-6 = Headache Impact Test; INR = international 
normalized ratio; IWRS = interactive web response system; MIDAS = Migraine Disability Assessment; MSQ v2.1 = Migraine Specific Quality of Life 
Questionnaire, Version 2.1; PGIC = Patient Global Impression of Change; PGI-S = Patient Global Impression – Severity; PHQ-9 = Patient Health Questionnaire; 
PK = pharmacokinetic; PRO = patient-reported outcome; PROMIS-PI = Patient-Reported Outcomes Measurement Information System Pain Interference – Short 
Form 6a; VCT = verified clinical trial; WPAI:MIGRAINE = Work Productivity and Activity Impairment Questionnaire: Migraine V2.0.
a
Visit 1, Visit 2, and either Visit 3 or Visit 4 must be conducted in office, to ensure laboratory assessments are performed within the first 4 weeks of study 
intervention.
b
Study medication to cover 1 remote study visit and urine pregnancy tests may be dispensed at an office visit (if the next visit is anticipated to be remote), for 
curbside pick-up or shipped to participants via an overnight courier.
c
Daily eDiary data collection includes: Headache Frequency, Duration, Characteristics, and Symptoms; Acute Medication Use and Triptan Use; AIM-D; 
Activity Level and Activity Limitation.
d
Female participants are to take an at-home pregnancy test (provided by sites) and report the results during virtual visits.
e
If available, participants will complete on a web-based portal.
f
Participants will complete in eDiary on Visit 1 to 7 and on the web-based portal (if available) at Visit 8 (Week 16).


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12.5
Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AIM-D
Activity Impairment in Migraine – Diary
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AR
adverse reaction
ASC-12
allodynia symptom checklist
AST
aspartate aminotransferase
BID
twice daily
BP
blood pressure
CBD
cannabidiol
CGRP
calcitonin gene-related peptide
CM
chronic migraine
CRF
case report form
C-SSRS 
Columbia-Suicide Severity Rating Scale
CYP3A4
cytochrome P450 3A4
DSMB
Data Safety Monitoring Board
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
EMA
European Medicines Agency
EQ-5D-5L
European Quality of Life – 5 Dimensional
ET
early termination
eTablet
electronic tablet
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HIPAA
Health Insurance Portability and Accountability Act
HIT-6
Headache Impact Test
HSG
hysterosalpingogram
HIV
Human immunodeficiency virus


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Term/Abbreviation
Definition
ICF
informed consent form
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone releasing system
IV
intravenous
IWRS
interactive web response system
MAR
missing-at-random
MI
multiple imputation
MIDAS
Migraine Disability Assessment
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MNAR
missing-not-at-random
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, Version 2.1
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic anion transporting polypeptide 1B1
OL
open-label
PD
pharmacodynamic
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression – Severity
PHQ-9
Patient Health Questionnaire
PK
pharmacokinetic
PMM
pattern-mixture model
PRO
patient-reported outcomes
PROMIS-PI
Patient-Reported Outcomes Measurement Information System 
Pain Interference – Short Form 6a
PSSM
Patient Satisfaction with Study Medication
QTcF
QT interval corrected for heart rate using Fridericia formula 
(QTcF = QT/(RR)⅓)
ROW
rest of world


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Term/Abbreviation
Definition
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAR
serious adverse reaction
SNRI
serotonin norepinephrine reuptake inhibitor
SOC
system organ class
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal
VAS
Visual Analogue Scale
VCT
verified clinical trials
WPAI:MIGRAINE
Work Productivity and Activity Impairment Questionnaire: 
Migraine Version V2.0


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12.6
Protocol Amendment 1 Summary
Title: 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)
Protocol 3101-303-002
Date of Amendment: 08 April 2019
Amendment Summary
This amendment includes changes made to Protocol 3101-303-002 dated 13 December 2018. 
The protocol was amended to: 
Add instructions for study conduct in China and Canada
Clarify primary and secondary endpoints for China, and Canada
Clarify prohibited medications
Update laboratory parameters
Update the subgroup analyses
Correct the study diagram for the estimand framework
Update the definition of failed migraine preventive medication
The table below provides details related to content changes that were made in the protocol, and a 
brief rationale for these changes. Minor editorial and document formatting revisions have not 
been summarized.


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Section
Revision
Rationale
Protocol Title Page
Added “Protocol Amendment 1 Date” to the title page
To reflect the approval 
date of Amendment 1
Protocol Summary
Changed the Condition/Disease from “CM with aura or 
migraine without aura” to “Chronic migraine”
For clarity
Protocol Summary
Changed text with regard to the primary efficacy 
endpoint to clarify that the primary efficacy endpoint is 
the same for all regulatory authorities
For clarity
Protocol Summary
Added text to clarify the secondary efficacy endpoints 
for China
Study will also be 
conducted in China
Protocol Summary
Added text to clarify the secondary efficacy endpoints 
for Canada
Study will also be 
conducted in Canada
Protocol Summary, 
Table 1 Schedule of Visits 
and Procedures
Clarified that VCT is applicable for United States and 
Canada only
For clarity
Protocol Summary, 
Table 1 Schedule of Visits 
and Procedures
Added HIT-6 to Visit 8
HIT-6 collection at Visit 8 
is needed for estimand 
framework
Section 1.1 Background
Added background information for China
Study will also be 
conducted in China
Section 3.1 Structure
Updated number of sites to approximately 140
For accuracy
Section 4.1 Number of 
Participants
Updated number of sites to approximately 140
For accuracy
Section 4.3 Exclusion 
Criteria, criterion 5
Added recently approved botulinum toxin injections, 
Myobloc® and JeuveauTM
For clarity and 
completeness
Section 4.3 Exclusion 
Criteria, criterion 24
Corrected a typographical error in the developmental 
name of atogepant (MK8031)
To correct an error
Section 4.4.2 Prohibited 
Medications/Treatments
Added language to exclude use of medications with 
demonstrated efficacy for the prevention of migraine for 
indications other than migraine prevention
For clarity
Section 4.4.2 Prohibited 
Medications/Treatments
Added recently approved botulinum toxin injections, 
Myobloc® and JeuveauTM
For clarity and 
completeness
Section 4.4.2 Prohibited 
Medications/Treatments
Added:

For China, South Korea, and Taiwan, herbal 
and traditional medicine is prohibited from the 
time the ICF is signed and for the duration of 
study participation.
To clarify that herbal and 
traditional medicines are 
prohibited in countries 
where they are commonly 
used
Section 6.1 Efficacy 
Measures
Corrected the Study Days and visit windows for the 
EQ-5D-5L
To correct an error
Section 6.5.3 Clinical 
Laboratory 
Determinations, Table 6-1 
Clinical Laboratory 
Parameters 
Deleted gamma glutamyl transferase
Parameter is not measured
Section 7.2.2 Secondary 
Efficacy Endpoints
Added text to clarify the secondary efficacy endpoints 
for China
Study will also be 
conducted in China
Section 7.2.2 Secondary 
Efficacy Endpoints
Added text to clarify the secondary efficacy endpoints 
for Canada
Study will also be 
conducted in Canada


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Section
Revision
Rationale
Section 7.2.3 Additional 
Efficacy Endpoints
Deleted text concerning countries for additional efficacy 
endpoints
For clarity, because 
additional efficacy 
endpoints are the same for 
all countries
Section 7.2.3 Additional 
Efficacy Endpoints
Added ≥ 30% as an additional range for responders
To add granularity to the 
analysis of additional 
efficacy endpoints
Section 7.2.3 Additional 
Efficacy Endpoints
Added Canada to the countries where “Change from 
baseline in the HIT-6 total score at Weeks 4 and 8” will 
be analyzed
Canada is using the 
European Union 
endpoints
Section 7.2.3 Additional 
Efficacy Endpoints
Added China to the countries where “Change from 
baseline in the HIT-6 total score at Weeks 4, 8, and 12” 
will be analyzed
China is using the United 
States endpoints
Section 7.2.3 Additional 
Efficacy Endpoints
Added Canada to the countries where “Change from 
baseline in mean monthly performance of daily activities 
domain score of the AIM-D across the 12-week 
treatment period” and “Change from baseline in mean 
monthly physical impairment domain score of the 
AIM-D across the 12-week treatment period” are 
analyzed
Canada is using the 
European Union 
endpoints
Section 7.5 Subgroup 
Analyses
Updated text for subgroup analysis
For clarity
Section 8.1.3 Procedure 
for Duplicate Participant 
Identification – Verified 
Clinical Trials
Changed ROW to Canada
VCT only used in the 
United States and Canada
Section 8.4.1 Visit 1 
(Screening/Baseline) 
Day -35 to Day -28
Changed “if applicable” to United States and Canada 
only
VCT only used in the 
United States and Canada
Section 8.4.3.1 Visit 
8/End of Study (Week 16)
Added HIT-6
HIT-6 is being collected 
for all participants at 
Week 16
Section 8.8.1 Participants 
Who Discontinue Study 
Intervention Early, 
Figure 2 Study Diagram 
for Estimand Framework
Replaced the study diagram
To correct an error
Section 10 Administrative 
Items
Added text to clarify that relevant local regulations 
should be followed
For clarity
Section 11 References
Added references for China background
Migraine background in 
China was added to 
Section 1.1
Section 12.2 Examples of 
Prohibited Medications
Aligned text for treatments prohibited 6 months prior to 
screening and throughout the study period with the text 
in the protocol body
For clarity and internal 
consistency


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Section
Revision
Rationale
Section 12.3.1 List of 
Migraine Preventive 
Medications With Proven 
Efficacy
Added “(non-United States only)” to Miscellaneous 
category
For clarity
Section 12.3.2 Criteria for 
Determining That a Prior 
Migraine Preventive 
Medication has Been 
Failed
Updated the failure definition
The definition of failure 
has changed


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12.7
Protocol Amendment 2 Summary
Title: 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)
Protocol 3101-303-002
Date of Amendment 2: 23 September 2019
Amendment Summary
This amendment includes changes made to Protocol 3101-303-002 Amendment 1, dated 
08 April 2019. The protocol was amended to: 

Add instructions for study conduct in Japan 

Add instruction regarding Visit 8 (follow-up) for participants in Japan and China who may 
rollover to a regional, long-term, extension, safety study

Clarify secondary efficacy endpoints for Europe and Canada, and for all other regions except 
Europe and Canada

Update description of the AIM-D health outcomes measure and endpoints

Describe 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

Describe weekly data analysis procedures for other efficacy analyses

Describe planned subgroup analyses to evaluate consistency of treatment across regions and 
subpopulations

Update description of safety analysis

Clarify criteria for sexual abstinence to be considered as a highly effective contraceptive 
method 
Add a benefit/risk assessment


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Add definition of the end of the study 
Clarify exclusion criterion based on hypersensitivity to study interventions
Clarify the instructions regarding prohibited medication/treatments
Clarify instructions for the participants
Clarify instructions regarding assessment of causality of adverse events
Add definition of adverse reaction, serious adverse reaction, and suspected unexpected serious 
adverse reaction
Clarify instruction regarding changes to the protocol.
The table below provides details on the content changes that were made in the protocol, and a 
brief rationale for these changes. Minor editorial and document formatting revisions have not 
been summarized.


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Section
Revision
Rationale
Protocol Summary
Bolded text added to Number of Participants: 
Approximately 750 participants will be randomized into 
this global study (North America, Europe, Japan, 
China, Other).
Clarification
Protocol Summary, 
Table 1 Schedule of Visits 
and Procedures, 
Section 3.1 Structure
Clarified end of study visit schedule for participants in 
Japan and China who may rollover to a regional, long-
term, extension, safety study
Clarification
Table 1 Schedule of Visits 
and Procedures
Consolidated rows pertaining to eDiary, AIM-D and 
activity level and activity limitation:
“Review eDiary data (headache duration, frequency, 
characteristics and symptoms, acute medication use, 
AIM-D, activity level and activity limitation) and 
compliancei”
Clarification, as AIM-D, 
activity level and activity 
limitation data are also 
recorded on eDiary
Table 1 Schedule of Visits 
and Procedures,
Section 8.4.2.3 Visit 7/ Early 
Termination Week 12),
Section 8.4.3.1 Visit 8/ End 
of Study (Week 16)
Clarified when the eDiary is to be collected for 
participants who complete the double-blind treatment 
period and for those patients who discontinue study 
intervention early
Clarification
Section 1.1 Background
Added background information for Japan
Study will also be 
conducted in Japan
Section 1.5 Benefit/ Risk 
Assessment
Added Section 1.5 Benefit/Risk Assessment 
Added in accordance 
with EU protocol review
Section 3.4 End of Study 
Definition
Added Section 3.4 End of Study Definition
“The end of the study is defined as the date of the last 
visit of the last participant in the study.”
Added in accordance 
with EU protocol review 
Section 4.3 Exclusion 
Criteria
Bolded text added to exclusion criterion #25:
25. History of hypersensitivity or clinically significant 
adverse reaction to a CGRP receptor antagonist or 
hypersensitivity to any component of the study 
interventions (atogepant or placebo).
Clarification 
Section 4.4.2 Prohibited 
Medications/Treatments
Bolded text added and strikethrough text removed:
Therapy considered necessary for the participant's 
welfare may be given at the discretion of the 
investigator. The decision to administer a prohibited 
medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, 
Allergan should be notified before the prohibited 
medication/treatment is administered. The sponsor
should be notified about administration of prohibited 
medication/treatment as soon as possible.
Asterisks added to indicate the specified medications that 
are not approved in Japan. 
Clarified that herbal and traditional medicine is also 
prohibited in Japan.
Clarification 


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Section
Revision
Rationale
Section 4.4.3 Definition of 
Women of (Non-) 
Childbearing Potential 
and/or Acceptable 
Contraceptive Methods
Bolded text added to definition of sexual abstinence
Sexual abstinence, defined as refraining from 
heterosexual intercourse for the entire duration of the 
study, from Visit 1 through the end of study (Visit 
8/Safety Follow-up Visit). 
o
Note: Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not 
an acceptable method of contraception. The 
reliability of sexual abstinence should be 
evaluated in relation to the duration of the 
clinical trial and the preferred and usual 
lifestyle of the participant.
Clarification in 
accordance with UK’s 
MHRA request
Section 4.4.4 Special Diet or 
Activities
Added mL equivalents to the definition of an alcohol 
drink.
Clarification
Protocol Summary,
Section 6.1 Efficacy 
Measures, 
Section 6.2.1 Activity 
Impairment in Migraine –
Diary (AIM-D),
Section 6.2.2 Activity Level 
and Activity Limitation
Updated description of AIM-D
Patient Difficulty in Concentrating and Difficulty in 
Thinking Clearly items are no longer considered stand-
alone items but part of the AIM-D
Based on psychometric 
(quantitative) analyses, 
AIM-D is now an 
11-item PRO measure
that includes the items 
'patient difficulty in 
concentrating' and 
'difficulty in thinking 
clearly'.
Protocol Summary,
Section 7.2.2 Secondary 
Efficacy Endpoints
Clarify secondary efficacy endpoints for Europe and 
Canada, and for all other regions except Europe and 
Canada
Updated secondary efficacy endpoints related to AIM-D 
To specify key 
secondary endpoints by 
region.
To align with updated 
AIM-D description
Section 7.2.3 Additional 
Efficacy Endpoints
Updated additional efficacy endpoints for HIT-6.
Added change from baseline in weekly migraine days at 
Weeks 1-4.
Updated additional efficacy endpoints related to AIM-D
To align with the 
estimand framework
To understand the onset 
effect
To align with updated 
AIM-D description
Section 7.3.2 Secondary 
Efficacy Analyses
Updated description of AIM-D endpoints
Added description of 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.
To align with updated 
AIM-D description
To align with PMDA’s 
feedback
Section 7.3.3 Additional 
Efficacy Analyses
Describe weekly data analysis procedures for other 
efficacy analyses.
To understand the onset 
effect
Section 7.3.4 Safety 
Analysis
Updated description of safety analyses.
Clarification


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Protocol 3101-303-002 Amendment 3
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Section
Revision
Rationale
Section 7.5.1 Subgroup 
Analyses for Evaluating the 
Consistency of Treatment 
Effects Across Regions and 
Subpopulations
Added description of subgroup analyses to evaluate 
consistency of treatment effects across regions and 
subpopulation.
Description of other subgroup analyses was moved to 
Section 7.5.2.
Study will be conducted 
in multiple regions. 
Section 8.1.3 Procedure for 
Duplicate Participant 
Identification – Verified 
Clinical Trials,
Section 8.4.1 Visit 1 
(Screening/Baseline) Day --5 
to Day -28
Added the phrase “at participating sites” to text 
describing VCT.
For clarification, as VCT 
is optional for sites in 
Canada
Section 8.4.2.2 Visits 3 to 6 
(Week 2 to 8),
Section 8.4.2.3 Visit 7/Early 
Termination (Week 12)
Removed duplicate bullet:

Review medication compliance
Clarification, as review 
of medication 
compliance is included 
in bullet that states: 
“Collect previous visit 
study intervention, 
review participant 
compliance, and perform 
accountability”
Section 8.5 Instructions for 
the Participants
Bolded text added to instruction for taking study 
intervention:
Study intervention may be taken with or without 
food. Water is allowed as desired.
Clarification 
Section 9.1.4 Assessment of 
Causality
Bolded text added to bullet point below:
•
For each AE or SAE, the investigator must document 
in the medical notes that he/she has reviewed the AE 
or SAE and has provided an assessment of causality. 
In evaluating causality, the investigator will need 
to make a Yes/No assessment (ie, related or not 
related) regarding a reasonable possibility that the 
study intervention caused the event.
Clarification 


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Section
Revision
Rationale
Section 9.1.6 Adverse 
Reactions, Serious Adverse 
Reactions, and Suspected 
Unexpected Serious Adverse 
Reactions
Added Section 9.1.6 Adverse Reactions, Serious Adverse 
Reactions, and Suspected Unexpected Serious Adverse 
Reactions with the following text:
“For the purposes of expedited reporting within the EU, 
the Sponsor will follow the applicable definitions for 
ARs, SARs, and SUSARs (for example, as outlined in 
Article 2 [n,o,p] of Directive 2001/20/EC, see below). 
Also, seriousness criteria for AEs/ARs (as would apply to 
SARs and SUSARs) are currently included in the 
protocol, listed in Section 9.1.2.
•
Adverse Reaction: all untoward and unintended 
responses to an investigational medicinal product 
related to any dose administered
•
Serious Adverse Reaction: an adverse reaction that 
results in death, is life-threatening, requires 
hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or 
birth defect (see Section 9.1.2 for further details 
pertaining to seriousness criteria)
•
Suspected Unexpected Serious Adverse Reaction: a 
serious adverse reaction, the nature or severity of 
which is not consistent with the applicable product 
information (eg, the Investigator’s Brochure).”
Added in accordance 
with EU protocol review 
Section 9.4 Exposure to 
Study Intervention During 
Pregnancy
Strikethrough font removed from statement below:
Abnormal pregnancy outcomes (eg, spontaneous or 
elective abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Elective abortions can be SAEs or AEs depending on the 
reason for the elective abortion (eg, fetal death, still birth, 
congenital anomalies, ectopic pregnancy, which would 
make the elective abortion an SAE).
Clarification
Section 10.3 Changes to the 
Protocol
Bolded text added:
The investigator must not implement any deviation from 
or changes of the protocol without approval by the 
sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC (and the 
appropriate regulatory agency, if required by 
national law) of a protocol amendment, except where 
necessary to eliminate immediate hazards to study 
participants, or when the changes involve only logistical 
or administrative aspects of the study (eg, change in 
monitors, change of telephone numbers).
Clarification 
Section 11 References
Updated reference list.
In accordance with 
amendment revisions
Section 12.2 Examples of 
Prohibited Medications
Asterisks added to indicate the specified medications that 
are not approved in Japan.
Clarification 


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12.8
Protocol Amendment 3 Summary
Title: 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)
Protocol 3101-303-002
Date of Amendment 3: 29 May 2020
Amendment Summary
This amendment includes changes made to Protocol 3101-303-002 Amendment 2, dated 
23 September 2019. 
The following is a summary of changes that were made to each section of the protocol, and a 
brief rationale for these changes.
Minor editorial and document formatting revisions have not been summarized.
Section
Revision
Rationale
Protocol Summary,
Study Design: 
Randomization/
Stratification
Added footnote 2:
Approximately 70% of randomized participants will have taken at least 
1 prior migraine prevention medication with proven efficacy (see 
Attachment 12.3).2
2: All French participants must have taken at least 1 prior migraine 
prevention medication with proven efficacy to be eligible for Study 
3101-303-002.
Requirement by 
French authorities.
Added text: 
Approximately 70% of randomized participants will have taken at least 
1 prior migraine prevention medication with proven efficacy (see 
Attachment 12.3).2 Randomization will be stratified based on migraine 
prevention medication exposure (Current Use, Past Use, or Never 
Used) with proven efficacy. Participants with current or past use will 
be further stratified based on the number of medications failed with 
unique mechanisms of action: “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” or “failed 2 to 4 
medications with different mechanisms of action” (see 
Attachment 12.3). Enrollment of participants with current use of a 
migraine prevention medication will be capped at ~15%.
Based on data 
review of recent 
migraine 
prevention studies
Added bullet:
Randomization will be stratified by region (ie, North America, 
Europe, Japan, China, Other)
Clarification of the 
randomization and 
stratification 
process to include 
region


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Section
Revision
Rationale
Protocol Summary,
Study Design: Visit 
Schedule
Revised text:
Participation will begin with a 4-week screening/baseline period. 
Participants who complete the 4-week screening/baseline period and meet 
all entry criteria will be randomized to the double-blind treatment period 
of the this study at Visit 2 (Randomization Visit). The double blind 
treatment period will last 12 weeks, with a subsequent follow-up period of 
4 additional weeks. 
There will be 8 scheduled clinic visits: Visit 1 (screening/baseline), 
Visit 2 (randomization), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 
(Week 6), Visit 6 (Week 8), Visit 7 (Week 12), and Visit 8 (follow-up). 
The Visit 8 (follow-up) must be completed for all participants who take at 
least 1 dose of study medication, except for participants rolling over into 
Study 3101-312-002 (long-term safety extension study in regions, 
excluding Japan and China), Study 3101-306-002 (long-term safety 
extension study in Japan), or Study 3101-311-002 (open-label safety 
extension study in China). For these rollover participants Visit 8 of Study 
3101-303-002 is not required, because the Follow-up Visit (Visit 8) will 
be performed after the OL treatment in the respective long-term safety 
study. For participants who screen fail for the long-term safety study, the
Follow-up Visit (Visit 8) of Study 3101-303-002 must be completed. For 
more details, see Table 1, Schedule of Visits and Procedures.
Clarified 
participation in 
Visit 8/EOS for 
rollover 
participants, by 
region and 
respective long-
term safety 
extension study, 
and added 
information to 
allow for 
participants to roll 
over to the 
respective OL 
long-term 
extension study.
Protocol Summary,
Study Population 
Characteristics, 
Number of 
Participants
Revised text:
(North America, Asia/Pacific, and Europe) was changed to: (ie, North 
America, Europe, Japan, China, Other)
Adapted 
description of 
regions for 
consistency with 
stratification
Protocol Summary,
General Statistical 
Methods and Types 
of Analyses
Revised text:
All efficacy analyses will be performed using the modified intent-to-treat 
(mITT) population, which consists of all randomized participants who 
received at least 1 dose of study intervention, had an evaluable baseline 
period of eDiary data and at least 1 evaluable postbaseline 4-week period 
(Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind 
treatment period. All safety analyses will be performed using the safety 
population, which consists of all participants who took at least 1 dose of 
study intervention. The analysis population for Off-treatment 
Hypothetical Estimand includes 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
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. This population is used for the primary estimand 
to support filing in Europe.
Clarification and 
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.
Protocol Summary,
General Statistical 
Methods and Types 
of Analyses, 
Primary Efficacy 
Endpoint
Added subsection on primary endpoint definition (matching protocol 
Section 7.2.1):
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in mean 
monthly migraine days across the 12-week treatment period. Baseline 
is defined as the number of migraine days during the last 28 days 
prior to the randomization date.
And edited sentence to add ‘region’ to statistical model: 
The statistical model will include treatment group, visit, region, acute 
medications during the baseline period (medication overuse Y/N), current 
and past use of migraine prevention medications and the number of 
medications failed with unique mechanisms of action (Current Use and 
“failed 0 medications or failed 1 or more medication(s) with the same 
Clarification of 
primary endpoint
and added the 
statistical model 
term ‘region’ to
the MMRM model
for primary 
analysis.


