Clinical trial NCT04437433
Conditions: Chronic Migraine Episodic Migraine
Keywords: Chronic Migraine Episodic Migraine Atogepant
Sponsor: AbbVie
Start date: 2020-06-18; Completion date: 2024-06-11
Enrollment: 186 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the long-term safety, efficacy and tolerability of atogepant 60 mg daily for the prevention of migraine in Japanese participants with chronic (CM) or episodic migraine (EM).

Detailed description:
The study recruited the following 2 cohorts:

3101-303-002 CM Completers: Japanese participants who completed lead-in Study 3101 303-002 (PROGRESS; NCT03855137), a Phase 3, multicenter, randomized, double-blind, placebo controlled, parallel-group study of atogepant for the prevention of CM. All 3101 303-002 CM Completers rolled over at Visit 7 (the end of the double-blind treatment period) of the lead-in study, which functioned as Visit 1 for this study, Study 3101-306-002.

De Novo EM Participants: Japanese participants with EM who were newly recruited for this study at selected sites. Participation began with a 4-week Screening/Baseline period starting at Visit -1, and those who completed the 4-week Screening/Baseline period and met all entry criteria were enrolled into the 52-week open-label treatment period at Visit 1.

Arms: arm 1: Participants with chronic migraine (CM) who completed lead-in Study 3101-303-002 (NCT03855137) received atogepant orally as 60 mg tablets once a day (QD) for 52 weeks. arm 2: Participants with episodic migraine (EM) who were newly recruited and met all study entry criteria received atogepant orally as 60 mg tablets once a day (QD) for 52 weeks.
Interventions: intervention 1: Atogepant 60 mg
Intervention descriptions: intervention 1: Tablets containing 60 mg atogepant

Protocol documents:
Prot_000.pdf: 


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Protocol 3101-306-002 Amendment 3
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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol, GCPs 
and all applicable laws and regulations.

Maintain all information supplied by Allergan (a subsidiary of AbbVie) 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
List of Tables ..............................................................................................................................7
List of Figures.............................................................................................................................7
Protocol Summary.......................................................................................................................8
1
Background and Clinical Rationale......................................................................................18
1.1
Background ................................................................................................................18
1.2
Overview of Atogepant...............................................................................................18
1.3
Study Rationale ..........................................................................................................19
1.4
Rationale for Doses and Dose Regimens Selected.......................................................20
2
Study Objective and Clinical Hypothesis.............................................................................20
2.1
Study Objectives.........................................................................................................20
2.2
Clinical Hypothesis.....................................................................................................20
3
Study Design.......................................................................................................................20
3.1
Structure.....................................................................................................................20
3.2
Data Safety Monitoring Board....................................................................................22
3.3
Adjudication Committee.............................................................................................22
4
Study Population and Entry Criteria ....................................................................................22
4.1
Number of Participants...............................................................................................22
4.2
Study Population Characteristics.................................................................................22
4.3
Inclusion Criteria........................................................................................................23
4.3.1
All Participants ...............................................................................................23
4.3.2
3101-303-002 Completers...............................................................................23
4.3.3
De Novo EM Participants................................................................................23
4.4
Exclusion Criteria.......................................................................................................24
4.4.1
All Participants ...............................................................................................24
4.4.2
De Novo EM Participants................................................................................25
4.5
Permissible and Prohibited Medications/Treatments ...................................................28
4.5.1
Permissible Medications/Treatments ...............................................................28
4.5.2
Prohibited Medications/Treatments .................................................................29
4.5.3
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods ...................................................................................30
4.5.4
Special Diet or Activities.................................................................................31
4.6
Screen Failures ...........................................................................................................31


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5
Study Intervention...............................................................................................................32
5.1
Study Intervention and Formulations ..........................................................................32
5.2
Control Intervention ...................................................................................................32
5.3
Methods for Masking/Blinding ...................................................................................32
5.4
Treatment Allocation Ratio .........................................................................................32
5.5
Method for Assignment to Treatment Groups..............................................................32
5.6
Treatment Regimen and Dosing..................................................................................33
5.7
Storage of Study Intervention .....................................................................................33
6
Response Measures and Summary of Data Collection Methods...........................................33
6.1
Safety Measures .........................................................................................................33
6.1.1
Adverse Events ...............................................................................................33
6.1.2
Adverse Events of Special Interest ..................................................................33
6.1.3
Clinical Laboratory Determinations.................................................................34
6.1.4
Vital Signs ......................................................................................................35
6.1.5
Physical Examination......................................................................................36
6.1.6
Electrocardiograms .........................................................................................36
6.1.7
Columbia-Suicide Severity Rating Scale (C-SSRS).........................................36
6.2
Efficacy Measures ......................................................................................................37
6.2.1
Migraine Day..................................................................................................37
6.2.2
Headache Day.................................................................................................38
6.2.3
Acute Medication Use Day and Triptan Use Day.............................................38
6.3
Health Outcome Measures..........................................................................................39
6.3.1
Activity Impairment in Migraine - Diary (AIM-D)..........................................39
6.3.2
Activity Level and Activity Limitation............................................................39
6.3.3
Patient Satisfaction with Study Medication .....................................................39
6.3.4
Headache Impact Test (HIT-6).........................................................................40
6.3.5
Migraine Disability Assessment (MIDAS) ......................................................40
6.3.6
Patient Global Impression of Change (PGIC) ..................................................40
6.3.7
Work Productivity and Activity Impairment Questionnaire: Migraine V2.0 
(WPAI:MIGRAINE) .......................................................................................40
6.3.8
European Quality of Life - 5 Dimensional (EQ-5D-5L)...................................40
6.3.9
Patient Global Impression - Severity (PGI-S)..................................................41
6.3.10 Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1) ......41
6.4
Other Study Supplies ..................................................................................................41
6.5
Summary of Methods of Data Collection....................................................................41
7
Statistical Procedures ..........................................................................................................42


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7.1
Analysis Populations ..................................................................................................42
7.2
Collection and Derivation of Efficacy Assessments.....................................................42
7.3
Hypothesis and Methods of Analysis ..........................................................................44
7.3.1
Safety Analyses...............................................................................................44
7.3.2
Efficacy Analyses............................................................................................45
7.4
Subgroup Analyses .....................................................................................................45
7.5
Sample Size Calculation .............................................................................................45
7.6
Interim Analyses.........................................................................................................46
8
Study Visit Schedule and Procedures...................................................................................46
8.1
Participant Entry Procedures.......................................................................................46
8.1.1
Overview of Entry Procedures.........................................................................46
8.1.2
Informed Consent and Participant Privacy.......................................................46
8.2
Washout Intervals/Run-in ...........................................................................................46
8.3
Procedures for Final Study Entry................................................................................46
8.4
Visits and Associated Procedures................................................................................47
8.4.1
Visit -1 (Screening/Baseline) Day -35 to Day -28............................................48
8.4.2
Open-label Treatment Period (52 Weeks) ........................................................49
8.4.2.1 Visit 1 (Day 1)........................................................................................49
8.4.2.2 Visits 2 to 13 (Weeks 4 to 48).................................................................50
8.4.2.3 Visit 14/Early Termination (Week 52).....................................................51
8.4.3
Safety Follow-up Period (4 Weeks) .................................................................52
8.4.3.1 Visit 15/End of Study (Week 56) ............................................................52
8.4.4
COVID-19 Pandemic-related Remote Visits....................................................52
8.5
Instructions for the Participants...................................................................................52
8.6
Unscheduled Visits .....................................................................................................53
8.7
Compliance with Protocol...........................................................................................53
8.8
Early Discontinuation of Participants..........................................................................53
8.9
Withdrawal Criteria ....................................................................................................54
8.10 Study Termination ......................................................................................................55
9
Adverse Events ...................................................................................................................55
9.1
Definitions..................................................................................................................55
9.1.1
Adverse Event.................................................................................................55
9.1.2
Serious Adverse Event ....................................................................................57
9.1.3
Intensity..........................................................................................................58
9.1.4
Assessment of Causality..................................................................................59


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9.1.5
Follow-up of Adverse Events and Serious Adverse Events ..............................59
9.2
Procedures for Reporting Adverse Events...................................................................60
9.3
Procedures for Reporting a Serious Adverse Event .....................................................60
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events.....................60
9.4
Exposure to Study Intervention During Pregnancy......................................................61
9.5
ALT or AST Elevations...............................................................................................61
9.5.1
Potential Hy’s Law Cases................................................................................63
10 Administrative Items ...........................................................................................................63
10.1 Protection of Human Participants................................................................................64
10.1.1 Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations.........................................................................64
10.1.2 Compliance with IRB or IEC Regulations .......................................................65
10.1.3 Compliance with Good Clinical Practice .........................................................66
10.1.4 Compliance with Electronic Records; Electronic Signatures Regulations (US
21CFR Part 11) ...............................................................................................66
10.2 Financial Disclosure ...................................................................................................66
10.3 Changes to the Protocol..............................................................................................66
10.4 Data Protection...........................................................................................................66
10.5 Participant Confidentiality..........................................................................................67
10.5.1 Participant Privacy..........................................................................................67
10.6 Documentation ...........................................................................................................67
10.6.1 Source Documents ..........................................................................................67
10.6.2 Case Report Form Completion ........................................................................68
10.6.3 Study Summary...............................................................................................69
10.6.4 Retention of Documentation............................................................................69
10.7 Labeling, Packaging, and Return or Disposal of Study Intervention............................70
10.7.1 Labeling/Packaging.........................................................................................70
10.7.2 Clinical Supply Inventory................................................................................70
10.7.3 Return or Disposal of Study Intervention and/or Supplies................................71
10.8 Monitoring by the Sponsor .........................................................................................71
10.9 Handling of Biological Specimens..............................................................................71
10.10
Publications .......................................................................................................71
10.11Coordinating Investigator ...........................................................................................72
11 References...........................................................................................................................73
12 Attachments ........................................................................................................................75


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12.1 Examination Procedures, Tests, Equipment, and Techniques: International 
Classification of Headache Disorders, 3rd Edition ......................................................75
12.2 Prohibited Medications...............................................................................................92
12.2.1 Examples of Prohibited Medications ...............................................................92
12.2.2 List of Migraine Preventative Medications With Proven Efficacy and Criteria 
for Determining Inadequate Response to a Prior Migraine Preventive 
Medication......................................................................................................94
12.3 New York Heart Association Functional Classification ...............................................95
12.4 Glossary of Abbreviations...........................................................................................96
12.5 Protocol Amendment 1 Summary ...............................................................................98
12.6 Protocol Amendment 2 Summary ...............................................................................99
12.7 Protocol Amendment 3 Summary .............................................................................104
List of Tables
Table 1.
Schedule of Visits and Procedures ................................................................13
Table 2.
Schedule of Procedures for Remote Visits ....................................................16
Table 5-1.
Study Intervention........................................................................................33
Table 6-1.
Clinical Laboratory Parameters ....................................................................35
List of Figures
Figure 1.
Study Diagram .............................................................................................12


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Protocol Summary
Study Compound: Atogepant (AGN-241689)
Phase: 3
Study Objectives:
Safety and tolerability: To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily when 
administered over 52 weeks for the prevention of migraine in Japanese participants with chronic migraine (CM) or 
episodic migraine (EM).
Efficacy: To evaluate the efficacy of treatment with atogepant 60 mg once daily when administered over 52 weeks 
for the prevention of migraine in Japanese participants with CM or EM.
Clinical Hypotheses:
Atogepant 60 mg once daily is safe and well-tolerated when administered over 52 weeks for the prevention of 
migraine in Japanese participants with CM or EM.
Study Design:
Structure: Multicenter, open-label, 52-week long-term safety extension study conducted in Japan.
Duration: The study will consist of a 52-week open-label treatment period and a 4-week safety follow-up period for 
all participants. For De Novo EM Participants only, a 4-week screening/baseline period will be required. Total study 
duration is 56-60 weeks.
Study Intervention: Atogepant 60 mg tablet
Control Intervention: Not applicable
Dosage/Dose Regimen: Atogepant 60 mg will be administered once daily for 52 weeks.
Randomization: Not applicable
Visit Schedule: There will be a screening visit 4 weeks prior to Visit 1 for De Novo EM Participants only. After 
Visit 1, study visits will occur every 4 weeks for the duration of the 52-week treatment period for all participants. 
A safety follow-up visit will occur 4 weeks after the last dose of atogepant. There will be a total of 15 scheduled 
clinic visits for 3101-303-002 Completers. There will be a total of 16 scheduled clinic visits for De Novo EM 
Participants. For details, please see Table 1, Schedule of Visits and Procedures.
Study Population Characteristics:
Number of Participants/Sites: All participants who either complete Study 3101-303-002 or are newly recruited and 
complete the screening/baseline period, and meet all eligibility requirements, may participate in this study. At least 
170 participants will be enrolled at approximately 25 centers in Japan, to meet a target of a minimum of 
100 participants with EM or CM at 1 year. A minimum of 30 participants enrolled (at selected sites only) must have 
EM and meet all eligibility criteria.
Condition/Disease: Migraine without aura, migraine with aura, or chronic migraine (ICHD-3 Section 1.1, 1.2 or 1.3;
see Section 12.1).


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Key Inclusion Criteria:
3101-303-002 Completers:

Eligible participants who completed Visit 7, and Visit 8 if applicable, of Study 3101-303-002 without 
significant protocol deviations (eg, noncompliance to protocol-required procedures), and who did not 
experience an AE that may indicate an unacceptable safety risk.
De Novo EM Participants:

Male or female participants ages 18 to 80 years, inclusive, at Visit -1.

Age of the participant at the time of migraine onset < 50 years.

At least a 1-year history of migraine with or without aura consistent with a diagnosis according to the 
ICHD-3, 2018 (Section 12.1).

History of 4 to 14 migraine days per month (see Section 6.2.1 for definition of migraine day) on average in 
the 3 months prior to Visit -1 in the investigator’s judgment.

4 to 14 migraine days in the 28-day baseline period per eDiary.

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.
Key Exclusion Criteria (for all participants unless noted otherwise):

Participants requiring any medication, diet, or nonpharmacological treatment on the list of prohibited 
concomitant medications or treatments (see Section 4.5.2 and Attachment 12.2), that cannot be 
discontinued or switched to an allowable alternative. Participants from lead-in study 3101-303-002 taking 
1 medication with demonstrated efficacy for the prevention of migraine may participate in the current study 
provided that the dose was stable and the medication was well-tolerated prior to the lead-in study and the 
participant is willing and able to continue (Attachment 12.2.2).

Participants with an ECG indicating clinically significant abnormalities at Visit -1 (De Novo EM 
Participants) or Visit 1 (3103-303-002 Completers).

Participants with hypertension (sitting systolic BP > 160 mm Hg or sitting diastolic BP > 100 mm Hg) at 
Visit -1 (De Novo EM Participants) or Visit 1 (for all participants).

Participants with a significant risk of self-harm (Columbia-Suicide Severity Rating Scale [C-SSRS]), or of
harm to others (investigator opinion); participants who report suicidal ideation with intent, with or without 
a plan, (ie, Type 4 or 5 on the C-SSRS) or report suicidal behavior in the past 6 months prior to Visit -1 
(De Novo EM Participants) or since the last visit at Visit 1 (for all participants), must be excluded.

Participants with clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease.


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De Novo EM Participants only:

Difficulty distinguishing migraine headaches from tension-type or other headaches.

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 chronic migraine, new persistent daily headache, trigeminal autonomic cephalgia 
(eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3, 2018.

Has ≥ 15 headache days per month (see Section 6.2.2 for definition of headache day) on average across the 
3 months prior to Visit -1 in the investigator’s judgment.

Has ≥ 15 headache days in the 28-day baseline period per eDiary.

Usage of opioids or barbiturates > 2 days/month, triptans or ergots ≥ 10 days/month, or simple analgesics 
(eg, aspirin, NSAIDs, acetaminophen) ≥ 15 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 through 
the duration of the study) (see Section 12.2.1).
Response Measures:
Safety:
AEs, physical examinations, clinical laboratory determinations, vital sign measurements, ECG parameters, and the 
C-SSRS.
Efficacy:
The efficacy of atogepant for the prevention of migraine will be assessed based on information recorded by the 
participant. An eDiary will be used daily at home to collect data on headache duration, headache characteristics, 
symptoms, and acute medication use, which will be collectively applied to define migraine days and headache days 
per the criteria listed in Sections 6.2.1, 6.2.2 and 6.2.3. 
Participants will be administered participant-reported outcome measures collected daily in the eDiary (AIM-D, 
Activity Level, and Activity Limitation) and at scheduled visits.
General Statistical Methods and Types of Analyses: 
All safety analyses will be performed using the safety population which consists of all participants who took at least 
1 dose of study intervention (atogepant) in this extension study. All efficacy analyses will be performed using the 
modified intent-to-treat (mITT) population, consisting of all participants who received at least 1 dose of study 
intervention (atogepant) in this study, an evaluable baseline (in this study for De Novo EM Participants or in the 
lead-in study for the rollover participants) and had at least 1 evaluable post-baseline 4-week period of eDiary data, in 
this extension study. 