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mechanism of action”, Current Use and “failed 2 to 4 medications with 
different mechanisms of action”, Past Use only and “failed 0 medications 
or failed 1 or more medication(s) with the same mechanism of action”, 
Past Use only and “failed 2 to 4 medications with different mechanisms of 
action”, and Never Used), and treatment group by visit interaction as 
categorical fixed effects.
Protocol Summary,
General Statistical 
Methods and Types 
of Analyses, 
Secondary Efficacy 
Endpoints for all 
regions, except 
Europe and 
Canada:
Revised text:
Change from baseline in mean AIM D monthly functioning and 
activity impairment score across the 12 week treatment period
Changed the above/previous AIM-D endpoint to the following 
2 endpoints:
Change from baseline in mean monthly Performance of Daily 
Activities domain score of the AIM-D across the 12-week treatment 
period.
Change from baseline in mean monthly Physical Impairment 
domain score of the AIM-D across the 12-week treatment period. 
Clarification of 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
Protocol Summary,
General Statistical 
Methods and Types 
of Analyses,
Secondary Efficacy 
Endpoints for all 
regions
Changed wording of secondary endpoints for all regions to:
At least a 50% reduction in 3-month average of monthly migraine 
days
To clarify 
secondary 
endpoints
Protocol Summary,
General Statistical 
Methods and Types 
of Analyses,
Secondary Efficacy 
Endpoints
Revised text:
The secondary endpoints for headache days, acute medication use days, 
MSQ v2.1 Role Function-Restrictive domain score, AIM D functioning 
and activity impairment scorePerformance of Daily Activities domain 
score of the AIM-D, Physical Impairment domain score of the 
AIM-D, and HIT-6 total score will be analyzed in the same manner as 
that used to analyze the primary endpoint.
The secondary endpoint of 50% responders, defined as participants 
with at least a 50% reduction from baseline in the 3-month average of 
monthly migraine days, will be assessed for each individual.The 
secondary endpoint of at least a 50% reduction from baseline in monthly 
migraine days will be summarized for each 4 week period during the 12
week treatment period.
A logistic regressiongeneralized linear mixed model will be used to 
analyze 50% responders as repeated measures across the 12-week 
treatment period. This model assumes a binary distribution for the 
response and uses a logit link. The analysis model will include treatment 
group, regionvisit, acute medications during the baseline period 
(medication overuse Y/N), current and past use of migraine prevention 
medications and the number of medications failed with unique 
mechanisms of action, and treatment group by visit interaction as 
categorical fixed effects; baseline value and baseline by visit interaction 
will be included as a covariates. Participants will be included as random 
effects with unstructured covariance matrix in the model to account for 
the correlation among repeated measurements. The analysis will be 
performed based on all postbaseline values using only the observed cases 
without imputation of missing values. The treatment difference in terms 
of odds ratio between each atogepant dose group and placebo will be 
estimated and tested from this model. 
Clarification that 
50% responder 
will be assessed 
for each 
individual. The 
corresponding 
model is changed 
consequently.
Clarification of 
statistical analysis 
model for 
secondary analysis


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Table 1 Schedule of 
Visits and 
Procedures 
Added table footnote a:
a: Visit 1, Visit 2, and either Visit 3 or Visit 4 must be conducted in 
office. All other visits, should be conducted in office unless it is 
necessary to conduct remote visits for the safety of participants (eg, 
COVID-19 or other pandemic): for details please refer to the Remote 
Visit Schedule of Assessments in Attachment 12.4)
Added table footnote c:
c: All participants who take at least 1 dose of study intervention must 
complete the follow-up period, except for participants rolling over 
into Study 3101-312-002 (long-term safety extension study in regions 
excluding Japan and China), participants rolling over into 
Study 3101-306-002 (long-term safety extension study in Japan), or 
Study 3101-311-002 (open-label safety extension study in China). For 
these rollover participants the Follow-up Visit will be performed after 
the completion of the OL treatment in the respective long-term safety 
extension study.
Added to table footnote j:
j: Clinicians will complete on eTablet. The screening/baseline 
assessment of the C-SSRS will be completed. At all other visits, the 
‘Since Last Visit’ C SSRS will be completed.
Added table footnote k:
k: Participant will complete on eTablet.
Added table footnote n:
n: eDiary will be collected on Visit 2 for screen failures.
Added table footnote q:
q: The first dose of study intervention should be taken at the study 
site.
To add flexibility 
and safety for 
participants and 
staff to the 
conduct of this 
study, when 
remote visits are 
necessary due to 
COVID-19 or 
other pandemic
Clarified 
participation in 
Visit 8/EOS for 
rollover 
participants, by 
region and 
respective long-
term safety 
extension study, 
added information 
to allow for 
participants to roll 
over to the 
respective OL 
long-term 
extension study.
Clarifications
Section 3 Study 
Design, Section 3.1 
Structure 
Added footnote 2: 
Approximately 70% of randomized participants will have taken at least 
1 prior migraine prevention medication with proven efficacy (see 
Attachment 12.3).2
2: All French participants must have taken at least 1 prior migraine 
prevention medication with proven efficacy to be eligible for Study 
3101-303-002. 
Requirement by 
French authorities.
Added text: 
Approximately 70% of randomized participants will have taken at least 
1 prior migraine prevention medication with proven efficacy (see 
Attachment 12.3).2 Randomization will be stratified based on migraine 
prevention medication exposure (Current Use, Past Use, or Never 
Used) with proven efficacy. Participants with current or past use will 
be further stratified based on the number of medications failed with 
unique mechanisms of action: “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” or “failed 2 to 
4 medications with different mechanisms of action” (see 
Attachment 12.3). Enrollment of participants with current use of a 
migraine prevention medication will be capped at ~15%.
Based on data 
review of recently 
published 
migraine 
prevention studies
Added bullet:
Randomization will be stratified by region (ie, North America, 
Europe, Japan, China, Other)
To clarify the 
randomization 
stratification 
process.


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Changed text:
Participation will begin with a 4-week screening/baseline period. 
Participants who complete the 4-week screening/baseline period and meet 
all entry criteria will be randomized to the double-blind treatment period 
of the this study at Visit 2 (Randomization Visit). The double blind 
treatment period will last 12 weeks, with a subsequent follow-up period of 
4 additional weeks. 
There will be 8 scheduled clinic visits: Visit 1 (screening/baseline), Visit 
2 (randomization), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), 
Visit 6 (Week 8), Visit 7 (Week 12), and Visit 8 (follow-up). The Visit 8 
(follow-up) must be completed for all participants who take at least 1 
dose of study medication, except for participants rolling over into 
Study 3101-312-002 (long-term safety extension study in regions, 
excluding Japan and China), Study 3101-306-002 (long-term safety 
extension study in Japan), or Study 3101-311-002 (open-label safety 
extension study in China). For these rollover participants Visit 8 of 
Study 3101-303-002 is not required, because the Follow-up Visit (Visit 
8) will be performed after the OL treatment in the respective long-
term safety study. For participants who screen fail for the long-term 
safety study, the Follow-up Visit (Visit 8) of Study 3101-303-002 must 
be completed. For more details on detailsstudy schedule, please see 
Table 1, Schedule of Visits and Procedures.
Only Japanese or Chinese participants completing the double blind 
treatment period in this study may be eligible to continue in either Study
3101 306 002 (long term safety extension study in Japan) or Study 3101
311 002 (long term safety extension study in China). For these rollover 
participants, a Visit 8 is not required in the present study, as the Follow
up Visit will be performed in the long term safety study. For participants 
who screen fail for the long term safety study, the Follow up Visit must 
be completed.
Clarified 
participation in 
Visit 8/EOS for 
rollover 
participants, by 
region and 
respective long-
term safety 
extension study. 
And added 
information to 
allow for 
participants to roll 
over into the 
respective OL 
long-term 
extension study.
Section 3.4 End of 
Study Definition
Added sentence:
The end of the study is defined as the date of the last visit of the last 
participant in the study. For Russia, end of study is defined as the last 
Close Out Visit.
To comply with 
Russian 
requirement to call 
it Close Out Visit
Section 4.1 Number 
of Participants
Revised text:
(North America, Asia/Pacific, and Europe) was changed to: (ie, North 
America, Europe, Japan, China, Other)
Adapted 
description of 
regions for 
consistency with 
stratification
Section 4.3, 
Exclusion Criterion 
number 14. 
Changed text:
14. Any clinically significant hematologic, endocrine, cardiovascular, 
cerebrovascular, pulmonary, renal, hepatic, gastrointestinal, or 
neurologic disease
Clarification 


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Section 4.4.2 
Prohibited 
Medications/
Treatments
Revised text and added bullet:

Medications with demonstrated efficacy for the prevention of 
migraine (eg, amitriptyline, propranolol, topiramate) are prohibited 
when used for any indication other than migraine prevention. See 
Attachment 12.3.
o
Participants taking one medication with demonstrated efficacy 
for the prevention of migraine may be randomized provided that 
in the opinion of the investigator:

Dose has been stable and the medication has been well-
tolerated for at least 12 weeks prior to Visit 1 AND

Participant is willing and able to maintain at a stable dose 
and dosage regimen during the study, which should be 
assessed to ensure compliance at each study visit

Enrollment of participants with current use of a 
migraine prevention medication will be capped at 
~15%

…

Cannabidiol (CBD) oil, cannabis.
Clarification
Section 4.5 Screen 
Failures
Revised text:
Screen failures are defined as participants who consent to participate in 
the study but are not subsequently randomized to treatment. Rescreening 
of screen failures is permitted in certain situations (ie, failure to 
adequately screen due to COVID-19), with permission from the 
sponsor. However, participants with clinically significant laboratory 
values at Visit 1 (ie, screening; including ALT or AST >1 × the ULN, 
total bilirubin >1 × ULN or serum albumin < 2.8 g/dL), or those with a 
positive UDS result at Visit 1 for recreational (including marijuana 
regardless of legality) or illicit drugs or non-disclosed5 concomitant 
medications are not allowed to be rescreened. 
Footnote 5: For participants in the People’s Republic of China, a 
positive UDS will result in screen failure regardless of disclosed 
concomitant medications.
And for Table 3 in Section 6.5.3, the same footnote was added as table
footnote
Clarification 
Section 5.2 Control 
Intervention(s)
Revised text:
5.2 Control Interventions and Formulations
Tablets containing matching placebo 30 mg (Formulation 011326X) for
atogepant 30 mg and matching placebo 60 mg (Formulation 011317X) 
for atogepant 60 mg .
Clarification 
Section 5.3 
Methods for 
Masking/Blinding
Revised text:
All participants will be instructed to take their study intervention twice 
daily (2 tablets in the morning and 2 tablets in the evening) at 
approximately the same times each day. Participants, therefore, will 
receive either placebo BID, atogepant 30 mg BID, or a morning dose of 
atogepant 60 mg with an evening dose of placebo.
Clarification of 
blinded study 
intervention taken 
by eligible 
participants
Section 5.4 
Treatment 
Allocation Ratio 
and Stratification
Added bullet:
Randomization will be stratified by region (ie, North America, 
Europe, Japan, China, Other)
Clarification of the 
randomization and 
stratification 
process to include 
region


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Section 5.6 Study 
Intervention 
Regimen and 
Dosing
Revised text and Table 2:
Treatments to be used in this trial are listed in Table 2. Participants who 
meet all the study entry criteria at Visit 2 will be randomized and 
provided with study intervention to be taken on an outpatient basis. Sites 
will subsequently dispense study intervention to participants at Visits 3, 4, 
5, and 6. Participants will take their first dose of study intervention at the 
clinic at Visit 2. All participants will be instructed to take their study 
intervention twice daily (2 tablets in the morning and 2 tablets in the 
evening) at approximately the same times each day. Details of PK 
samples with respect to timing of study intervention are provided in 
Section 6.3. Study intervention will be administered orally for 12 weeks, 
and participants will be followed for 4 weeks following study completion 
or discontinuation of study intervention.
Table 2 Study Interventions
Drug/
Dose
Study Intervention Product 
and Matching Placebo
Study 
Intervention 
Frequency
Route of 
Admini-
stration
Placebo
Placebo 30 mg and Placebo 60 mg
BID
Oral
Atogepant 
30 mg 
Atogepant 30 mg and Placebo 60 
mg
BID
Oral
Atogepant 
60 mg 
AM: Atogepant 60 mg and
Placebo 30 mg
BID
Oral
PM: Placebo 30 mg and Placebo 
60 mg
AM = morning dose; BID = twice daily; PM = evening dose.
Clarification of 
blinded study 
intervention taken 
by eligible 
participants
Section 6.2.1 
Activity 
Impairment in 
Migraine – Diary 
(AIM-D)
Revised text:
The AIM-D is an 11-item daily diaryPRO measure that assesses the 
impact of migraine functioning and is comprised of two domains that 
evaluate performance of daily activities (7 items) and physicalactivity
impairment (4 items).in migraine patients. Participants are asked to rate 
the level of difficulty experienced in the past 24 hours with performance 
of daily activitiesfunctioning and activity impairment (ie, 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 (ie, difficulty walking, 
moving body, bending forward, moving head) , concentrating, and 
thinking clearly) using the 6-point rating scale: ranging from “Not 
difficult at all,” “A little difficult,” “Somewhat difficult,” “Very difficult,” 
“Extremely difficult,” and “I could not do it at all.” Three items include a 
response of “I did not…,” for example, “I did not have errands planned.” 
The AIM-D was developed as an electronica daily deDiary with the same 
set of questions administered in headache and non-headache versions. The 
Headache version is administered on days when a participant reports a 
headache and the Non-Headache version is administered on days when a 
participant does not report having a headache. The AIM-D instructs 
participants to answer each question based on the level of difficulty 
experienced in the past 24 hours for both versions, with “during your 
headache” indicated for the AIM-D Headache version. In addition to the 
two domainAIM D scores, a total score using all 11 items can also be 
calculated. Each raw daily domain score, as well as the raw daily total 
Clarification of the 
AIM-D diary 
questionnaire, 
based on 
psychometric 
evidence of the 
AIM-D consisting 
of 2 domains, 
performance of 
daily activities and 
physical 
impairment


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score, are transformed to a range from 0-100 scale, to 5 with higher 
scores indicating greater impact of migraine (ie, higher disease 
burden).in functioning and activity impairment.
Section 6.7 
Summary of 
Methods of Data 
Collection
Revised text:
An IWRS will be used to randomize participants and manage study 
intervention inventory. All office visit data (ie, non-diary data) for this 
study will be collected by either on the eTablet or, if conducted remotely 
(Attachment 12.4), utilizing a web-portal (eg, questionnaires for PROs) 
or eCRFs via an electronic data capture system.
To adapt text to 
remote visits 
necessary due to 
COVID-19
Section 7.1 
Analysis 
Populations
Added text to first paragraph:
The ITT population will consist of all randomized participants. All 
efficacy analyses will be performed using the mITT population, consisting 
of 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 postbaseline 4-week period (Weeks 1 to 4, 5 to 8, and 
9 to 12) of eDiary data during the double-blind treatment period. All 
safety analyses will be performed using the safety population, consisting 
of all participants who received at least 1 dose of study intervention. 
Added 2nd paragraph:
The primary efficacy analysis population to support filing in Europe 
for off-treatment estimand (defined in Section 7.4) includes 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 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. 
Clarification and 
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.
Section 7.2 
Collection and 
Derivation of 
Primary and 
Secondary Efficacy 
Assessments
Revised text:
On a daily basis during the 28-day baseline period and throughout the 
studydouble blind treatment period, participants are to record, into an 
eDiary, information on the daily total duration of headache, headache 
specific characteristics and symptoms, the worst pain severity, and use of 
any acute medication. 
Therefore, for data analysis purposes, the number of migraine days during 
the last 28 days prior to the randomization date of the baseline phase 
(ie, Day 28 to 1), will serve as the baseline, and change from baseline 
will be calculated for consecutive 28-day periods beginning with the date 
of the first dose of study interventionDay 1.
Clarification of 
collection of 
migraine days and 
baseline for 
migraine days 
Section 7.2.1 
Primary Efficacy 
Endpoint
Revised text:
The primary efficacy endpoint is the change from baseline in mean 
monthly migraine days across the 12-week treatment period. Baseline is 
defined as the number of migraine days during the last 28 days prior to 
the randomization date. of the baseline phase (ie, Day 28 to 1)
Clarification of 
primary endpoint 
Section 7.2.2 
Secondary Efficacy 
Endpoints for all 
regions, except 
Europe and Canada
Revised text:
Change from baseline in mean AIM D monthly functioning and 
activity impairment score across the 12 week treatment period
Changed the above/previous AIM-D endpoint to the following 
2 endpoints:
Change from baseline in mean monthly Performance of Daily 
Activities domain score of the AIM-D across the 12-week treatment 
period.
Change from baseline in mean monthly Physical Impairment 
domain score of the AIM-D across the 12-week treatment period. 
Clarification of 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


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Section 7.2.2 
Secondary Efficacy 
Endpoints 
Secondary Efficacy 
Endpoints for all 
regions, except 
Europe and Canada, 
and for Europe and 
Canada
Changed wording of secondary endpoints to:
At least a 50% reduction in 3-month average of monthly migraine 
days
To clarify that 
50% responder 
will be assessed 
for each 
individual. The 
corresponding 
model is changed 
consequently.
Section 7.2.3 
Additional Efficacy 
Endpoints
Added text:
Additional efficacy endpoints for the United States and the Europe 
are provided below. Related analysis will be documented in the SAP.
Added text for 
clarification 
Section 7.2.3 
Additional Efficacy 
Endpoints
Changed, added, and deleted additional efficacy endpoints:
≥ 25%, ≥ 30%, ≥ 75%, 100% improvement (decrease) in 3-month 
average of monthly migraine days across the 12 week treatment 
period
Change from baseline in monthly headache free days at Weeks 1 to 4, 5 
to 8, 9 to 12, and average across the 12 week treatment period
Change from baseline in monthly headache day pain intensity at Weeks 
1 to 4, 5 to 8, 9 to 12, and average across the 12 week treatment period
Participant having a migraine day on the day of initial dose and on 
each day of the 6 days post the initial dose.
Participant assessed by the PGIC as “much better” or “very much 
better” at Week 12
Participant reporting “satisfied” or “extremely satisfied” with study 
medication for migraine prevention at Weeks 4, 8, and 12
Change from baseline in EQ 5D 5L descriptive system index score at 
Weeks 1 to 2, at specified windows around Weeks 4, 6, 8, 12, and 
Week 16
Change from baseline in the EQ 5D 5L VAS score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 12, and Week 16
Change from baseline in monthly Performance of Daily Activities 
domain score of the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
Change from baseline in monthly Physical Impairment domain 
score of the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
Change from baseline in mean monthly Performance of Daily 
Activities domain score of the AIM-D across the 12-week treatment 
period (for Europe and Canada only)
Change from baseline in mean monthly Physical Impairment 
domain score of the AIM-D across the 12-week treatment period 
(for Europe and Canada only)
Change from baseline in monthly AIM-D total score at Weeks 1 to 
4, 5 to 8, 9 to 12, and average across the 12-week treatment period
Change from baseline in AIM D monthly functioning and activity 
impairment score at Weeks 1 to 4, 5 to 8, and 9 to 12
Change from baseline in mean AIM D monthly functioning and 
activity impairment score across the 12 week treatment period (for 
Europe and Canada)
Change from baseline in PROMIS PI total score at Weeks 4, 8, and 12
To remove 
redundancy 
because monthly 
headache free days 
will be 
complementary to 
monthly headache 
day, and headache 
pain intensity can 
be interpreted 
using monthly 
moderate/severe 
days. 
To add the 
endpoint for 
evaluating the 
onset effect.


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Section 7.2.3.1 
Other Health 
Outcome Variables
Moved the following additional efficacy endpoints from Section 7.2.3 to
this subsection:
Change from baseline in EQ-5D-5L descriptive system index score 
at Weeks 1 to 2, at specified windows around Weeks 4, 6, 8, 12, and 
16
Change from baseline in the EQ-5D-5L VAS score at Weeks 1 to 2, 
at specified windows around Weeks 4, 6, 8, 12, and 16
Change from baseline in PROMIS-PI total score at Weeks 4, 8, and 
12
To classify other 
health outcomes 
together because 
related analyses 
will be described 
in the health 
economics and 
outcomes research 
SAP.
Section 7.3.1 
Primary Efficacy 
Analysis
Added 2 sentences to the 2nd paragraph in this section (description of the 
primary analysis with the MMRM model): 
This is the primary analysis method for the primary efficacy endpoint 
in support of the US filing. Only data collected during the double-
blind period will be included in the analysis. Participants are always 
analyzed based on the treatment group assigned by randomization.
Added the following 2 new subsections, each describing a different 
sensitivity analysis, as outlined below (no bold font used, for preserving 
the overview on subsections):
7.3.1.1 Sensitivity Analyses in Missing Data Handling
Multiple sensitivity analyses for missing data handling will be conducted 
and summarized below. Details of the sensitivity analyses will be 
provided in the SAP.
ANCOVA Model Based on 3-month Average of the Monthly Migraine 
Days
A supportive analysis will be performed on the primary endpoint using an 
ANCOVA model. The response variable for the ANCOVA model is the 
change from baseline in the calculated average monthly migraine days 
during the 12-week treatment period for each participant. The ANCOVA 
model includes terms for treatment, region, acute medications during the 
baseline period (medication overuse Y/N), current or past use of migraine 
prevention medications and the number of medications failed with unique 
mechanisms of action, and baseline score. The treatment difference for 
atogepant doses versus placebo will be estimated and reported along with 
the corresponding 95% CI and nominal p-value for superiority testing.
Within-group Imputation Based on Observed Data
Sensitivity analysis will be performed based on imputation using 
participants from the same treatment group with observed data under the 
MAR assumption. Missing data for participants who prematurely 
discontinued are assumed to copy the profile of participants in the same 
treatment group with observed data.
Copy-Reference Approach
Copy-reference approach will be performed on the primary endpoint to 
assess the robustness of the MMRM analysis to possible violation of the 
missing at random (MAR) assumption. This sensitivity analysis is one 
type of pattern mixture models (PMM), under which data could be 
missing not at random (MNAR), with repeated analyses combined via the 
reference based multiple imputation (MI) procedure. Participants who 
discontinued in the Atogepant groups are assumed to have no treatment 
effect after the discontinuation. Participants are assumed to copy the 
profile of placebo arm and missing values are imputed based on the 
distribution estimated from the placebo group under the MAR using copy 
reference approach.
MMRM Based on Primary Measures Collected during the Double-blind 
and Follow-up Periods
Added text to the 
description of the 
primary analysis 
with the MMRM 
model.
To align with the 
atogepant clinical 
program.


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The details for this analysis are provided in Section 7.4. The primary 
analysis in support of EU filing will serve as one sensitivity analysis in 
support of US filing.
7.3.1.2 Sensitivity Analysis for Possible Violation of Normality 
Assumption
The normality test is performed on the residuals which are generated by 
the same MMRM as used for the primary efficacy analysis. The residuals 
are scaled by the inverse Cholesky root of its estimated variance-
covariance matrix. The Kolmogorov-Smirnov test for normality is applied 
to the de-correlated and scaled residuals and normality test is rejected if 
p-value from the Kolmogorov-Smirnov test is less than 0.01. 
If the normality test is rejected, the sensitivity analysis uses MI in 
conjunction with robust regression to assess the robustness of the primary 
MMRM analysis to the possible violation of normality assumption. This 
method has been described and referred as ADAP [R] in Mehrotra 2012. 
The detail of the sensitivity analyses will be provided in the SAP.
Section 7.3.2 
Secondary Efficacy 
Analysis
Changed 1st and 2nd paragraph:
The secondary endpoints for headache days, acute medication use days, 
MSQ v2.1 Role Function-Restrictive domain score, AIM D functioning 
and activity impairment scorePerformance of Daily Activities domain 
score of the AIM-D, Physical Impairment domain score of the 
AIM-D, and HIT-6 total score will be analyzed in the same manner as 
that used to analyze the primary endpoint.
The secondary endpoint of 50% responders, defined as participants 
with at least a 50% reduction from baseline in the 3-month average of 
monthly migraine days, will be assessed for each individual. A logistic 
regressiongeneralized linear mixed model will be used to analyze 50% 
responders as repeated measures across the 12-week treatment period. 
This model assumes a binary distribution for the response and uses a logit 
link. The analysis model will include treatment group, regionvisit, acute 
medications during the baseline period (medication overuse Y/N), current 
and past use of migraine prevention medications and the number of 
medications failed with unique mechanisms of action, and treatment 
group by visit interaction as categorical fixed effects; baseline value and 
baseline by visit interaction will be included as a covariates. Participants 
will be included as random effects with unstructured covariance matrix in 
the model to account for the correlation among repeated measurements.
The analysis will be performed based on all postbaseline values using 
only the observed cases without imputation of missing values. The 
treatment difference in terms of odds ratio between each atogepant dose 
group and placebo will be estimated and tested from this model.
Clarification of 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.
To clarify that 
50% responder 
will be assessed 
for each 
individual. The 
corresponding 
model is changed 
consequently.
Section 7.3.3 
Additional Efficacy 
Analysis
Changed paragraph:
Descriptive statistics will be provided by visit for each efficacy variable 
by treatment group. Analysis of some variables will be limited to 
descriptive summary statistics. For ASC 12, the number and percentage of 
randomized participants will be summarized by presence of allodynia as 
measured by the sum of score (absence: 0 to 2, presence > 2). Details will 
be specified in the SAP.
Clarification


Allergan Confidential
Protocol 3101-303-002 Amendment 3
140
Section
Revision
Rationale
Section 7.4 Off-
treatment 
Hypothetical 
Estimand 
Framework for 
EMA
Clarified section title and added text with subsections (no bold font used 
to preserve overview over subsections) as follows:
7.4 Off-Treatment Hypothetical Estimand Framework for EMA
This section defines an estimand, termed as off-treatment hypothetical 
estimand, which will be the primary estimand in support of EU filing and 
serve as one sensitivity analysis in support of US filing.
7.4.1 Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-
blind treatment period. In addition, permissible and prohibited mediations 
are described below:
Participants are allowed to take acute migraine medications 
(Section 4.4.1) to keep the participants in the study
Medications with demonstrated efficacy for the prevention of migraine 
(eg, amitriptyline, propranolol, topiramate) are prohibited when used 
for any indication other than migraine prevention. See Attachment 12.3
o Participants taking one medication with demonstrated efficacy 
for the prevention of migraine may be randomized provided that 
in the opinion of the investigator:

Dose has been stable and the medication has been well-
tolerated for at least 12 weeks prior to Visit 1 AND

Participant is willing and able to maintain at a stable 
dose and dosage regimen during the study, which should 
be assessed to ensure compliance at each study visit

Enrollment of participants with current use of a migraine 
prevention medication will be capped at ~15%
To align with ICH 
E9R1 (issued on 
Nov 20, 2019) 
Section A.3.3.
Section 7.4.4 
Accounting of
Intercurrent Events
Changed text:
Intercurrent events and their handling rules are as follows:

Participants who started a new migraine prevention treatment 
after the first dose of DB treatment will have their data after the 
end of DB treatment period following the start of the new 
migraine prophylaxis treatment excluded from the 
analysis.Participants who discontinue study intervention and switch 
to other prophylaxis treatment will have their data collected after 
switching treatment, but such data collected after discontinuation of 
study intervention will be excluded from the analysis.

Participants who discontinue study intervention due to all reasons 
other than starting a new migraine prophylaxis 
treatmentswitching treatment will have their data collected after 
discontinuation of study intervention, and those off-treatment data 
will be included in the analysis.
Participants with missing data up to 12 week treatment period will have 
their data imputed using participants in the same treatment group who 
provide data while off study intervention. Detailed methods and 
procedures will be documented in the SAP prior to the study completion.
To align with 
atogepant clinical 
program
Section 7.4.5 
Population-Level 
Summary
Added the following text as 2nd paragraph:
Participants are always analyzed based on their treatment assignment 
by randomization. To obtain the estimate of treatment effect defined 
in the off-treatment hypothetical estimand, a MMRM similar to the 
primary analysis specified in Section 7.3.1 will be performed on 
observed data including both on-treatment and off-treatment 
monthly migraine days.
To propose the 
analysis method to 
obtain the 
population-level 
summary for the 
primary endpoint.


Allergan Confidential
Protocol 3101-303-002 Amendment 3
141
Section
Revision
Rationale
Section 7.4.6 Off-
treatment 
Hypothetical 
Estimand Approach 
for the Secondary 
Endpoints
Clarified text in 2nd paragraph:
Secondary endpoint of 50% responders will be derived using both 
on-treatment and off-treatment observed data as defined in the primary 
endpoint above. The population-level summary for this endpoint is the 
odds ratio for each atogepant group relative to placebo.
Clarification
Section 7.5.2 Other 
Subgroup Analyses
Changed first sentence to:
A subgroup analysis by exposure to migraine prevention medication, 
preventive medication failures, and by acute medication overuse is 
planned for the following efficacy endpoints:
Changed wording of secondary endpoints to:
At least a 50% reduction in 3-month average of monthly migraine 
days
At least a 75% reduction in 3-month average of monthly migraine 
days
A 100% reduction in 3-month average of monthly migraine days
Deleted the following text:
Subgroup analyses by number of preventive medications failed with 
unique mechanisms of action, by ≥ 1, ≥ 2, and ≥ 3 preventive medication 
failures (irrespective of class) and by medication overuse are also planned 
for the following efficacy endpoints:

Change from baseline in mean monthly migraine days across the 
12 week treatment period

Change from baseline in mean monthly headache days across the 
12 week treatment period

Change from baseline in mean monthly acute medication use 
days across the 12 week treatment period

At least a 50% reduction in 3 month average of monthly 
migraine days
Modified the 
description of 
responders to be 
consistent with 
Sections 7.2.2 and 
7.2.3
Subgroup analyses 
for presence of 
allodynia will be 
included in SAPs 
in support of 
business 
objectives such as 
a separate SAP 
relevant to health 
technology 
assessment and 
publications.
Section 11. 
References
Added reference:
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical 
trials with missing data using multiple imputation in conjunction with 
robust regression. Biometrics. 2012;68(4):1250-1259. 
As per text 
additions in 
Section 7.3.1 


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Protocol 3101-303-002 Amendment 3
142
Section
Revision
Rationale
Attachment 12.3
Added bullet: 
The criteria below should be used to determine how to stratify each 
participant based on the number of prior migraine preventive medications 
failed with unique mechanisms of action. Failure of a migraine preventive 
medication can be assessed on the basis of tolerability or efficacy and is 
based on investigator judgment.
For efficacy, investigators must consider:
o Failure is defined as no meaningful reduction in frequency of 
migraine days after an adequate trial of at least 2 months at 
generally accepted therapeutic doses, per investigator judgement 
and participant interview.
o Medications must have been started within the past 7 years.
o Note the following for participants who are currently taking a 
stable dose of one of the migraine prevention medications listed 
and meet the efficacy criteria:

If the participant meets all study entry criteria, this 
participant is eligible to be randomized provided that the 
participant agrees to continue to take this migraine 
preventive medication for the duration of the study.

This medication should be considered as one of the 
failed drugs for the prevention of migraine.

Enrollment of participants with current use of a 
migraine prevention medication will be capped at 
~15%
Clarification
Additional 
Attachment 12.4
Added Attachment 12.4 with text (see below) and Table 5 Remote Visits 
Schedule of Assessments, to explain in more detail the conduct of remote 
study visit for the safety of participants and site staff (ie, COVID-19 or 
other pandemic).
Remote study visits, conducted virtually or by phone, are permitted if 
the Investigator determines there to be a public health risk due to 
viral infection (eg, COVID-19) to the participant or site staff. During 
remote study visits, the Remote Visit Schedule of Assessments 
(Table 12 1) should be followed. Remote visits may be conducted 
between Visit 3 – Visit 8 but participants must attend in office 
assessments at Visit 3 or Visit 4 to ensure laboratory samples are 
obtained within the first 4-weeks of treatments and remote visits 
should not be performed for greater than 8 weeks. Missed in-person 
safety assessments (ie, clinical laboratory samples, vital signs and 
ECGs) should be collected at the next in-person visit. Patient reported 
outcomes collected on the eTablet during in-office visits, will be 
collected using a web-based portal during remote visits, if available. 
To outline conduct 
of study when 
remote visits are 
necessary due to 
COVID-19

SAP_001.pdf: 
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12 July 2021
1.0
TITLE PAGE
3101-303-002
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)
STATISTICAL ANALYSIS PLAN – AMENDMENT 1
Date: 10 April 2019
Amendment 1 (Final draft): 12 July 2021
Amendment 1 Signoff:  24 January 2022
Confidentiality Statement
This document is the property of Allergan plc and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan plc.
NCT03855137


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TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................................................1
2.0
TABLE OF CONTENTS................................................................................................................................2
List of Tables...................................................................................................................................................3
List of Figures .................................................................................................................................................4
3.0
LIST OF ABBREVIATIONS .........................................................................................................................5
4.0
INTRODUCTION...........................................................................................................................................8
5.0
STUDY OBJECTIVES.................................................................................................................................14
6.0
PARTICIPANT POPULATIONS.................................................................................................................15
6.1
Intent-to-Treat Population...............................................................................................................15
6.2
Safety Population............................................................................................................................15
6.3
Modified Intent-to-Treat Population...............................................................................................15
6.4
Off-treatment Hypothetical Estimand Population...........................................................................15
7.0
PARTICIPANT DISPOSITION ...................................................................................................................16
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ......................................................18
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ..............................................................20
9.1
Extent of Exposure..........................................................................................................................20
9.2
Measurement of Treatment Compliance.........................................................................................20
10.0
EFFICACY ANALYSES..............................................................................................................................21
10.1
Efficacy and Health Outcome Measures.........................................................................................21
10.1.1
Efficacy Measures ............................................................................................................21
10.1.2
Health Outcome Measures................................................................................................23
10.1.3
Efficacy Endpoints............................................................................................................27
10.1.4
Stratification Variables in Modeling.................................................................................30
10.2
Efficacy Analyses for Filings except Europe and Canada ..............................................................30
10.2.1
Primary Efficacy Analysis................................................................................................30
10.2.2
Secondary Efficacy Analysis............................................................................................36
10.2.3
Analyses for Additional Efficacy Endpoints and Health Outcome Endpoints..................41
10.3
Efficacy Analyses for European Medicians Agency.......................................................................47
10.3.1
Attributes of Off-treatment Hypothetical Estimand..........................................................47
10.3.2
Primary Efficacy Analysis................................................................................................49
10.3.3
Secondary Efficacy Analysis............................................................................................52
10.3.4
Additional Efficacy Endpoints and Health Outcomes Analysis .......................................56
10.4
Efficacy Analysis for Health Canada..............................................................................................56
10.4.1
Primary Efficacy Analysis................................................................................................56
10.4.2
Secondary Efficacy Analysis............................................................................................56
10.4.3
Additional Efficacy Endpoints and Health Outcomes Analysis .......................................57
11.0
SAFETY ANALYSES..................................................................................................................................58
11.1
Adverse Events ...............................................................................................................................58
11.2
Clinical Laboratory Parameters.......................................................................................................60
11.3
Vital Signs.......................................................................................................................................65
11.4
Electrocardiogram...........................................................................................................................66
11.5
Columbia-Suicide Severity Rating Scale ........................................................................................68


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SUBGROUP ANALYSES............................................................................................................................69
12.1
Subgroup Analyses for Evaluating the Consistency of Treatment Effects Across Regions and 
Subpopulations................................................................................................................................69
12.2
Other Subgroup Analyses ...............................................................................................................70
13.0
INTERIM ANALYSIS..................................................................................................................................72
14.0
DETERMINATION OF SAMPLE SIZE......................................................................................................73
15.0
STATISTICAL SOFTWARE .......................................................................................................................74
16.0
DATA HANDLING CONVENTIONS ........................................................................................................75
16.1
Visit Time Windows .......................................................................................................................75
16.2
Derived Efficacy and Health Outcome Data...................................................................................81
16.2.1
Derivation of Efficacy Endpoints Based on eDiary Data .................................................81
16.2.2
Derivation of Health Outcome Endpoints Based on eDiary Data.....................................83
16.3
Repeated or Unscheduled Assessments of Safety Parameters ........................................................90
16.4
Missing Date of the Last Dose of STudy Treatment.......................................................................90
16.5
Missing Severity Assessment for Adverse Events..........................................................................90
16.6
Missing Causal Relationship to stuDy drug for Adverse Events ....................................................91
16.7
Missing Date Information for Adverse Events................................................................................91
16.8
Missing Date Information for Prior or Concomitant Medications ..................................................92
16.8.1
Incomplete Start Date .......................................................................................................92
16.8.2
Incomplete Stop Date .......................................................................................................93
16.9
Character Values of Clinical Laboratory Parameters......................................................................94
16.10
Actual Randomization Stratification Derivation.............................................................................94
16.11
Identifying Participants Who Took a New Migraine Prophylaxis Treatment with Proven Efficacy 
Based on Concomitant Medications Reported in eCRF for the Intercurrent Events Specified in the 
Off-Treatment Hypothetical Estimand............................................................................................96
17.0
COVID-19 RELATED ANALYSES............................................................................................................97
17.1
Efficacy Evaluation.........................................................................................................................97
17.2
Safety and Other Evaluations..........................................................................................................98
18.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ......................................................................100
19.0
REFERENCES............................................................................................................................................101
20.0
APPENDICES.............................................................................................................................................102
20.1
List of Parameters Reported in Conventional Unit .......................................................................102
20.2
Analysis and Reporting Format in Conventional Units ................................................................103
20.3
Summary of Changes from Final SAP to SAP Amendment 1......................................................104
LIST OF TABLES
Table 4-1.
Schedule of Activities (SoA) ...................................................................................................11
Table 10.1-1.
Efficacy and Health Outcome Endpoints.................................................................................28
Table 10.1-2.
Stratification Variables used in the modeling ..........................................................................30
Table 10.2-1.
Multiple Comparisons Procedure Definitions for the US filing...............................................39
Table 10.2-2.
Statistical Methodology ...........................................................................................................44
Table 10.2-3.
Analysis of Additional Efficacy Endpoints and Health Outcomes ..........................................45


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Table 10.3-1.
Monotone Missing Data Patterns.............................................................................................51
Table 10.3-2.
Multiple Comparisons Procedure Definitions for EU Filing ...................................................54
Table 11.2-1.
Criteria for Potentially Clinically Significant Laboratory Results...........................................62
Table 11.2-2.
Criteria for Hepatic Laboratory Abnormalities........................................................................64
Table 11.3-1.
Criteria for Potentially Clinically Significant Vital Signs........................................................66
Table 11.4-1.
Criteria for Potentially Clinically Significant Electrocardiograms ..........................................67
Table 12.2-1.
Statistical Power for Primary and the First Three Secondary Endpoints .................................73
Table 16.1-1.
Efficacy Analysis Visit Definitions for eDiary Data ...............................................................75
Table 16.1-2.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand Approach for 
eDiary Data..............................................................................................................................75
Table 16.1-3.
Efficacy Analysis Visit Definitions for eDiary Data in the First Monthly Period ...................76
Table 16.1-4.
Efficacy Analysis Visit Definitions for eDiary Data ...............................................................76
Table 16.1-5.
Efficacy Analysis Visit Definitions for MSQ v2.1 and HIT-6.................................................76
Table 16.1-6.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand Approach for 
MSQ v2.1 and HIT-6...............................................................................................................77
Table 16.1-7.
Efficacy Analysis Visit Definitions for EQ-5D-5L..................................................................77
Table 16.1-8.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand Approach for 
EQ-5D-5L................................................................................................................................77
Table 16.1-9.
Efficacy Analysis Visit Definitions for PGI-S, WPAI: MIGRAINE, and PROMIS-PI ..........78
Table 16.1-10.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand Approach for 
PGI-S, WPAI: MIGRAINE, and PROMIS-PI.........................................................................78
Table16.1-11.
Efficacy Analysis Visit Definitions for PGIC..........................................................................78
Table 16.1-12.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand Approach for 
PGIC ........................................................................................................................................78
Table 16.1-13.
Efficacy Analysis Visit Definitions for Patient Satisfaction with Study..................................79
Table 16.1-14.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand Approach for 
Patient Satisfaction with Study ................................................................................................79
Table 16.1-15.
Efficacy Analysis Visit Definitions for MIDAS and PHQ ......................................................79
Table 16.1-16.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand Approach for 
MIDAS and PHQ.....................................................................................................................79
Table 16.1-17.
Safety Data Analysis Visit Definitions ....................................................................................80
Table 16.2-1.
Item Values for MSQ Item Responses.....................................................................................85
Table 16.2-2.
Item Values for HIT-6 Item Responses ...................................................................................87
Table 16.2-3.
PROMIS-PI Raw Score Transformation..................................................................................89
Table 17.1-1.
Summary of Collection Devices for Primary and Key secondary endpoints...........................98
Table 20.1-1.
List of Selected Parameters Reported in Conventional Unit..................................................102
Table 20.2-1.
Presenting Laboratory Data Using SI and Conventional Units in Narratives ........................103
LIST OF FIGURES
Figure 4-1.
Study Design............................................................................................................................10
Figure 10.2-1.
Multiple Comparisons Procedure for US Filing ......................................................................40
Figure 10.3-1.
Multiple Comparisons Procedure for Europe and Canada.......................................................55


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LIST OF ABBREVIATIONS
AE
adverse event
AIM-D
Activity Impairment in Migraine – Diary
ALP
alkaline phosphatase 
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
APAC
Asia-Pacific
ASC-12
allodynia symptom checklist
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
bpm
beats per minute
CFB
change from baseline
CI
confidence interval
CM
chronic migraine
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
Diastolic blood pressure
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
ECG
electrocardiogram, electrocardiographic
eDiary
electronic diary
eCRF
electronic case report form
ePRO
electronic Patient Reported Outcome
EQ-5D-5L
European Quality of Life – 5 Dimensional
ET
early termination
EU
European Union
eTablet
electronic tablet
FWER
familywise error rate


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GLMM
generalized linear mixed model
HIT-6
Headache Impact Test 
INR
international normalized ratio 
ITT
intent-to-treat
IWRS
interactive web response system; 
K-S
Kolmogorov-Smirnov
LLN
lower limit of normal value
LOCF
last observation carried forward
LS
least square
MAR
missing-at-random
MCMC
Markov chain Monte Carlo
MI
multiple imputation
MIDAS
Migraine Disability Assessment 
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MNAR
missing-not-at-random
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, Version 2.1
NSAID
nonsteroidal anti-inflammatory drug
OL
open label
PCS
potentially clinically significant
PDRS
Protocol Deviation Requirement Specifications
PGIC
Patient Global Impression of Change 
PGI-S
Patient Global Impression – Severity 
PHQ-9
Patient Health Questionnaire
PID
participant identification
PK
pharmacokinetic
PMM
pattern-mixture model


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PRO
patient reported outcomes
PROMIS-PI
Patient-Reported Outcomes Measurement Information Systems Pain Interference – Short 
Form 6a
PSSM
Patient Satisfaction with Study Medication
Q1
first quartile
Q3
third quartile
QD
once daily
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SE
standard error
SI
Le Système International d’Unités (International System of Units)
SoA
Schedule of Activities
TBL
total bilirubin 
TEAE
treatment-emergent adverse event 
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
VAS
visual analogue scale
VCT
verified clinical trial
WHO
World Health Organization
WPAI: MIGRAINE
Work Productivity and Activity Impairment Questionnaire: Migraine Version V2.0


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INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the final protocol
(version dated 13 December 2018), protocol amendment 1 (version dated 08 April 2019), protocol 
amendment 2 (version dated 23 September 2019), and protocol amendment 3 (version dated 
29 May 2020) of Study 3101-303-002. Specifications of tables, figures, and data listings are 
contained in a separate document.
The analyses of the study for global submissions in various geographic regions (US, Europe, etc.)
are documented in the main body of this SAP. Additional analyses for subjects enrolled at study 
sites in China, Japan, Korea, and Taiwan that will be used to provide additional support for 
marketing authorization in the above countries or region are documented in region-specific SAP 
Addenda.
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study 
conducted at approximately 110 sites worldwide. Approximately 750 participants will be 
randomized to 1 of 3 treatment arms (placebo, Atogepant 30 mg twice daily [BID], and Atogepant 
60 mg once daily [QD]) in a 1:1:1 ratio.
Participants will be stratified by:

Randomization will be stratified by use of acute headache medications during the baseline 
period (acute headache medication overuse Yes or No). Acute headache medication overuse 
(Yes) will be defined as follows: use of triptans on ≥10 days OR use of ergots on ≥10 days 
OR use of simple analgesics (ie, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], or 
acetaminophen) on ≥ 15 days OR use of any combination of triptans, ergots or simple 
analgesics on ≥10 days.


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
Approximately 70% of randomized participants will have taken at least 1 prior migraine 
prevention medication with proven efficacy. Randomization will be stratified based on 
migraine prevention medication exposure (Current Use, Past Use, or Never Used) with proven 
efficacy. Participants with current or past use will be further stratified based on the number of 
medications failed with unique mechanisms of action: “failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” or “failed 2 to 4 medications with different 
mechanisms of action”. Enrollment of participants with current use of a migraine prevention 
medication will be capped at ~15%.

Randomization will be stratified by regions: North America, Europe, China, Japan and the 
Asia-Pacific (APAC).
Participation will begin with a 4-week screening/baseline period. Participants who complete the 
4-week screening/baseline period and meet all entry criteria will be randomized to the double-
blind treatment period of this study at Visit 2 (Randomization Visit). The double-blind treatment 
period will last 12 weeks, with a follow-up period of 4 additional weeks. There will be 8 scheduled 
clinic visits: Visit 1 (screening/baseline), Visit 2 (randomization), Visit 3 (Week 2), Visit 4 
(Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ Early Termination (ET) (Week 12), and 
Visit 8 (follow-up). The Visit 8 (follow-up) must be completed for all participants who take at 
least 1 dose of study medication, except for participants rolling over into Study 3101-312-002 
(long-term safety extension study in regions, excluding Japan and China), Study 3101-306-002 
(long-term safety extension study in Japan), or Study 3101-311-002 (open-label safety extension 
study in China). For these rollover participants Visit 8 of Study 3101-303-002 is not required, 
because the Follow-up Visit (Visit 8) will be performed after the OL treatment in the respective 
long-term safety study. For participants who screen fail for the long-term safety study, the Follow-
up Visit (Visit 8) of Study 3101-303-002 must be completed.
Due to the COVID-19 pandemic, Section 17.0 is added to specify analyses for evaluating the 
impact of COVID-19.


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Figure 4-1.
Study Design
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 






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ASC-12 = 12-item Allodynia Symptom Checklist; AIM-D = Activity Impairment in Migraine–Diary; C-SSRS = Columbia Suicide Severity Rating Scale;
ECG = electrocardiogram; eDiary = electronic diary; EQ-5D-5L = European Quality of Life – 5 Dimensional; ET = early termination; eTablet = electronic tablet;
HIT-6 = Headache Impact Test; INR = international normalized ratio; IWRS = interactive web response system; MIDAS = Migraine Disability Assessment; 
MSQ v2.1 = Migraine Specific Quality of Life Questionnaire, Version 2.1; OL = open-label; PGIC = Patient Global Impression of Change; PGI-S = Patient 
Global Impression – Severity; PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; PRO = patient-reported outcome; PROMIS-PI = Patient-Reported 
Outcomes Measurement Information System Pain Interference – Short Form 6a; PSSM = Patient Satisfaction with Study Medication; VCT = verified clinical 
trial; WPAI: MIGRAINE = Work Productivity and Activity Impairment Questionnaire: Migraine V2.0.
a.
Visit 1, Visit 2, and either Visit 3 or Visit 4 must be conducted in office. All other visits, should be conducted in office unless it is necessary to conduct
remote visits for the safety of participants (eg, COVID-19 or other pandemic): for details please refer to the Remote Visit Schedule of Assessments in
Attachment 12.4.
b.
Effort should be made by site to not schedule Visit 7 earlier than Day 85 to ensure that participants complete the full 12 weeks of treatment and have eDiary 
data through Day 84.
c.
All participants who take at least 1 dose of study intervention must complete the follow-up period, except for participants rolling over into
Study 3101-312-002 (long-term safety extension study in regions excluding Japan and China), participants rolling over into Study 3101-306-002 (long-term
safety extension study in Japan), or Study 3101-311-002 (open-label safety extension study in China). For these rollover participants the Follow-up Visit will
be performed after the completion of the OL treatment in the respective long-term safety extension study.
d.
Vital sign measurements: height, weight, sitting Vital sign measurements: height, weight, sitting and standing pulse rate, respiratory rate, sitting and standing 
blood pressure, and body temperature. Height will be measured only at Visit 1.
e.
For women of childbearing potential only, a urine pregnancy test will be performed at all visits
f.
Clinical laboratory determinations include chemistry, hematology, INR, and urinalysis to be collected for all visits. Samples for serology and the urine drug 
screen will be collected only at screening (Visit 1).
g.
PK sample should be collected prior to the first dose at Visit 2. One sample should be collected prior to the morning dose during one of the Visits 3 to 7, and 
the remaining samples should be collected 1 to 10 hours postdose. 
h.
Participant should begin using the eDiary as soon as it is dispensed. If it is subsequently determined that the participant has failed entry criteria, the eDiary 
should be returned to the site.
i.
Participants must bring the eDiary to visits and review with coordinators.
j.
Clinicians will complete on eTablet. The screening/baseline assessment of the C-SSRS will be completed. At all other visits, the ‘Since Last Visit’ C-SSRS
will be completed.
k.
Participant will complete on eTablet.
l.
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol (eg, during Randomization Visit 2, 
some tests will be conducted prior to PROs for eligibility).
m. EQ-5D-5L will be given on eDiary during 7 days in the baseline period and during specific time periods for Visit 1 to 7, except at Visit 8 (Week 16) where it 
will be administered on an eTablet.
n.
eDiary will be collected on Visit 2 for screen failures.
o.
Collected at Visit 7/ET only for participants who complete the double-blind treatment period.
p.
Collected at Visit 8/Follow-up only for participants who discontinue from the double-blind treatment period.
q.
The first dose of study intervention should be taken at the study site.


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5.0
STUDY OBJECTIVES

To evaluate the safety and tolerability of atogepant 30 mg BID and atogepant 60 mg QD for 
the prevention of chronic migraine (CM).

To prospectively test for superiority of atogepant 30 mg BID and atogepant 60 mg QD versus 
placebo for the prevention of CM.


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6.0
PARTICIPANT POPULATIONS
6.1
INTENT-TO-TREAT POPULATION
The Intent-to-Treat (ITT) Population will consist of all randomized participants.
6.2
SAFETY POPULATION
The Safety Population will consist of all participants who received at least 1 dose of study 
intervention. All safety analyses will be performed using the Safety Population. For safety 
analyses, the participants will be analyzed according to actual treatment received which is defined 
as the study treatment received for majority of treatment period (rather than as randomized).
6.3
MODIFIED INTENT-TO-TREAT POPULATION
The Modified Intent-to-Treat (mITT) Population will consist of all randomized participants who 
received at least 1 dose of study intervention, had an evaluable baseline period of electronic diary 
(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. All efficacy analyses described 
in Sections 0 will be performed using the mITT population. For efficacy analyses, data will be 
analyzed according to participants’ randomization assignments, regardless of actual treatment 
received.
6.4
OFF-TREATMENT HYPOTHETICAL ESTIMAND POPULATION
The analysis population for Off-treatment Hypothetical Estimand is defined to be all randomized 
participants who received at least 1 dose of study treatment, 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, 9 to 
12) of eDiary, regardless of whether on study treatment or off study treatment. This population is 
used for the primary estimand in support of EU filing.


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7.0
PARTICIPANT DISPOSITION
The number of participants screened will be summarized overall by study center; the number of 
participants in the ITT, Safety, mITT, and Off-treatment Hypothetical Estimand Populations will 
be summarized by treatment group and study center.
The number and percentage of participants in the ITT Population will be summarized by treatment 
group for the following two categories:

IWRS randomization stratification: acute headache medication overuse (Yes or No), migraine 
prevention medication exposure (Current Use, Past Use, or Never Used) and number of 
medications failed with unique mechanisms of action (“failed 0 medications or failed 1 or more 
medication(s) with the same mechanism of action” or “failed 2 to 4 medications with different 
mechanisms of action”). The number and percentage of participants in the ITT Population will 
also be summarized by treatment group for each randomization stratum of 10 strata (the 
combination of 2 levels of “acute headache medications during the baseline period” (acute 
medication overuse Yes/No) and 5 levels of “current and past use of migraine prevention 
medications and the number of medications failed with unique mechanisms of action” (Current 
Use and “failed 0 medications or failed 1 or more medication(s) with the same mechanism of 
action”, Current Use and “failed 2 to 4 medications with different mechanisms of action”, Past 
Use only and “failed 0 medications or failed 1 or more medication(s) with the same mechanism 
of action”, Past Use only and “failed 2 to 4 medications with different mechanisms of action”, 
and Never Used) .

Derived stratification: raw data from the database will be used to re-derive the “actual” 
stratification based on algorithms detailed in the SAP Section 16.10.
A summary table and list of participants with inconsistent randomization stratum against IWRS
will be provided.
Screen-failure participants (ie, participants screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for all screened participants. The number 
and percentage of participants who enter the double-blind treatment period, complete the double-
blind treatment period and of participants who prematurely discontinue during the double-blind 
treatment period will be presented for each treatment group and pooled across treatment groups 


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for all randomized participants. The reasons for premature discontinuation from the double-blind 
treatment period as recorded on the termination pages of the electronic case report forms will be 
summarized (number and percentage) by treatment group. The percentage is relevant to the total 
number of randomized participants. Similar disposition information to the double-blind treatment 
period will be presented for the safety follow-up period and estimand follow-up period defined in 
Figure 2 in Section 8.8.1 of the Protocol. All randomized participants who prematurely discontinue 
during the double-blind treatment period or the safety follow-up period or the estimand follow-up 
period will be listed by discontinuation reason. The number of randomized participants who signed 
informed consent for extension studies will be provided.