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The safety parameters 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 baseline value in this extension 
study is defined as:

The baseline value in the lead-in study (Study 3101-303-002) for 3101-303-002 Completers.

The last nonmissing safety assessment before the first dose of study drug for De Novo EM Participants.
Continuous variables will be summarized by the number of participants and mean, standard deviation, median, 
minimum, and maximum values. Categorical variables will be summarized by number and percentage of 
participants.
Efficacy endpoints include change from baseline in monthly migraine days, change from baseline in monthly 
headache days, at least a 50% reduction from baseline in monthly migraine days, and other endpoints.
For monthly endpoints, baseline in this extension study is defined as:

The baseline value in the lead-in study (Study 3101-303-002) for 3101-303-002 Completers.

The last 28 days of the screening/baseline period for De Novo EM Participants.
For efficacy endpoints that are assessed at clinical visits, baseline in this extension study is defined as:

The last nonmissing efficacy assessment before the first dose of study intervention in the lead-in study 
(3101-303-002) for 3103-303-002 Completers.

The last nonmissing efficacy assessment before the first dose of study drug for De Novo EM Participants.
For analysis purposes, 4 weeks (28 days) will be considered as 1 month. Descriptive statistics will be provided by 
visit for all efficacy endpoints based on the mITT population using the observed cases approach. 
Sample Size Calculation: 
At least 170 participants will be enrolled into this long-term, open-label, safety extension study including at least 
140 participants from the lead-in study (Study 3101-303-002) and approximately 30 De Novo EM Participants (from 
selected sites only) to meet a target of a minimum of 100 participants at 1 year. 


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Figure 1.
Study Diagram
EM = episodic migraine; EOS = end of study; ET = early termination; V = visit.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.
Schedule of Visits and Procedures
Study Period
Screening/ 
Baseline 
Period 
(4 weeks)a
Open-label Treatment Period (52 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Visit #
Visit -1
Visit 1b Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit 14/
ET
Visit 15/
EOS
Day/Week
Week -4
Day 1
Week 4
(Day 28)
Week 8
(Day 56)
Week 12
(Day 84)
Week 16
(Day 112)
Week 20
(Day 140)
Week 24
(Day 168)
Week 28
(Day 196)
Week 32
(Day 224)
Week 36
(Day 252)
Week 40
(Day 280)
Week 44
(Day 308)
Week 48
(Day 336)
Week 52
(Day 364)
Week 56
(Day 392)
Visit Windows
Day -35 to 
-28
N/A
± 3 days ± 3 days ± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Obtain Informed consent 
and participant privacyc
X
Xd
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect demographic 
information
X
Assess 
inclusion/exclusion 
criteria
X
Xe
Collect medical historyf
X
Xd
Collect 
migraine/headache 
history and confirm 
diagnosis
X
Collect start date (first 
day) of last menstrual 
cycle for women having 
menstrual cycles
X
Review and record prior 
medications taken in the 
past 6 months and all 
prior headache 
medications and 
concomitant medications
X
Perform physical 
examination
X
X
X
X
Collect vital sign 
measurementsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Perform ECG
X
Xd
X
X
X
X
Perform urine pregnancy 
testh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory 
determinationsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Period
Screening/ 
Baseline 
Period 
(4 weeks)a
Open-label Treatment Period (52 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Visit #
Visit -1
Visit 1b Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit 14/
ET
Visit 15/
EOS
Day/Week
Week -4
Day 1
Week 4
(Day 28)
Week 8
(Day 56)
Week 12
(Day 84)
Week 16
(Day 112)
Week 20
(Day 140)
Week 24
(Day 168)
Week 28
(Day 196)
Week 32
(Day 224)
Week 36
(Day 252)
Week 40
(Day 280)
Week 44
(Day 308)
Week 48
(Day 336)
Week 52
(Day 364)
Week 56
(Day 392)
Visit Windows
Day -35 to 
-28
N/A
± 3 days ± 3 days ± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Provide eDiary device 
with instructions and 
trainingj
X
Xd
Participant eDiary data 
collectionj,k
X
Review eDiary data
(headache duration, 
frequency, characteristics 
and symptoms, acute 
medication use, AIM-D, 
Activity Level, and 
Activity Limitation) and 
compliancel
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS (eTablet)m,n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect ASC-12 
(eTablet)o,p
X
HIT-6 (eTablet)o,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGIC (eTablet)o,p
X
X
X
X
X
PGI-S (eTablet)o,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI:MIGRAINE 
(eTablet) o,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Satisfaction with 
Study Medication
(eTablet)o,p 
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L (eTablet)o,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MIDAS (eTablet)o,p
X
X
X
X
X
X
MSQ v2.1 (eTablet)o,p
X
X
X
X
X
X
X
Collect eDiary
Xq
X
Dispense study 
intervention 
(ie, atogepant)
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Period
Screening/ 
Baseline 
Period 
(4 weeks)a
Open-label Treatment Period (52 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Visit #
Visit -1
Visit 1b Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit 14/
ET
Visit 15/
EOS
Day/Week
Week -4
Day 1
Week 4
(Day 28)
Week 8
(Day 56)
Week 12
(Day 84)
Week 16
(Day 112)
Week 20
(Day 140)
Week 24
(Day 168)
Week 28
(Day 196)
Week 32
(Day 224)
Week 36
(Day 252)
Week 40
(Day 280)
Week 44
(Day 308)
Week 48
(Day 336)
Week 52
(Day 364)
Week 56
(Day 392)
Visit Windows
Day -35 to 
-28
N/A
± 3 days ± 3 days ± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Review of study 
intervention (ie, 
atogepant) compliance 
and accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
Concomitant 
medications/
concurrent procedures
X
a
De Novo EM Participants only.
b
After providing informed consent for this study, Visit 7 of the lead-in study (Study 3101-303-002 [Phase 3 CM study]) will function as Visit 1 for this study (see Section 3 for further information)
c
Obtained from the participant.
d
3101-303-002 Completers only.
e
Review of inclusion/exclusion criteria includes the review of eDiary data and compliance during Screening/Baseline for De Novo EM Participants.
f
Medical history will be collected for 3101-303-002 Completers who have a gap between the last visit of the lead-in study and Visit 1 of this extension study and also for De Novo EM Participants.
g
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.
h
For WOCBP only, a urine pregnancy test will be performed at all visits. At the first study visit, discuss the method of contraception with WOCBP and document this method. Counsel participants on 
the importance of maintaining their agreed upon method of contraception throughout the study.
i
Clinical laboratory determinations include chemistry, hematology, coagulation parameters (INR), and urinalysis to be collected for all visits. Samples for serology and the urine drug screen will be 
collected only at Visit 1 for 3101-303-002 Completers and only at Visit-1 for De Novo EM Participants.
j
Participants should begin using the eDiary as soon as it is dispensed and for the duration of the screening/baseline (for De Novo EM Participants) and treatment period (for all participants). Training 
for the eDiary will be provided for qualified participants during the first study visit (Visit -1 for De Novo EM Participants and Visit 1 for 3101-303-002 Completers).
k
Daily eDiary data collection includes: headache frequency, duration, characteristics, symptoms, acute medication use, AIM-D, Activity Level, and Activity Limitation.
l
Participants must bring their eDiary to all visits (except Visit 15). 
m
At all visits except Visit -1, the “Since Last Visit” C-SSRS will be completed for all participants. For Visit -1, the ‘Screening/Baseline’ assessment of the C-SSRS will be completed for the 
participant’s lifetime history and for the 6 months prior to screening.
n
Clinicians will complete on eTablet.
o
Participant will complete on eTablet.
p
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol.
q
eDiary will be collected on Visit 1 for screen failures (De Novo EM Participants only).


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Table 2.
Schedule of Procedures for Remote Visits
Study Period
Open-label Treatment Period (52 weeks)
Safety 
Follow-up 
Period
(4 weeks)
Potential for Remote Visita
Visit #
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit 14/ 
ET
Visit 15/ 
EOS
Day/Week
Week 4
(Day 28)
Week 8
(Day 56)
Week 12
(Day 84)
Week 16
(Day 112)
Week 20
(Day 140)
Week 24
(Day 168)
Week 28
(Day 196)
Week 32
(Day 224)
Week 36
(Day 252)
Week 40
(Day 280)
Week 44
(Day 308)
Week 48
(Day 336)
Week 52
(Day 364)
Week 56
(Day 392)
Visit Windows
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Dispense study intervention (ie, 
atogepant)b
X
X
X
X
X
X
X
X
X
X
X
X
Review of study intervention (i.e., 
atogepant) compliance and 
accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant daily eDiary data 
collectionc
X
Review eDiary data and compliancec
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect eDiaryd
X
X
Perform urine pregnancy testb,e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS (eTablet or web portal)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIT-6g (web portal)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGICg (web portal)
X
X
X
X
X
PGI-Sg (web portal)
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI:MIGRAINEg (web portal)
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Satisfaction with Study 
Medicationg (web portal)
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5Lg (web portal)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MIDASg (web portal)
X
X
X
X
X
MSQ v2.1g (web portal)
X
X
X
X
X
X
Adverse events
X
Concomitant medications/ 
concurrent procedures
X


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a
Visit -1 and Visit 1 must be performed onsite.
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, AIM-D, Activity Level, and Activity Limitation.
d
Device may be dropped off or returned at Visit 15/EOS.
e
WOCBP only are to take an at-home pregnancy test (provided by sites) and report the results during virtual visits.
f
The “Since the Last Visit C-SSRS” will be completed. Clinicians will complete the C-SSRS on eTablet or web-based backup portal.
g
If available, participants will complete on a web-based portal.


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1
Background and Clinical Rationale
1.1
Background
The Global Burden of Disease Survey 2010 (Vos 2013) 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. Migraine was ranked seventh highest among specific causes of disability globally 
(Steiner 2013). 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 observed a 5.9-fold higher risk of 
migraine than men (Takeshima 2004). Migraine affects 18% of women and 6% of men in the 
United States with peak prevalence occurring between the ages of 25 and 55 years. 
Approximately one-third of patients with migraines have 3 or more migraine attacks 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).
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 in 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. 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 2004; ICHD-3 2018). This study will evaluate the long-term safety and 
tolerability of atogepant in Japanese participants with CM or EM.
1.2
Overview of Atogepant
Atogepant (AGN-241689) is a potent, selective oral CGRP receptor antagonist being developed 
for migraine prevention. Additional information on nonclinical pharmacology, toxicology, and 
PK properties of atogepant can be found in the investigator’s brochure.


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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 twice daily, atogepant 60 mg 
once daily and atogepant 60 mg twice daily to placebo. Overall, all the atogepant doses tested 
were well-tolerated. 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 with placebo in patients with EM. A recently 
completed Phase 3 clinical study (Study 3101-301-002) evaluated the efficacy, safety, and 
tolerability of atogepant 10 mg once daily, atogepant 30 mg once daily, and atogepant 60 mg 
once daily compared to placebo in the prevention of migraine in participants with EM after 
12 weeks of treatment. All atogepant doses demonstrated clinically meaningful and statistically 
significant improvement over placebo for the primary endpoint of change from baseline in mean 
monthly migraine days across the 12-week treatment period with least squares mean (LSMD) for 
atogepant versus placebo being -1.21, -1.38, and -1.72 days for atogepant 10 mg once daily, 
30 mg once daily, and 60 mg once daily, respectively. The LS mean change from baseline for 
monthly migraine days was -2.48, -3.69, -3.86, and -4.20 days for placebo, atogepant 10 mg once 
daily, 30 mg once daily, and 60 mg once daily, respectively. Furthermore, atogepant 30 mg once 
daily and 60 mg once daily demonstrated statistically significant improvement over placebo for 
all secondary endpoints of the study. Results suggested a clinically relevant dose response 
relationship, and atogepant 60 mg once daily demonstrated the highest therapeutic effect. All 
atogepant doses were well-tolerated and no significant difference was detected in the AE profile 
of the 3 atogepant doses.
In addition to the 12-week Study 3101-301-002 described above, a 52-week Phase 3 study that 
evaluated the long-term safety, tolerability, and efficacy of atogepant 60 mg once daily 
compared to standard of care has completed (Study 3101-302-002) in the prevention of EM. 
Similar to the 12-week studies, atogepant 60 mg once daily dose was safe and well-tolerated. 
A clinically relevant reduction in mean monthly migraine days, mean monthly headache days, 
mean monthly acute medication use days, and mean monthly triptan use days was achieved 
within the first month and was sustained over the 1-year treatment period. The LS mean change 
from baseline in the monthly migraine days was -3.84 days at Weeks 1-4 and -5.19 days at 
Weeks 49-52.
Atogepant was approved in the US for the preventive treatment of EM in adults in 
September 2021.
1.3
Study Rationale
The purpose of this study is to evaluate the safety and tolerability of atogepant 60 mg once daily, 
in Japanese participants, when taken for 52 weeks for the prevention of CM or EM.


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1.4
Rationale for Doses and Dose Regimens Selected
The Phase 3 pivotal studies to evaluate atogepant are testing a maximum total daily dose of 
60 mg. For this reason, the dose of 60 mg once daily has been selected for this study to evaluate 
the long-term safety and tolerability of atogepant in Japanese participants when taken for the 
prevention of CM or EM.
2
Study Objective and Clinical Hypothesis 
2.1
Study Objectives
Safety and tolerability: To evaluate the safety and tolerability of treatment with atogepant 60 mg 
once daily when administered over 52 weeks for the prevention of migraine in Japanese 
participants with CM or EM.
Efficacy: To evaluate the efficacy of treatment with atogepant 60 mg once daily when 
administered over 52 weeks for the prevention of migraine in Japanese participants with CM or 
EM.
2.2
Clinical Hypothesis
Atogepant 60 mg once daily is safe and well-tolerated when administered over 52 weeks for the 
prevention of migraine in Japanese participants with CM or EM.
3
Study Design
3.1
Structure
This is a multicenter, open-label, 52-week, long-term safety extension study conducted in Japan 
and will enroll at least 170 participants from approximately 25 sites, to meet a target of a 
minimum of 100 participants exposed to atogepant at 1 year. Participants will be treated with 
atogepant 60 mg once daily.
The study will consist of a 52-week open-label treatment period and a 4-week safety follow-up 
period for all participants. For De Novo EM Participants only, a 4-week screening/baseline 
period will be required.
The study will recruit 2 cohorts:
3101-303-002 Completers:
Japanese participants may directly rollover from Study 3101-303-002 (Phase 3 CM study); 
hereinafter referred to as the lead-in study. As such, participants will have Visit 7 from the 


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lead-in study function as Visit 1 for this study after the participant signs the informed consent. 
After Visit 1, study visits will occur every 4 weeks for the duration of the study. An EOS Visit 
will occur 4 weeks after the last dose of atogepant.
Note, there may be participants who complete Visit 7 in the lead-in study before extension Study 
3101-306-002 has been initiated. Those participants should complete Visit 7/ET and Visit 8/EOS 
Visit (including discontinuation of study intervention) per the lead-in study Schedule of Visits 
and Procedures.
Depending on the timing of the initiation of this extension study, in relation to each participant’s 
planned Visit 8 schedule in the lead-in study, Visit 1 for Study 3101-306-002 can be conducted 
on the same day as Visit 8/EOS Visit for the lead-in study, or soon thereafter.
1. If this extension study is initiated prior to the participant’s planned Visit 8 in the 
lead-in study, then Visit 8/EOS Visit in the lead-in study should be conducted on the 
same day as Visit 1 for Study 3101-306-002.
2. If this extension study is not initiated prior to the participant’s planned Visit 8 in the 
lead-in study (ie, there is a gap between Visit 8 and Visit 1), then Visit 8/EOS Visit 
should be conducted as planned per the lead-in study Schedule of Visits and 
Procedures. When this extension study is initiated the participant should return to the 
clinic as soon as possible, and Visit 1 should be conducted per the 
Study 3101-306-002 Schedule of Visits and Procedures.
De Novo EM Participants:
Japanese participants with EM will be newly recruited at selected sites only. Participation will 
begin with a 4-week screening/baseline period starting at Visit -1. Participants who complete the 
4-week screening/baseline period and meet all entry criteria will be enrolled into the 52-week 
open-label treatment period at Visit 1.
For all participants, after Visit 1 study visits will occur every 4 weeks for the duration of the 
52-week treatment period. Participants will return to the clinic for safety assessments at 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks relative to Visit 1 (Day 1). An EOS visit will 
occur 4 weeks after the last dose of atogepant 60 mg once daily. For details, please see Table 1, 
Schedule of Visits and Procedures.
The primary objective of the study is to assess the long-term safety and tolerability of atogepant 
treatment in Japanese participants. The planned safety assessments include collection of AEs, 


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clinical laboratory determinations, ECGs, vital sign measurements, physical examinations, and 
the C-SSRS.
3.2
Data Safety Monitoring Board
An independent DSMB will be established to review safety data and summary reports, identify 
any safety issues and trends, and make recommendations to the Sponsor, including modification 
or early termination 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 described in a 
separate DSMB Charter.
3.3
Adjudication Committee
An Adjudication Charter will be established and will describe the process for the surveillance, 
monitoring, and adjudication by the external Clinical Adjudication Committee of events of 
post-treatment elevations of ALT and/or AST ≥ 3 × ULN. The purpose of this charter will be to 
provide a standardized process for the adjudication of the events in order to determine whether 
the elevation was related to atogepant.
4
Study Population and Entry Criteria
4.1
Number of Participants
All participants who either complete Study 3101-303-002 or are newly recruited and complete 
the screening/baseline period, and meet all eligibility requirements, may participate in this study. 
At least 170 participants will be enrolled at approximately 25 centers in Japan, to meet a target of 
a minimum of 100 participants at 1 year. A minimum of 30 participants enrolled (at selected sites
only) must be classified as De Novo EM Participants (see definition below).
4.2
Study Population Characteristics
There will be 2 cohorts of participants eligible to participate in this study.
1. 3101-303-002 Completers:
Participants eligible to participate in this study will have completed Visit 7, and 
Visit 8 if applicable, of Study 3101-303-002 without significant protocol deviations 
(eg, noncompliance to protocol-required procedures), meet the inclusion criteria and 
do not meet the exclusion criteria for this study.