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8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (age; age group [< 20, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥70]; 
race; race group [white, all other races]; ethnicity; sex; region and country [North America, Europe, 
East Asia]), baseline characteristics (weight; height; and body mass index, calculated as weight 
[kg]/(height [m])2 will be summarized descriptively by treatment group for the Safety, mITT and 
Off-treatment Hypothetical Estimand Populations. Continuous variables will be summarized by 
number of participants and mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of participants.
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 24.0. The number and percentage of participants with 
abnormalities in medical and surgical histories in each system organ class and preferred term will 
be summarized by treatment group for the Safety Population.
Migraine history, including diagnosis, duration of disorder, use of migraine prevention medication 
in the past, average number of migraine or headache days per month in the last 3 months, acute 
medications taken to treat migraine headaches, and advice on lifestyle alterations will be reported 
in total and by treatment group for the Safety Population.
Prior migraine prevention medication use and the corresponding mechanism or medication failure 
information will be summarized by treatment group for both ITT and Safety Population. In 
addition, the number and percentage of participants with prior migraine prevention medication use 
will be tabulated by mechanism of action and medication, further tabulated for the participants
who met the medication failure definition and by the reason for stopping the medication.
Prior medication is defined as any medication taken before the first dose of double-blind study 
treatment. Concomitant medication is defined as any medication taken on or after the date of the 
first dose of the double-blind study treatment.
Prior medication use will be summarized by the number and percentage of participants in each 
treatment group receiving each medication within each therapeutic class for the Safety Population.
Concomitant medication use will be summarized by the number and percentage of participants in 


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each treatment group receiving each medication within each therapeutic class for the double-blind 
treatment period, the safety follow-up period and the estimand follow-up period for the Safety 
Population. If a participant took a specific medication multiple times or took multiple medications 
within a specific therapeutic class, that participant would be counted only once for the coded drug 
name or therapeutic class. Any prior and concomitant medications will be included in listings.
The World Health Organization (WHO) Drug Dictionary Enhanced, March 2017 or newer, will be 
used to classify prior and concomitant medications by therapeutic class and drug name.
Protocol deviations will be defined in Protocol Deviation Requirement Specification (PDRS), 
including importance classification. The number and percentage of participants with important 
protocol deviations will be summarized by treatment group for all categories specified in PDRS
for randomized participants.
Baseline efficacy parameters (monthly migraine days, monthly headache days, monthly acute 
medication use days, monthly performance of daily activities domain score of the Activity 
Impairment in Migraine - Diary [AIM-D], monthly physical impairment domain score of the 
AIM-D, Migraine Specific Quality of Life Questionnaire [MSQ] v2.1 Role Function-Restrictive 
domain score, and Headache Impact Test [HIT-6] total score) will be summarized by treatment 
group for mITT Population and Off-Treatment Hypothetical Estimand population.


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to double-blind study treatment for the Safety Population during the treatment period 
will be summarized for treatment duration, calculated as the number of days from the date of the 
first dose of double-blind study treatment taken to the date of the last dose taken, inclusive. The 
number and percentage of participants with each treatment duration of ≥ 1 day, ≥ 7 days, ≥14 days, 
≥ 21 days, ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥56 days, ≥ 63 days, ≥70 days, ≥ 77 days, 
≥ 84 days will be summarized by treatment group respectively. Descriptive statistics (number of 
participants, mean, SD, median, Q1, Q3, minimum, and maximum) will also be summarized by 
treatment group.
Participant-years, defined as exposure to the study treatment in years, will be summarized by 
treatment group for the Safety Population.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for a specified period is defined as the total number of double-blind study 
medications actually taken by a participant during that period divided by the number of double-
blind study medications that were expected to be taken during the same period multiplied by 100. 
The total number of capsules actually taken during a specific period will be calculated from the 
study medication record. The prescribed number of tablets during a specific period will be 
calculated as following: 4 tablets/day × the number of days during the period. Descriptive statistics 
for double-blind study medication dosing compliance together with the compliance categories 
(< 80%, 80% - 120%, > 120%) will be summarized by treatment group for each period between 
2 consecutive visits, as well as for the period from the first dose of the double-blind study 
interventions actually taken to the last dose of double-blind study intervention actually taken for 
the Safety Population.


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10.0
EFFICACY ANALYSES
10.1
EFFICACY AND HEALTH OUTCOME MEASURES
10.1.1
Efficacy Measures
Migraine Day
A migraine day is defined as any calendar day on which a headache occurs which meets criteria 
A, B, and C OR meets criteria D and E, as listed below, as per participant eDiary. Calendar days 
begin at midnight and last until 11:59 PM (23:59).
A. Headache has at least two of the following four characteristics:
i.
Unilateral location
ii.
Pulsating quality
iii.
Moderate or severe pain intensity
iv.
Aggravated by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs)
B. At least one of the following:
i.
Nausea and/or vomiting 
ii.
Photophobia and phonophobia
iii.
Typical aura (ie, visual, sensory, or speech/language) accompanying or within 
60 minutes before headache begins
C. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, migraine-
specific medication (ie, triptan or ergot derivative) was used after the start of the headache, 
in which case no minimum duration will be specified
OR


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D. Any headache which fulfills one criterion from (1) and at least one criterion from (2) OR
fulfills at least two criteria from (1) and no criteria from (2).
1) Headache characteristics:
i. Unilateral location
ii. Pulsating quality
iii. Moderate or severe pain intensity
iv. Aggravated by or causing avoidance of routine physical activity 
(eg, walking or climbing stairs)
2) Symptoms:
i. Nausea and/or vomiting
ii. Photophobia and phonophobia
iii. Typical aura (ie, visual, sensory, or speech/language) accompanying or 
within 60 minutes before headache begins
E. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, migraine-
specific medication (ie, triptan or ergot derivative) was used after the start of the headache, 
in which case no minimum duration will be specified.
Headache Day
A headache day is defined as any calendar day on which headache pain lasting 2 hours or longer 
occurs unless an acute headache medication (eg, ibuprofen, triptan) was used after the start of the 
headache, in which case no minimum duration will be specified. Note that antiemetics will not be 
counted as an acute headache medication for headache day identification. Calendar days begin at 
midnight and last until 11:59 PM (23:59).
Acute Medication Use Day and Triptan Use Day
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 allowed medications include the 
following categories of drugs: triptans, ergots, opioids, analgesics (including acetaminophen), 
NSAIDs (including aspirin), and antiemetics.


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A triptan use day is defined as any day on which a participant reports intake of a triptan to treat a 
migraine per participant diary.
Headache Day Pain Intensity
Headache day pain intensity is defined as the worst pain intensity on any headache day where 
headache pain intensity will be subjectively rated by the participant on a scale from 1 (mild) to 3 
(severe):

Mild pain (=1)

Moderate pain (=2)

Severe pain (=3)
If participants experience no headache in a day, then the corresponding pain intensity of that day 
will be set as missing.
10.1.2
Health Outcome Measures
Activity Impairment in Migraine - Diary (AIM-D) 
The AIM-D is an 11-item daily diary measure that assesses the impact of migraine and is 
comprised of two domains that evaluate performance of daily activities (7 items) and physical 
impairment (4 items). Participants are asked to rate the level of difficulty experienced in the past 
24 hours with performance of daily activities (i.e., 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 (i.e., difficulty walking, moving 
body, bending forward, moving head) using a 6-point rating scale ranging from “Not difficult at 
all,” “A little difficult,” “Somewhat difficult,” “Very difficult,” “Extremely difficult,” and “I could 
not do it at all.” Three items include a response of “I did not…,” for example, “I did not have 
errands planned.” The AIM-D was developed as an electronic daily diary with the same set of 
questions administered in headache and non-headache versions. The Headache version is 
administered on days when a participant reports a headache and the Non-Headache version is 
administered on days when a participant does not report having a headache. The AIM-D instructs 
participants to answer each question based on the level of difficulty experienced in the past 
24 hours for both versions, with “during your headache” indicated for the AIM-D Headache 


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version. In addition to the two domain scores, a total score using all 11 items can also be calculated. 
Each raw daily domain score, as well as the raw daily total score, are transformed to a 0-100 scale, 
with higher scores indicating greater impact of migraine (i.e., higher disease burden).
Activity Level and Activity Limitation
Two items based on a 24-hour recall will be administered daily using Headache and Non-Headache 
versions as additional health outcome measures and for evaluation of the AIM-D.
The first item will be used to assess activity level within the past 24 hours with a 5-level response 
ranging from “No activity - Spent all day lying down” to “Exercised - Brisk walk, running, jogging, 
biking or other activity for 30 or more minutes.” The second item will be used to evaluate activity 
limitation with a 5-level response ranging from “Not at all limited - I could do everything” to 
“Extremely limited.”
Headache Impact Test (HIT-6)
The HIT-6 is a 6-question assessment used to measure the impact that 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).
Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1)
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 assesses how migraines limit one’s daily social and work related activities; Role 
Function-Preventive assesses how migraines prevent these activities; and the Emotional Function 
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.


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Patient Satisfaction with Study Medication (PSSM)
Overall satisfaction with the study medication for prevention of migraine will be assessed using a
single item and a 7-point rating scale ranging from extremely satisfied (0) to extremely dissatisfied 
(6).
Migraine Disability Assessment (MIDAS)
The Migraine Disability Assessment (MIDAS) is a 7-item questionnaire designed to quantify 
headache-related disability over a 3-month period. The MIDAS score is the sum of missed work 
or school days, days at work or school plus days of household work where productivity was 
reduced by half or more, missed household work days, and missed non-work activity days due to 
headaches and in the last 3 months.
Patient Global Impression of Change (PGIC)
The Patient Global Impression of Change (PGIC) is a single item used to measure the participant’s 
impression of overall change in migraine since the first dose of study intervention. The measure 
uses a 7-point rating scale with responses ranging from “very much better” to “very much worse.”
Patient Global Impression - Severity (PGI-S)
The Patient Global Impression - Severity (PGI-S) is a single item used to measure the participant’s 
impression of severity in relation to migraine symptoms overall at the time of administration of 
the measure. The measure uses a 5-point rating scale with responses ranging from “none” to “very 
severe.”


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Work Productivity and Activity Impairment Questionnaire: Migraine V2.0 (WPAI: 
MIGRAINE)
The Work Productivity and Activity Impairment Questionnaire: Migraine v2.0 (WPAI: 
MIGRAINE) is used to assess work productivity specific to migraine. The measure uses a 1 week 
recall and contains 6 questions related to work productivity. The WPAI measures both 
presenteeism and absenteeism. The measure yields four scores expressed as impairment 
percentages ranging from 0 to 100%: Percent work time missed, percent impairment while 
working, percent overall work impairment, and percent activity impairment due to migraine.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is a concise, self-administered, validated, screening and diagnostic tool for mental 
health disorder, which has been field-tested in office practice. The screener is quick and user 
friendly, improves the recognition rate of depression, and facilitates diagnosis and treatment. The 
PHQ-9 consists of the 9 diagnostic criteria for depressive disorders in the past 2 weeks from the 
DSM-IV. Participants are asked to indicate the frequency with which they have been bothered by 
9 symptoms of depressive disorders over the previous 2 weeks, on a 4-point scale: 0 (not at all), 
1 (several days), 2 (more than half the days), and 3 (nearly every day). The total score ranges from 
0 to 27 (from best to worst). A score of 15 to 19 is considered as moderately severe depression and 
20 to 27 as severe depression.
European Quality of Life - 5 Dimensional (EQ-5D-5L)
EQ-5D-5L is a generic instrument for use as a measure of health status. As of 2009, the European 
Quality of Life - 5 Dimension - 5-Level (EQ-5D-5L) has also been available for use; this version 
was developed to improve the sensitivity of the instrument and to reduce ceiling effects 
(The EuroQol Group, 2020). The EQ-5D-5L consists of 2 components - the EQ-5D descriptive 
system and the EQ VAS, but only EQ-5D descriptive system will be summarized in this extension 
study.
The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). The mobility dimension queries the participant’s walking 
ability. The self-care dimension queries the participant’s ability to wash or dress by himself. The 


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usual activities dimension assesses the participant’s performance in “work, study, housework, 
family or leisure activities”. The pain/discomfort dimension measures how much pain or 
discomfort a participant has. The anxiety/depression dimension assesses how anxious or depressed 
a participant is. The respondent is asked to indicate his/her health state by ticking (or placing a 
cross) in the box against the most appropriate statement in each of the 5 dimensions. The scoring 
range of the EQ-5D descriptive system is typically from 0 (dead) to 1 (full health). The second 
component of the EQ-5D-5L is a visual analogue scale (EQ-VAS) by which participants can rate 
their overall health from 0 (worst imaginable health state) to 100 (best imaginable health state).
Patient-Reported Outcomes Measurement Information System Pain Interference - Short 
Form 6a (PROMIS-PI)
The PROMIS-PI measures self-reported interference of pain on relevant aspects of daily life (ie, 
social, cognitive, emotional, physical, recreational) over the past 7 days. A 5-level response scale 
for all six items ranges from “Not at all” to “Very much.” Scores range from 6 to 30, with higher 
scores indicating greater pain interference.
The detailed algorithms for derivation of the above health outcome measures are presented in 
Section 16.2.2.
10.1.3
Efficacy Endpoints
All efficacy and health outcome endpoints are summarized in the Table 10.1-1.


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Table 10.1-1.
Efficacy and Health Outcome Endpoints
Region
Endpoints
Primary efficacy 
endpoint
All regions
Change from baseline in mean monthly migraine days across the 
12-week treatment period
Secondary efficacy
endpoints
All regions except 
Europe and 
Canada
Change from baseline in mean monthly headache days across the 
12-week treatment period
Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period
At least a 50% reduction in 3-month average of monthly migraine days
Change from baseline in MSQ v2.1 Role Function-Restrictive domain 
score at Week 12
Change from baseline in mean monthly Performance of Daily
Activities domain score of the AIM-D across the 12-week treatment 
period
Change from baseline in mean monthly Physical Impairment domain 
score of the AIM-D across the 12-week treatment period
Secondary efficacy 
endpoints
Europe, Canada
Change from baseline in mean monthly headache days across the 
12-week treatment period
Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period
At least a 50% reduction in 3-month average of monthly migraine days
Change from baseline in the HIT-6 total score at Week 12
Change from baseline in MSQ v2.1 Role Function-Restrictive domain 
score at Week 12
Additional 
Efficacy Endpoints
All regions (with 
restrictions 
specified for 
individual 
endpoints)
≥ 25%, ≥ 30%, ≥ 50%, ≥75%, 100% improvement (decrease) in 
monthly migraine days at Weeks 1 to 4, 5 to 8, and 9 to 12
≥ 25%, ≥ 30%, ≥ 75%, 100% improvement (decrease) in 3-month 
average of monthly migraine days 
Change from baseline in monthly migraine days at Weeks 1 to 4, 5 to 
8, and 9 to 12
Change from baseline in monthly headache days at Weeks 1 to 4, 5 to 
8, and 9 to 12
Change from baseline in monthly cumulative headache hours at Weeks 
1 to 4, 5 to 8, 9 to 12, and average across the 12-week treatment period
Change from baseline in monthly acute medication use days at Weeks 
1 to 4, 5 to 8, and 9 to 12
Change from baseline in monthly triptan use days at Weeks 1 to 4, 5 to 
8, 9 to 12, and average across the 12-week treatment period
Change from baseline in monthly moderate/severe headache days at 
Weeks 1 to 4, 5 to 8, 9 to 12, and average across the 12-week 
treatment period
Change from baseline in monthly severe headache days at Weeks 1 to 
4, 5 to 8, 9 to 12, and average across the 12-week treatment period
Change from baseline in weekly migraine days at Weeks 1-4
Participants having a migraine day on the day of initial dose and on 
each day of the 6 days post the initial dose
Change from baseline in the HIT-6 total score at Weeks 4, 8 and 16 
(for Europe and Canada)
Change from baseline in the HIT-6 total score at Weeks 4, 8, 12 and 
16 (for all regions except Europe and Canada)


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Region
Endpoints
At least a 5-point improvement (decrease) from baseline in HIT-6 total 
score at Weeks 4, 8, 12, and 16
Participant assessed by the PGIC as “much better” or “very much 
better” at Week 12
Participant reporting “satisfied” or “extremely satisfied” with study 
medication for migraine prevention at Weeks 4, 8, and 12
Change from baseline in percent work time missed, percent 
impairment while working, percent overall impairment, and percent 
activity impairment due to migraine at Weeks 4, 8, and 12 as assessed 
by the WPAI: MIGRAINE
Change from baseline in the MIDAS total score at Week 12
Change from baseline in MIDAS absenteeism score (Questions 1, 3, 
and 5) at Week 12
Change from baseline in MIDAS presenteeism score (Questions 2 and 
4) at Week 12
Change from baseline in PGI-S score at Weeks 4, 8, and 12
Change from baseline in the MSQ v2.1 Role Function-Restrictive 
domain score at Weeks 4, 8, and 16
Change from baseline in the MSQ v2.1 Role Function-Preventive 
domain score at Weeks 4, 8, 12, and 16
Change from baseline in the MSQ v2.1 Emotional Function domain 
score at Weeks 4, 8, 12, and 16
Change from baseline in monthly Performance of Daily Activities 
domain score of the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
Change from baseline in monthly Physical Impairment domain score 
of the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
Change from baseline in mean monthly Performance of Daily 
Activities domain score of the AIM-D across the 12-week treatment 
period (for Europe and Canada)
Change from baseline in mean monthly Physical Impairment domain 
score of the AIM-D across the 12-week treatment period (for Europe 
and Canada)
Change from baseline in monthly AIM-D total score at Weeks 1-4, 
5-8, and 9-12, and average across the 12-week treatment period
Change from baseline in monthly activity level at Weeks 1 to 4, 5 to 8, 
9 to 12, and average across the 12-week treatment period
Change from baseline in monthly activity limitation at Weeks 1 to 4, 5 
to 8, 9 to 12, and average across the 12-week treatment period
Change from baseline in PHQ-9 score at Week 12
Change from baseline in EQ-5D-5L descriptive system index score at 
Weeks 1 to 2, at specified windows around Weeks 4, 6, 8, 12, and 16
Change from baseline in the EQ-5D-5L VAS score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 12, and 16
Change from baseline in PROMIS-PI total score at Weeks 4, 8, and 12


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10.1.4
Stratification Variables in Modeling
The three stratification variables used in the modeling are listed in the Table 10.1-2.
Table 10.1-2.
Stratification Variables used in the modeling
Abbreviated Name
Variable
Stratification
Stratification of acute 
medication overuse
Actual stratification of acute 
headache medication overuse 
during the baseline period

Yes

No
Stratification of migraine 
prevention medication
use and number of 
failures
Current and past use of migraine 
prevention medications and the 
number of medications failed 
with unique mechanisms of 
action based on derivation

Never Used

Current Use

Past Use only and “failed 0 medications 
or failed 1 or more medication(s) with the 
same mechanism of action”

Past Use only and “failed 2 or more 
medications with different mechanisms of 
action”
Stratification of Region
Region

North America

Europe

East Asia
10.2
EFFICACY ANALYSES FOR FILINGS EXCEPT EUROPE AND 
CANADA
10.2.1
Primary Efficacy Analysis
The primary null hypothesis is that atogepant 30 mg BID and 60 mg QD are each equally effective 
as placebo in mean change from baseline in mean monthly migraine days across the 12-week 
treatment period. The alternative hypothesis is that at least 1 of the 2 doses of atogepant has a 
greater effect than placebo.
The primary efficacy endpoint is the change from baseline in mean monthly migraine days across 
the 12-week treatment period. Baseline is defined as the number of migraine days during the last 
28 days prior to the randomization date. The primary efficacy analyses will be based on the mITT 
Population.
The primary comparison between treatment groups will be done by a mixed model for repeated 
measures (MMRM) of the change from baseline. The response variable is the change from baseline 
to each postbaseline month in monthly migraine days. The statistical model will include treatment 
group, visit, stratification of region, stratification of acute medication overuse, stratification of 


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migraine prevention medication use and number of failures, and treatment group-by-visit 
interaction as categorical fixed effects. The statistical model will also include the baseline monthly 
migraine days and baseline-by-visit interaction as covariates. The analysis will be performed based 
on all evaluable post-baseline values using only the observed cases without imputation of missing 
values. Only data collected during the double-blind treatment period will be included in the 
analysis. Participants are always analyzed based on the treatment group assigned by 
randomization.
Restricted maximum likelihood method will be used. The within-participant correlation will be 
modeled using the unstructured covariance matrix. If the model does not converge, then the 
Toeplitz covariance structure will be used. If the model with the Toeplitz covariance structure does 
not converge, then the compound symmetry covariance structure will be used. The Kenward-Roger 
approximation (Kenward 1997) will be used to estimate denominator degrees of freedom. 
Contrasts will be constructed to obtain the average treatment effects across the 12-week treatment 
period to compare each atogepant treatment group versus the placebo group. Each treatment effect 
and treatment comparisons will be estimated by the least square (LS) Means and their differences 
in LS Means, along with their standard error (SE) and 95% confidence intervals, and the p-value 
corresponding to the between-treatment group difference.
The sample SAS code is given as follows.
proc mixed data = efficacy_dataset METHOD=REML;
  class trt stratum1 stratum2 stratum3 visit subjid;
  model chg = trt visit stratum1 stratum2 stratum3 trt*visit base 
base*visit / s ddfm= kr;
  Repeated visit / type = UN subject = subjid;
  lsmestimate trt*visit 
  '30BID vs placebo' -1 -1 -1 1 1 1 0 0 0 divisor = 3,
  '60QD vs placebo' -1 -1 -1 0 0 0 1 1 1 divisor = 3 / CL;
run;
Note: Placebo is the reference for “trt”. Month 1, 2 and 3 are for “visit”.
stratum1 = Stratification of acute medication use.
stratum2 = Stratification of migraine prevention medications use.
stratum3 = Stratification of Region.


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The impact of dropouts on the primary efficacy measure will be explored graphically by plotting 
the response profiles by the dropout reason. Plot of mean change from baseline in the number of 
migraine days versus visit (month) based on the observed cases will be provided in each treatment 
group by major reason of early termination, such as, adverse events, lack of efficacy, withdrawal 
of consent, lost to follow-up, etc. Similar plot for completers in each treatment group will be 
provided as a reference.
10.2.1.1
Sensitivity Analyses in Missing Data Handling
The sensitivity analyses for missing data handling will be conducted and summarized in this 
section based on the mITT Population.  The random seed for all multiple imputation procedures 
will be 1234.
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
The response variable for the ANCOVA model is the change from baseline in the calculated 
average monthly migraine days during the 12-week treatment period for each participant. The 
ANCOVA model includes fixed effects for treatment group, stratification of region, stratification 
of acute medication use, stratification of migraine prevention medication use and baseline monthly 
migraine days as a covariate. The treatment difference for atogepant doses versus placebo will be 
estimated and reported along with the corresponding 95% confidence intervals and nominal 
p-values for superiority testing. This analysis was recommended by FDA at the End of Phase 2 
meeting and termed as a supportive analysis. There are no missing data based on this derivation 
because patients who discontinued the treatment are assumed to maintain the same mean (observed 
while on treatment) for 3 months (12 weeks).
Within-group Imputation Based on Observed Data 
A sensitivity analysis will be performed based on imputation using participants from the same 
treatment group with observed data under the MAR assumption.


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Missing data for participants who prematurely discontinued are assumed to copy the profile of 
participants in the same treatment group with observed data. The details of imputation are as 
follows:
1. Create partial imputation dataset using MI based on the MCMC approach in each treatment 
group. Imputed dataset will consist of 100 copies of original dataset and is assumed to follow 
monotone missing pattern.
2. Impute missing data in each existing copy by treatment group using observed data in the 
corresponding treatment group based on monotone regression. Each of the 100 imputed 
datasets will then be analyzed using an ANCOVA model with terms for treatment, 
stratification of region, stratification of acute medication use, stratification of migraine 
prevention medication use, and baseline monthly migraine days as a covariate.
3. The ANCOVA analysis results from 100 completed datasets are combined for overall 
estimation and inference using Rubin’s rule (Rubin 1987) to produce a pooled estimate of LS 
mean difference, its SE, and corresponding p-value for the test of null hypothesis of no 
treatment effect.
Copy-Reference Approach
The copy-reference approach is one type of pattern-mixture models (PMM), under which data 
could be missing-not-at-random (MNAR), with repeated analyses combined via the reference 
based multiple imputation (MI) procedure (Carpenter et al, 2013). This approach is to assess the 
robustness of the MMRM analysis to possible violation of the missing-at-random (MAR) 
assumption in the primary analysis.
Step 1. A few intermittent missing values will be imputed by the Markov Chain Monte Carlo 
(MCMC) at first. The MCMC imputation assumes missing-at-random (MAR) for intermittent 
missing data. The MCMC method will be implemented using SAS PROC MI statement “MCMC 
impute=monotone”. This is achieved with the use of option IMPUTE = MONOTONE in the 
MCMC statement. Then the rest of the missing data will follow monotone missing pattern.