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2. De Novo EM Participants:
Participants with EM who meet eligibility criteria.
4.3
Inclusion Criteria
4.3.1
All Participants
The following are inclusion criteria for all participants:
1. Written informed consent and participant privacy information (eg, written 
authorization for use and release of health and research study information and written 
data protection consent, per Japan regulations) obtained from the participant prior to 
initiation of any study-specific procedures.
2. Participants must be using a medically acceptable and effective method of birth 
control during the course of the entire study, as defined in Section 4.5.3.
4.3.2
3101-303-002 Completers
The following is inclusion criterion for 3101-303-002 Completers only:
3. Eligible participants who completed the double-blind treatment period (Visit 7) and 
the follow-up period (Visit 8), if applicable, depending on the timing of study 
initiation, of Study 3101-303-002 without significant protocol deviations (eg, 
noncompliance to protocol-required procedures) and who did not experience an AE 
that, in the investigator’s opinion, may indicate an unacceptable safety risk.
4.3.3
De Novo EM Participants
The following are inclusion criteria for De Novo EM Participants only:
4. Male or female participants ages 18 to 80 years, inclusive, at Visit -1.
5. At least a 1-year history of migraine with or without aura consistent with a diagnosis 
according to the ICHD-3, 2018 (Section 12.1).
6. Age of the participant at the time of migraine onset < 50 years.
7. History of 4 to 14 migraine days per month (see Section 6.2.1 for definition of 
migraine day) on average in the 3 months prior to Visit -1 in the investigator’s 
judgment.


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8. 4 to 14 migraine days in the 28-day baseline period per eDiary.
9. 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.
4.4
Exclusion Criteria
4.4.1
All Participants
The following are criteria for exclusion from participating in the study for all participants unless 
noted otherwise:
1. Requirement for any medication, diet (ie, grapefruit or grapefruit juice), or 
nonpharmacological treatment that is on the list of prohibited concomitant 
medications or treatments (see Section 4.5.2 and Attachment 12.2) that cannot be 
discontinued or switched to an allowable alternative medication or treatment. 
Participants from lead-in Study 3101-303-002 taking 1 medication with demonstrated 
efficacy for the prevention of migraine may participate in the current study provided 
that the dose was stable and the medication was well-tolerated for at least 12 weeks 
prior to Visit 1 of the lead-in study and the participant is willing and able to maintain 
taking this medication at a stable dose and dosage regimen throughout the study. 
(Attachment 12.2.2).
2. Female participant 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 (De Novo EM Participants) and Visit 1 (for all 
participants).
3. An ECG with clinically significant abnormalities at Visit -1 (De Novo EM 
Participants) or Visit 1 (3101-303-002 Completers) as determined by the investigator.
4. Hypertension as defined by sitting systolic BP > 160 mm Hg or sitting diastolic 
BP > 100 mm Hg at Visit -1 (De Novo EM Participants) or Visit 1 (for all 
participants). Vital sign measurements that exceed these limits may be repeated only 
once.


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5. 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) or report suicidal behavior in the past 6 months prior to Visit -1 
(De Novo EM Participants) or since the last visit at Visit 1 (for all participants).
6. Any clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, 
hepatic, gastrointestinal, or neurologic disease.
o
If there is a history of such a disease, but the condition has been stable for more 
than 1 year prior to Visit -1 (De Novo EM Participants) and is judged by the 
investigator as not likely to interfere with the participant’s participation in the 
study, the participant may be included.
o
Participants on dialysis for renal failure will be excluded.
7. 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.
8. 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 participation in the study.
4.4.2
De Novo EM Participants
The following are criteria for exclusion from participating in the study for De Novo EM 
Participants only:
9. Difficulty distinguishing migraine headaches from tension-type or other headaches.
10. Has a history of migraine accompanied by diplopia or decreased level of 
consciousness or retinal migraine as defined by ICHD-3, 2018.
11. Has a current diagnosis of chronic migraine, new persistent daily headache, 
trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy 
as defined by ICHD-3, 2018.
12. Has ≥ 15 headache days per month (see Section 6.2.2 for definition of headache day) 
on average across the 3 months prior to Visit -1 in the investigator’s judgment.
13. Has ≥ 15 headache days in the 28-day baseline period per eDiary.


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14. History of an inadequate response to > 4 medications (2 of which have different 
mechanisms of action) prescribed for the prevention of migraine (see Section 12.2.2
for classification of inadequate response to migraine-preventive medications).
15. Usage of opioids or barbiturates > 2 days/month, triptans or ergots ≥ 10 days/month, 
or simple analgesics (eg, aspirin, NSAIDs, acetaminophen) ≥ 15 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 through the duration of the 
study) (see Section 12.2.1).
16. QTcF > 450 msec for males and QTcF > 470 msec for females at Visit -1 based on 
the central reviewer’s final ECG report.
17. Clinically significant cardiovascular or cerebrovascular disease per the investigator’s 
opinion including, but not limited to:
o
Clinically significant ischemic heart disease (eg, unstable angina pectoris).
o
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).
o
Myocardial infarction, transient ischemic attack, or stroke within 6 months prior 
to Visit -1.
o
Heart failure defined as New York Heart Association functional classification 
system, Class III or IV (Section 12.3).
18. Clinically significant laboratory values OR any of the following laboratory values at 
Visit -1:
o
ALT or AST > 1 × ULN OR
o
Total bilirubin > 1 × ULN (except for participants with a diagnosis of Gilbert’s 
disease) OR
o
Serum albumin < 2.8 g/dL.
19. History of acute hepatitis within 6 months of Screening (Visit -1); or chronic liver 
disease (including nonalcoholic fatty liver disease, viral chronic hepatitis, and 
cirrhosis); or a positive result on anti-hepatitis A IgM antibody, hepatitis B surface 
antigen, anti-hepatitis C antibody testing, or anti-hepatitis E IgM antibody.


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20. In the opinion of the investigator, confounding psychiatric conditions, dementia, 
epilepsy, or significant neurological disorders other than migraine.
21. 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).
22. 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.
23. History of any GI prior procedures or GI 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 will not be excluded.
24. 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.
25. Positive result on the urine drug screen at Visit -1 unless explained by concomitant 
medication use (eg, opioids prescribed for migraine pain).
26. 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).
27. Previous exposure to:
o
Atogepant (AGN-241689 or MK-8031) OR
o
Injectable monoclonal antibodies blocking the CGRP pathway within the last 
6 months OR
o
Any other investigational CGRP-receptor antagonist (RA).
28. History of hypersensitivity or clinically significant adverse reaction to a CGRP 
receptor antagonist or hypersensitivity to any component of the study intervention 
(atogepant).
29. Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a 
participant has signs/symptoms suggestive of SARS-CoV-2 infection, the participant 
must have a negative molecular (eg, polymerase chain reaction [PCR]) test result to 
be considered for inclusion in the study.


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(Note: Participants who do not meet SARS-CoV-2 infection eligibility criteria must be 
screen failed and may only rescreen after they meet the following SARS-CoV-2 
infection viral clearance criteria: at least 14 days since first negative PCR test result 
have passed in asymptomatic participants or 14 days since recovery, defined as 
resolution of fever without use of antipyretics and improvement in symptoms.)
30. Unremitting symptoms of "long COVID" due to prior SARS-CoV-2 infection or any 
other lasting symptoms 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.
4.5
Permissible and Prohibited Medications/Treatments
4.5.1
Permissible Medications/Treatments
Medications that are not specifically prohibited in Section 4.5.2 and Attachment 12.2 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
Herbal medications are allowed during the study with the exception of herbal medications for the 
treatment of migraine.
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
SSRI or SNRI will be permitted, provided that treatment is stable for at least 60 days prior to the 
first study visit 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 
Sponsor.
4.5.2
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to the first study visit (unless otherwise 
indicated) for all participants and throughout the study (see Attachment 12.2).

Strong and moderate CYP3A4 inhibitors, including but not limited to: systemic (oral/IV) 
itraconazole, ketoconazole, fluconazole, erythromycin, clarithromycin, telithromycin1, 
ciprofloxacin, diltiazem, verapamil, aprepitant, cyclosporine, nefazodone1, cimetidine, 
quinine, and HIV protease inhibitors

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

Strong OATP1B1 inhibitors (eg, gemfibrozil1, 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, 
topiramate, propranolol), excepting 1 medication with demonstrated efficacy for the 
prevention of migraine taken at a stable dose and well-tolerated during 
Study 3101-303-002 which may be continued if the participant is willing and able to do 
so (see Exclusion Criterion 1, Section 4.4 and Attachment 12.2.2).

Herbal medications with efficacy for the prevention of migraine (eg, feverfew)

CBD oil

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, Botox®, Xeomin®, 
Myobloc®, Jeuveua™) into areas of the head, face, or neck within 6 months prior to the 
first study visit and throughout the study period
                                               
1 Not approved in Japan


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
Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™, 
Emgality™, Ajovy®) within 6 months prior to the first study visit and through the study 
period.
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. Sponsor should be notified about 
administration of prohibited medication/treatment as soon as possible.
4.5.3
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, 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, 
intravaginal2, or transdermal2 (ie, pill, vaginal ring2, patch2)

Progestogen--only hormonal contraception (with inhibition of ovulation) that are oral, 
injectable2, or implantable2

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 duration of 
the study)
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)
                                               
2 Contraceptive methods not approved in Japan.


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
Male or female condom with or without spermicide2 (female and male condoms should 
not be used together)

Cap3, diaphragm3 or sponge3 with spermicide

A combination of male condom with either cap3, diaphragm3 or sponge3 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 participation in the study.
If a woman becomes pregnant during the study, the investigator will notify Sponsor immediately 
after the pregnancy is confirmed and the participant will be discontinued from the study after 
appropriate safety follow-up. The investigator will (1) notify the participant’s physician that the 
participant was being treated with 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 Sponsor.
4.5.4
Special Diet or Activities
Participants should refrain from consuming grapefruit or grapefruit juice from the time the ICF 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 355 mL can/bottle of beer, a 118 mL glass of wine, or 30 mL of liquor.
4.6
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently treated.
                                               
3 Contraceptive methods not approved in Japan.


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For De Novo EM Participants only: Rescreening of screen failures is permitted in certain 
situations, with permission from the Sponsor. However, participants with clinically significant 
laboratory values at Visit -1 (including ALT or AST > 1 × 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 nondisclosed 
concomitant medications, are not allowed to be rescreened.
5
Study Intervention
5.1
Study Intervention and Formulations
Tablets containing atogepant 60 mg (Formulation Number: 11281X).
5.2
Control Intervention 
Not applicable.
5.3
Methods for Masking/Blinding
This is an open-label study.
5.4
Treatment Allocation Ratio
All participants will be treated with atogepant 60 mg once daily.
5.5
Method for Assignment to Treatment Groups
Prior to initiation of atogepant in this open-label extension study, each participant who provides 
informed consent will maintain his/her lead-in study participant number. This number will serve 
as the participant identification number on all study documents. For De Novo EM Participants,
participant identification numbers will be newly assigned at study entry.
At Visit 1, eligible participants will receive one bottle of atogepant 60 mg.
Before the study is initiated, log-in information and directions for the IWRS will be provided to 
each site.
The atogepant bottles will be labeled with kit numbers. The IWRS system will provide the site 
with the specific medication kit number(s) for each participant at Visit 1. Sites will dispense 
atogepant according to the IWRS instructions. Sites will also log onto the IWRS at subsequent 
visits to obtain a kit number for dispensing atogepant. Sites will receive the IWRS confirmation 
notifications for each transaction. All notifications are to be maintained with the study source 
documents.


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Atogepant bottles will be dispensed at the study visits summarized in the Schedule of Visits and 
Procedures. Returned atogepant bottles should not be redispensed to the participants.
5.6
Treatment Regimen and Dosing
Participants who meet all of the study entry criteria at Visit -1 and/or Visit 1 will be treated with 
atogepant 60 mg once daily. Atogepant to be used in this study is listed in Table 5-1.
Participants will be instructed to take their atogepant at approximately the same time each day. 
Atogepant will be administered orally for 52 weeks, and participants will be followed for 
4 weeks following completion or discontinuation of atogepant.
Table 5-1.
Study Intervention
Drug/Dose
Study Intervention Frequency
Route of Administration
Atogepant 60 mg
Once daily
Oral
5.7
Storage of Study Intervention
Atogepant bottles must be stored at room temperature in a securely locked cabinet. Further 
details regarding the storage of atogepant are in the Study Reference Manual.
6
Response Measures and Summary of Data Collection Methods
6.1
Safety Measures
6.1.1
Adverse Events
Adverse events 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 study or control intervention, and detail any other treatment measures taken for 
the AE. For events noted as SAEs, Sponsor must be notified immediately to meet their reporting 
obligations to appropriate regulatory authorities.
6.1.2
Adverse Events of Special Interest
Selected nonserious and serious adverse events are AESIs and will require immediate reporting, 
recording and follow-up. The following events will be closely monitored:

Treatment-emergent suicidal ideations with intent, with or without a plan (ie, Type 4 or 5 
on the C-SSRS) or any suicidal behaviors


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
Treatment-emergent elevated ALT or AST laboratory value that is ≥ 3 x ULN

Potential Hy’s law cases: elevated ALT or AST laboratory value that is ≥ 3 x ULN and 
an elevated total bilirubin laboratory value that is ≥ 2 x ULN and, at the same time, an 
alkaline phosphatase laboratory value that is < 2 x 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 be captured 
in the eTablet and monitored by Sponsor. These AEs or events determined to be SAEs must be 
reported appropriately via the designated eCRFs and safety forms.
6.1.3
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at the visits outlined in 
Table 1. Hematology, chemistry, INR, and urinalysis will be conducted at these visits. Serology 
and the urine drug screen will only be conducted at Visit -1 (De Novo EM Participants) and at 
Visit 1 (3101-303-002 Completers). 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 withdrawal criteria, 
or positive results on the urine drug screen Visit -1 or Visit 1 will be excluded/withdrawn 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 1 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 6-1.


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Table 6-1.
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 examination including red blood cells/high-power field, white 
blood cells/high-power field, and casts/low-power field
Coagulation
INR 
Serology
At Visit -1 (De Novo EM Participants) and Visit 1 (3101-303-002 Completers) 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 (De Novo EM Participants) or Visit 1 (3101-303-002 Completers). Those 
with a positive result on the Visit -1 or Visit 1 urine drug screen for recreational 
(including marijuana, regardless of legality) or illicit drugs or nondisclosed 
concomitant medications are not allowed to be repeated. For all other positive 
results, the urine drug screen may be repeated with permission from 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 study 
participation.
IgM = immunoglobulin M; INR = International Normalized Ratio.
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.
6.1.4
Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature and weight, will be performed at every visit. Height will be 
measured only at Visit -1. 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).


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6.1.5
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 
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.
6.1.6
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 a source document. 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.
6.1.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
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 Visit -1 (Screening/Baseline, De Novo EM Participants only), the C-SSRS will be completed 
for the participant’s lifetime history and for the 6 months prior to screening. At all other visits the 
C-SSRS will be completed for ideation and behavior since last visit for all participants. 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 


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ideation section or “yes” to any question in the suicidal behavior section of the C-SSRS at 
Visits 2 through 13 must be withdrawn from the study and should receive appropriate follow-up 
as in routine clinical practice, including the ET (Visit 14) and the safety follow-up (Visit 15).
6.2
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 duration, headache characteristics, symptoms, and 
acute medication use, which will be collectively applied to define migraine days and headache 
days per the criteria listed in Sections 6.2.1, 6.2.2 and 6.2.3.
The AIM-D, Activity Level, and Activity Limitation will also be collected daily via an eDiary. 
Additional health outcome measures, namely, the Patient Satisfaction with Study Medication 
scale, HIT-6, MIDAS, PGIC, WPAI:MIGRAINE, EQ-5D-5L, PGI-S, and MSQ v2.1 will be 
administered in an eTablet at specified clinic visits.
6.2.1
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 two of the following 4 characteristics:

Unilateral location

Pulsating quality

Moderate or severe pain intensity

Aggravated by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs)
B. At least 1 of the following:

Nausea and/or vomiting

Photophobia and phonophobia

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


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OR
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.
6.2.2
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).
6.2.3
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 eDiary.