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Step 2. Implementation of the copy-reference method are as follows:
1. The reference-based approach uses the placebo group as the reference. The missing values in 
the reference group are imputed using the observed data in that group under the missing-at-
random assumption. The missing pattern is defined by the participant’s last visit with a non-
missing value. The mean vector and the covariance matrix of the multivariate normal 
distribution are estimated for reference group. The imputation of missing data is not based on 
each of the reasons of early termination, because there may not be sufficient non-missing 
efficacy data in each of the reason categories to serve as a stable reference.
2. For atogepant treatment groups, missing values are imputed based on the distribution 
estimated from the reference group (placebo group).
The first PROC MI will be performed 100 times using MCMC method for partial imputation of 
the data with a non-monotone missing pattern. The output dataset will then be used as the input 
dataset for the next PROC MI. Note that the output dataset already contains 100 copies of the 
original dataset. With the next invocation of MI procedure, the missing data will be filled in (Step 1 
and 2) for the existing copies. This is achieved with the use of NIMPUTE=1 and a BY 
_Imputation_ statement. Finally, each of the 100 imputed datasets will be analyzed using an 
analysis of covariance (ANCOVA) model. For a given imputed dataset, the average change from 
baseline in monthly migraine days is calculated across the 3 post-baseline months and is used as 
the response variable in the model. The model includes treatment, stratification of region, 
stratification of acute medication use, stratification of migraine prevention medication use, and 
baseline monthly migraine days as a covariate. The LS mean difference and corresponding SE is 
estimated from the model comparing each atogepant treatment group with the placebo group.
The ANCOVA analysis results from 100 completed datasets are combined for overall estimation 
and inference using Rubin’s rule (Rubin 1987) to produce a pooled estimate of LS mean difference, 
its SE, and corresponding p-value for the test of null hypothesis of no treatment effect.


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MMRM Based on Primary Measures Collected during the Double-blind and Follow-up 
Periods
The details for this analysis are provided in Section 10.2.1. The primary analysis in support of EU 
filing will serve as one sensitivity analysis in support of US filing.
10.2.1.2
Sensitivity Analysis for Possible Violation of Normality Assumption
The sensitivity analyses for possible violation of normality assumption will be conducted and 
summarized in this section based on both mITT to support US filling.
Another sensitivity analysis uses MI in conjunction with robust regression to assess the robustness 
of the primary MMRM analysis to the possible violation of normality assumption. This method 
has been described and referred as ADAP [R] in Mehrotra et al. 2012. The details of this method 
are as follows.
The normality test is performed on the residuals which are generated by the same MMRM as used 
for the primary efficacy analysis. The residuals are scaled by the inverse Cholesky root of its 
estimated variance-covariance matrix. The Kolmogorov-Smirnov (K-S) test for normality is 
applied to the de-correlated and scaled residuals and normality test is rejected if p-value from the 
K-S test is less than 0.01.
The sensitivity analysis below will be performed:
1. Create complete datasets using MI based on the Markov chain Monte Carlo (MCMC) 
approach. Imputed data will consist of 20 complete datasets. Each of the 20 complete datasets 
will be analyzed using robust regression (M-estimation) to protect against either observed 
outliers in the original incomplete dataset, or imputed outliers in the complete datasets. For a 
given complete dataset, the average change from baseline in monthly migraine days is 
calculated across the 3 post-baseline months and is used as the response variable in the robust 
regression model. The model includes treatment group, stratification of region as fixed factors
and baseline monthly migraine days as a covariate. The model will also include stratification 
of acute medication use, stratification of migraine prevention medication prevention 


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medication use as categorical fixed effects. The mean difference and corresponding SE are
estimated from the model comparing each atogepant treatment group with the placebo group.
The robust regression analysis results from 20 complete datasets are combined for overall 
estimation and inference using Rubin’s rule (Rubin 1987) to produce a pooled estimate of 
treatment difference, its SE, and corresponding p-value for the test of null hypothesis of no 
treatment effect.
10.2.2
Secondary Efficacy Analysis
The secondary efficacy analyses will be based on the mITT Population to support US filling.
The secondary endpoints for headache days, acute medication use days, performance of daily 
activities domain score of the AIM-D, and physical impairment domain score of the AIM-D, will 
be analyzed in the same manner as that used to analyze the primary endpoint.
For MSQ v2.1 Role Function-Restrictive domain score, the analysis will be performed similarly 
to the primary MMRM, with focus on the pairwise contrasts of each dose group to placebo at 
Week 12. Some participants may have their MSQ v2.1 assessed at Visit 8, which will not be 
included in MMRM, and instead the summary statistics will be provided.
The 50% responders, defined as participants with at least a 50% reduction from baseline in the 
3-month average of monthly migraine days, will be assessed for each participant. A logistic 
regression model will be used to analyze the 50% responders across the 12-week treatment period. 
This model assumes a binary distribution for the response and uses a logit link. The analysis model 
will include treatment group, stratification of region and stratification of acute medication use, 
stratification of migraine prevention medication use as categorical fixed effects; baseline value
will be included as a covariate. The analysis will be performed based on only the observed cases 
without imputation of missing values. The treatment difference in terms of odds ratio between each 
atogepant group and placebo will be estimated and tested from this model. The sample SAS is 
given as follows


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proc logistic data = in_data1;
  class trt stratum1 stratum2 stratum3 subjid/param=glm;
  model responder (event = "1")= trt stratum1 stratum2 stratum3 base;
  lsmeans trt / e diff oddsratio cl;   
  ods output diffs = oddsratio;
run;
Note: Placebo is the reference for “trt”. stratum1, stratum2, and stratum3 are the same with those 
in primary analysis. 
10.2.2.1
Multiplicity Adjustment
Multiplicity adjustments will be generated based on mITT population and will be generated based 
on primary and the US set of secondary efficacy endpoints listed in the Table 10.1-1.
The overall familywise error rate (FWER) will be controlled at α = 0.05 for each set of primary 
and secondary endpoint comparisons between each atogepant group vs placebo. Specifically, the 
overall type I error rate for multiple comparisons across two atogepant groups and the primary and 
secondary efficacy endpoints will be controlled at the 0.05 level using a graphical approach with 
weighted-Bonferroni test procedure (Bretz 2009).
The overall graphic approach procedure for primary and secondary efficacy endpoints for US is 
defined in the Table 10.2-1 and Figure 10.2-1.
In the graph, each of the nodes is corresponding to one null hypothesis, for example, 30 BID/P1 
represents the null hypothesis that there is no statistically significant difference comparing 30 mg 
BID versus placebo on the primary endpoint. The number inside each node is the proportion of 
overall alpha initially allocated to that hypothesis. The number on the edge between two nodes 
represents the proportion of local alpha propagated from one hypothesis to the other given the 
rejection of preceding null hypothesis.
The initial allocation of the overall significant level to 2 primary hypotheses will be 1/2 of the 
overall significance level for each dose, and no initial  is allocated to the hypotheses for secondary 
endpoints.
Within each individual dose, testing will start from the primary endpoint, and then test the 
secondary endpoints in a prespecified order. The order of testing for the first three secondary 


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endpoints is determined by the power of individual endpoints based on the results from Phase 2/3 
study CGP-MD-01. Endpoints related to AIM-D and MSQ are placed in the last three positions in 
the testing hierarchy. If the null hypotheses for both the primary and the first three secondary 
endpoints are rejected for one of the doses, 1/3 of the associated alpha is passed to the other dose 
to increase the chances of success for the other dose in testing endpoints in the primary positions 
of the hierarchy, and the remaining 2/3 of the associated alpha is reserved for testing HO endpoints 
within the same dose. If hypotheses for three HO endpoints are rejected within a dose based on 
remaining alpha, the alpha for this dose will be propagated to the other dose to make full use of 
the alpha.


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Table 10.2-1.
Multiple Comparisons Procedure Definitions for the US filing
Nodes
Alternate Hypothesis
Weight
Initial Local 
Significance 
Level
30mgBID P1
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly migraine days across the 
12-week treatment period (P1)
1/2
α×(1/2) = α/2
60mgQD P1
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly migraine days across the 
12-week treatment period (P1)
1/2
α×(1/2) = α/2
30mgBID S1
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 
12-week treatment period (S1)
0
α×0=0
60mgQD S1
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 
12-week treatment period (S1)
0
α×0=0
30mgBID S2
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly acute medication use days 
across the 12-week treatment period (S2)
0
α×0=0
60mgQD S2
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly acute medication use days 
across the 12-week treatment period (S2)
0
α×0=0
30mgBID S3
30 mg BID atogepant is significantly different from placebo in 
proportion of participants with at least a 50% reduction in 3-
month average of monthly migraine days (S3)
0
α×0=0
60mgQD S3
60 mg QD atogepant is significantly different from placebo in 
proportion of participants with at least a 50% reduction in 3-
month average of monthly migraine days (S3)
0
α×0=0
30mgBID S4
30 mg BID atogepant is significantly different from placebo in 
change from baseline in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 (S4)
0
α×0=0
60mgQD S4
60 mg QD atogepant is significantly different from placebo in 
change from baseline in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 (S4)
0
α×0=0
30mgBID S5
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly performance of daily 
activities domain score of the AIM-D across the 12-week 
treatment period (S5)
0
α×0=0
60mgQD S5
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly performance of daily 
activities domain score of the AIM-D across the 12-week 
treatment period (S5)
0
α×0=0
30mgBID S6
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly physical impairment 
domain score of the AIM-D across the 12-week treatment period
(S6)
0
α×0=0
60mgQD S6
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly physical impairment 
domain score of the AIM-D across the 12-week treatment period
(S6)
0
α×0=0




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10.2.3
Analyses for Additional Efficacy Endpoints and Health Outcome Endpoints
For variables with a continuous response range, analyses will be performed similarly to that used 
for the primary analysis, focusing again on the pairwise contrasts of each dose group to placebo. 
Baseline in the primary MMRM model will be replaced with corresponding endpoint baseline. 
There is only one post-baseline assessment for MIDAS and PHQ-9, and thus ANCOVA model 
will be used to analyze MIDAS and PHQ-9 related endpoints with model terms including treatment 
group, stratification of region, stratification of acute medication use, stratification of migraine 
prevention medication use, and corresponding baseline score. For the endpoint change from 
baseline in each MSQ v2.1 domain score and HIT-6 total score, Week 16 (follow up visit) will not 
be included in MMRM model fitting.
For variables where the data are essentially binary, comparisons between treatment groups will be 
done using a generalized linear mixed model for variables with multiple postbaseline assessments. 
A generalized linear mixed model will assume a binary distribution for the response and uses a 
logit link. The analysis model will include treatment group, visit, stratification of region, 
stratification of acute medication overuse, stratification of migraine prevention medication use and
number of failures, and treatment group-by-visit interaction as categorical fixed effects; baseline 
value and baseline-by-visit interaction will be included as covariates. Participants will be included 
as random effects with unstructured covariance matrix in the model to account for the correlation 
among repeated measurements. If the model does not converge, then the Toeplitz covariance 
structure will be used. If the model with the Toeplitz covariance structure does not converge, then 
the compound symmetry covariance structure will be used. The analysis will be performed based 
on all postbaseline values using only the observed cases without imputation of missing values. As 
there is no baseline assessment for the endpoint patient’s satisfaction with study medication, 
baseline monthly migraine days will be included in the model.
For binary endpoints with only one postbaseline assessment (for example, PGIC responder) or 
responders across 12-week double-blind treatment period, a logistic regression model will be used 
to model the probability of a response or event with model terms including treatment group, 
stratification of region, stratification of acute medication overuse, stratification of migraine 
prevention medication and number of failures, and corresponding baseline. As there is no baseline 


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assessment for PGIC, baseline monthly migraine days will be used in the logistic regression model 
as a covariate for PGIC responder analyses.
For daily efficacy variables, the number and percentage of participants with a migraine day will 
be summarized by each day under consideration. A generalized linear mixed model as described 
above will be used to analyze the proportion of participants with a migraine day as repeated 
measures from the initial dose day to 6 days after. Here baseline value is the daily rate for 
participants with a migraine day during the baseline period.
In addition, percent reduction in the proportion of participants with a migraine day will be provided 
by each day under consideration. It is defined as:
100×(1-(proportion of participants with a migraine day on a specific day)/(baseline daily rate of 
participants with a migraine day ).
The proportion of participants with a migraine day will be calculated relative to the number of 
participants in mITT Population with available eDiary record on the day of consideration. The 
numerator will be the number of participants with a migraine day on that day. The baseline daily 
rate of participants with a migraine day will be calculated as the average of monthly migraine days 
(prorated if less than 28 days of baseline data are reported) at baseline period for participants in 
mITT Population divided by 28.
Plots of fitted (least squares) mean changes and their standard errors for monthly migraine days, 
monthly headache days and monthly acute medication use days from the MMRM will be presented 
by treatment group and 4-week interval.
Plots of proportions of participants with at least 25%, at least 30%, at least 50%, at least 75%, and 
100% reduction in migraine days will be presented by treatment group and 4-week interval, 
respectively.
In addition, cumulative distribution graph of percent improvement (decrease) in mean monthly 
migraine days across 12-week treatment period will be provided by treatment group.
The distribution of change from baseline in mean monthly migraine days across the 12-week 
treatment period in histogram by treatment group in bins of 2-day interval will be presented. The 


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x-axis will represent the change from baseline in mean monthly migraine days across the 12-week 
treatment period. Both positive and negative values will be included on the x-axis. The y-axis will 
represent the relative frequency (% of participants in the mITT population of the treatment group).
Another distribution analysis will be presented as a histogram by treatment group, based on the 
percentage change from baseline in mean monthly migraine days across the 12-week treatment 
period with the x-axis displayed as bins of 0 - ≤ 25%, >25% - ≤50%, >50% - ≤75% and > 75% -
≤ 100% reduction from baseline in mean monthly migraine days across the 12-week treatment 
period. The y-axis would be displayed as % of total participants in the mITT population of the 
treatment group.
Table 10.2-2 provides a summary of analysis of health outcomes parameters and Table 10.2-3
provides an analysis summary for all additional efficacy endpoints.


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Table 10.2-2.
Statistical Methodology
Methodology
Description
Categorical
descriptive

Number and percentage of participants in individual categories
•
Participants with ≥ 1 qualifying event counted once per individual 
category

N1 if proportion denominator ≠ number of participants in the population 
(standard percentage denominator)

N1 = participants with non-missing value
Continuous
descriptive
N1, mean, standard deviation (SD), median, minimum, maximum
N1 = number of participants with non-missing value
CFB MMRM
Continuous descriptive for baseline, postbaseline, and CFB values at each analysis 
visit
o N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Analysis of the health outcome endpoints will be performed similarly to the 
primary analysis using MMRM, as specified in Section 10.2.1.
Estimates derived from the MMRM for CFB value controlling for visit as a 
categorical fixed effect, baseline score, baseline-by-visit interaction as covariates, 
with an unstructured covariance matrix (Toeplitz or compound symmetry 
covariance matrix if convergence fails), treatment group, visit, stratification of 
region, stratification of acute medication overuse, stratification of migraine 
prevention medication use and number of failures, and treatment group-by-visit 
interaction as categorical fixed effects. 
Observed cases without missing value imputation will be used in the analysis.
ANCOVA
The model will include treatment group, stratification of region, actual 
randomization stratification of acute medication overuse, stratification of migraine
prevention medication use and number of failures, and baseline.
Logistic regression model
Similar to the logistic regression model specified for secondary endpoint, the 
model assumes a binary distribution for the response and uses a logit link.
The analysis model will include treatment group, stratification of region and
stratification of acute medication overuse, stratification of migraine prevention 
medication use and number of failures as categorical fixed effects; baseline will be 
included as a covariate. 
Generalized
linear mixed model 
(GLMM
The model assumes a binary distribution for the response and uses a logit link. The 
model will include treatment group, visit, stratification of region, stratification of 
acute medication overuse, stratification of migraine prevention medication use and 
number of failures, and treatment group-by-visit interaction as categorical fixed 
effects; baseline and baseline-by-visit interaction will be included as covariates. 
Participants will be included as random effects with unstructured covariance 
matrix (Toeplitz or compound symmetry covariance matrix if convergence fails) in 
the model to account for the correlation among repeated measurements.
CFB = change from baseline; MMRM = mixed model for repeated measures


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Table 10.2-3.
Analysis of Additional Efficacy Endpoints and Health Outcomes
Assessment/ 
Term
Endpoint
Timing
Methodology
Monthly 
migraine days

CFB in monthly migraine days
Weeks 1-4, 5-8, 
and 9-12
CFB MMRM

≥ 25%, ≥ 30%, ≥ 50%, ≥75%, 100% 
improvement (decrease) in monthly 
migraine days
Weeks 1-4, 5-8, 
and 9-12
GLMM

≥ 25%, ≥ 30%, ≥ 75%, 100% 
improvement (decrease) in monthly 
migraine days 
Average across the 
12-week treatment 
period
Logistic regression 
model
Monthly 
headache days

CFB in monthly headache days
Weeks 1-4, 5-8, 
and 9-12
CFB MMRM
Monthly 
cumulative 
headache hours

CFB in monthly cumulative headache 
hours
Weeks 1-4, 5-8, 
and 9-12, and 
average across the 
12-week treatment 
period
CFB MMRM
Monthly acute 
medication use 
days

CFB in monthly acute medication use 
days
Weeks 1-4, 5-8, 
and 9-12, and 
average across the 
12-week treatment 
period
CFB MMRM
Monthly triptan 
use days

CFB in monthly triptan use days 
Weeks 1-4, 5-8, 
and 9-12, and 
average across the 
12-week treatment 
period
CFB MMRM
Monthly 
moderate/severe 
headache day

CFB in monthly moderate/severe 
headache days
Weeks 1-4, 5-8, 
and 9-12, and 
average across the 
12-week treatment 
period
CFB MMRM
Monthly severe 
headache days

CFB in monthly severe headache days
Weeks 1-4, 5-8, 
and 9-12, and 
average across the 
12-week treatment 
period
CFB MMRM
Weekly 
migraine days

CFB in weekly migraine days
Week 1-4
CFB MMRM
Migraine day

Participants having a migraine day on the 
day of initial dose and on each day of the 
6 days post the initial dose
Continuous descriptive
AIM-D

CFB in monthly Performance Daily 
Activities domain score at Weeks 1-4, 5-
8, and 9-12, and across the 12-week 
treatment period;

CFB in mean monthly Physical 
Impairment domain score at Weeks 1-4, 
5-8, and 9-12, and across the 12-week 
treatment period; 

CFB in monthly total score at Weeks 1-4, 
5-8, and 9-12, and average across the 
12-week treatment period
Weeks 1-4, 5-8, 
9-12, and average 
across the 12-week 
treatment period
CFB MMRM


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Assessment/ 
Term
Endpoint
Timing
Methodology
Activity level 
and activity 
limitation

CFB in monthly activity level at Weeks 
1-4, 5-8, and 9-12, and average across the 
12-week treatment period;

CFB in monthly activity limitation scores 
at Weeks 1-4, 5-8, and 9-12, and average 
across the 12-week treatment period
Weeks 1-4, 5-8, 
9-12, and average 
across the 12-week 
treatment period
CFB MMRM
HIT-6

CFB in total score at Weeks 4, 8, 12, and 
16 (week 16 summary only)

At least a 5-point improvement
(decrease) from baseline in total score at 
Weeks 4, 8, 12, 16
Weeks 4, 8, 12, 16
CFB MMRM
GLMM
MSQ v2.1

CFB in Role Function-Restrictive 
domain score at Weeks 4, 8, and 16
(week 16 summary only);

CFB in Role Function-Preventive domain 
score at Weeks 4, 8, 12, and 16 (week 16 
summary only);

CFB in Emotional Function domain score 
at Weeks 4, 8, 12, and 16 (week 16 
summary only).
Weeks 4, 8, 16
CFB MMRM
Patient 
Satisfaction
with Study 
Medication 
(PSSM)
Participants response as “satisfied” or 
“extremely satisfied” with study medication 
for migraine prevention at Weeks 4, 8, and 12
Weeks 4, 8, 12
GLMM
MIDAS

CFB in total score at Weeks 12

CFB in absenteeism score (questions 1, 
3, 5) at Weeks 12

CFB in presenteeism score (questions 2, 
4) at Weeks 12
Weeks 12
ANCOVA 
PGIC
Participant assessed as “much better” or “very 
much better” at Week 12
Weeks 12
Logistic regression 
model 
WPAI: 
MIGRAINE
CFB in percent work time missed, percent 
impairment while working, percent overall 
work impairment, and percent activity 
impairment due to migraine at Week 12
Week 4, 8, 12
CFB MMRM
PGI-S
CFB (as categorical in levels) in score at 
Weeks 4, 8, and 12
Weeks 4, 8, 12
MMRM
PHQ-9
CFB in PHQ-9 score at Week 12
Week 12
ANCOVA


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Assessment/ 
Term
Endpoint
Timing
Methodology
EQ-5D-5L

CFB in descriptive system index score 
US-based values at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 
and 12

CFB in descriptive system index score 
US-based values at Week 16 (follow-up 
visit)
Double-blind 
treatment 
period
CFB MMRM
Week 16
Continuous descriptive

CFB in the VAS score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 
and 12 
Double-blind 
treatment 
period
CFB MMRM

CFB in the VAS score at Week 16 
(follow-up visit)
Week 16
Continuous descriptive
PROMIS-PI
CFB in total score at Weeks 4, 8 and 12
Weeks 4, 8, 12
CFB MMRM
10.3
EFFICACY ANALYSES FOR EUROPEAN MEDICIANS AGENCY
The section defines an estimand, termed as “off-treatment hypothetical estimand”, which will be 
the primary estimand in support of EU filing.
10.3.1
Attributes of Off-treatment Hypothetical Estimand
The attributes of the estimand corresponding to the primary efficacy endpoint are summarized as 
following:
Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-blind treatment period. 
In addition, permissible and prohibited medications are described below:

Participants are allowed to take acute migraine medications (Section 4.4.1 of Protocol) to keep 
the participants in the study

Medications with demonstrated efficacy for the prevention of migraine (e.g., amitriptyline, 
propranolol, topiramate) are prohibited when used for any indication other than migraine 
prevention 
o
Participants taking one medication with demonstrated efficacy for the prevention of 
migraine may be randomized provided that in the opinion of the investigator:


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
Dose has been stable and the medication has been well-tolerated for at least 12 weeks 
prior to Visit 1, and

Participant is willing and able to maintain at a stable dose and dosage regimen during 
the study, which should be assessed to ensure compliance at each study visit

Enrollment of participants with current use of a migraine prevention medication will 
be capped at ~15%
Population
The target population is patients suffering from CM satisfying the inclusion and exclusion criteria 
as specified in Section 4 of the protocol.
The analysis population for off-treatment hypothetical estimand is defined to be all randomized 
participants who received at least 1 dose of study treatment, 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, or 9 to 
12) of eDiary data, regardless of whether on study treatment or off study treatment.
On study treatment is from the first dose till the last dose of study intervention. As the analysis-
visit mapping window (Table 16.1-2) is defined for the entire postbaseline period (not limited to 
the double-blind treatment period for participants who prematurely discontinued), the number of 
participants in the analysis population for this estimand approach is greater than or equal to the 
number of participants in the mITT Population for the primary analysis.
Variable
The variable is the same as the primary efficacy endpoint defined in Section 10.2, which is the 
change from baseline in the participant’s mean monthly (4-weeks) migraine days across the 
12-week treatment period as derived from the eDiary data. 


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Accounting of Intercurrent Events
Intercurrent events and their handling rules are as follows:

Participants who started a new migraine prevention treatment after the first dose of double-
blind treatment will have their data after starting the new migraine prophylaxis treatment 
during the follow-up period excluded from the analysis. 

Participants who discontinue study intervention due to all reasons other than starting a new 
migraine prophylaxis treatment will have their data collected after discontinuation of study 
intervention, and those off-treatment data will be included in the analysis.
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable means 
between each atogepant group and placebo.
10.3.2
Primary Efficacy Analysis
The primary efficacy endpoint is the change from baseline in mean monthly migraine days across 
the 12-week treatment period. Baseline is defined as the number of migraine days during the last 
28 days prior to the randomization date. The primary efficacy analyses will be based on the Off-
treatment Hypothetical Estimand Population.
To obtain the estimate of treatment effect defined in the off-treatment hypothetical estimand, an 
MMRM similar to the primary analysis specified in Section 10.2.1 will be performed on observed 
data without imputation before switching to other prophylaxis treatment during the follow up 
periods. The model terms include treatment group, visit (derived as month), stratification of region, 
stratification of acute medication overuse, stratification of migraine prevention medication use and 
number of failures, treatment-by-visit interaction, the baseline monthly migraine days and 
baseline-by-visit interaction. The analysis will be performed based on all evaluable post-baseline 
values using only the observed cases without imputation of missing values. Participants are always 
analyzed based on the treatment group assigned by randomization.


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10.3.2.1
Sensitivity Analyses in Missing Data Handling
The sensitivity analyses for missing data handling will be conducted and summarized in this 
section based on the Off-treatment Hypothetical Estimand Population.
Multiple Imputation
The following multiple imputation sensitivity analysis cannot be completed and has been 
eliminated from the final SAP due to the low number of participants observed in some of the 
pattern groups.
If a participant provides less than 14 days of efficacy data during a monthly period regardless on 
or off study treatment, then he/she is considered to have missing data during that monthly period. 
When a participant provides at least 14 days of efficacy data during a monthly period, if the number 
of days with available efficacy data while on study treatment is no less than the one while off study 
treatment, then he/she is considered to have efficacy data on study treatment during that monthly 
period; otherwise, he/she is considered to have efficacy data off study treatment during that 
monthly period.
Missing data are assumed to follow monotone pattern. Any intermediate missing values will be 
imputed first by the same method discussed in Section 10.2.1.1. Possible monotone missing data 
patterns are discussed below, and a summary is provided in Table 10.3-1.
Participants may provide three-month efficacy data in the following patterns:

Three months on study treatment (pattern group 1)

Two months on study treatment and one month off study treatment (pattern group 2)

One month on study treatment and two months off study treatment (pattern group 3)

Three months off study treatment (pattern group 4)
Participants may provide two-month efficacy data in the following patterns: 

Two months on study treatment (pattern group 5)

One month on study treatment and the other month off study treatment (pattern group 6)

Two months off study treatment (pattern group 7)
Participants may provide only one-month efficacy data while on or off study treatment (pattern 
groups 8 and 9, respectively). 


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The number and percentage of participants in each pattern group will be summarized by treatment 
group for the estimand analysis population defined in Section 10.3.1.
Table 10.3-1.
Monotone Missing Data Patterns
Pattern Group
Month 1
Month 2
Month 3
1
x
x
x
2
x
x
o
3
x
o
o
4
o
o
o
5
x
x
.
6
x
o
.
7
o
o
.
8
x
.
.
9
o
.
.
x = available efficacy data on study treatment; 
o = available efficacy data off study treatment; 
.  = missing data
Participants with missing data up to the 12-week treatment period will have their data imputed 
using participants in the same treatment group who provide data while off study treatment. Same 
as before (Section 10.2.1), the imputation of missing data is not based on each of the reasons of 
early termination, because there may not be sufficient non-missing efficacy data in each of the 
reason categories to serve as a stable reference.
The details of imputation are as follows:
Step 1. Impute month 2 missing data in pattern groups 8 and 9 by treatment group using data from 
pattern groups 3, 4, 6, and 7 in the corresponding treatment group based on monotone regression.
Step 2. Impute month 3 missing data in pattern groups 5 - 9 respectively by treatment group using 
data from pattern groups 2, 3, and 4 in the corresponding treatment group based on monotone 
regression.
Repeat the above procedures 20 times, then we have 20 complete datasets. The ANCOVA analysis 
results from these completed datasets are combined for overall estimation and inference using 


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Rubin’s rule (Rubin 1987) to produce a pooled estimate of LS mean difference, its SE, and 
corresponding p-value for the test of null hypothesis of no treatment effect.
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
The response variable for the ANCOVA model is the change from baseline in the calculated 
3-month average of the monthly migraine days including both on- and off-treatment data during 
the 12-week treatment period for each participant.
The ANCOVA model includes fixed effects for treatment group, stratification of region, 
stratification of acute medication use, stratification of migraine prevention medication use and 
baseline monthly migraine days as a covariate. The treatment difference for atogepant doses versus 
placebo will be estimated and reported along with the corresponding 95% confidence intervals and 
nominal p-values for superiority testing. There are no missing data based on this derivation because 
patients who discontinued the treatment are assumed to maintain the same mean (observed while 
on treatment) for 3 months (12 weeks).
10.3.3
Secondary Efficacy Analysis
The Secondary efficacy endpoints are listed in the Table 10.1-1. The secondary efficacy analyses 
will be based on the Off-treatment Hypothetical Estimand Population to support EU filling.
The secondary endpoints for headache days and acute medication use days, , will be analyzed in 
the same manner as that used to analyze the primary endpoint.
For HIT-6 total score and MSQ v2.1 Role Function-Restrictive domain score, the analysis will be 
performed similarly to the primary MMRM, with focus on the pairwise contrasts of each dose 
group to placebo at Week 12. Some participants may have their HIT-6 total score or MSQ v2.1 
assessed at Visit 8, which will not be included in MMRM, and instead the summary statistics will 
be provided.
The secondary endpoint of 50% responders are derived as at least a 50% reduction from baseline 
in the 3-month average of monthly migraine days based on the observed on- and off-treatment data 
collected throughout the study before switching to other prophylaxis treatment during the follow-
up period. The similar logistic regression model as described in 10.2.2 will be used for analysis. 


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The population-level summary for this endpoint is the odds ratio from a logistic regression for 
each atogepant group relative to placebo with baseline monthly migraine days as a covariate,
stratification of region, stratification of acute medication overuse, stratification of migraine 
prevention medication and number of failures, and treatment group as fixed factors.
The graphical approach to control the overall Type I error rate described in Section 10.3.3
(Table 10.3-1 and Figure 10.3-1) will be conducted for primary and secondary efficacy endpoints 
based on the off-treatment hypothetical estimand analysis population.
10.3.3.1
Multiplicity Adjustment
Multiplicity adjustments will be generated based on Off-treatment Hypothetical Estimand 
Population for Europe. The multiplicity adjustments will be applied to primary endpoint and the 
European set of the Secondary efficacy endpoints listed in Table 10.1-1.
The overall graphic approach procedure for primary and secondary efficacy endpoints for Europe 
is defined in the Table 10.3-2 and Figure 10.3-1.
The initial allocation of the overall significant level to 2 primary hypotheses will be 1/2 of the 
overall significance level for each dose, and no initial  is allocated to the hypotheses for secondary 
endpoints.
Within each individual dose, testing will start from the primary endpoint, and then test the 
secondary endpoints in a prespecified order. The order of testing for the first three secondary 
endpoints is determined by the power of individual endpoints based on the results from Phase 2/3 
study CGP-MD-01. Endpoints related to HIT-6 and MSQ v2.1 are placed in the last two positions 
in the testing hierarchy. If the null hypotheses for both the primary and the first three secondary 
endpoints are rejected for one of the doses, 1/3 of the associated alpha is passed to the other dose 
to increase the chances of success for the other dose in testing endpoints in the primary positions 
of the hierarchy, and the remaining 2/3 of the associated alpha is reserved for testing HO endpoints 
within the same dose. If hypotheses for two HO endpoints are rejected within a dose based on 
remaining alpha, the alpha for this dose will be propagated to the other dose to make full use of 
the alpha.


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Table 10.3-2.
Multiple Comparisons Procedure Definitions for EU Filing
Nodes
Alternate Hypothesis
Weight
Initial Local 
Significance 
Level
30mgBID P1
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly migraine days across the 
12-week treatment period (P1)
1/2
α×(1/2) = α/2
60mgQD P1
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly migraine days across the 
12-week treatment period (P1)
1/2
α×(1/2) = α/2
30mgBID S1
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 
12-week treatment period (S1)
0
α×0=0
60mgQD S1
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 
12-week treatment period (S1)
0
α×0=0
30mgBID S2
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly acute medication use days 
across the 12-week treatment period (S2)
0
α×0=0
60mgQD S2
60 mg QD atogepant is significantly different from placebo in 
change from baseline in mean monthly acute medication use days 
across the 12-week treatment period (S2)
0
α×0=0
30mgBID S3
30 mg BID atogepant is significantly different from placebo in 
proportion of participants with at least a 50% reduction in 3-
month average of monthly migraine days (S3)
0
α×0=0
60mgQD S3
60 mg QD atogepant is significantly different from placebo in 
proportion of participants with at least a 50% reduction in 3-
month average of monthly migraine days (S3)
0
α×0=0
30mgBID S4
30 mg BID atogepant is significantly different from placebo in 
change from baseline in the HIT-6 total score at Week 12 (S4)
0
α×0=0
60mgQD S4
60 mg QD atogepant is significantly different from placebo in 
change from baseline in the HIT-6 total score at Week 12 (S4)
0
α×0=0
30mgBID S5
30 mg BID atogepant is significantly different from placebo in 
change from baseline in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 (S5)
0
α×0=0
60mgQD S5
60 mg QD atogepant is significantly different from placebo in 
change from baseline in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 (S5)
0
α×0=0




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10.3.4
Additional Efficacy Endpoints and Health Outcomes Analysis
In general, all additional efficacy endpoint analyses are performed at the nominal significance 
level, without adjusting for multiplicity and will be based on the Off-treatment Hypothetical 
Estimand Population.
The additional endpoints are described in Section 10.1.3 and the analysis methods are the same 
with those analysis methods in support of US filing, which are described in Section 10.2.3.
10.4
EFFICACY ANALYSIS FOR HEALTH CANADA
10.4.1
Primary Efficacy Analysis
The primary efficacy analyses in support of Canadian filing will be based on the mITT Population. 
The primary endpoint, change from baseline in mean monthly migraine days across the 12-week 
treatment period, will be analyzed in the same manner as that used to analyze the primary endpoint 
in support of US filing.
10.4.2
Secondary Efficacy Analysis
The secondary efficacy analyses will be based on the mITT Population.
The secondary efficacy endpoints are listed in the Table 10.1-1. All secondary endpoints will be 
handled using the same approaches defined in the Section 10.2.2. The analysis of HIT-6 total score 
is similar to that of MSQ v2.1 role function restrictive domain score.
Multiplicity adjustments will be generated based on mITT population and will be generated based 
on primary and the Canadian set of secondary efficacy endpoints listed in the Table 10.1-1. The 
overall graphic approach procedure for primary and secondary efficacy endpoints for Canada is 
the same with that used in the Section 10.3.3.


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10.4.3
Additional Efficacy Endpoints and Health Outcomes Analysis
In general, all additional efficacy endpoint analyses are performed at the nominal significance 
level, without adjusting for multiplicity and will be based on the mITT Population.
The additional endpoints are described in Section 10.1.3 and the analysis methods are the same 
with those analysis methods in support of US filing, which are described in Section 10.2.3.


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11.0
SAFETY ANALYSES
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs), clinical laboratory, vital sign, electrocardiographic (ECG), and 
C-SSRS. For each safety parameter of the clinical laboratory, vital sign, and ECG, the last 
nonmissing safety assessment before the first dose of study treatment will be used as the baseline 
for all analyses of that safety parameter. Continuous variables will be summarized by number of 
participants and mean, SD, median, Q1, Q3, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants.
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.1.
An AE will be considered as a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of double-
blind study treatment. However, an AE that occurs more than 30 days after the last dose of double-
blind study treatment or Visit 8 whichever comes later will not be counted as a TEAE. Per case 
report form instructions, a new AE record will be created with a new AE onset date for any AE 
that worsens. Therefore, TEAEs can simply be identified as those AEs with recorded onset date 
on or after the date of the first dose of double-blind study treatment and within 30 days after the 
last dose of double-blind study treatment or Visit 8 whichever comes later. TEAEs that started after 
the date of last dose of study treatment will be considered as newly emergent.
Only AEs captured in study 3101-303-002 will be considered for TEAEs in this study. For 
participants rolling over into studies 3101-306-002, 3101-311-002 or 3101-312-002 (extension 
studies) who start the first dose on Visit 1 or beyond, AEs captured in those studies will be 
summarized in those studies although some AEs might occur within 30 days after the last dose 
from study 3101-303-002.
Overall summary of AEs will be provided on a per-participant basis for categories of TEAEs, 
treatment-related TEAEs, serious adverse events (SAEs), deaths, and AEs leading to study
intervention discontinuation.


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The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by descending percentage in Atogepant 60 mg QD group, by system organ class and 
preferred term, and further categorized by severity and causal relationship to the study treatment. 
If more than 1 AE is coded to the same preferred term for the same participant, the participant will 
be counted only once for that preferred term using the greatest severity and strictest causality for 
the summarization by severity and causal relationship.
For “current use” of migraine prevention medication participants, the number and percentage of 
participants reporting TEAEs in each treatment group will be tabulated by system organ class and 
preferred term.
The number and percentage of participants reporting newly emergent TEAEs in each treatment 
group will be tabulated by system organ class and preferred term for the safety follow-up period.
The total number of TEAEs by severity and causal relationship to the study treatment will be 
summarized by treatment group.
The incidence of common (≥2% of participants [after rounding] in any treatment group) TEAEs 
will be summarized by preferred term and treatment group and sorted by decreasing frequency in 
the Atogepant 60 mg QD group. A similar 5% table will be provided as well.
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that additionally meets any SAE criterion.
The number and percentage of participants who have TESAEs will be summarized by system 
organ class and preferred term by treatment group. In addition, the incidence of on-therapy SAEs 
that led to death will be summarized separately by preferred term for each treatment group.
The number and percentage of participants in the Safety Population who have TEAEs and TESAEs 
leading to premature discontinuation of the study intervention will be summarized by system organ 
class, preferred term and treatment group.
The number and percentage of participants reporting newly emergent SAEs and those that led to 
death will be summarized respectively by preferred term and treatment group for the safety follow-
up period.


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For all screened participants, separate tabular displays will be presented for participants who died, 
participants with SAEs, and participants with AEs leading to study intervention discontinuation.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in International System of units [SI]) at 
baseline, postbaseline, and changes from baseline values at each postbaseline timepoint will be 
presented by treatment group for the following laboratory parameters:
Hematology:
Hemoglobin, hematocrit, red blood cell count, red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration), white blood cell count, white blood cell count
differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), 
and platelet count
Chemistry:
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, lactate dehydrogenase, creatine kinase, total protein, 
albumin, calcium, phosphorus, uric acid, total cholesterol, estimated glomerular 
filtration rate
Urinalysis:
Specific gravity, pH
In addition, descriptive statistics for values and changes from the baseline values in conventional 
units at each assessment time point will be presented for selected clinical laboratory parameters 
listed in Appendix 20.1. A description of reporting the lab values in conventional units in 
participant narratives (along with the standard reporting in SI units) is presented at the end of 
Appendix 0.
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 11.2-1. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by treatment group. The percentages will be calculated relative to the number of participants with 
available non-PCS baseline values and at least 1 postbaseline assessment for the double-blind 


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treatment period. The numerator will be the total number of participants with available non-PCS 
baseline values and at least 1 PCS postbaseline value during the study. A supportive tabular display 
of participants with PCS postbaseline values will be provided, including the participant 
identification (PID) number, baseline and all postbaseline (including non-PCS) values.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
Shift tables from baseline to end of double-blind treatment period for clinical laboratory 
parameters will be presented by treatment group for the following categories: low, normal, and 
high, which are provided by lab vendor.
Participants who meet the potential Hy’s Law criteria from the first dose of study drug to the end 
of study will be summarized. Supportive tabular displays will also be provided.


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Table 11.2-1.
Criteria for Potentially Clinically Significant Laboratory Results
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.8 × LLN
> 1.2 × ULN
Alanine aminotransferase
U/L
—
≥3.0 × ULN
Alkaline phosphatase
U/L
—
≥3.0 × ULN
Aspartate aminotransferase
U/L
—
≥3.0 × ULN
Bicarbonate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Bilirubin, total
μmol/L
—
≥1.5 × ULN
Blood urea nitrogen
mmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.6 × ULN
Creatinine
μmol/L
—
> 1.5 × ULN
Creatine kinase
U/L
—
> 2.0 × ULN
Estimated glomerular filtration rate
mL/min/1.73m2
<60 mL/min/1.73m2
—
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 2.0 × ULN
Lactate dehydrogenase (LDH)
U/L
—
> 3.0 × ULN
Phosphorus
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Uric acid 
μmol/L
—
> 1.2 × ULN
HEMATOLOGY
Basophils, absolute cell count
109/L
—
> 2.0 × ULN
Eosinophils, absolute cell count
109/L
—
> 2.0 × ULN
Hematocrit
Ratio
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Lymphocytes, absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Monocytes, absolute cell count
109/L
< 0.5 × LLN
> 2.0 × ULN
Neutrophils, absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.9 × LLN
> 1.5 × ULN
URINALYSIS
pH
pH
< 0.9 × LLN
> 1.1 × ULN
Glucose
—
—
At least 1+
Protein 
—
—
At least 1+
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value; ULN = upper limit of normal value; normal value provided by laboratory.
SI = Le Système International d’Unités (International System of Units).


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The number and percentage of participants meeting each of the following criteria for postbaseline 
hepatic laboratory abnormalities listed in Table 11.2-2 will be summarized by treatment group. 
The percentages will be calculated relative to the number of participants with at least 1 
available postbaseline assessment. The numerator will be the total number of participants having 
at least 1 postbaseline value that meets the specific category during the study. A supportive listing 
will also be provided.


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Table 11.2-2.
Criteria for Hepatic Laboratory Abnormalities
Laboratory Parameter
Categories
ALT
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT or AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Bilirubin Total
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Alkaline Phosphatase
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Concurrent Elevations1
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 1.5 × ULN
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 2 × ULN
Potential Hy’s Law1
ALT or AST ≥ 3 × ULN and Bilirubin Total ≥ 2 × ULN and ALP < 2 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ALP = alkaline phosphatase; 
ULN = upper limit of normal (value provided by the laboratory).
1 Elevations are from the same day 


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Participants with an adjudicated case (i.e. ALT ≥ 3 × ULN or AST ≥ 3 × ULN) will be listed with 
their ALT and AST assessments, adjudication dates, relationship of ALT or AST elevation to study 
medication, and confounding factor(s). Additional listings will be provided for participants who 
meet ALT ≥ 3 × ULN or AST ≥ 3 × ULN and/or potential Hy’s law and have one of the following
categories: at least 1 abnormal liver biochemistry risk factor, at least 1 liver disease sign and 
symptom, at least 1 liver diagnostic test performed, consultation with a specialist for liver 
evaluation, liver lab tests performed, and drug screen performed, respectively.
11.3
VITAL SIGNS
Descriptive statistics for vital signs (systolic and diastolic blood pressures [sitting and standing], 
pulse rate [sitting and standing], respiratory rate, temperature, weight, orthostatic systolic blood 
pressure, orthostatic diastolic blood pressure, and orthostatic pulse rate) values at baseline, 
postbaseline, and changes from baseline values at each postbaseline timepoint will be presented 
by treatment group. Orthostatic vital sign values (orthostatic systolic and diastolic blood pressures, 
and orthostatic pulse rate) are defined as the corresponding standing measurement minus sitting 
measurement of systolic and diastolic blood pressures and pulse rate respectively.
Vital sign values will be considered PCS if they meet both the observed-value criterion and the 
change-from-baseline-value criterion, if both criteria are available, or meet either the observed-
value criterion or the change-from-baseline-value criterion as listed in Table 11.3-1. The number 
and percentage of participants who have PCS postbaseline vital sign values will be tabulated by 
study treatment. The percentages will be calculated relative to the number of participants who have 
available baseline or non-PCS baseline (for parameters with only the observed value criterion) 
values and at least 1 postbaseline assessment. The numerator will be the total number of 
participants with at least 1 PCS postbaseline value during the study. A supportive listing of 
The number and percentage of participants with an adjudicated case (i.e., ALT ≥ 3 × ULN and/or 
AST ≥ 3 × ULN) will be summarized by treatment group and by relationship of ALT or AST 
elevation to study medication. The percentages will be calculated relative to the number of 
participants with at least 1 adjudicated case. The numerator will be the number of participants with 
at least 1 adjudicated case in the specific category of relationship. If a participant has more than 1 
adjudicated case, he or she will be counted in the most relevant category of relationship.


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participants with PCS postbaseline values will be provided. In addition, a tabular display showing 
all AEs that occurred in participants who had PCS postbaseline vital sign values will be provided.
Table 11.3-1.
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteria
Observed Value
Change from Baseline
Systolic blood pressure, mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic blood pressure, mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥7%
Low
—
Decrease of ≥7%
Orthostatic SBP change, mm Hg
Low
≤ -20
—
Orthostatic DBP change, mm Hg
Low
≤ -15
—
Orthostatic Pulse rate change, bpm
High
≥ 25
—
SBP = Systolic blood pressure, DBP = Diastolic blood pressure, bpm = beats per minute.
11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QT interval corrected for heart rate [QTc]) at baseline, postbaseline, and changes 
from baseline values at each assessment time point to the end of study will be presented by 
treatment group. The QTc will be calculated using both the Bazett and Fridericia corrections (if 
the vendor does not provide).
ECG parameter values are considered PCS if ECG values meet either the actual value or change 
from baseline PCS high criteria listed in Table 11.4-1. The number and percentage of participants 
with PCS postbaseline values will be tabulated by treatment group. The percentages will be 
calculated relative to the number of participants with an available non-PCS baseline value and at 
least 1 postbaseline assessment. The numerator will be the total number of participants with an 
available non-PCS baseline value and at least 1 PCS postbaseline ECG value during the study. A 


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supportive listing of participants with PCS postbaseline values will be provided. A listing of all 
AEs for participants with PCS ECG values will also be provided.
Table 11.4-1.
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Actual Value
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTc (QTcB or QTcF) interval
msec
> 500
QTc (QTcB or QTcF) interval
msec
Increase from baseline > 60
QTc = QT interval corrected for heart rate. 
QTcB = QT interval corrected for heart rate using the Bazett formula.
QTcF = QT interval corrected for heart rate using the Fridericia formula.
To evaluate ECG postbaseline values of clinical interest, the number and percentage of participants
with post-baseline QTcF >450 msec, >480 msec, or >500 msec will be tabulated by treatment 
group. A supportive listing of participants with postbaseline clinical interest will be provided. A 
listing of all AEs for participants with postbaseline clinical interest will also be provided.
The number and percentage of participants with an increase > 30 msec but ≤ 60 msec, and with an 
increase > 60 msec in QTcF will be tabulated. Participants will be counted only once for the most 
severe category. A supportive listing of participants with postbaseline QTcF increases > 30 msec 
will be provided, including the PID number, study center, and all QTc values (including changes 
from baseline). A listing of all AEs for participants with postbaseline QTcF increases > 30 msec 
will also be provided.
A shift table from baseline to the end of double-blind treatment period in the investigator’s overall 
interpretation of the ECG will be presented by treatment group for the following categories: 
normal; abnormal, not clinically significant; abnormal, clinically significant. A tabular display of 
participants with postbaseline clinically significant ECG abnormalities according to the 
investigator’s overall interpretation will be provided.


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11.5
COLUMBIA-SUICIDE SEVERITY RATING SCALE
For C-SSRS, the number and percentage of participants with suicidal ideation or suicidal behavior 
as recorded on the C-SSRS will be summarized by treatment group for the Safety Population. The 
distribution of responses for most severe suicidal ideation and most severe suicidal behavior in the 
participant’s lifetime history, in the past 6 months, in the double-blind treatment period, and in the 
safety follow-up period will also be presented by treatment group. Supportive listings will be 
provided and will include the PID number, study center number, treatment group, lifetime history, 
and postbaseline values. Intensity of suicidal ideation and suicidal behavior type will also be 
included in these listings. A listing of all AEs occurring in participants who have suicidal ideation 
or suicidal behavior will also be provided.


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12.0
SUBGROUP ANALYSES
12.1
SUBGROUP ANALYSES FOR EVALUATING THE CONSISTENCY OF 
TREATMENT EFFECTS ACROSS REGIONS AND SUBPOPULATIONS
To estimate the treatment effect on the primary efficacy endpoint for regions (North America, 
Europe, and East Asia [China, Japan and APAC including Korea and Taiwan]), the same model as 
that of the primary MMRM model in primary efficacy analysis in Section 10.2.1 will be utilized
based on mITT population in support of US filing and on the Off-treatment Hypothetical Estimand 
Population in support of EU filing. In addition, the model will include region, region by treatment 
(2-way interaction) and region by treatment by visit (3-way interaction) as categorical fixed effects. 
An unstructured covariance matrix will be used to model the covariance of within participant 
repeated measurements. Pairwise contrasts in the MMRM model will be used to compare each 
atogepant dose to placebo for treatment effect in patients enrolled in each region.
The estimate of the between-group treatment effect (with a 95% CI) for each atogepant dose versus 
placebo for the primary efficacy endpoint for each region and overall treatment effect will be 
plotted in the forest plot to visualize the consistency of treatment effect across regions.
For key efficacy endpoints (change from baseline in mean monthly headache days across the 
12-week treatment period, change from baseline in mean monthly acute medication use days 
across the 12-week treatment period, and at least a 50% reduction in 3-month average of monthly 
migraine days), the estimate of the between-group treatment effect (with 95% CI) for each 
atogepant dose versus placebo will be summarized overall and for each region in a table to facilitate 
the comparison. The test of treatment-by-region interaction will be provided as recommended in 
ICH E17 Section 2.2.7 on Examination of Consistency across Regions and Subpopulations.


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12.2
OTHER SUBGROUP ANALYSES
The subgroup analyses will be based on mITT population in support of US filing and the Off-
treatment Hypothetical Estimand Population in support of EU filing.
The subgroup analysis will be based on the following four endpoints and ten subgroup categories.
Endpoints:

Change from baseline in mean monthly migraine days across the 12-week treatment period

Change from baseline in mean monthly headache days across the 12-week treatment period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

At least a 50% reduction in 3-month average of monthly migraine days
Subgroup Categories:

Age group: < 40 years; 40 to <65 years; >=65 years

Sex: Male; Female

Race: White; Asian; All other races

BMI: Underweight or normal (<25); Overweight (>=25- <30); Obese (>=30)

Baseline monthly migraine days: <18 days; > =18 days

Acute medication overuse: Yes; No

Preventive medication current use: Yes; No

Prior exposure to a migraine prevention medication with proven efficacy: Yes; No

Migraine prevention medication use and number of failures: 
o
Current use
o
Past Use only and “failed 0 medications or failed 1 or more medication(s) with the 
same mechanism of action”
o
Past Use only and “failed 2 or more medications with different mechanisms of action
o
Never used

Number of migraine prevention medication failures:
o
Current use or past use and “failed 0 medication”
o
Current use or past use and “failed 1 or more medication(s) with the same mechanism 
of action”


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o
Current use or past use and “failed 2 or more medications with different mechanisms 
of action”
o
Never used
Within each subgroup category, data will be divided into mutually exclusive subsets and then a 
separate analysis will be performed for each subset (e.g., for the “Sex” category, a separate analysis 
will be performed for all Male participants and the same analysis will be performed for all Female 
participants). For efficacy endpoints, point estimates along with corresponding confidence 
intervals will be provided for parameters of interests in tables. 
If models do not converge, descriptive statistics for subgroups will be provided.


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13.0
INTERIM ANALYSIS
No interim analysis is planned for this study.


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14.0
DETERMINATION OF SAMPLE SIZE
A total sample size of 250 participants will be randomized per treatment group and that will provide 
at least 96% power to detect the treatment difference between each of the 2 atogepant doses 
(assumed equally effective) and placebo for the primary efficacy endpoint. The sample size of this 
study was selected to provide sufficient power for the first 3 secondary endpoints as shown in 
Table 12.2-1. The power calculations are based on the following assumptions:
1) The treatment difference from placebo will be similar to the average value across the CM 
prevention studies for Botox (Aurora 2010, Diener 2010) and TEV-48125 (Bigal 2015, 
Silberstein 2017). In particular, the assumed treatment difference from placebo in change from 
baseline in mean monthly migraine days across the 12-week treatment period is -2 days, and 
the standard deviation is 5.5 days. Detailed treatment difference and standard deviation 
assumptions are listed in Table 12.2-1.
2) The study statistical testing plan controls the overall type I error at 5%. The power calculations 
of the primary and secondary endpoints have taken the multiple comparisons into consideration 
by testing each dose versus placebo at a 0.025 significance level, 2-sided. Once the primary 
endpoint for each dose is significant at 0.025, 2-sided, the secondary endpoints will be tested
sequentially in Section 10.2.
Table 12.2-1.
Statistical Power for Primary and the First Three Secondary Endpoints
Hypothesis 
Testing
Endpoint
Treatment 
Difference from 
Placebo
Standard 
Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across the 12-
week treatment period
–2
5.5
96%
Secondary 1
Change from baseline in mean 
monthly headache days across the 12-
week treatment period
–2
6.0
93% a
Secondary 2
Change from baseline in mean 
monthly acute medication use days 
across the 12-week treatment period
–1.8
5.5
92% a
Secondary 3
At least a 50% reduction in mean 
monthly migraine days across the 
12-week treatment period
33% Placebo 
Rate
49% Atogepant 
Rate
92% a
a
Statistical powers for secondary endpoints are conditional on success of prior endpoints (assuming independence among the 
endpoints) in the sequence for the comparisons of each dose versus placebo.