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6.3
Health Outcome Measures
6.3.1
Activity Impairment in Migraine - Diary (AIM-D)
The AIM–D is an 11-item PRO measure that assesses functioning and activity impairment in 
migraine patients. Participants are asked to rate the level of difficulty experienced in the past 
24 hours with functioning and activity impairment (ie, difficulty with household chores, errands, 
leisure activities at home, leisure or social activities outside the home, strenuous physical 
activities, walking, moving body, bending forward, moving head, concentrating and thinking 
clearly) using the following 6point 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 2 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).
6.3.2 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 scale 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 scale ranging from “Not at all limited 
– I could do everything” to “Extremely limited”.
6.3.3
Patient Satisfaction with Study Medication
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).


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6.3.4
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).
6.3.5
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, missed household 
work days, days at work or school plus days of household work where productivity was reduced 
by half or more, and missed non-work activity days due to headaches in the last 3 months.
6.3.6
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.”
6.3.7
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 six 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.
6.3.8
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, 
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, visual analogue scale 


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where the endpoints are labeled “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).
6.3.9
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.”
6.3.10
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.
6.4
Other Study Supplies
The following will be provided by Sponsor or Sponsor designee:

All supplies needed for blood and urine sampling (central laboratory analysis)

All supplies needed for on-site urine pregnancy test

Shipping materials for shipment of laboratory samples to central laboratory

All supplies needed for ECG assessment including ECG machine

eDiaries

eTablet(s)
6.5
Summary of Methods of Data Collection
An IWRS will be used to manage atogepant inventory. All office visit data (ie, nondiary data) for 
this study will be collected by either the eTablet (eg, questionnaires for PROs) or eCRFs via an 


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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 
Laboratory Procedure Manual.
All participants will use an eDiary daily to record the daily total duration of headache, headache 
characteristics, associated symptoms, the worst pain severity, acute medication use, AIM-D, 
Activity Level, and Activity Limitation during the open-label treatment period until Visit 14. 
Participants should begin using the eDiary as soon as it is dispensed and for the duration of the 
screening/baseline (for De Novo EM Participants) and treatment period (for all participants). 
Training for the eDiary will be provided for qualified participants during the first study visit 
(Visit -1 for De Novo EM Participants and Visit 1 for 3101-303-002 Completers).
7
Statistical Procedures
7.1
Analysis Populations
All safety analyses will be performed using the safety population, consisting of all participants 
who received at least 1 dose of study intervention (atogepant) in this extension study.
All efficacy analyses will be performed using the mITT population, consisting of participants 
who received at least 1 dose of study intervention (atogepant) in this study, an evaluable baseline 
(in this study for De Novo EM Participants or in the lead-in study for the rollover participants), 
and had at least 1 evaluable post-baseline 4-week period of eDiary data in this extension study.
7.2
Collection and Derivation of Efficacy Assessments
Since the primary objective of this study is to assess the long-term safety and tolerability of 
atogepant treatment, efficacy variables are not classified as primary, secondary, or additional.
Efficacy endpoints for long-term efficacy evaluation in the atogepant arm are listed below.

Change from baseline in monthly migraine days at each monthly period

Change from baseline in monthly headache days at each monthly period

Change from baseline in monthly acute medication use days at each monthly period


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
≥ 25%, ≥50%, ≥ 75%, and 100% improvement (decrease) in monthly migraine days at 
each monthly period

Change from baseline in monthly cumulative headache hours at each monthly period

Change from baseline in monthly triptan use days at each monthly period

Change from baseline in monthly moderate/severe headache days at each monthly period

Change from baseline in monthly severe headache days at each monthly period

Change from baseline in the HIT-6 total score at each monthly period

At least a 5-point improvement (decrease) from baseline in total HIT-6 score at each 
monthly period

Participants reporting “satisfied” or “extremely satisfied” with study medication for 
migraine prevention at each monthly period

Rating of “much better” or “very much better” at Weeks 12, 24, 36, 48, and 52 assessed 
by the PGIC

Change from baseline in percent work time missed, percent impairment while working, 
percent overall impairment, and percent activity impairment due to migraine at each 
monthly period as assessed by the WPAI:MIGRAINE

Change from baseline in EQ-5D-5L descriptive system index score at each monthly 
period

Change from baseline in the EQ-5D-5L VAS score at each monthly period

Change from baseline in the MIDAS total score at Weeks 12, 24, 36, 48, and 52

Change from baseline in MIDAS absenteeism score (Questions 1, 3, and 5) at Weeks 12, 
24, 36, 48, and 52

Change from baseline in MIDAS presenteeism score (Questions 2 and 4) at Weeks 12, 
24, 36, 48, and 52

Change from baseline in PGI-S at each monthly period


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
Change from baseline in the MSQ v2.1 Role Function Preventive domain score at 
Weeks 12, 24, 36, 48, 52, and 56

Change from baseline in the MSQ v2.1 Role Function Restrictive domain score at 
Weeks 12, 24, 36, 48, 52, and 56

Change from baseline in the MSQ v2.1 Emotional Function domain score at Weeks 12, 
24, 36, 48, 52, and 56

Change from baseline in monthly Performance of Daily Activities domain score of the 
AIM-D at each monthly period

Change from baseline in monthly Physical Impairment domain score of the AIM-D at 
each monthly period

Change from baseline in monthly AIM-D total score at each monthly period

Change from baseline in monthly activity level at each monthly period

Change from baseline in monthly activity limitation at each monthly period
7.3
Hypothesis and Methods of Analysis
7.3.1
Safety Analyses
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 baseline value 
in this extension study is defined as:

The baseline value in the lead-in study (Study 3101-303-002) for 3101-303-002 
Completers.

The last nonmissing safety assessment before the first dose of study drug for De Novo 
EM Participants.
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.


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7.3.2
Efficacy Analyses
The efficacy analyses will be based on the mITT population. For analysis purposes, four weeks 
(28 days) will be considered as 1 month.
For monthly endpoints, baseline in this extension study is defined as:

The baseline value in the lead-in study (3101-303-002) for 3103-303-002 Completers

The last 28 days of the screening/baseline period for De Novo EM Participants.
For efficacy endpoints that are assessed at clinical visits, baseline in this extension study is 
defined as:

The last nonmissing efficacy assessment before the first dose of study intervention in the 
lead-in study (3101-303-002) for 3103-303-002 Completers

The last nonmissing efficacy assessment before the first dose of study drug for De Novo 
EM Participants.
Monthly efficacy endpoints are defined in a prorated fashion. For example, monthly migraine 
days are 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.
Descriptive statistics will be provided by visit for all efficacy endpoints based on the mITT 
population using the OC approach. No inferential statistical analyses will be performed for the 
efficacy parameters unless otherwise specified in the Statistical Analysis Plan (SAP).
7.4
Subgroup Analyses
For selected safety and efficacy endpoints, analyses will be performed separately for 
3101-303-002 Completers and De Novo EM Participants. Details will be provided in the SAP.
7.5
Sample Size Calculation
The study sample size was driven by regulatory safety requirements for the duration and number 
of participants exposed rather than statistical considerations. At least 170 participants will be 
enrolled into this long-term, open-label, safety extension study including at least 140 participants 
from the lead-in study (Study 3101-303-002) and approximately 30 De Novo EM Participants 
(from selected sites only) to meet a target of a minimum of 100 participants exposed to atogepant 
at 1 year.


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7.6
Interim Analyses
No interim analyses are 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.
8.1
Participant Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective participants as defined by the criteria in Sections 4.3 and 4.4 (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; a participant wishing to participate and their 
legally authorized representative if applicable, must give informed consent prior to any 
study-related procedures or change in treatment. The participant and their legally authorized 
representative if applicable, must also give authorization, and other written documentation, in 
accordance with Japanese and local privacy requirements (where applicable) prior to any 
study-related procedures or change in treatment.
3101-303-002 Completers will maintain their lead-in study (Study 3101-303-002) participant 
identification number; this will serve as the participant identification number that will be used on 
all participant documentation throughout the study. For De Novo EM Participants, participant 
identification numbers will be newly assigned at study entry.
8.2
Washout Intervals/Run-in
This study will not include a washout period.
8.3
Procedures for Final Study Entry
For 3101-303-002 Completers: 

Participants will directly rollover from their lead-in study (Study 3101-303-002 [Phase 3 
CM study]). As such, participants will have Visit 7 from the lead-in study function as 
Visit 1 for this study after the participant signs the informed consent. At Visit 1 
participants must meet all of the inclusion criteria and must not meet any of the exclusion 
criteria.


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
Note, there may be participants who complete Visit 7 in the lead-in study before 
extension Study 3101-306-002 has been initiated. Those participants should complete 
Visit 7/ET and Visit 8/EOS Visit (including discontinuation of study intervention) per the 
lead-in study Schedule of Visits and Procedures.

Depending on the timing of the initiation of this extension study in relation to each 
participant’s planned Visit 8 schedule in the lead-in study, Visit 1 for 
Study 3101-306-002 can be conducted on the same day as Visit 8/EOS Visit for the lead-
in study, or soon thereafter.

If this extension study is initiated prior to the participant’s planned Visit 8 in the lead-in 
study, then Visit 8/EOS Visit for the lead-in study should be conducted on the same day 
as Visit 1 for Study 3101-306-002.

If this extension study is not initiated prior to the participant’s planned Visit 8 in the lead-
in study (ie, there is a gap between Visit 8 and Visit 1), then Visit 8/EOS Visit should be 
conducted as planned per the lead-in study Schedule of Visits and Procedures. When this 
extension study is initiated, the participant should return to the clinic as soon as possible 
and Visit 1 should be conducted per the Study 3101-306-002 Schedule of Visits and 
Procedures.
For De Novo EM Participants:

At Visit -1 (Screening/Baseline) and Visit 1, 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 (Section 4.6).
8.4
Visits and Associated Procedures
There will be a total of 15 scheduled clinic visits for 3101-303-002 Completers: Visit 1 (Day 1), 
Visit 2 (Week 4), Visit 3 (Week 8), Visit 4 (Week 12), Visit 5 (Week 16), Visit 6 (Week 20), 
Visit 7 (Week 24), Visit 8 (Week 28), Visit 9 (Week 32), Visit 10 (Week 36), Visit 11 
(Week 40), Visit 12 (Week 44), Visit 13 (Week 48), Visit 14/ET (Week 52), and Visit 15/EOS. 
For details, please see Table 1, Schedule of Visit and Procedures.
There will be a total of 16 scheduled clinic visits for De Novo EM Participants: Visit -1, Visit 1 
(Day 1), Visit 2 (Week 4), Visit 3 (Week 8), Visit 4 (Week 12), Visit 5 (Week 16), Visit 6 
(Week 20), Visit 7 (Week 24), Visit 8 (Week 28), Visit 9 (Week 32), Visit 10 (Week 36), 
Visit 11 (Week 40), Visit 12 (Week 44), Visit 13 (Week 48), Visit 14/ET (Week 52), and 
Visit 15/EOS. For details, please see Table 1, Schedule of Visit and Procedures.


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8.4.1
Visit -1 (Screening/Baseline) Day -35 to Day -28
Visit -1 is to be performed for De Novo EM Participants only.

Obtain informed consent and participant privacy.

Register participant in IWRS.

Collect demographic information.

Collect medical history.

Collect migraine/headache history and confirm diagnosis.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Review and record prior medications taken in the past 6 months and all prior headache 
medications and concomitant medications.

Assess C-SSRS on eTablet (the ‘Screening/Baseline’ assessment of the C-SSRS will be 
completed); the C-SSRS will be completed for the participant’s lifetime history and for 
the 6 months prior to screening.

Collect ASC-12 on eTablet.

Perform physical examination.

Collect 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.

Perform and transmit ECG.

Perform urine pregnancy test for WOCBP. Discuss the method of contraception with 
WOCBP and document this method. Counsel participants on the importance of 
maintaining their agreed upon method of contraception throughout the study.

Collect blood and urine samples for clinical laboratory determinations (chemistry, 
hematology, INR, urinalysis, and serology).

Collect urine sample for drug screen.


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
Verify if the participant meets inclusion/exclusion criteria at this point.

Provide eDiary, along with training and instructions. Participants to bring eDiary to all 
visits.
8.4.2
Open-label Treatment Period (52 Weeks)
8.4.2.1 Visit 1 (Day 1)

Obtain informed consent and participant privacy (3101-303-002 Completers only).

Register participant in IWRS (3101-303-002 Completers only).

Review and update concomitant medications and concurrent procedures.

Perform urine pregnancy test for WOCBP. Discuss the method of contraception with 
WOCBP and document this method. Counsel participants on the importance of 
maintaining their agreed upon method of contraception throughout the study.

Perform and transmit ECG (3101-303-002 Completers only).

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting 
and standing pulse rate, respiration rate, temperature, and weight).

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Collect medical history for participants who have a gap between the last visit of the 
lead-in study and Visit 1 of this extension study (3101-303-002 Completers only).

Assess inclusion/exclusion criteria.

Note: review of inclusion/exclusion criteria includes the review of eDiary data and 
compliance during Screening/Baseline for De Novo EM Participants.
If the participant continues to meet study entry criteria, including acceptable results from Visit 1 
ECGs (3101-303-002 Completers only), pregnancy tests and vital sign measurements (see 
Section 6.1) the following procedures will be carried out at Visit 1.

Prior to any other test or evaluations, administer the following PRO measures: HIT-6, 
PGI-S, WPAI:MIGRAINE, EQ-5D-5L, MIDAS, and MSQ v2.1.

Perform physical examination.


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
Collect blood and urine for clinical laboratory determinations including: chemistry, 
hematology, serology, coagulation parameters (INR), and urinalysis. (Note: serology 
samples to be collected for 3101-303-002 Completers only).

Collect urine for drug screen (3101-303-002 Completers only).

Review and assess AEs.

Provide eDiary instructions and training (3101-303-002 Completers only).

Access IWRS and obtain the kit number for atogepant bottle and dispense atogepant 
bottle.
8.4.2.2 Visits 2 to 13 (Weeks 4 to 48)

Prior to any other test or evaluations, administer the following PRO measures:
o
HIT-6, PGI-S, WPAI:MIGRAINE, Patient Satisfaction with Study Medication, 
and EQ-5D-5L (at every visit).
o
PGIC, MIDAS and MSQ v2.1 at Visit 4 (Week 12), Visit 7 (Week 24), Visit 10 
(Week 36), and Visit 13 (Week 48).

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting 
and standing pulse rate, respiration rate, temperature, and weight).

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG (Visit 4 [Week 12], Visit 7 [Week 24] and Visit 10 [Week 36] 
only).

Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.

Review and assess AEs.

Review and update concomitant medications and concurrent procedures.


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
Review eDiary data and compliance.

Access IWRS to dispense atogepant bottle and enter accountability.
8.4.2.3 Visit 14/Early Termination (Week 52)
Effort should be made by the site to not schedule Visit 14 earlier than 52 weeks after Day 1, to 
ensure participants complete the full 52 weeks of atogepant and have eDiary data through 
Day 364.

Prior to any other test or evaluations, administer the following PRO measures: HIT-6, 
PGIC, PGI-S, WPAI:MIGRAINE, Patient Satisfaction with Study Medication, 
EQ-5D-5L, MIDAS, and MSQ v2.1.

Perform physical examination.

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting 
and standing pulse rate, respiration rate, temperature, and weight). 

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG.

Review and assess AEs.

Review and update concomitant medications and concurrent procedures.

Review eDiary data and compliance.

Collect eDiary.

Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.

Access IWRS to enter study visit and accountability.


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8.4.3
Safety Follow-up Period (4 Weeks)
8.4.3.1 Visit 15/End of Study (Week 56)

Prior to any other test or evaluations, administer the following PRO measures: HIT-6, 
EQ-5D-5L and MSQ v2.1.

Perform physical examination.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting 
and standing pulse rate, respiration rate, temperature, and weight).

Perform urine pregnancy test for women of childbearing potential.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Review and assess AEs.

Update concomitant medications and concurrent procedures.