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS.


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16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS
For analysis purposes, Day 1 is defined as the date of the first dose of double-blind study 
intervention. On-treatment Period is defined as from the first dose till the last dose.
The analysis visit windows for monthly efficacy endpoints based on daily eDiary data for mITT 
Population are defined as follows.
Table 16.1-1.
Efficacy Analysis Visit Definitions for eDiary Data
Analysis Phase
Analysis Visit (Derived)
eDiary Window
Pretreatment
Baseline
The last 28 days prior to randomization
Double-Blind Treatment 
Period
Weeks 1 – 4
Treatment Day [1, 28]
Weeks 5 – 8
Treatment Day [29, 56]
Weeks 9 – 12
Treatment Day [57, min (end of the double-blind 
treatment period, 84)]
The analysis visit windows for monthly efficacy endpoints based on daily eDiary data for Off-
treatment Hypothetical Estimand Population are defined as follows.
Table 16.1-2.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand 
Approach for eDiary Data
Analysis Phase
Analysis Visit (Derived)
eDiary Window
Pretreatment
Baseline
The last 28 days prior to randomization
On or after the first 
dose of study 
Weeks 1 – 4
(on/off study treatment)
Days [1, 28]
intervention
Weeks 5 – 8
(on/off study treatment)
Days [29, 56]
Weeks 9 – 12
(on/off study treatment)
Days [57, min(end of the last visit, 84)]
Day 1 = the date of the first dose of double-blind study intervention.
The analysis visit windows for weekly efficacy endpoints in the first monthly period based on 
daily eDiary data for mITT Population are defined as follows.


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Table 16.1-3.
Efficacy Analysis Visit Definitions for eDiary Data in the First Monthly Period
Analysis Phase
Analysis Visit (Derived)
eDiary Window
Pretreatment
Baseline
The last 28 days prior to randomization
Double-Blind 
Week 1
Treatment Day [1, 7]
Treatment Period
Week 2
Treatment Day [8, 14]
Week 3
Treatment Day [15, 21]
Week 4
Treatment Day [22, 28]
The analysis visit windows for daily efficacy endpoints in the first weekly period based on daily 
eDiary data for mITT population are defined as follows:
Table 16.1-4.
Efficacy Analysis Visit Definitions for eDiary Data
Analysis Phase
Analysis Visit (Derived)
eDiary Window
Pretreatment
Baseline
The last 28 days prior to randomization
Double-blind treatment 
period
Initial Dose Day
Treatment Day 1
1 Day after Initial Dose
Treatment Day 2
2 Days after Initial Dose
Treatment Day 3
3 Days after Initial Dose
Treatment Day 4
4 Days after Initial Dose
Treatment Day 5
5 Days after Initial Dose
Treatment Day 6
6 Days after Initial Dose
Treatment Day 7
The analysis visit windows for MSQ v2.1 and HIT-6 for mITT Population and Off-treatment
Hypothetical Estimand Population are defined as follows:
Table 16.1-5.
Efficacy Analysis Visit Definitions for MSQ v2.1 and HIT-6
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Pretreatment
Baseline
Visit 2 
(Randomization)
Treatment Day ≤ 1
Double-Blind
Week 4
Visit 4
Treatment Day [2, 41]
Treatment
Week 8
Visit 6
Treatment Day [42, 69]
Period
Week 12
Visit 7/ET
Treatment Day [70, end of the double-
blind treatment period]
Follow-up
Week 16 (Follow-up)
Visit 8
Treatment Day [end of the double-blind 
treatment period +1, min(end of last study 
visit, 115)]
ET = early termination. Follow-up visit will not be included in the MMRM analysis and will only be used in summary 
statistics.


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Table 16.1-6.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand 
Approach for MSQ v2.1 and HIT-6
Analysis Phase
Analysis Visit (Derived)
Window
Pretreatment
Baseline
Treatment Day ≤ 1
On or after the first dose of 
study intervention
Week 4
Treatment Day [2, 41]
Week 8
Treatment Day [42, 69]
Week 12
Treatment Day [70, 97]
Week 16
Treatment Day [98, end of last study visit]]
ET = early termination. Follow-up visit will not be included in the MMRM analysis and will only be used in summary statistics.
The analysis visit windows for EQ-5D-5L for mITT Population and Off-treatment Hypothetical 
Estimand Population are defined as follows:
Table 16.1-7.
Efficacy Analysis Visit Definitions for EQ-5D-5L
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Pretreatment
Baseline
Visit 2 
(Randomization)
Treatment Day [-7, -1]
Double-Blind
Treatment
Period
Week 1-2
Visit 3
Treatment Day [1, 14]
Week 4
Visit 4
Treatment Day [25, 31]
Week 6
Visit 5
Treatment Day [39, 45]
Week 8
Visit 6
Treatment Day [53, 59]
Week 12
Visit 7/ET
Treatment Day [77, minimum(end of the 
double-blind treatment period, 83)]
Follow-up
Week 16 (Follow-up)
Visit 8
Treatment Day [end of the double-blind 
treatment period +1, min(end of last study 
visit, 115)]
ET = early termination. Follow-up visit will not be included in the MMRM analysis and will only be used in summary 
statistics.
Table 16.1-8.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand 
Approach for EQ-5D-5L
Analysis Phase
Analysis Visit (Derived)
Window
Pretreatment
Baseline
Treatment Day [-7, -1]
On or after the first dose of 
study intervention
Week 1-2
Treatment Day [1, 14]
Week 4
Treatment Day [25, 31]
Week 6
Treatment Day [39, 45]
Week 8
Treatment Day [53, 59]
Week 12
Treatment Day [77, 83]
Week 16
Treatment Day [98, end of last study visit]


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The analysis visit windows for PGI-S, WPAI: MIGRAINE, and PROMIS-PI for mITT Population 
and Off-treatment Hypothetical Estimand Population are defined as follows:
Table 16.1-9.
Efficacy Analysis Visit Definitions for PGI-S, WPAI: MIGRAINE, and PROMIS-PI
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Pretreatment
Baseline
Visit 2 
(Randomization)
Treatment Day ≤ 1
Double-blind 
Treatment Period
Week 4
Visit 4
Treatment Day [2, 41]
Week 8
Visit 6
Treatment Day [42, 69]
Week 12
Visit 7/ET
Treatment Day [70, end of the double-blind 
treatment period]
ET = early termination.
Table 16.1-10.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand
Approach for PGI-S, WPAI: MIGRAINE, and PROMIS-PI
Analysis Phase
Analysis Visit (Derived)
Window
Pretreatment
Baseline
Treatment Day ≤ 1
On or after the first dose of 
study intervention
Week 4
Treatment Day [2, 41]
Week 8
Treatment Day [42, 69]
Week 12
Treatment Day [70, end of last study visit]
The analysis visit windows for PGIC for mITT Population and Off-treatment Hypothetical 
Estimand Population are defined as follows:
Table16.1-11.
Efficacy Analysis Visit Definitions for PGIC
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Double-blind 
Treatment Period
Week 12
Visit 7/ET
Treatment Day [2, end of the double-blind 
treatment period]
ET = early termination.
Table 16.1-12.
Efficacy Analysis Visit Definitions in the Off-treatment Hypothetical Estimand 
Approach for PGIC
Analysis Phase
Analysis Visit (Derived)
Window
On or after the first dose of 
study intervention
Week 12
Treatment Day [2, end of last study visit]


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The analysis visit windows for Patient Satisfaction with Study for mITT Population and Off-
treatment Hypothetical Estimand Population are defined as follows:
Table 16.1-13.
Efficacy Analysis Visit Definitions for Patient Satisfaction with Study
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Double-blind 
Treatment Period
Week 4
Visit 4
Treatment Day [2, 41]
Week 8
Visit 6
Treatment Day [42, 69]
Week 12
Visit 7/ET
Treatment Day [70, end of the double-blind 
treatment period]
ET = early termination.
Table 16.1-14.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand 
Approach for Patient Satisfaction with Study
Analysis Phase
Analysis Visit (Derived)
Window
On or after the first dose of 
study intervention
Week 4
Treatment Day [2, 41]
Week 8
Treatment Day [42, 69]
Week 12
Treatment Day [70, end of last study visit]
The analysis visit windows for MIDAS and PHQ for mITT Population and Off-treatment 
Hypothetical Estimand Population are defined as follows:
Table 16.1-15.
Efficacy Analysis Visit Definitions for MIDAS and PHQ
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Pretreatment
Baseline
Visit 2 
(Randomization)
Treatment Day ≤ 1
Double-blind 
Treatment Period
Week 12
Visit 7/ET
Treatment Day [2, end of the double-blind 
treatment period]
Table 16.1-16.
Efficacy Analysis Visit Definitions in the Off-Treatment Hypothetical Estimand 
Approach for MIDAS and PHQ
Analysis Phase
Analysis Visit (Derived)
Window
Pretreatment
Baseline
Treatment Day ≤ 1
On or after the first dose of 
study intervention
Week 12
Treatment Day [2, end of last study visit]


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The analysis visit windows for safety endpoints are defined as follows:
Table 16.1-17.
Safety Data Analysis Visit Definitions
Analysis Phase
Analysis Visit 
(Derived)
Scheduled Study 
Visit (eCRF)
Window
Pretreatment
Baseline
Visit 2 
(Randomization)
Treatment Day ≤ 1
Double-Blind 
Treatment
Period
Week 2
Visit 3
Treatment Day [2, 20]
Week 4
Visit 4
Treatment Day [21, 34]
Week 6
Visit 5
Treatment Day [35, 48]
Week 8
Visit 6
Treatment Day [49, 69]
Week 12
Visit 7/ET
Treatment Day [70, end of the Double-blind 
Treatment Period]
End of Double-blind 
Treatment Period
Last available assessment during double-blind 
treatment period
Week 16 (Safety 
follow-up)
Visit 8
Treatment Day [end of double-blind treatment period
+1, end of safety follow-up period]
Estimand Follow-up
Treatment Day [end of safety follow-up period +1, 
the last study visit]
End of study
Last available assessment after treatment start date, 
i.e. occurs at final visit (expected Day 112) or ET
Safety follow-up visit will be presented in analysis tables for clinical laboratory values and vital signs.
End of Double-blind Treatment Period is defined as the last available assessment during double-blind treatment period. End of 
Double-blind Treatment Period results will be presented in analysis tables for clinical laboratory values and vital signs.
End of Study is defined as the last available assessment during the study, including double-blind and safety follow-up period. 
End of Study results will be presented in analysis tables for safety parameters, including but not limited to electrocardiograms, 
clinical laboratory values, and vital signs.
ET = early termination.
For endpoints collected by visit (not for eDiary data), if a participant has 2 or more visits within 
the same window, the last visit with a non-missing value will be used for analysis, unless specified 
otherwise.
The following algorithm is used to define the double-blind treatment period and the follow-up 
periods unless specified otherwise. The double-blind treatment period starts with the date of the 
first dose of double-blind study treatment and ends with the latest date of the last study medication 
date, and the last scheduled assessment date of Visit 2 to Visit 7 for participants who entered the 
safety follow-up period; or ends with the latest date of the last study medication date, and last 
assessment date for participants who did not enter the safety follow-up period. The safety follow-
up period starts with the 1 day after the end of the double-blind period and ends with the last 
scheduled assessment date of Visit 8 for participants who entered the estimand follow-up period; 


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or ends with the last assessment date for participants who did not enter the estimand follow-up 
period. The estimand follow-up period starts with the 1 day after the end of the safety follow-up 
period and ends with the last assessment date for participants who entered the estimand follow-up 
period.
16.2
DERIVED EFFICACY AND HEALTH OUTCOME DATA
16.2.1
Derivation of Efficacy Endpoints Based on eDiary Data
For analysis purposes, four weeks (28 days) will be considered as one month. On a daily basis 
during the 4-week baseline period and throughout the study, participants are to record eDiary 
information on the duration of headache, headache specific characteristics and symptoms, the pain 
severity, and use of any acute headache pain medication. Daily headache diary data consists of 
data from “today’s diary” completed on that day and “yesterday’s diary” completed on the 
following day. Participants are to report headache data in “today’s diary” in the evening 19:00 to 
23:59 and to complete “yesterday’s diary” on the following day to add the remaining headache 
data of previous evening until midnight. In case participants miss “today’s diary”, they can report 
the whole-day headache data in “yesterday’s diary” on the following day. In case participants miss 
“yesterday’s diary”, headache data from “today’s diary” alone will be used as daily headache diary 
data. If both “today’s diary” and “yesterday’s dairy” are missing on one day, the daily headache 
diary data will be treated as missing.
Daily headache diary data will be merged from “today’s diary” and “yesterday’s diary” as 
following and will be used to derive migraine day and headache day.

Daily headache total duration: summation of headache durations from “today’s diary” and 
“yesterday’s diary”

Daily headache pain severity: the worst pain severity from “today’s diary” and “yesterday’s 
diary”

Daily headache characteristics and symptoms: present if present in one of “today’s diary” 
and “yesterday’s diary” 

Daily acute headache medication usage: combination of acute headache medications usage 
from “today’s diary” and “yesterday’s diary”


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Moderate/severe headache day is defined as a headache day during which the maximum pain 
severity is either moderate or severe.
Severe headache day is defined as a headache day during which the maximum pain severity is 
severe.
If a participant confirmed no headache for the Question 1 in eDiary, then the participant will not 
answer subsequent questions related to headache symptoms, duration, and acute headache 
mediation use by design. Thus, the acute medication use for that diary (‘today’ or ‘yesterday’) will 
be treated as ‘No’ when deriving acute medication use day.
If a participant reported multiple records on the same day for one specific category (‘Today’ or 
‘Yesterday’) and records are inconsistent, then the records for that eDiary category on the date 
with discrepancy will be excluded from endpoint derivation and thus excluded from the analyses. 
The corresponding records will be flagged in the analysis datasets. If there are duplicated records 
of daily diary data for the same participant on the same day with the same type, the set of records 
with the last form access datetime will be used in the analysis because records are duplicated.
The monthly migraine days is defined as the total number of recorded migraine days in the eDiary 
divided by the total number of days with eDiary records during each monthly period and multiplied 
by 28. For baseline, a minimum of 20 days’ eDiary data during the 4-week baseline period is 
required for the migraine days to be evaluable. A minimum of 14 days’ eDiary data during a 
postbaseline monthly treatment period is required for the migraine days to be evaluable for that 
particular period. If a participant does not have at least 14 days of diary data for a monthly 
treatment period, the migraine days for that period will be considered as missing. Migraine days 
will be derived for each participant at baseline and for each postbaseline monthly treatment period 
(Weeks 1-4, 5-8, 9-12). The same method to derive monthly migraine days will be used to derive 
monthly headache days, monthly acute medication use days, monthly triptan use days, monthly 
cumulative headache hours, monthly headache day pain intensity, monthly moderate/severe 
headache days, and monthly severe headache days.
If a participant confirmed that acute medications were taken and entered medications in the eDiary, 
then the acute medication use day will be set to ‘Yes’. If a subject reports ‘Yes’ to the intake of 


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allowed medication(s) to treat an acute migraine but does not list any of them in the diary, then the 
acute medication use days will not be counted in this situation and vice versa.
For weekly data analysis purposes, baseline is defined to be the baseline derived in monthly basis 
divided by 4, and change from baseline in the weekly migraine days will be calculated for 
consecutive 7-day periods beginning with Day 1. Subsequent to treatment start, the number of 
headache days will be counted in successive and non-overlapping 1-week (i.e., 7-day) windows. 
Headaches that continue into a subsequent 1-week period will be counted (with recorded severity 
and duration) as occurring in each period. If any postbaseline eDiary window for a participant has 
at least 4 but less than 7 days of reported data, the prorated approach will be used. If a participant 
reports less than 4 days of headache data, the participant’s observed counts in that particular 7-day 
eDiary window will be set to missing for that window.
16.2.2
Derivation of Health Outcome Endpoints Based on eDiary Data
A separate SAP will be provided for additional efficacy endpoints related to health outcome.
Details regarding derivation for those endpoints are provided in that document. This section covers 
health outcome endpoints which are related to primary and secondary efficacy endpoints.
If a participant reported multiple records on the same day and records are inconsistent, then the 
records on the date with discrepancy will be excluded from endpoint derivation and thus excluded 
from the analyses. The corresponding records will be flagged in the analysis datasets.
AIM-D Related Endpoints Derivation
As described in SAP Section 10.1.2 (copied from protocol Section 6.2.1), the AIM-D was 
developed as a daily eDiary with a recall period 24 hours. By design, it is collected in the today 
diary only. The scoring of the following endpoints is completed in 2 steps.

Monthly Performance of Daily Activities domain score of the AIM-D

Monthly Physical Impairment domain score of the AIM -D

Monthly AIM -D total score


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Step 1: Calculate AIM-D daily domain score and total score
Daily performance of daily activities score will be calculated based on the summation of items 1-5 
and 10 and 11, ranging from 0-35. A daily performance of daily activities domain score will be 
calculated if 4 or more item scores have non-missing responses. When the response category “I 
did not have <errands, leisure or social, strenuous activities> planned” (items 2, 4, and 5), is 
selected, the response will be considered missing. The corresponding performance of daily 
activities domain score will be calculated by summing the non-missing item scores and dividing 
by the number of non-missing items and then multiplying by 7, provided that 4 or more item scores 
are available; otherwise it will be set to missing. The raw daily score will be transformed to a 0-100 
scale by multiplying by 100 and dividing by the highest raw score (35).
Daily physical impairment scores will be calculated based on the summation of items 6-9, ranging 
from 0-20. A daily physical Impairment score will be calculated if 2 or more item scores have non-
missing responses. The corresponding physical Impairment score will be calculated by summing 
the non-missing item scores and dividing by the number of non-missing items and then multiplying 
by 4, provided that 2 or more item scores are available; otherwise it will be set to missing. The raw 
daily score will be transformed to a 0-100 scale by multiplying by 100 and dividing by the highest 
raw score (20).
A daily total score will be calculated based on the summation of items 1-11, ranging from 0-55. A 
Total Score will be calculated if 6 or more items scores have non-missing responses. When the 
response category “I did not have <errands, leisure or social, strenuous activities> planned” 
(items 2, 4, and 5), is selected, the response will be considered missing. The corresponding Total 
Score will be calculated by summing the non-missing item scores and dividing by the number of 
non-missing items and then multiplying by 11, provided that 6 or more item scores are available; 
otherwise it will be set to missing. The raw score will be transformed to a 0-100 scale by 
multiplying by 100 and dividing by the highest raw score (55).
Step 2: Calculate Monthly Scores and Baseline Score
Monthly scores will be calculated using the average daily scores only if there are at least 14 non-
missing daily scores in the corresponding monthly (28-day) period. The corresponding monthly 


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scores will be calculated by summing the non-missing daily domain scores and dividing by the 
number of non-missing daily domain, provided that 14 or more daily scores are available; 
otherwise it will be set to missing.
Monthly activity level score will be calculated by summing the non-missing daily scores and 
dividing by the number of these scores, provided that 14 or more daily scores are available in the 
corresponding monthly (28-day) period; otherwise it will be set to missing. Same rule will be 
applied to the calculation of monthly activity limitation score.
MSQ Related Endpoints Derivation
MSQ v2.1 consists of 14 items with a 4-week recall period. The scoring of the MSQ is completed 
in following 3 steps.
Step 1: Final item value assignment.
Precoded item values and final item values for each MSQ item response are shown in Table 16.2-1.
Table 16.2-1.
Item Values for MSQ Item Responses
Response Categories
Precoded Item Value
Final Item Value
None of the time
1
6
A little bit of the time
2
5
Some of the time
3
4
A good bit of the time
4
3
Most of the time
5
2
All of the time
6
1
Step 2: Computation of raw domain (dimension) scores
Once a final item value has been assigned to each item, a raw score can be computed for each
MSQ domain. Role Function-Restrictive domain includes Items 1 - 7, Role Function-Preventive 
domain includes Items 8 - 11, and Emotional Function domain includes Items 12 - 14. The raw 
score for each domain is the algebraic sum of the final item values for all items in that domain.


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Missing data handling: if a respondent answered at least half of the items in a domain (or half plus 
one in the case of scales with an odd number of items), a missing item value can be estimated using 
the average of the other completed items within the same dimension.
In detail, for MSQ v2.1 Role Function-Restrictive domain, the 7 individual item responses using 
final item value will be summed, resulting in the raw domain score ranging from 7 to 42 with 
higher scores indicating better quality of life. If there are missing item responses, the raw domain 
score will be calculated by summing the non-missing item responses using final item value and 
dividing by the number of non-missing items and then multiplying by 7 provided that 4 or more 
items in the domain are completed; otherwise it will be set to missing. For MSQ v2.1 Role 
Function-Preventive and Emotional domains, the raw domain scores will be calculated similarly 
using final item value respectively. If there are missing item responses, the corresponding raw 
domain score will be calculated by summing the non-missing item responses using final item value 
and dividing by the number of non-missing items and then multiplying by the number of questions 
in that domain provided that 2 or more domain items are completed; otherwise it will be set to 
missing.
Step 3: Linear transformation to a 0 to 100 scale.
The transformation formula for each MSQ 2.1 domain are listed below

Role Function-Restrictive: 
(	 
)∗


Role Function-Preventive: 
(	 
)∗


Emotional Function:           
(	 
)∗

HIT-6 Total Score Derivation
For HIT-6 total score, precoded item values and final item values for each item response are shown 
in Table 16.2-2. Total score is calculated by summing 6 sub-item responses, resulting in the total 
score ranging from 36 to 78 with higher scores indicating greater impact. If any sub item is missing, 
then total score will be missing.


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Table 16.2-2.
Item Values for HIT-6 Item Responses
Response Categories
Precoded Item Value
Final Item Value
Never
0
6
Rarely
1
8
Sometimes
2
10
Very Often
3
11
Always
4
13
The HIT-6 instrument has a recall period of 4 weeks for 3 of the 6 items.
MIDAS Related Endpoints Derivation
MIDAS total score is derived as the sum of first 5 of questions (i.e., the sum of days missing work 
or school, productivity at work or school reduced, not do household work, productivity in 
household work reduced, miss family social or leisure activities). If any sub item is missing, the 
MIDAS total score will be missing. 
The MIDAS absenteeism score is derived as the sum of Questions 1, 3 and 5. If any sub item is 
missing, then the MIDAS absenteeism score will be missing. The MIDAS presenteeism score is 
derived as the sum of Questions 2 and 4. If any sub item is missing, then the MIDAS presenteeism 
score will be missing.
WPAI:MIGRAINE Related Endpoints Derivation 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity, i.e., worse outcomes, as follows:
Questions:

Q1 = currently employed (working for pay).

Q2 = missed work hours because of problems associated with your migraine

Q3 = missed work hours due to other reason.

Q4 = hours actually worked.


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
Q5 = migraine affected productivity while working.

Q6 = migraine affected regular daily activity.
Scores:
Multiply scores by 100 to express in percentages.