Access IWRS to enter study visit.
8.4.4
COVID-19 Pandemic-related Remote Visits
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 2) will be 
followed. After Visit 1, remote study visits may be performed for up to 8 weeks at the discretion 
of the investigator after which, participants who cannot attend in-person for a study visit must 
discontinue from the study. Missed in-person safety assessments (ie, clinical laboratory samples, 
vital signs and ECGs) should be collected at the next in-person visit. If available, PROs will be 
collected using a web-based portal during remote visits.
8.5
Instructions for the Participants
Section 4.5.4 provides diet and activity instructions for participants enrolled in the study.
Participants will be provided with instructions on daily completion of the eDiary at their first 
study visit. 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, 


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prohibited medications should be reviewed with the participants. Participants will be instructed 
to bring their eDiary to each clinic visit and return their atogepant bottle(s), both used and 
unused.
Participants should be instructed to take atogepant 60 mg once daily at approximately the same 
time each day (approximately 24 hours between doses). 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 (Section 4.5.3).
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.
Atogepant 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 atogepant.
8.8
Early Discontinuation of Participants
A premature discontinuation will occur when a participant who signed the ICF 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

Noncompliance with study intervention (ie, atogepant)


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
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 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 14/ET and Visit 15/EOS; 4 weeks after the last dose of atogepant.
8.9
Withdrawal Criteria
Study 3101-303-002 Completers with the following at Visit 1 must be withdrawn from the study:

Laboratory Results:
o
ALT or AST > 1 x ULN OR
o
Total bilirubin > 1 x ULN (except for participants with a diagnosis of Gilbert’s 
disease) OR
o
Serum albumin < 2.8 g/dL
o
Positive result on the urine drug screen unless explained by concomitant 
medication use (eg, opioids prescribed for migraine pain).
o
Positive result on anti-hepatitis A IgM antibody, hepatitis B surface antigen, anti-
hepatitis C antibody, or anti-hepatitis E IgM antibody testing.

ECG Results:
o
QTcF > 450 msec for males and QTcF > 470 msec for females on the final central 
vendor ECG report
o
Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial 
fibrillation, second- or third-degree heart block)


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Participants must be withdrawn from the study if they meet any of the following at any study 
visit:

Female participants who become pregnant (Section 9.4)

Participants who meet atogepant 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 atogepant.

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 2 through 
13 must be withdrawn from the study.

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 should be withdrawn from 
treatment.
All withdrawn participants should receive appropriate follow-up as in routine clinical practice, 
including the ET (Visit 14) and the EOS (Visit 15) assessments.
8.10
Study Termination
The study may be stopped at his/her study site at any time by the site investigator. 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 eCRF. 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 clinical study participant associated with the use 
of atogepant, whether or not considered related. 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 atogepant. In addition, during the screening 
period and Visit 1, AEs will be assessed regardless of the administration of a pharmaceutical 
product.


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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to atogepant or study procedures, or that caused the 
participant to discontinue atogepant or the study (see Section 8.8).
All AEs from the signing of the ICF until the EOS visit (Visit 15), or 30 days after the last dose 
of atogepant if the EOS visit is not done, will be collected at the timepoints specified in the 
Schedule of Visits and Procedures (Table 1), and as observed or reported spontaneously by study 
participants.
Investigators are not obligated to actively seek AE information after conclusion of the study 
participation.
AEs will be assessed, documented, and recorded in the eCRF throughout the study (ie, after 
informed consent has been obtained). At each visit, the investigator will begin by querying for 
AEs by asking each participant a general, nondirected question such as “How have you been 
feeling since the last visit?” Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrences. Care will be taken not to introduce bias 
when detecting AEs and/or SAEs. All reported AEs will be documented on the appropriate 
eCRF.


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9.1.2
Serious Adverse Event
An SAE is any AE occurring at any dose that results in any of the following outcomes:
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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.


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Sponsor considers all cancer AEs as SAEs. In addition, Sponsor considers any abortion 
(spontaneous or elective) as an SAE.
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
participant requires hospitalization is not reportable as an SAE.
Any preplanned 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 Sponsor.
9.1.3
Intensity
The intensity assessment for a clinical AE must be completed using the following definitions as 
guidelines:
Assessment of Intensity
MILD
A type of AE that is usually transient and may require only minimal
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
MODERATE
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant.
SEVERE
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
An event is defined as serious when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.


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9.1.4
Assessment of Causality
Assessment of Causality
1.
The investigator is obligated to assess the relationship between atogepant medication 
and each occurrence of each AE or SAE.
2.
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
3.
The investigator will use clinical judgment to determine the relationship.
4.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to atogepant administration 
will be considered and investigated.
5.
The investigator will also consult the investigator’s brochure in his/her assessment.
6.
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.
7.
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to Sponsor.
8.
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
9.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
9.1.5
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs and nonserious AEs of special interest (as defined in 
Section 6.1.2) will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 8.8).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
healthcare professionals.


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Prior to database lock, new or updated information will be recorded in the originally completed 
eCRF. If the event is an SAE, it will also need to be reported on the SAE reporting form. Post 
database lock, new or updated SAE information will only be reported on the SAE reporting 
form.
The investigator will submit any updated SAE data to Sponsor within 24 hours of receipt of the 
information.
9.2
Procedures for Reporting Adverse Events
All AEs must be recorded on the appropriate eCRF.
All AEs that are atogepant-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 EOS 
visit (Visit 15) or 30 days after the last dose of atogepant if the EOS visit is not done must be 
immediately reported but no later than 24 hours after learning of an SAE. SAEs must be reported 
to Sponsor as listed on the Sponsor 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 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 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 (ie, atogepant) under clinical investigation are met. For Japan, the 
investigator must promptly report the SAE to the head of the study center.

Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention (ie, atogepant) under clinical 
investigation. Sponsor will comply with country-specific regulatory requirements relating 
to safety reporting to the regulatory authority, IRBs/ IECs, and investigators. For Japan, 
the head of the study center must also be informed.


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
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor 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 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 atogepant and until the EOS visit (Visit 15) or 30 days after the last 
dose of atogepant if the EOS 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[s]: +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.
9.5
ALT or AST Elevations
A treatment-emergent ALT ≥ 3 × ULN and/or AST ≥3 × ULN is considered an AESI. Any
participant with this laboratory result after atogepant 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 performed: hematology and chemistry panels, INR, serum acetaminophen level, urine 
drugs of abuse screen, and blood alcohol level. A 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.
All AESIs must be reported to 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 


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elements of history, physical examination, diagnostic testing results, and other relevant medical 
reports are to be reported for each AESI.
If an ALT or AST ≥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 Sponsor medical 
personnel. In general, the chemistry panel should be repeated 1 to 2 times per week to follow the 
course of ALT/AST elevation.
Atogepant 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 atogepant only after consultation with the Sponsor
Medical Monitor. For participants who are not rechallenged, the participant should be 
discontinued from the study and complete an ET visit and an EOS Visit 4 weeks later. 
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 x ULN. All ALT/AST elevations must be followed until 
ALT and AST return to < 1.5 x ULN and there is full clinical resolution.


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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 atogepant:

ALT or AST ≥ 3 x ULN AND

Total bilirubin ≥ 2 x ULN AND

Alkaline phosphatase < 2 x 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 atogepant (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 
Sponsor immediately when the above criteria have been met. A possible Hy’s law case must be 
faxed to 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 SAE/Pregnancy fax number, even if no 
AE has occurred. If the event is serious, please complete the AESI/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.
10 Administrative Items
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines (eg, the ICH Guideline on GCP).


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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 enrollment into the 
study and/or from the participant’s legally authorized representatives. The informed consent 
form includes explanation of the following:

That the study involves research

The objectives of the study

The study procedures

The expected duration of the participant’s participation in the study

The approximate number of participants involved in the study

The reasonably foreseeable risks or inconveniences to the participant

The alternative procedures or courses of interventions that may be available to the 
participant, and their important potential benefits and risks

The compensation and/or intervention available to the participant in the event of 
study-related injury

That the participant’s participation in the study is voluntary and that the participant may 
refuse to participate or withdraw from the study at any time, without penalty or loss of 
benefits to which the participant is otherwise entitled

That the participant will be informed in a timely manner if information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study

The foreseeable circumstances and/or reason under which the participant’s participation 
in the study may be terminated

That the monitors, auditors, the IRB, and the regulatory authorities may provide direct 
access to the participant’s original medical records. In such cases, the confidentiality of 
the participant should be protected, and by signing and sealing an informed consent form, 
the participant is authorizing such access.


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
If the results of the study are published, the participant’s identity will remain confidential.

The anticipated expenses, if any, to the participant for participating in the study

The anticipated prorated payment, if any, to the participant for participating in the study

The name, title, and address of the investigator to contact

The person(s) to contact for further information regarding the clinical study and the rights 
of participants, and whom to contact in the event of study-related injury

The type of the IRB engaged in the assessment and deliberation about the acceptability of 
the study, items subject to the assessment of each IRB, and other IRB-related items 
relating to the study

The participant’s responsibilities
10.1.2
Compliance with IRB or IEC Regulations

This protocol is to be conducted in accordance with ethical principles based on the 
Declaration of Helsinki and the guidance stipulated in Article 14, Paragraph 3 and Article 
80-2 of the Pharmaceutical Affairs Law, MHW Ordinance on Good Clinical Practice 
(MHW Ordinance No 28 [27 Mar 1997]).

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the head of the 
study center, and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
1. Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
2. Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures


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3. This study is to be conducted in accordance with IRB regulations. The investigator 
must obtain approval from a properly constituted IRB prior to initiating the study and 
reapproval or review at least annually. Allergan Japan K.K. (a subsidiary of AbbVie) 
is to be notified immediately if the responsible IRB has been disqualified or if 
procedures leading to disqualification have begun. Copies of all IRB correspondence 
with the investigator should be provided to Allergan Japan K.K (a subsidiary of 
AbbVie).
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 signatures.
10.2
Financial Disclosure
Investigators and subinvestigators will provide Sponsor with sufficient, accurate financial 
information as requested to allow 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 to the protocol without 
approval by Sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC 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).
10.4
Data Protection
Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to Sponsor will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred.


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The participant must be informed that his/her personal study-related data will be used by 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 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 
Sponsor 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.
10.5.1
Participant Privacy
Written authorization 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, in accordance with the applicable privacy requirements (eg, HIPAA).
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous participant data from the study.
10.6
Documentation
10.6.1
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 laboratory 
tests, and ECGs. The investigator's copy of the eCRFs 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


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
The date that the participant entered the study, participant number, and participant 
medication kit number

The study title and/or the protocol number of the study and the name of Sponsor

A statement that informed consent was obtained (including the date). A statement that 
written authorization or other country and local participant privacy required 
documentation for this study has been obtained (including the date).

Dates of all participant visits

Participant’s medical history

Information regarding participant’s diagnosis of migraine headache

All concurrent medications (list all prescription and nonprescription 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
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).
10.6.2
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 Sponsor in a timely manner at the completion of the study, or as otherwise specified by 
Sponsor, and will be maintained in a central data repository.


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10.6.3
Study Summary
An investigator's summary will be provided to Sponsor within a short time after the completion 
of the study, or as designated by Sponsor. A summary is also to be provided to the responsible 
IRB/IEC.
10.6.4
Retention of Documentation
Allergan Japan K.K. (a subsidiary of AbbVie) requires that it be notified in writing if the head of 
the study site 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.
Study Site
The study site should retain the essential documents to be kept at the study site, such as source 
documents, contracts, informed consent form, protocol, records on control of the study 
intervention, or other study-related documents until either item 1 or 2 listed below, whichever is 
later. However, when the sponsor requires that these documents are to be retained for a longer 
period, the study site should discuss with Allergan Japan K.K. (a subsidiary of AbbVie) the 
period and method of preservation. The record retainer designated for each record should be 
responsible for the preservation.
1. The date of approval for manufacturing and marketing applications of the relevant 
study interventions (in case of discontinuing its development, until at least 3 years 
after the date of development discontinuation)
2. At least 3 years after the date of termination or completion of the clinical study
The study site and the record retainer should take measures in such a way that these records are 
not lost or abandoned during the designated period of preservation and that they are presented 
upon request.
Institutional Review Board
The IRB should retain all relevant records such as SOPs, membership lists (including 
qualifications of the members), submitted documents, minutes of meetings, and correspondence 
until either item 1 or 2 listed below, whichever is later. However, when it is necessary to retain 
longer by Allergan Japan K.K. (a subsidiary of AbbVie), the organizer should discuss with 
Allergan Japan K.K. (a subsidiary of AbbVie) the period and method of retaining, and make 
them available upon request from the regulatory authorities.


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1. The date of approval for manufacturing and marketing applications of the relevant 
study interventions (in case of discontinuing its development, until at least 3 years 
after the date of development discontinuation)
2. At least 3 years after the date of termination or completion of the clinical study
When the study site or the sponsor requests the SOPs and membership lists, the IRB should 
comply with the request.
Sponsor (Allergan Japan K.K. [a subsidiary of AbbVie])
The sponsor should retain the relevant essential documents until the day specified in item 1 or 
2 listed below, whichever is later.
3. At least 5 years after the date of approval for manufacturing and marketing 
applications of the relevant study intervention (or, in case of a study intervention for 
which development is prematurely terminated, 3 years after the date on which the 
termination of development was decided). When the sponsor is required to conduct 
reexamination for an approved drug, the sponsor must store all GCP study documents 
until 5 years after approval or reexamination finish, whichever is later.
4. At least 3 years after the date of the premature termination or completion of the 
clinical study
When the essential documents to be retained by the study site or by the IRB no longer need to be 
kept, the sponsor should notify the study site and IRB of this fact.
10.7
Labeling, Packaging, and Return or Disposal of Study Intervention
10.7.1
Labeling/Packaging
Atogepant will be supplied in bottles and will be labeled with the protocol number, storage 
information, warning language, and instructions to take the tablets as directed. The bottle will 
also include the kit number. Immediately before dispensing the bottle, the investigator or 
designee will write the participant number and date on the bottle.
10.7.2
Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units 
received from Sponsor, dispensed or administered to the participants, the number of units 
returned to the investigator by the participant, and the number of units returned to Sponsor 


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during and at the completion of the study. A detailed inventory must be completed for atogepant. 
Atogepant must be dispensed or administered only by an appropriately qualified person to 
participants in the study. Atogepant is to be used in accordance with the protocol for participants 
who are under the direct supervision of an investigator.
10.7.3
Return or Disposal of Study Intervention and/or Supplies
All atogepant and/or supplies will be returned to Sponsor or Sponsor designee for destruction.
10.8
Monitoring by the Sponsor
A representative of 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 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.
10.9
Handling of Biological Specimens
Urine pregnancy test kits will be provided by the central laboratory; all urine pregnancy testing 
will be administered on site according to instructions in the central laboratory manual.
Samples of blood and urine for evaluation of hematology, blood chemistry, urinalysis, urine drug 
screen, INR, and serology will be analyzed at a central clinical laboratory with certification from 
a recognized accreditation agency (eg, College of American Pathology or Clinical Laboratory 
Improvement Amendments certification).
All samples will be returned to Sponsor or Sponsor’s designee for destruction. 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.
10.10 Publications
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, Allergan Japan K.K. (a subsidiary of AbbVie), or the governing health 


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authorities (ie, PMDA) if they inspect the study records. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information.
10.11 Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the clinical study 
report.


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11 References
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Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in 
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Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United 
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International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
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.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, AMPP Advisory Group. 
Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 
2007;68:343-349.
Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene- related
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1997;17:15-22.
Schürks M, Diener HC, Goadsby P. Update on the Prophylaxis of Migraine. Current Treatment 
Options in Neurology. Springer US [New York]; 2008 Jan;10(1):20-29.
Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, and Ashman E. Evidence-based 
guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology 
2012;78:1337-1345.


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Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010;11:289–299.
Takeshima T, Ishizaki K, Fukuhara Y, Ijiri T, Kusumi M, Wakutani Y, et al. Population-based 
door-to-door survey of migraine in Japan: the Daisen study. Headache. 2004;44(1):8-19.
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
Examination Procedures, Tests, Equipment, and Techniques: 
International Classification of Headache Disorders, 3rd Edition


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
Migraine
o
Migraine without aura
o
Migraine with aura

Migraine with typical aura

Typical aura with headache

Typical aura without
headache

Migraine with brainstem aura

Hemiplegic migraine

Familial hemiplegic 
migraine (FHM)
o
Familial hemiplegic 
migraine type 1 (FHM1)
o
Familial hemiplegic 
migraine type 2 (FHM2)
o
Familial hemiplegic 
migraine type 3 (FHM3)
o
Familial hemiplegic 
migraine, other loci

Sporadic hemiplegic 
migraine (SHM)

Retinal migraine
o
Chronic migraine
o
Complications of migraine

Status migrainosus

Persistent aura without
infarction

Migrainous infarction

Migraine aura-triggered seizure
o
Probable migraine

Probable migraine without aura

Probable migraine with aura
o
Episodic syndromes that may be 
associated with migraine

Recurrent gastrointestinal
disturbance

Cyclical vomiting syndrome

Abdominal migraine

Benign paroxysmal vertigo

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 


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physical activity and association with nausea and/or 
photophobia and phonophobia.
Diagnostic criteria:
•
At least ﬁve attacks1 fulﬁlling criteria B–D
•
Headache attacks lasting 4–72 hours (when 
untreated or unsuccessfully treated)2,3
•
Headache has at least two of the following 
four characteristics:
•
unilateral location
•
pulsating quality
•
moderate or severe pain intensity
•
aggravation by or causing avoidance of 
routine physical activity (e.g. walking 
or climbing stairs)
•
During headache at least one of the following:
•
nausea and/or vomiting
•
photophobia and phonophobia
•
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 associated
medication 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 to pain activation. This contrasts
with
the
pathognomonic
spreading oligaemia of
1.2 Migraine with aura. While the bulk of the 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 gained increasing 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 
acute treatment of migraine attacks. Because of their 
high receptor-speciﬁcity, their mechanisms ofaction pro-
vide new insight into migraine mechanisms. It is now 
clear that 1.1 Migraine without aura is a neurobiological 


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disorder, while clinical as well as basic neuroscience
studies 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:

At least two attacks fulﬁlling criteria B and C

One or more of the following fully reversible 
aura symptoms:
o
visual
o
sensory
o
speech and/or language
o
motor
o
brainstem
o
retinal

At least three of the following six
characteristics:
o
at least one aura symptom spreads 
gradually over 5 minutes
o
two or more aura symptoms occur in
succession
o
each individual aura symptom lasts 
5–60 minutes1
o
at least one aura symptom is
unilateral2
o
at least one aura symptom is
positive3
o
the aura is accompanied, or followed 
within 60 minutes, by headache

Not better accounted for by another ICHD-3 
diagnosis.
Notes:

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.

Aphasia is always regarded as a unilateral 
symptom; dysarthria may or may notbe.

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 phasehas 
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 affectinga 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 
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


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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:
1.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
2.
Aura with both of the following:
a.
fully reversible visual, sensory 
and/or speech/ language symptoms
b.
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:
1.
Attacks fulﬁlling criteria for 1.2.1 Migraine 
with typical aura and criterion B below
2.
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 with- out
headache.
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 (e.g. 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 (e.g. hemianopia) or when aura is 


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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:
• at least two of the following fully reversible 
brainstem symptoms:
• dysarthria1
• vertigo2
• tinnitus
• hypacusis3
• diplopia4
• ataxia not attributable to sensory
deﬁcit
• decreased level of consciousness
(GCS ≤13)5
• 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:
1. Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
2.
Aura consisting of both of the following:

fully reversible motor weakness2

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 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.


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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.
1.2.3.1
Familial
hemiplegic
migraine
may
be
mistaken 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
apparentlysporadic 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 (e.g. scintillations, 
scotomata or blindness) conﬁrmed during an 
attack by either or both of the following:
•
clinical visual ﬁeld examination
•
the patient’s drawing of a monocular 
ﬁeld defect (made after clear
instruction)
2.
at least two of the following:
•
spreading gradually over ≥ 5 minutes
•
symptoms last 5–60 minutes
•
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 


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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 ofmigraine
headache.
Diagnostic criteria:

Headache (migraine-like or tension-type-like1) on 
15 days/month for >3 months, and fulﬁlling
criteria B and C

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

On 8 days/month for >3 months, fulﬁlling any of 
the following2:

criteria C and D for 1.1 Migraine without
aura

criteria B and C for 1.2 Migraine with aura

believed by the patient to be migraine at 
onset and relieved by a triptan or ergot
derivative

Not better accounted for by another ICHD-3 
diagnosis.3–5
Notes:
A.
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).
B.
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.
C.
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.
D.
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.
E.
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 relevantdiagnoses, 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
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.


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Notes:

Remissions of up to 12 hours due to medication 
or sleep are accepted.

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 fulﬁllingcriteria 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 
brainlesion in the appropriate territory demonstrated 
by neuroimaging, with onset during the course of a 
typical migraine with aura attack.
Diagnostic criteria:
1
A migraine attack fulﬁlling criteria B and C
2
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
3
Neuroimaging demonstrates ischaemic infarction 
in a relevant area
4
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
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 


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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 (e.g. 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:
1.
Attacks fulﬁlling all but one of criteria A–C for
1.2 Migraine with aura or any of its subtypes
2.
Not fulﬁlling ICHD-3 criteria for any other head-
ache disorder
3.
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.
Diagnostic criteria:
•
At least ﬁve attacks with distinct episodes of 
abdominal pain and/or discomfort and/or 
nausea and/or vomiting
•
Normal gastrointestinal examination and 
evaluation
•
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.


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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.
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:

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.


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
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:
1. Recurrent attacks1 in a young child, fulﬁlling 
criteria B and C
2. Tilt of the head to either side, with or without 
slight rotation, remitting spontaneously after 
minutes to days
3. At least one of the following ﬁve associated 
symptoms or signs:
•
pallor
•
irritability
•
malaise
•
vomiting
•
ataxia2
4. Normal neurological examination between attacks
5. 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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1.2.3 Hemiplegic migraine
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1.2.4 Retinal migraine
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1.3 Chronic migraine
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1.4.1 Status migrainosus
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1.4.2 Persistent aura without infarction
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1.4.3 Migrainous infarction
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Bousser 
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Clinical and Scientiﬁc Committee of the Faculty of 
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Olesen J, Friberg L, Olsen TS, et al. Ischaemia-induced 
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Rothrock JF, Walicke P, Swenson MR, et al. 
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Schulz UG, Blamire AM, Davies P, et al. Normal 
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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 
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characteristics of acute migrainous infarction. 
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1.4.4 Migraine aura-triggered seizure
Belcastro V Striano P, Kasteleijn-Nolst Trenite´ DGet al. 
Migralepsy, 
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Davies PT and Panayiotopoulos CP. Migraine triggered 
seizures and epilepsy triggered
headache
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Friedenberg S and Dodick DW. Migraine-associated 
seizure: a case of reversible MRI abnormalities and 
persistent nondominant hemisphere
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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. 
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Merlino G, Valente MR, D’Anna S, et al. Seizures with
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Parisi 
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Rogawski MA. Common pathophysiologic mechanisms 
in migraine and epilepsy. Arch Neurol 2008; 65: 
709–714.
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call for revision of the deﬁnition. Epilepsia 2009; 50: 
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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 
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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-
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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-
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International
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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–
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Dignan F, Abu-Arafeh I and Russell G. The prognosis 
of childhood abdominal migraine. Arch Dis Child 
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Drossman DA and Dumitrascu DL. Rome III: new 
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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 
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Li BU. Cyclic vomiting syndrome: age-old syn- drome 
and new insights. Semin Pediatr Neurol 2001; 8:
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Li BUK, Lefevre F, Chelimsky GG, et al. North 
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Thiessen PN. Recurrent abdominal pain. Pediatr Rev 
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Welch KM. Scientiﬁc basis of migraine: speculation on 
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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 
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Fenichel GM. Migraine as a cause of benign paroxysmal 
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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 
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12.2
Prohibited Medications
12.2.1
Examples of Prohibited Medications
The following medications are prohibited 30 days prior to the first study visit (unless otherwise 
indicated) and throughout the study: 

Strong OATP1B1 inhibitors eg, gemfibrozila, cyclosporine

CBD oil
Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Anti-depressants/ 
Anti-anxiety
Barbiturates 
Amobarbital 
Aprobarbitala
Butalbitala
Butabarbitala
Mephobarbitala
Pentobarbital 
Phenobarbital 
Secobarbital 
Nefazodonea
Anti-seizure
Carbamazepine
Oxcarbazepinea
Phenytoin 
Primidone 
Diabetes 
Pioglitazone 
Troglitazonea
Antiemetic
Aprepitant
Anti-hypertension
Diltiazem 
Verapamil 
Glucocorticoid 
(Systemic)
Betamethasone 
Dexamethasone 
Hydrocortisone 
Methylprednisolone 
Prednisolone 
Prednisonea
Triamcinolone 
Antibiotics
Rifabutin 
Rifampicin/Rifampina
Erythromycin 
Clarithromycin 
Telithromycina
Ciprofloxacin
Anti-fungal
Fluconazole 
Itraconazole 
Ketoconazole 
Anti-HIV
Efavirenz 
Nevirapine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Immune Suppressant
Cyclosporine - Oral/IV only 
Antacid/heartburn
Cimetidine


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Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Other
St John’s wort 
Enzalutamide
Modafinil
Armodafinila
Buprenorphine 
Quinine
Drugs with narrow therapeutic margins 
with potential for CYP drug interactions
Warfarin 
Digoxin 
Cisapridea
Pimozide 
Nonpharmacologic headache interventions
Acupuncture
Noninvasive 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 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)
a
Not approved in Japan.
The following treatments are prohibited 6 months prior to the first study visit and 
throughout the study period:

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport, Botox, Xeomin, 
Myobloc, Jeuveua) into areas of the head, face, or neck

Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig, Emgality, 
Ajovy)


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12.2.2
List of Migraine Preventative Medications With Proven Efficacy and 
Criteria for Determining Inadequate Response to a Prior Migraine 
Preventive Medication
Medications with demonstrated efficacy for the prevention of migraine are prohibited for all 
participants for 30 days prior to the first study visit and throughout the study, excepting 
1 medication with demonstrated efficacy for the prevention of migraine taken at a stable dose 
and well-tolerated during Study 3101-303-002. This medication which may be continued if the 
participant is willing and able to do so.
Below is a list of migraine preventative medications considered effective or probably effective 
sorted by mechanism of action during Study 3101-303-002.
Pharmacologic Category
Drug Name
Antiepileptic
Valproic acid, sodium valproate, divalproex sodiuma
Topiramate
Tricyclic antidepressant
Amitriptyline
Nortriptyline
Beta-blockers
Metoprolol
Bisoprolol
Atenolol
Nadolol
Propranolol
Timolola
Calcium channel blocker
Flunarizinea, lomerizine, verapamil
Angiotensin receptor blocker (ARB)
Candesartan
Angiotensin-converting enzyme (ACE) inhibitor
Lisinopril
Serotonin-norepinephrine reuptake inhibitor (SNRI)
Desvenlafaxinea
Venlafaxine
Miscellaneous
Pizotifena
Source: Evers 2009, Hoffmann 2014, Schürks 2008, Silberstein 2012, Steiner 2007.
a
Not approved in Japan.
Failure of a migraine-preventive medication can be assessed on the basis of efficacy or 
tolerability and is based on investigator judgment. The criteria below should be used to 
determine eligibility related to the number of prior failed migraine-preventive medications with 
unique mechanisms of action.


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For efficacy:

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 judgment and participant interview.

Medications must have been started within the past 7 years.
For tolerability:

Failure is defined as discontinuation of a drug treatment due to adverse effects.

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.
12.3
New York Heart Association Functional Classification
The table below describes the New York Heart Association Functional Classification system 
(adapted from Criteria Committee NY Heart Association 1994). It places patients in 1 of 
4 categories based on how much they are limited during physical activity.
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If 
any physical activity is undertaken, discomfort increases.


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12.4
Glossary of Abbreviations
Term/Abbreviation
Definition
ASC-12
12-item Allodynia Symptom Checklist
AE
adverse event
AESI
adverse event of special interest
AIM-D
Activity Impairment in Migraine - Diary
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CBD
Cannabidiol,
CGRP
calcitonin gene-related peptide
CGRP-RA
calcitonin gene-related peptide-receptor antagonist
CM
chronic migraine
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A4
cytochrome P450 3A4
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
EOS
end of study
EQ-5D-5L
European Quality of Life - 5 Dimensional
ET
early termination
eTablet
electronic tablet
FDA
Food and Drug Administration
GBD2010
Global Burden of Disease Survey 2010
GCP
Good Clinical Practice
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HIT-6
Headache Impact Test
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
IEC
independent ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
INR
international normalized ratio
IRB
institutional review board


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Term/Abbreviation
Definition
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWRS
interactive web response system
LSMD
least squares mean
MIDAS
Migraine Disability Assessment
mITT
modified intent-to-treat
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, Version 2.1
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic anion transporting polypeptide 1B1
OC
observed cases
PCR
polymerase chain reaction
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression – Severity
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PRO
patient-reported outcome
QTcF
QT interval corrected for heart rate using Fridericia formula (QTcF = 
QT/(RR)⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SNRI
serotonin norepinephrine reuptake inhibitor
SOP
standard operating procedure
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
V
Visit
VAS
Visual Analogue Scale
Wk
Week
WOCBP
women of childbearing potential
WPAI:MIGRAINE
Work Productivity and Activity Impairment Questionnaire: Migraine V2.0


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12.5
Protocol Amendment 1 Summary
Title: A PHASE 3, MULTICENTER, OPEN-LABEL 52-WEEK EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF ORAL ATOGEPANT 
FOR THE PREVENTION OF MIGRAINE IN JAPANESE PARTICIPANTS WITH CHRONIC 
OR EPISODIC MIGRAINE
Protocol 3101-306-002
Date of Amendment 1: 25th November 2019
Amendment Summary
This amendment includes changes made to Protocol 3101-306-002, dated 15 October 2019. This 
protocol was amended to clarify Japan-specific approvals and to correct minor editorial errors.
The table below provides details on the content changes that were made in the protocol, and a 
brief rationale with these changes. Minor editorial and document formatting revisions have not 
been summarized.
Section 
Revision
Rationale
4.5.3 Definition of (Non-) 
Childbearing Potential and/or 
Acceptable Contraceptive Methods:
Footnotes amended to clarify 
contraceptive methods not 
approved in Japan
Clarification
Section 12.2.1 Examples of 
Prohibited Medications
Indication of specified medications 
that are not approved in Japan
Clarification
12.2.2 List of Migraine 
Preventative Medications With 
Proven Efficacy (Text above Table)
Below is a list of migraine 
preventative medications 
considered effective or probably 
effective
sorted by mechanism of action 
during Study 3101-303-002. Of 
note, topiramate and valproic acid 
derivatives are considered
separate categories.
Clarification
12.2.2 List of Migraine 
Preventative Medications With 
Proven Efficacy (Table)
Indication added of specified 
medications that are not approved 
in Japan 
Clarification




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Section 
Revision
Rationale
3.1 Structure
Updated.
To reflect addition of De Novo EM 
Participants, which created 2 
cohorts (De Novo EM Participants 
and 3101-303-002 Completers), a 
4-week screening/baseline period 
for De Novo EM Participants only, 
and a larger sample size (changed 
from 140 participants to 170 
participants [30 De Novo EM 
Participants enrolled at selected 
sites only]). All references to lead-
in Study 3101-305-002 were 
removed from the protocol.
3.2 Data Safety Monitoring Board
Updated.
To reflect the involvement of a 
DSMB.
4.1 Number of Participants
Updated.
To reflect addition of De Novo EM 
Participants.
4.2 Study Population 
Characteristics
Updated.
To reflect the 2 cohorts.
4.3.1 Inclusion Criteria
Updated.
To reflect inclusion criteria 
applicable for all participants.
4.3.2 3101-303-002 Completers 
(Amendment 2 section)
New section was added.
To reflect inclusion criteria for 
3101-303-002 Completers only.
4.3.3 De Novo EM Participants 
(Amendment 2 section)
New section was added.
To reflect inclusion criteria for De 
Novo EM Participants only.
4.4 Exclusion Criteria
Updated.
To reflect exclusion criteria 
applicable for all participants 
(unless noted otherwise).
4.4.1 De Novo EM Participants 
(Amendment 2 section)
New section was added.
To reflect exclusion criteria 
applicable for De Novo EM 
Participants.
4.6 Screen Failures
Updated.
To allow rescreening of screen 
failures for De Novo EM 
Participants.
5.5 Method for Assignment to 
Treatment Groups
For De Novo EM Participants, 
participant identification 
numbers will be newly assigned at 
study entry.
To account for De Novo EM 
Participants.
5.6 Treatment Regimen and Dosing
Updated.
To incorporate Visit -1 for De 
Novo EM Participants only.
6.1.3 Clinical Laboratory 
Determinations
Updated.
To incorporate Visit -1 for De 
Novo EM Participants only and to 
clarify Visit 1 serology and urine 
drug screen are for 3101-303-002 
Completers only.


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Section 
Revision
Rationale
Table 6-1 Clinical Laboratory 
Parameters
Updated.
To incorporate Visit -1 for De 
Novo EM Participants only and to 
clarify Visit 1 serology and urine 
drug screen are for 3101-303-002 
Completers only.
6.1.4 Vital Signs
Vital sign measurements, including 
sitting and standing BP, sitting and 
standing pulse rate, respiratory rate, 
temperature and weight, will be 
performed at every visit. Height 
will be measured only at Visit -1. 
For clarification.
6.1.7 Columbia-Suicide Severity 
Rating Scale (C-SSRS)
At Visit -1 (Screening/Baseline, 
De Novo EM Participants only), 
the C-SSRS will be completed for 
the participant’s lifetime history 
and for the 6 months prior to 
screening.
To account for De Novo EM 
Participants.
6.3.1 Activity Impairment in 
Migraine – Diary (AIM-D)
In addition to the 2 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).AIM D scores 
range from 0 to 5 with higher scores 
indicating greater impact in 
functioning and activity 
impairment.
For clarification.
7.1 Analysis Populations
All efficacy analyses will be 
performed using the mITT 
population, consisting of 
participants who received at least 1 
dose of study intervention 
(atogepant) in this study, an 
evaluable baseline (for the De 
Novo EM Participants), and had at 
least 1 evaluable post-baseline 4-
week period of eDiary data in this 
extension study.
To account for De Novo EM 
Participants.