Percent work time missed due to migraine (absenteeism): Q2/(Q2 + Q4)

Percent impairment while working due to migraine (presenteeism): Q5/10

Percent overall work impairment due to migraine (overall work productivity loss): 
Q2/(Q2 + Q4) + [(1- (Q2/(Q2 + Q4)))x( Q5/10)]

Percent activity impairment due to migraine (regular activity impairment): Q6/10
If the response to Q1 (“Currently employed?”) is No or missing, absenteeism, presenteeism, and 
overall work productivity loss will all be set to missing.
PHQ-9 Depression Severity 
The PHQ-9 consists of the 9 diagnostic criteria for depressive disorders in the past 2 weeks from 
the DSM-IV. Participants are asked to indicate the frequency with which they have been bothered 
by 9 symptoms of depressive disorders over the previous 2 weeks, on a 4-point scale: 0 (not at all), 
1 (several days), 2 (more than half the days), and 3 (nearly every day). The total score ranges from 
0 to 27 (from best to worst). A score of 15 to 19 is considered as moderately severe depression and 
20 to 27 as severe depression. 
Patient-Reported Outcomes Measurement Information System Pain Interference - Short 
Form 6a (PROMIS-PI) Related Endpoints Derivation 
The PROMIS-PI measures self-reported interference of pain on relevant aspects of daily life (i.e., 
social, cognitive, emotional, physical, recreational) over the past 7 days. A 5-level response scale 
for all 6 items ranges from 1 to 5, corresponding to item response of “Not at all” to “Very much.” 
The raw score of PROMIS-PI is the sum of all 6 items, ranging from 6 to 30. If one or more items 


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are missing, the raw score will be set to missing. A raw score can be standardized into a T-score 
with a mean of 50 and standard deviation of 10 using the table as follows. Higher raw or T-scores 
indicate greater pain interference.
Table 16.2-3.
PROMIS-PI Raw Score Transformation
The PROMIS-PI will be completed by the participants at Day 1 (randomization), Weeks 4, 8 and 
12.
European Quality of Life - 5 Dimensional (EQ-5D-5L)
EQ-5D-5L is a generic instrument for use as a measure of health status. As of 2009, the EQ-5D-5L 
has also been available for use; this version was developed to improve the sensitivity of the 
instrument and to reduce ceiling effects (The EuroQol Group, 2020). The EQ-5D-5L consists of 2 
components - the EQ-5D descriptive system and the EQ VAS, but only EQ-5D descriptive system
will be summarized in this extension study.
The descriptive system comprises 5 dimensions
(mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). The mobility dimension queries the participant’s walking 
ability. The self-care dimension queries the participant’s ability to wash or dress by himself. The 
usual activities dimension assesses the participant’s performance in “work, study, housework, 
family or leisure activities”. The pain/discomfort dimension measures how much pain or 
discomfort a participant has. The anxiety/depression dimension assesses how anxious or depressed 
a participant is. The respondent is asked to indicate his/her health state by ticking (or placing a 
cross) in the box against the most appropriate statement in each of the 5 dimensions. The scoring 
range of the EQ-5D descriptive system is typically from 0 (dead) to 1 (full health). The second 
component of the EQ-5D-5L is a visual analogue scale (EQ-VAS) by which participants can rate 
their overall health from 0 (worst imaginable health state) to 100 (best imaginable health state).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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With the EQ-5D-5L, rating levels can be coded as numbers 1, 2, 3, 4 or 5 which correspond to 
having no problems, having slight problems, having moderate problems, having severe problems, 
and being unable to do/having extreme problem. As a result, a participant’s health state can be 
defined by a 5-digit number by combining the numeric levels from the 5 dimensions, ranging from 
11111 (having no problems in all 5 dimensions) to 55555 (having extreme problem in all 
5 dimensions). The US-based value set for the EQ-5D-5L will be derived using an international 
standardized protocol (Pickard et al., 2019).
EQ-5D-5L will be captured on eDiary during 7 days in the screening/baseline period and during 
specific time periods for Visit 1 to 7, except at Visit 8 (Week 16) where it will be administered 
on an eTablet. The index score and VAS score for a specific period will be calculated as the 
average of available scores in that period respectively if at least 50% of daily scores are 
available; otherwise, the scores will be set as missing. For example, for a period of 14 days, at 
least 7 assessments are required; and for a period of 7 days, at least 4 assessments are required.
16.3
REPEATED 
OR 
UNSCHEDULED 
ASSESSMENTS 
OF 
SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of the first treatment, the results from the 
final nonmissing assessment made prior to the start of the study treatment will be used as baseline.
If a participant has 2 or more visits within the same window, the last visit with a nonmissing value 
will be used for summary over time. If end-of-study assessments are repeated or if unscheduled 
visits occur, the last nonmissing postbaseline assessment will be used as the end-of-study 
assessment for generating summary statistics. However, all postbaseline assessments will be used 
for PCS value determinations, and all assessments will be presented in the data listings.
16.4
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT
When the date of the last dose of study treatment is missing for a participant in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the last available dosing record date will be used as the last dose date.
16.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of study treatment, an
intensity of mild will be assigned. If severity is missing for an AE that started on or after the date 


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of the first dose of study treatment, an intensity of severe will be assigned. The imputed values for 
severity assessment will be used for the incidence summary; the values will be shown as missing
in the data listings.
16.6
MISSING CAUSAL RELATIONSHIP TO STUDY DRUG FOR ADVERSE 
EVENTS
If the causal relationship to the study treatment is missing for an AE that started on or after the 
date of the first dose of study treatment, a causality of yes will be assigned. The imputed values 
for causal relationship to study treatment will be used for the incidence summary; the values will 
be shown as missing in the data listings.
16.7
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(ie, partly missing).
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study treatment, 
the month and day of the first dose of study treatment will be assigned to the missing fields

If the year of the incomplete start date is before the year of the first dose of study treatment, 
December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
first dose of study treatment, the day of the first dose of study treatment will be assigned to the 
missing day


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
If either the year of the incomplete start date is before the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is before 
the month of the date of the first dose of study treatment, the last day of the month will be 
assigned to the missing day

If either the year of the incomplete start date is after the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is after 
the month of the date of the first dose of study treatment, the first day of the month will be 
assigned to the missing day
If the stop date is complete and the imputed start date as above is after the stop date, the start date 
will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date:

If the stop date is after the date of the first dose of study treatment, the date of the first dose of 
study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of study treatment, the stop date will be 
assigned to the missing start date
16.8
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
16.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study treatment, 
the month and day of the first dose of study treatment will be assigned to the missing fields

If the year of the incomplete start date is before the year of the first dose of study treatment, 
December 31 will be assigned to the missing fields


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
If the year of the incomplete start date is after the year of the first dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
first dose of study treatment, the day of the first dose of study treatment will be assigned to the 
missing day

If either the year of the incomplete start date is before the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is before 
the month of the date of the first dose of study treatment, the last day of the month will be 
assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is after 
the month of the date of the first dose of study treatment, the first day of the month will be 
assigned to the missing day
16.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
impute it as descripted in Section 16.4. If the imputed stop date is before the start date (imputed or 
nonimputed start date), the imputed stop date will be equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study treatment, 
the month and day of the last dose of study treatment will be assigned to the missing fields

If the year of the incomplete stop date is before the year of the last dose of study treatment, 
December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study treatment, 
January 1 will be assigned to the missing fields


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Missing month only

If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
last dose of study treatment, the day of the last dose of study treatment will be assigned to the 
missing day

If either the year of the incomplete stop date is before the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is before 
the month of the date of the last dose of study treatment, the last day of the month will be 
assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is after 
the month of the date of the last dose of study treatment, the first day of the month will be 
assigned to the missing day
16.9
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
coded value must be appropriately determined for use in the statistical analyses. The actual values, 
however, as reported in the database will be presented in the data listings.
16.10
ACTUAL RANDOMIZATION STRATIFICATION DERIVATION
As mentioned in the current SAP Section 7.0, ‘derived stratification’ will be used in the statistical 
models rather than IWRS. 
Per study design and IWRS, the participants are stratified into 10 following strata:
1. Acute medication overuse (Yes) and Migraine prevention medication past use and not 
current use, Failed 0 to 1 or more with the same mechanism of action;
2. Acute medication overuse (Yes) and Migraine prevention medication past use and not 
current use, Failed 2 to 4 with different mechanisms of action;
3. Acute medication overuse (Yes) and Migraine prevention medication Current use 
regardless of past use, Failed 0 to 1 or more with the same mechanism of action;
4. Acute medication overuse (Yes) and Migraine prevention medication Current use 
regardless of past use, Failed 2 to 4 with different mechanisms of action;


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5. Acute medication overuse (Yes) and Migraine prevention medication Never used;
6. Acute medication overuse (NO) and Migraine prevention medication past use and not 
current use, Failed 0 to 1 or more with the same mechanism of action;
7. Acute medication overuse (NO) and Migraine prevention medication past use and not 
current use, Failed 2 to 4 with different mechanisms of action;
8. Acute medication overuse (NO) and Migraine prevention medication Current use 
regardless of past use, Failed 0 to 1 or more with the same mechanism of action;
9. Acute medication overuse (NO) and Migraine prevention medication Current use 
regardless of past use, Failed 2 to 4 with different mechanisms of action;
10. Acute medication overuse (NO) and Migraine prevention medication Never used;
To derive the actual participant stratification, the algorithm will be as follows:

First, the acute headache medication overuse during the baseline period will be derived as Yes 
or No, based on eDiary data. Acute headache medication overuse is defined as Yes, when use 
of triptans on ≥10 days OR use of ergots on ≥10 days OR use of simple analgesics (ie, aspirin, 
nonsteroidal anti-inflammatory drugs [NSAIDs], or acetaminophen) on ≥ 15 days OR use of 
any combination of triptans, ergots or simple analgesics on ≥10 days. The baseline period is 
defined here as all 28 days prior to the randomization visit;

Next, migraine prevention medication exposure (Current Use, Past Use, or Never Used) will 
be derived based on concomitant data from eCRF (and Excel spreadsheet with prevention 
medication list provided by Clinical team). For participants who took medications before/at 
the screening visit with the preferred names in excel spreadsheet with prevention medication 
list provided by Clinical team and those medications were classified as “Migraine Prevention 
Medication” in the prior and concomitant medications eCRF, these participants were further 
classified as participants with current use (ongoing at the screening visit) or past use (stopped 
prior to screening), the number of migraine prevention medications failed with unique 
mechanisms of action: “failed 0 medications or failed 1 or more medication(s) with the same 
mechanism of action” or “failed 2 or more medications with different mechanisms of action”. 
If both start and end date for a migraine prevention medication are missing, it will be 
considered when determining the number of migraine prevention medications failed and the 
number of mechanisms of action. If the medication is noted as “ongoing” it will be considered 
current use, and if it is not noted as “ongoing” then it will be considered past use. Otherwise, 


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participants who did not took qualified medications as specified above were classified into the 
category “Never used”.

The study will be conducted in 5 regions: North America, Europe, China, Japan and APAC.
The regions used as a stratification factor in the analysis are North America, Europe, and East 
Asia (includes China, Japan, and APAC).
16.11
IDENTIFYING PARTICIPANTS WHO TOOK A NEW MIGRAINE 
PROPHYLAXIS TREATMENT WITH PROVEN EFFICACY BASED ON 
CONCOMITANT MEDICATIONS REPORTED IN ECRF FOR THE 
INTERCURRENT EVENTS SPECIFIED IN THE OFF-TREATMENT 
HYPOTHETICAL ESTIMAND
To identify the participants who started a new migraine prophylaxis treatment as specified in
Section 10.3.1 (Attributes of Off-treatment Hypothetical Estimand), the following criteria are 
used: A participant has taken prophylaxis medications during the double-blind or follow-up period
with preferred names, and the concomitant medications are classified as “Migraine Prevention 
Medication” in concomitant medications eCRF.


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17.0
COVID-19 RELATED ANALYSES
To eliminate immediate potential hazards to participants and study staff due to the COVID-19 
pandemic while ensuring participant safety and maintaining data integrity, the protocol 
clarification letter and corresponding protocol amendment were sent to sites during the pandemic 
to allow remote visits (as described in the protocol Table 1 Schedule of Visits and Procedures).
This section specifies analyses for evaluating the impact of COVID-19.
17.1
EFFICACY EVALUATION
Efficacy Endpoints
Table 17.1-1 describes the collection devices for primary and key secondary endpoints. The 
primary endpoint and most of key secondary endpoints are collected via eDiary according to the 
protocol. Minimal disruption is expected for these endpoints because participants are expected to 
complete eDiary at home and submit the responses everyday.
The endpoints, “MSQ v2.1 Role Function-Restrictive domain score at Week 12” and “HIT-6 total 
score at Week 12”, will be collected using eTablet as one electronic patient reported outcome 
(ePRO) at site. Participants are required to complete the ePRO measures remotely at Visit 7 
(Week 12) according to remote-visit procedure. To evaluate the missing rate for this endpoint at 
Week 12, the number of participants who missed at least one ePRO assessment due to COVID-19 
will be summarized at each visit in the mITT Population (efficacy analyses population).


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Table 17.1-1.
Summary of Collection Devices for Primary and Key secondary endpoints
Endpoint
Collection 
Device
Change from baseline in mean monthly migraine days across the 12-week treatment period
eDiary
Change from baseline in mean monthly headache days across the 12-week treatment period
eDiary
Change from baseline in mean monthly acute medication use days across the 12-week treatment 
period
eDiary
≥ 50% reduction in 3-month average of monthly migraine days 
eDiary
Change from baseline in mean monthly Performance of Daily Activities domain score of the AIM-
D across the 12-week treatment period
eDiary
Change from baseline in mean monthly Physical Impairment domain score of the AIM -D across 
the 12-week treatment period
eDiary
Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12
eTablet
Change from baseline in the HIT-6 total score at Week 12
eTablet
17.2
SAFETY AND OTHER EVALUATIONS
This section specifies analyses related to COVID-19 pandemic from the following aspects:

Disposition

Study visit (missing entire visit due to COVID-19 or missing assessments due to 
COVID-19)

Protocol deviation 

Study drug disruption due to COVID-19

TEAEs related with COVID-19 and supplemental signs and symptoms

COVID-19 status (COVID-19 testing results or contact with a COVID-19 positive person)
Safety Population will be used for the planned analyses described above. The number of 
participants impacted by COVID-19 during the study will be summarized by treatment group and 
overall. In addition, the number of participants impacted by COVID-19 and their corresponding 
disposition status in the double-blind treatment period and the follow-up period will be 
summarized respectively.
The number of participants who missed at least one entire visit due to COVID-19 will be 
summarized by treatment group and overall. Furthermore, the number of participants who missed 
at least one assessment due to COVID-19 will be summarized by assessment category (laboratory, 


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C-SSRS, urine pregnancy test, vital signs, ECG, and ePRO) and overall. Similar summaries will 
be provided by visit.
The number of participants with significant protocol deviation due to COVID-19 will be provided. 
The number of participants with study drug disruption due to COVID-19 will be provided as well. 
The number of participants with TEAEs related to coronavirus infection or coronavirus test 
positive will be provided. Supporting listings for the described analyses above will also be 
provided.


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18.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
All health outcome endpoints have been added to this SAP.


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19.0
REFERENCES
Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, 
Brin MF; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of 
chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the 
PREEMPT 1 trial. Cephalalgia. 2010 Jul;30(7):793-803.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and 
efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 
2015;14:1081-1090.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biometrical Journal. 53 (2011) 6, 894-913.
Carpenter J., Roger J., and Kenward M. Analysis of Longitudinal Trials with Protocol Deviation: 
A Framework for Relevant, Accessible Assumptions, and Inference Via Multiple Imputation. 
Journal of Biopharmaceutical Statistics 2013;23:1352-1371.
EuroQol Group available from https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997;53:983-97.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data using 
multiple imputation in conjunction with robust regression. Biometrics. 2012 Dec;68(4):1250-9.
Pickard AS, Law EH, Jiang R, Pullenayegum E, Shaw JW, Xie F, Oppe M, Boye KS, Chapman 
RH, Gong CL, Balch A, Busschbach JJV. United States Valuation of EQ-5D-5L Health States 
Using 
an 
International 
Protocol. 
Value 
Health. 
2019 
Aug;22(8):931-941. 
doi: 
10.1016/j.jval.2019.02.009. Epub 2019 May 25. PMID: 31426935.
Rubin D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York, NY: Wiley.
Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T et al. 
Fremanezumab
for the Preventive Treatment of Chronic Migraine, N Engl J Med 
2017;377:2113-2122.


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20.0
APPENDICES
All laboratory parameters are reported in the International System (SI) units as standard practice. 
In addition, selected laboratory parameters (listed in Table 20.1-1) will be reported in conventional 
units to facilitate interpretation and reporting for the CSR and future labeling.
20.1
LIST OF PARAMETERS REPORTED IN CONVENTIONAL UNIT 
The list of selected parameters required to be reported in conventional unit is provided in
Table 20.1-1.
Table 20.1-1.
List of Selected Parameters Reported in Conventional Unit
Number
Laboratory Parameter
Conventional Unit
Decimal Places
1
Alanine Aminotransferase (SGPT)
U/L
0
2
Albumin
g/dL
1
3
Alkaline Phosphatase
U/L
0
4
Aspartate Aminotransferase (SGOT)
U/L
0
5
Bilirubin, Direct (Conjugated)
mg/dL
1
6
Bilirubin, Indirect (Unconjugated)
mg/dL
1
7
Bilirubin, Total
mg/dL
1
8
Blood Urea Nitrogen
mg/dL
0
9
Calcium
mg/dL
1
10
Cholesterol, HDL
mg/dL
0
11
Cholesterol, LDL
mg/dL
0
12
Cholesterol, LDL direct and calculated (combined)
(This lab parameter could be the same as #11) 
mg/dL
0
13
Cholesterol, Total
mg/dL
0
14
Creatine Kinase
U/L
0
15
Creatinine
mg/dL
1
16
Glucose
mg/dL
0
17
Insulin
uIU/mL
1
19
Uric Acid
mg/dL
1
20
Hemoglobin
g/dL
1


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20.2
ANALYSIS AND REPORTING FORMAT IN CONVENTIONAL UNITS
1) For individual clinical study reports for the CNS projects, the descriptive statistics for the 
selected laboratory parameters (Table 20.2-1) will be reported in conventional units using 
the similar layout for the summary table in SI unit.
2) Patient narratives generated by the statistical programming team will also include the 
values in conventional units for the selected lab parameters (Table 20.2-1). That will be 
accomplished by presenting the values in conventional units within the parentheses next to 
the values in SI units. An example is provided in Table 20.2-1. for lab parameter ‘Bilirubin, 
Total’, for which ‘umol/L’ is the SI unit and ‘mg/dL’ is the conventional unit.
Table 20.2-1.
Presenting Laboratory Data Using SI and Conventional Units in Narratives
LABORATORY DATA
Lab Test
Test Name
Normal Range
VISIT01 
VISIT05 
VISIT07 
Low
High
2012-07-03 2012-08-07 
2012-09-04 
…
CHEMISTRY Bilirubin, Total (umol/L (mg/dL)) 
0 (0) 18.81 (1.1) 
6.84 (0.4) 
5.13 (0.3) 
5.13 (0.3) 
…
3) Details of reporting the selected laboratory parameters in conventional units as detailed in 
this document should be included in SAP for various CNS projects.


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20.3
SUMMARY OF CHANGES FROM FINAL SAP TO SAP AMENDMENT 1
Date
Section
Description
December 3, 2019
4.0

Added protocol amendment 2 information

Added Japan related appendix 2 in text

Replaced SoA table

Clarified the stratification method by adding another 
bullet of “region”
December 3, 2019
6.2
Further clarified mITT definition by adding “while on study 
treatment……”.
December 3, 2019
6.4
Added estimand population definition
December 3, 2019
8.0

Added “Other” in region definition

Added “off-treatment hypothetical estimand” population 
for demographic summary

Changed the population of ASC-12 summary to “safety 
and mITT”

Updated AIM-D endpoint definition in baseline efficacy 
summary
December 3, 2019
10.1.2
Updated AIM-D endpoint definition 
December 3, 2019
10.3

Updated region definition for secondary efficacy 
endpoints

Updated definitions for binary endpoints

Updated definition of 50% responder to be the “3-month 
average”

Updated AIM-D endpoint definition

Further clarified and added details for analyses for 
secondary efficacy endpoints (i.e., use logistic regression 
model instead of generalized linear mixed model)

Updated multiplicity control figures and tables due to 
AIM-D’s new definition; also added another edge after 
testing S5

Clarified that the multiplicity control for Europe and 
Canada will be based on the analysis population for off-
treatment hypothetical estimand
December 3, 2019
10.4

Updated definitions for binary endpoints

Added a new endpoint of “weekly migraine days”

Added week 16 for HIT-6

Updated AIM-D endpoint definition

Added two more graphical analyses as detailed in the 
last two paragraphs of this section
December 3, 2019
10.5.1
Further clarified and added details for estimand population
December 3, 2019
10.5.3
Added a new sensitivity analysis
December 3, 2019
10.5.5
Further clarified and added details for estimand approach for 
secondary efficacy endpoints
December 3, 2019
11.1

Used “study intervention discontinuation” for AE as the 
default instead of “study discontinuation”

Clarified “after rounding” and also the sorting order for 
the “2%” table


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Date
Section
Description
December 3, 2019
11.2

Deleted “conventional units”

Updated “Higher Limit” in Urinalysis
December 3, 2019
11.4
Added new criteria
December 3, 2019
13.0

Updated definitions for binary endpoints

Added “if model does not converge……”

Added section 13.1 to align with protocol and 
renumbered section 13.2
December 3, 2019
17.1

Updated table 17.1-1

Added new windows for estimand and weekly endpoint

Updated table of “safety data analysis” for clarity and 
consistency across atogepant program
December 3, 2019
17.2.1
Added a new endpoint of “weekly migraine days”
December 3, 2019
17.2.2
Updated AIM-D endpoint definition
December 3, 2019
Appendix 1

Added “Other” in region definition

Added consistency criterion for key secondary efficacy 
endpoints

Added a test for treatment-by-region interaction

Added “if model does not converge……”

Clarified sample size calculation
December 3, 2019
Appendix 2
Created it newly for Japan
December 3, 2019
Appendix 3
Added a new column of “decimal places”
January 17, 2020
11.2
Updated shift table to “Shift tables from baseline to end of 
double-blind treatment period for clinical laboratory 
parameters will be presented”
February 25, 2020
11.2
Updated eGFR’s PCS lower limit in Table 11.2–1 since 
central lab did not provide the lower level of normal
February 25, 2020
Appendix 3
Updated unit of Albumin and Hemoglobin for CDISC 
compliance purpose
March 24, 2020
9.2
Clarified double blind treatment period and algorithm
March 24, 2020
Throughout

Re-updated all AIM-D related sections to go back to 
2 domains

Updated algorithms of all HEOR endpoints
March 24, 2020
7.0
10.2, 10.3, 
10.5
17.10

Added “region” stratification factor into the primary 
analysis model

Added “actual randomization stratification” related 
summary 

Clarified “actual randomization stratification” will be 
used in the models rather than IWRS

Updated responder endpoint definition
September 1, 2020
4.0

Added protocol amendment 3 related information (e.g., 
extension studies, COVID-19, etc.)

Updated the stratification regarding “current use” as per 
protocol amendment 3
September 1, 2020
6.2, 6.4
Updated population definitions for mITT and estimand
September 1, 2020
10.1.1
Updated “headache day” definition


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Date
Section
Description
September 1, 2020
10.2, 10.3

Restrucured and clarified to align with the entire 
atogepant program

Updated the entire sensitivity analysis section
September 1, 2020
10.4
Clarified to align with the entire atogepant program 
September 1, 2020
10.5

Added a new element as per final ICH E9 R1

Updated the entire section of intercurrent events

Updated the estimand approach for secondary endpoints
September 1, 2020
17

Updated all visit time windows to align with the entire 
atogepant program

Clarified and provided more details regarding eDiary 
data derivation for efficacy endpoints

Added 17.11 for intercurrent event handling
September 1, 2020
18
Newly added for COVID-19 impact
By 17May 2021

Added all HO endpoints

Added Appendix 3 for subgroup

updated visit time windows

Added Actual randomization startification algorithm in 
Section 17.10.
20May2021
17.11

Added Sections 17.11 and 17.12
By July 12, 2021
1

Delete the wording about stand-alone pharmacometrics 
analysis plan. 

Update the wording about regional statistical analysis
By July 12, 2021
10.1.2

Update the wording about AIM-D
By July 12, 2021
10.1.3

Add the Section 10.1.3 to list all efficacy endpoints
By July 12, 2021
10.1.4

Add the Section 10.1.4 to describe the stratification 
variables in the modeling
By July 12, 2021
10.2

Update the Section 10.2 for efficacy analysis for filing 
except Europe and Canada, including the primary 
efficacy analysis, secondary efficacy analysis, and 
analysis for additional efficacy endpoints and health 
outcome endpoints
By July 12, 2021
10.3

Update the Section 10.3 for efficacy analysis for 
European Medication Agency filing
By July 12, 2021
10.4

Update the Section 10.4 for efficacy analysis for Health 
Canada filing
By July 12, 2021
12

Delete the original Section 12 for additional efficacy 
endpoints and other health outcomes analysis
By July 12, 2021
12

Update the subgroup analysis
By July 12, 2021
16.1

Delete the Table 17.1.7
By July 12, 2021
16.10

Update the wording for stratification of migraine 
prevention medication exposure
By July 12, 2021
16.11

Add the Section 16.11to identify the participants who 
started a new migraine prophylaxis treatment
By January 24, 2022

Minor typos corrected and clarifications made 
throughout
By January 24, 2022
3.0

Added missing abbreviations


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Date
Section
Description
By January 24, 2022
7.0

A summary table of participants with inconsistent 
randomization strata will also be produced
By January 24, 2022
8.0, 12.1

Region summary “other” updated to “East Asia”
By January 24, 2022
8.0

Updated MedDRA version to 24.0
By January 24, 2022
10.1.4, 10.2.1, 
10.2.3, Table 
10.2-2, 
10.3.2, 10.3.3, 
12.2, 16.10

Updated abbreviated names of derived strata to more 
closely match protocol

Updated “failed 2 to 4 medications with different 
mechanisms of action” to “failed 2 or more medications 
with different mechanisms of action”
By January 24, 2022
10.2.1.1

Specify random seed for multiple imputation sensitivity 
analyses
By January 24, 2022
10.2.1.2

Robust regression will be presented of results of K-S test 
for normality
By January 24, 2022
10.2.3, 
Table 10.2-2

Specify covariance structures to be used in the event that 
the model does not converge with an unstructured 
covariance matrix

Specified that PHQ-9 would be analyzed using an 
ANCOVA as it is collected at one post-baseline time 
point

Specified that HIT-6 total score change from baseline 
analysis would not include Week 16 in the MMRM
By January 24, 2022
Table 10.2-2

Changed “GLIMMIX” (SAS procedure name) to 
“GLMM” (statistical analysis abbreviation)

≥ 25%, ≥ 30%, ≥ 50%, ≥75%, 100% improvement 
(decrease) in monthly migraine days at each 4 week 
interval will be analyzed with a GLMM

WPAI is collected at weeks 4, 8, and 12 and will be 
analyzed using an MMRM

Deleted “Only data collected during the double-blind 
treatment period will be included in the analysis” which 
applies only to the analysis for the mITT population.  
For the off-treatment estimand, data will be included as 
noted in section 10.3.1.
By January 24, 2022
10.3.2

Deleted “Only data collected during the double-blind 
treatment period will be included in the analysis”.  For 
the off-treatment estimand, data will be included as 
noted in section 10.3.1.
By January 24, 2022
10.3.2.1

Due to the low number of subjects in several of the 
monotone missing data pattern categories, the  multiple 
imputation sensitivity analysis for the off-treatment 
estimand cannot be completed and has been eliminated.
By January 24, 2022
10.3.3

AIM-D removed from second paragraph as it is an 
exploratory, not secondary, endpoint in the EU
By January 24, 2022
11.1

Noted TESAEs will be summarized by SOC and PT
By January 24, 2022
11.4

Corrected typo – changed “post-treatment” to “post-
baseline”


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Atogepant
3101-303-002 Statistical Analysis Plan Amendment 1 Final Draft for FDA Review
12 July 2021
Date
Section
Description
By January 24, 2022
16.1

Analysis windows for the  mITT and off-treatment 
estimand clarified throughout and specified where not 
previously done so
By January 24, 2022
16.2.1

Defined what it means for baseline to be evaluable 
By January 24, 2022
16.2.2

Specified method of data collection and rules for 
analysis of the EQ-5D-5L
By January 24, 2022
16.10

Stratification of region used in the analysis specified as 
noted in Table 10.1-2