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Section 
Revision
Rationale
7.2 Collection and Derivation of 
Efficacy Assessments
The efficacy endpoints of change 
from baseline in monthly headache-
free days, and headache day pain 
intensity at each monthly period 
were removed from the protocol.
The efficacy endpoints of 
participants reporting “satisfied” or 
“extremely satisfied” with study 
medication for migraine prevention 
and change from baseline in 
monthly AIM-D total score at each 
monthly period were added.
Other edits include:
1
Change from baseline in the 
MSQ v2.1 Role Function 
Preventive domain score at 
Weeks 12, 24, 36, 48, and 52, 
and 56
2
Change from baseline in the 
MSQ v2.1 Role Function 
Restrictive domain score at 
Weeks 12, 24, 36, 48, and 52, 
and 56
3
Change from baseline in the 
MSQ v2.1 Emotional 
Function domain score at 
Weeks 12, 24, 36, 48, and 52, 
and 56
4
Change from baseline in 
AIM D monthly functioning 
Performance of Daily 
Activities domain score of 
the AIM-D at each monthly 
period
5
Change from baseline in
and monthly Physical 
Impairment domain score 
of the AIM-D and activity 
impairment score at each 
monthly period
No longer completing these 
measures.
For clarification.
7.3.1 Safety Analyses
Definition of baseline value was 
edited.
To account for De Novo EM 
Participants and for clarification.
7.3.2 Efficacy Analyses
Definition of baseline value was 
edited.
To account for De Novo EM 
Participants and for clarification.
7.4 Subgroup Analyses
For selected safety and efficacy 
endpoints, analyses will be 
performed separately, for 3101-
303-002 Completers and De Novo 
EM Participants. Details will be 
provided in the SAP. No subgroup 
analysis is planned.
For clarification.


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Section 
Revision
Rationale
7.5 Sample Size Calculation
Updated.
To reflect addition of De Novo EM 
Participants
8.1.2 Informed Consent and 
Participation Privacy
Updated.
To incorporate Visit -1 and 
assignment of participant 
identification numbers for De 
Novo EM Participants.
8.3 Procedures for Final Study 
Entry
Updated.
To incorporate Visit -1 and 
clarified Visit 1 study entry 
procedures applicable to 
3101-303-002 Completers only.
8.4 Visits and Associated 
Procedures
Updated.
To clarify the visits for the 
2 cohorts.
8.4.1 Visit -1 (Screening/Baseline) 
Day -35 to Day -28 (Amendment 2 
section)
New section was added.
To detail Visit -1 procedures.
8.4.2.1 Visit 1 (Day 1) (Amendment 
2 section)
Updated.
To clarify which Visit 1 procedures 
are for 3101-303-002 Completers 
only and that review of eligibility 
criteria includes the review of 
eDiary data and compliance during 
Screening/Baseline for De Novo 
EM Participants.
8.4.4 COVID-19 Pandemic-related 
Remote Visits (Amendment 2 
section)
New section was added.
To outline remote visit procedures 
in the event of a COVID-19 
infection.
8.9 Withdrawal Criteria
Updated.
To reflect withdrawal criteria 
pertaining to 3101 303-002 
Completers only with the addition 
of positive result on anti-hepatitis 
A IgM antibody, hepatitis B 
surface antigen, anti-hepatitis C 
antibody, or anti-hepatitis E IgM 
antibody testing.
11 References
Criteria Committee of the New 
York Heart Association reference 
was added.
As needed for De Novo EM 
Participants exclusion criteria.
Section 12.2.2 List of Migraine 
Preventative Medications With 
Proven Efficacy and Criteria for 
Determining Inadequate 
Response to a Prior Migraine 
Preventive Medication 
(Amendment 2 section)
Updated.
To include criteria for determining 
inadequate response to a prior 
migraine preventive medication 
and to add ciprofloxacin.
Section 12.3 New York Heart 
Association Functional 
Classification (Amendment 2 
section)
New attachment was added to 
describe the New York Heart 
Association Functional 
Classification system.
As needed for De Novo EM 
Participants exclusion criteria.


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12.7
Protocol Amendment 3 Summary
Title: A PHASE 3, MULTICENTER, OPEN-LABEL 52-WEEK EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF ORAL ATOGEPANT 
FOR THE PREVENTION OF MIGRAINE IN JAPANESE PARTICIPANTS WITH CHRONIC 
OR EPISODIC MIGRAINE
Protocol 3101-306-002
Date of Amendment 3: 07 July 2022
Amendment Summary
This amendment includes changes made to Protocol 3101-306-002 Amendment 2, dated 
22 December 2021. This protocol was amended to correct Visit 1 to Visit -1 for select inclusion 
and exclusion criteria; clarify the visits associated with eDiary training, permissible and 
prohibited medications language, and discussion of the method of contraception with WOCBP; 
update consent of participants aged 18 or 19 and the Sponsor name; incorporate formatting edits 
from protocol administrative change 1, dated 17 February 2022; and correct minor editorial 
errors.
The table below provides details on the content changes that were made in the protocol, and a 
brief rationale with these changes. Minor editorial and document formatting revisions have not 
been summarized.
Section 
Revision
Rationale
Global change
“(a subsidiary of AbbVie” was 
added after “Allergan” or 
“Allergan” was changed to 
“Sponsor” as applicable.
Allergan was acquired by AbbVie
Protocol Summary and Section 
Section 4.3.3 De Novo EM 
Participants
History of 4 to 14 migraine days per 
month (see Section 6.2.1 for 
definition of migraine day) on 
average in the 3 months prior to 
Visit -1 in the investigator’s 
judgment.
Corrected Visit 1 to Visit -1
Protocol Summary and Section
4.4.2 De Novo EM Participants
Has ≥ 15 headache days per month 
(see Section 6.2.2 for definition of 
headache day) on average across 
the 3 months prior to Visit -1 in the 
investigator’s judgment.
Corrected Visit 1 to Visit -1


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Section 
Revision
Rationale
Protocol Summary and 
Section 4.4.2 De Novo EM 
Participants
Usage of opioids or barbiturates 
> 2 days/month, triptans or ergots 
≥10 days/month, or simple 
analgesics (eg, aspirin, NSAIDs, 
acetaminophen) ≥ 15 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 through the duration of the 
study) (see Section 12.2.1).
Corrected Visit 1 to Visit -1
Section 4.4.2 De Novo EM 
Participants
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).
Corrected as this is an open-label 
study with no placebo.
Table 1. Schedule of Visits and 
Procedures
Participant eDiary data collection
was extended to include Visit -1.
Clarification
Global change (Table 1. Schedule 
of Visits and Procedures footnote c, 
Section 4.3.1 All Participants, 
Section 8.1.2 Informed Consent and 
Participant Privacy, Section 8.4.1 
Visit -1 [Screening/Baseline] 
Day -35 to Day -28), and Section 
10.5.1 Participant Privacy
Consent should have been obtained 
from legally authorized 
representatives of 3101-303-002 
Completers aged 18 or 19 only at 
Visit 1. No longer required for De 
Novo EM Participants aged 18 or 
19 at Visit -1.
Updated or Deleted (Section 8.4.1 
only) as per the change of Japan's 
legal age of adulthood age to 18, 
starting from 1 Apr 2022.
Table 1. Schedule of Visits and 
Procedures footnote h
For WOCBP only, a urine 
pregnancy test will be performed at 
all visits. At the first study visitFor 
Visit 1, discuss the method of 
contraception with WOCBP and 
document this method. Counsel 
participants on the importance of 
maintaining their agreed upon 
method of contraception throughout 
the study.
Clarification
Table 1. Schedule of Visits and 
Procedures footnote j
Participants should begin using the 
eDiary as soon as it is dispensed 
and for the duration of the 
screening/baseline (for De Novo 
EM Participants) and treatment 
period (for all participants). 
Training for the eDiary will be 
provided for qualified 
participants during the first study 
visit (Visit -1 for De Novo EM 
Participants and Visit 1 for 
3101-303-002 Completers).
Clarification


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Section 
Revision
Rationale
Section 4.4.2 De Novo EM 
Participants
QTcF > 450 msec for males and 
QTcF > 470 msec for females at 
Visit -1 based on the central 
reviewer’s final ECG report.
Corrected Visit 1 to Visit -1
Global change within Section 4.5 
Permissible and Prohibited 
Medications/Treatments and 
Section 12.2 Prohibited 
Medications
Updated “Visit 1” to “the first study 
visit” for prohibited medications.
Clarification
Section 6.5 Summary of Methods of 
Data Collection
All participants will use an eDiary
daily to record the daily total 
duration of headache, headache 
characteristics, associated 
symptoms, the worst pain severity, 
acute medication use, AIM-D, 
Activity Level, and Activity 
Limitation during the open-label 
treatment period until Visit 14. 
Participants should begin using 
the eDiary as soon as it is 
dispensed and for the duration of 
the screening/baseline (for De 
Novo EM Participants) and 
treatment period (for all 
participants). Training for the 
eDiary will be provided for 
qualified participants during 
Visit 1the first study visit (Visit -1 
for De Novo EM Participants and 
Visit 1 for 3101-303-002 
Completers).
Clarification
Section 8.4.2.1 Visit 1 (Day 1)
Perform urine pregnancy test for 
women of childbearing 
potentialWOCBP. Discuss the 
method of contraception with 
WOCBP and document this 
method. Counsel participants on 
the importance of maintaining 
their agreed upon method of 
contraception throughout the 
study.
Clarification
Section 8.4.2.1 Visit 1 (Day 1)
If the participant continues to meet 
study entry criteria, including 
acceptable results from Visit 1 
ECGs (3101-303-002 Completers 
only), pregnancy tests and vital sign 
measurements (see Section 6.1) the 
following procedures will be carried 
out at Visit 1.
Clarification


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Section 
Revision
Rationale
Section 8.5 Instructions for the 
Participants
Participants will be provided with 
instructions on daily completion of 
the eDiary at their first study visit. 
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 
medications should be reviewed 
with the participants. Participants 
will be instructed to bring their 
eDiary to each clinic visit and 
return their atogepant bottle(s), both 
used and unused.
Clarification
Section 8.9 Withdrawal Criteria
Study 3101-303-002 Completers 
with the following at Visit 1 must 
be withdrawn from the study:
Clarification
Section 8.9 Withdrawal Criteria
Participants must be withdrawn 
from the study if they meet any 
ofwith the following at any study 
visit:
Clarification
Section 9.1.1 Adverse Events
An AE is any untoward medical 
occurrence in a clinical study 
participant associated with the use 
of atogepant, whether or not 
considered related. 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 atogepant. In 
addition, during the screening 
period and Visit 1, AEs will be 
assessed regardless of the 
administration of a pharmaceutical 
product.
Clarification
Section 12.2.1 Examples of 
Prohibited Medications
The superscript “a” (for footnote a) 
was added to Prednisone and 
Rifampicin/Rifampin.
To indicate these medications are
not approved in Japan.

SAP_001.pdf: 
CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 1 of 65 
Title Page 
Protocol Title: A PHASE 3, MULTICENTER, OPEN-LABEL 52-WEEK EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF 
ORAL ATOGEPANT FOR THE PREVENTION OF MIGRAINE IN JAPANESE 
PARTICIPANTS WITH CHRONIC OR EPISODIC MIGRAINE 
Protocol Number:  3101-306-002 
Compound Number: AGN-241689 
Sponsor Name: Allergan Pharmaceuticals International Limited (a subsidiary of AbbVie) 
Legal Registered Address:  Marlow International 
The Parkway, Marlow SL7 1YL  
United Kingdom 
 
Japan Agent: 
Allergan Japan K.K. (AJKK) 
Yebisu Garden Place Tower 35F 
4-20-3 Ebisu 
Shibuya-ku, Tokyo, Japan 150-6035 
 
SAP Final: 10 Sep 2020 
SAP Amendment 1: 02 Feb 2023 
SAP Amendment 2: 26 Jun 2024 
 
NCT04437433


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 2 of 65 
Table of Contents 
Title Page .................................................................................................................................... 1 
Table of Contents ........................................................................................................................ 2 
List of Tables .............................................................................................................................. 4 
List of Figures ............................................................................................................................. 4 
SAP Version History ................................................................................................................... 5 
1. 
Introduction .................................................................................................................. 8 
1.1. 
Objectives and Endpoints ............................................................................................. 8 
1.2. 
Study Design .............................................................................................................. 10 
1.2.1. 
Schema ....................................................................................................................... 10 
1.2.2. 
Schedule of Activities ................................................................................................. 12 
2. 
Statistical Hypotheses ................................................................................................. 21 
3. 
Sample Size Determination ......................................................................................... 22 
4. 
Populations for Analysis ............................................................................................. 23 
5. 
Statistical Analyses ..................................................................................................... 24 
5.1. 
General Considerations ............................................................................................... 24 
5.2. 
Participant Dispositions .............................................................................................. 24 
5.3. 
Efficacy Endpoint Analyses and Health Outcome Measures ....................................... 25 
5.3.1. 
Definition of Endpoints .............................................................................................. 25 
5.3.2. 
Main Analytical Approach .......................................................................................... 27 
5.3.3. 
Key Efficacy Measures ............................................................................................... 28 
5.3.4. 
Health Outcome Measures .......................................................................................... 29 
5.3.4.1. 
HIT-6 ............................................................................................................. 29 
5.3.4.2. 
Migraine Disability Assessment (MIDAS) ...................................................... 29 
5.3.4.3. 
Patient Global Impression of Change (PGIC) .................................................. 30 
5.3.4.4. 
Work Productivity and Activity Impairment 
Questionnaire: Migraine V2.0 (WPAI:MIGRAINE) ....................................... 30 
5.3.4.5. 
European Quality of Life - 5 Dimensional (EQ-5D-5L) .................................. 30 
5.3.4.6. 
Patient Global Impression  Severity (PGI-S) ................................................. 30 
5.3.4.7. 
Patient Satisfaction with Study Medication ..................................................... 31 
5.3.4.8. 
Activity Impairment in Migraine  Diary (AIM-D) ......................................... 31 
5.3.4.9. 
Activity Level and Activity Limitation ........................................................... 31 
5.3.4.10. 
Migraine Specific Quality of Life Questionnaire, Version 
2.1 (MSQ v2.1)............................................................................................... 32 
5.4. 
Safety Analyses .......................................................................................................... 32 
5.4.1. 
Extent of Exposure ..................................................................................................... 32 
5.4.2. 
Treatment Compliance ................................................................................................ 32 
5.4.3. 
Adverse Events ........................................................................................................... 33 
5.4.4. 
Additional Safety Assessments ................................................................................... 34 
5.4.4.1. 
Clinical Laboratory Parameters ....................................................................... 34 
5.4.4.2. 
Vital Signs ...................................................................................................... 36 
5.4.4.3. 
Electrocardiogram .......................................................................................... 37 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 3 of 65 
5.4.4.4. 
Columbia-Suicide Severity Rating Scale ......................................................... 37 
5.5. 
Other Analyses ........................................................................................................... 38 
5.5.1. 
Subgroup analyses ...................................................................................................... 38 
5.6. 
Interim Analyses......................................................................................................... 38 
6. 
Supporting Documentation ......................................................................................... 39 
6.1. 
Appendix 1: List of Abbreviations .............................................................................. 39 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses ................................................... 40 
6.3. 
Appendix 3: Supporting Study Information ................................................................ 40 
6.3.1. 
Demographic .............................................................................................................. 40 
6.3.2. 
Baseline and Disease Characteristics........................................................................... 40 
6.3.3. 
Protocol Deviations .................................................................................................... 41 
6.3.4. 
Medical History .......................................................................................................... 41 
6.3.5. 
Prior/Concomitant/Follow-up medications .................................................................. 41 
6.3.6. 
Adverse Events of Special Interest .............................................................................. 42 
6.3.7. 
Potentially Clinically Significant Criteria for Safety Endpoints ................................... 42 
6.3.7.1. 
Laboratory values in Conventional Unit .......................................................... 43 
6.3.7.2. 
Potentially Clinically Significant Criteria for Clinical 
Laboratory Parameters .................................................................................... 45 
6.3.7.3. 
Criteria for Hepatic Laboratory Abnormalities ................................................ 46 
6.3.7.4. 
Potentially Clinically Significant Criteria for Vital Signs ................................ 47 
6.3.7.5. 
Potentially Clinically Significant Criteria for ECG 
parameters ...................................................................................................... 47 
6.4. 
Data handling convention ........................................................................................... 47 
6.4.1. 
Analysis Window ....................................................................................................... 48 
6.4.2. 
Derived Efficacy Data ................................................................................................ 52 
6.4.2.1. 
Derivation of Efficacy Endpoints Based on eDiary Data ................................. 52 
6.4.3. 
Derivation of Health Outcome Endpoints.................................................................... 53 
6.4.4. 
Repeated or Unscheduled Assessments of Safety Parameters ...................................... 58 
6.4.5. 
Missing Date of the Last Dose of Study Treatment ..................................................... 58 
6.4.6. 
Missing Severity Assessment for Adverse Events ....................................................... 59 
6.4.7. 
Missing Causal Relationship to Study treatment for Adverse 
Events......................................................................................................................... 59 
6.4.8. 
Missing Date Imputation............................................................................................. 59 
6.4.9. 
Missing Date Information for Prior or Concomitant Medications ................................ 60 
6.4.9.1. 
Incomplete Start Date ..................................................................................... 60 
6.4.9.2. 
Incomplete Stop Date ..................................................................................... 61 
6.4.10. Character Values of Clinical Laboratory Parameters ................................................... 62 
7. 
Covid-19 Related Analyses ......................................................................................... 63 
7.1. 
Efficacy Evaluation .................................................................................................... 63 
7.2. 
Safety and Other Evaluations ...................................................................................... 63 
8. 
References .................................................................................................................. 65 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 4 of 65 
List of Tables 
Table 1-1 
Schedule of Activities (as per the Original Protocol) ....................................... 12 
Table 1-2 
Schedule of Procedures for Remote Visits ....................................................... 19 
Table 6-1 
List of Selected Parameters Reported in Conventional Unit ............................. 43 
Table 6-2 
Presenting Laboratory Data Using SI and Conventional Units in Narratives .... 44 
Table 6-3 
Potentially Clinically Significant Criteria for Clinical Laboratory Parameters . 45 
Table 6-4 
Criteria for Hepatic Laboratory Abnormalities ................................................ 46 
Table 6-5 
Potentially Clinically Significant Criteria for Vital Signs................................. 47 
Table 6-6 
Potentially Clinically Significant Criteria for ECG parameters ........................ 47 
Table 6-7 
Efficacy Analysis Visit Definitions for eDiary Data (Monthly) ....................... 48 
Table 6-8 
Efficacy Analysis Visit Definitions for MSQ v2.1, PGIC, and MIDAS ........... 49 
Table 6-9 
Efficacy Analysis Visit Definitions for HIT-6, EQ-5D-5L, PGI-S, Patient 
Satisfaction with Study Medication, and WPAI:MIGRAINE........................... 50 
Table 6-10 
Safety Analysis Visit Definitions..................................................................... 51 
Table 6-11 
Item Values for MSQ Item Responses ............................................................. 55 
Table 6-12 
Item Values for HIT-6 Item Response ............................................................. 57 
 
List of Figures 
Figure 1-1 
Study Schema ................................................................................................. 11 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 5 of 65 
SAP Version History 
This Statistical Analysis Plan (SAP) for Study 3101-306-002 is based on the Protocol 
Amendment 3 dated 08Jul2022. 
Summary of Changes from the Final SAP to SAP Amendment 1: 
Date 
Section: Description 
Reason 
03/18/21 
Added EQ-5D-5L text in Sections 5.3.4.5 
and 6.4.3 
Consistent with 3101-301-002 and -302 
HO SAP text 
03/18/21 
Section 5.1: replaced 'extension' to 'lead-in' 
in baseline definition. 
to align with other extension Atogepant 
studies 
03/18/21 
Section 6.3.1: replaced 'White' by 'Asian' 
study is Japanese 
03/18/21 
Section 6.3.2: removed 'migraine severity' 
specified neither in the study protocol, nor 
in prior Atogepant studies. 
03/18/21 
Table 6-1: removed 'Insulin' 
Because it is not collected. 
03/24/21 
Added 'evaluable baseline' to Section 4. 
 
5/20/21 
Updated analysis visit windows 
 
5/20/21 
Added 95% CI for primary and key 
secondary endpoints from 3101-303-002 
study 
Consistent with current Atogepant LTS 
extension studies (except for study 311 due 
to small sample size). 
7/6/2021 
In Section 1.1, added six endpoints, 
Change from baseline in monthly severe 
headache days at each monthly period, 
Change from baseline in monthly 
cumulative headache hours at each 
monthly period, At least a 5-point 
improvement (decrease) from baseline in 
total HIT-6 score at each monthly period, 
Change from baseline in the EQ-5D-5L 
VAS score at each monthly period, Change 
from baseline in MIDAS absenteeism score 
(Questions 1, 3, and 5) at Weeks 12, 24, 
36, 48, and 52, and Change from baseline 
in MIDAS presenteeism score (Questions 2 
and 4) at Weeks 12, 24, 36, 48, and 52 
To align with the protocol. 
7/6/2021 
In Section 5.3.1, updated analysis methods 
Consistent with current Atogepant LTS 
extension studies (except for study 311 due 
to small sample size). 
7/6/2021 
In Section 6.3.4, updated the derivation for 
AIM-D total score, MIDAS absenteeism 
score, and MIDAS presenteeism score. 
New endpoints added. 
12/7/2022 
In Section 1, updated the wording in 
introduction 
To align with the protocol. 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 6 of 65 
Date 
Section: Description 
Reason 
12/7/2022 
In Section 1.1, added three endpoints, 
Change from baseline in monthly AIM-D 
total score at each monthly period, Change 
from baseline in monthly activity level at 
each monthly period and Change from 
baseline in monthly activity limitation at 
each monthly period 
To align with the protocol. 
12/7/2022 
In Section 1.2, updated study design, study 
schema, and schedule of activities 
To reflect addition of De Novo EM 
Participants in Protocol Amendment 3. 
12/7/2022 
In Section 3, updated sample size 
To reflect addition of De Novo EM 
Participants in Protocol Amendment 3. 
12/7/2022 
In Section 4, updated the definition of 
Screened population and mITT population  
To account for De Novo EM 
Participants and for clarification. 
12/7/2022 
In Section 5.1, updated the definition of 
baseline for monthly endpoints and 
efficacy endpoints and updated MedDRA 
version to 25.1 
To account for De Novo EM 
Participants and for clarification. 
12/7/2022 
In Section 5.2, updated enrollment 
category 
To account for De Novo EM 
Participants. 
12/7/2022 
In Section 5.3.1, updated endpoints, same 
to Section 1.1; updated the definition of a 
headache day 
To align with the protocol. 
For clarification. 
12/7/2022 
In Section 5.3.4, added text for activity 
level and activity limitation 
To align with the protocol. 
12/7/2022 
In Section 5.4.3, updated MedDRA version 
to 25.1; added summary for treatment-
related TESAEs 
To be consistent with TFLs. 
12/7/2022 
Added new Section 5.5.1 Subgroup 
Analyses 
To account for De Novo EM 
Participants and for alignment with 
protocol. 
12/7/2022 
In Section 6.2, updated Changes to 
Protocol-Planned Analyses 
To align with protocol 
12/7/2022 
In Section 6.3, updated supporting study 
information 
To account for De Novo EM 
Participants and for clarification. 
12/7/2022 
In Section 6.4.1, updated analysis windows 
To account for De Novo EM 
Participants and for clarification. 
12/7/2022 
In Section 6.4.2, removed "monthly 
headache day pain intensity,"  
To align with protocol. 
12/7/2022 
In Section 6.4.3, added Monthly Total 
Score of the AIM-D 
New endpoints added. 
12/7/2022 
In Section 7, updated Covid-19 related 
analysis 
To align with other Atogepant studies. 
12/7/2022 
Updated Appendix 1 List of Abbreviations 
For clarification. 
 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 7 of 65 
Summary of Changes from the SAP Amendment 1 to SAP Amendment 2: 
Date 
Section: Description 
Reason 
11/7/2023 
In Section 6.4.2.1, added text for diary time 
handling. 
For clarification. 
12/12/2023 In Section 5.4.3, updated MedDRA version 
to 27.0; added treatment-related TESAEs 
in overall summary of AEs; updated the 
description for the incidence of comment 
TEAEs. 
To be consistent with TFLs. 
For clarification. 
12/12/2023 In Section 5.4.4.2, added BMI in vital signs 
for descriptive statistics. 
To be consistent with TFLs. 
12/12/2023 In Section 5.4.4.4, added a listing of all 
AEs occurring in participants who have 
suicidal ideation or suicidal behavior 
To be consistent with TFLs. 
12/26/2023 In Section 1.1, added one endpoint ≥ 30% 
improvement (decrease) in monthly 
migraine days at each monthly period. 
To align with the endpoints in the lead-in 
Study 3101-303-002. 
12/26/2023 In Section 5.4.4.3 and Section 6.3.7.5, 
removed QTc calculated using the Bazett 
correction (QTcB). 
To algin with protocol. 
12/26/2023 In Section 5.5.1, updated efficacy subgroup 
analyses. 
For better interpretation in analysis result.  
12/26/2023 In Section 6.2, added the new endpoint as 
changes to protocol-planned analyses. 
 
12/26/2023 In Section 6.3.1, updated the age group. 
To align with the other Japan atogepant 
study. 
12/26/2023 In Section 6.4.6, updated "intensity" to 
"severity." 
To align with data collection. 
3/28/2024 
In Section 5.4.3, added one table for 
treatment-related TEAEs by SOC, PT, and 
AE onset time interval. 
Per Japan team's request. 
5/10/2024 
In Section 6.3.3, updated protocol 
deviation information. 
To clarify the categories for significant 
deviations. 
5/10/2024 
Updated Appendix 1 List of Abbreviations 
For clarification. 
5/30/2024 
In Section 5.3.4, added clarification 
sentences for AIM-D. 
For clarification. 
5/30/2024 
In Section 6.4.3, removed unused sentence 
for EQ-5D-5L derivation 
For clarification. 
 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 8 of 65 
1. 
Introduction 
This SAP provides a more technical and detailed elaboration of the statistical analyses of the 
clinical Phase 3 data as outlined and specified in the protocol amendment 3 of 
Study 3101-306-002 dated 08Jul2022. Specifications of tables, figures, and data listings are 
contained in a separate document.  
1.1. 
Objectives and Endpoints 
Each study objective is presented with corresponding endpoint below: 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and tolerability of 
treatment with atogepant 60 mg once daily 
when administered over 52 weeks for the 
prevention of migraine in Japanese 
participants with chronic migraine (CM) 
or episodic migraine (EM). 
 
Other 
• To evaluate the efficacy of treatment with 
atogepant 60 mg once daily when 
administered over 52 weeks for the 
prevention of migraine in Japanese 
participants with CM or EM. 
 
Safety Assessments 
Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram (ECG), 
Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
 
 
Endpoints 
• Change from baseline in monthly 
migraine days at each monthly period 
• Change from baseline in monthly 
headache days at each monthly period 
• Change from baseline in monthly acute 
medication use days at each monthly 
period 
• ≥ 25%, ≥ 30%, ≥ 50%, ≥ 75%, and 100% 
improvement (decrease) in monthly 
migraine days at each monthly period 
• Change from baseline in monthly triptan 
use days at each monthly period 
• Change from baseline in monthly 
moderate/severe headache days at each 
monthly period 
• Change from baseline in monthly severe 
headache days at each monthly period 
• Change from baseline in monthly 
cumulative headache hours at each 
monthly period 
• At least a 5-point improvement (decrease) 
from baseline in total HIT-6 score at each 
monthly period 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 9 of 65 
Objectives 
Endpoints 
• Change from baseline in the HIT-6 total 
score at each monthly period 
• Rating of "much better" or "very much 
better" at Weeks 12, 24, 36, 48, and 52 
assessed by the PGIC 
• Change from baseline in percent work 
time missed, percent impairment while 
working, percent overall impairment, and 
percent activity impairment due to 
migraine at each monthly period as 
assessed by the WPAI:MIGRAINE 
• Change from baseline in EQ-5D-5L 
descriptive system index score at each 
monthly period 
• Change from baseline in the EQ-5D-5L 
VAS score at each monthly period 
• Participants "satisfied" or "extremely 
satisfied" with study medication for 
migraine prevention at each monthly 
period 
• Change from baseline in monthly 
Performance of Daily Activities domain 
score of the AIM-D at each monthly 
period 
• Change from baseline in monthly Physical 
Impairment domain score of the AIM-D at 
each monthly period 
• Change from baseline in monthly AIM-D 
total score at each monthly period 
• Change from baseline in monthly activity 
level at each monthly period 
• Change from baseline in monthly activity 
limitation at each monthly period 
• Change from baseline in the MIDAS total 
score at Weeks 12, 24, 36, 48, and 52 
• Change from baseline in MIDAS 
absenteeism score (Questions 1, 3, and 5) 
at Weeks 12, 24, 36, 48, and 52 
• Change from baseline in MIDAS 
presenteeism score (Questions 2 and 4) at 
Weeks 12, 24, 36, 48, and 52 
• Change from baseline in PGI-S at each 
monthly period 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 10 of 65 
Objectives 
Endpoints 
• Change from baseline in the MSQ v2.1 
Role Function-Restrictive domain score at 
Weeks 12, 24, 36, 48, 52, and 56 
• Change from baseline in the MSQ v2.1 
Role Function-Preventive domain score at 
Weeks 12, 24, 36, 48, 52, and 56 
• Change from baseline in the MSQ v2.1 
Emotional Function domain score at 
Weeks 12, 24, 36, 48, 52, and 56 
 
1.2. 
Study Design 
The study design can be described as below with schema and schedule activities to follow in the 
subsections. 
• It is a Phase 3 safety extension study enrolling participants with chronic migraine 
(3101-303-002 study completers) or De Novo participants with episodic migraine. 
• It is a multicenter, open-label study to evaluate the long-term safety and tolerability of 
oral atogepant for the prevention of migraine. 
• At least 170 participants will be enrolled to meet a target of a minimum of 100 
participants with EM or CM exposed to atogepant for 1 year. A minimum of 30 De Novo 
participants (enrolled at selected sites only) must have EM and meet all eligibility 
criteria. 
• Participants will be treated with atogepant 60 mg once daily. 
• The study will consist of a 4-5 weeks screening/baseline period (for De Novo EM 
participant only), a 52-week treatment period and a 4-week safety follow-up period; total 
study duration is 56-61 weeks. 
• No interim analyses are planned for this study. 
 
1.2.1. 
Schema 
Presented below is the study schema. 
  
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 11 of 65 
Figure 1-1 
Study Schema 
 
EOS  end of study; ET  early termination; V  visit. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 12 of 65 
1.2.2. 
Schedule of Activities  
Study procedures are to be done in sequence as listed in the schedule below. 
Table 1-1 
Schedule of Activities (as per the Original Protocol) 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
Obtain 
Informed 
consent and 
participant 
privacyc 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Access IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect 
demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess 
inclusion/ 
exclusion 
criteria 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect medical 
historyf 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 13 of 65 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
Collect 
migraine/ 
headache 
history and 
confirm 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect start 
date (first day) 
of last 
menstrual cycle 
for women 
having 
menstrual 
cycles 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review and 
record prior 
medications 
taken in the past 
6 months and 
all prior 
headache 
medications and 
concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 14 of 65 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
Perform 
physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Collect vital 
sign 
measurementsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform ECG 
X 
Xd 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Perform urine 
pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
laboratory 
determinationsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide eDiary 
device with 
instructions and 
trainingj  
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant 
eDiary data 
collectionj,k 
 
X 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 15 of 65 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
Review eDiary 
data (headache 
duration, 
frequency, 
characteristics 
and symptoms, 
acute 
medication use, 
AIM D activity 
level and 
activity 
limitation) and 
compliancel 
 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C SSRS 
(eTablet)m,n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect ASC 12 
(eTablet)o,p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIT 6 
(eTablet)o,p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGIC 
(eTablet)o,p 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 16 of 65 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
PGI S 
(eTablet)o,p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
WPAI 
MIGRAINE 
(eTablet)o,p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient 
Satisfaction 
with Study 
Medication  
(eTablet)o,p 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ 5D 5L 
(eTablet)o,p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MIDAS 
(eTablet)o,p 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
MSQ v2.1 
(eTablet)o,p 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Collect eDiary 
 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study 
intervention 
(i.e., atogepant) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
Page 17 of 65 
Study Period 
Screening/ 
Baseline 
Period 
(4 weeks)a 
Open-label Treatment Period (52 weeks) 
Safety  
Follow-
up 
Period 
(4 weeks) 
Visit # 
Visit -1 Visit 1b Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12 Visit 13 Visit 14/ 
ET 
Visit 15/ 
EOS 
Day/Week 
Week 4 
Day 1 Week 4 
(Day 28) 
Week 8 
(Day 56) 
Week 12 
(Day 
84) 
Week 16 
(Day 
112) 
Week 20 
(Day 
140) 
Week 24 
(Day 
168) 
Week 28 
(Day 
196) 
Week 32 
(Day 
224) 
Week 36 
(Day 
252) 
Week 40 
(Day 
280) 
Week 44 
(Day 
308) 
Week 48 
(Day 
336) 
Week 52 
(Day 
364) 
Week 56 
(Day 
392) 
Visit Windows Day -35 to 
-28 
N/A 
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days + 3 days ± 3 days 
Review of study 
intervention 
(i.e., atogepant) 
compliance and 
accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
Concomitant 
medications/ 
concurrent 
procedures 
X 
a. 
De Novo EM Participants only. 
b. 
After providing informed consent for this study, Visit 7 of the lead in study (Study 3101 303 002 [Phase 3 CM study]) will function as Visit 1 for this study (see Section 3 for 
further information). 
c. 
Obtained from the participant. 
d. 
3101 303 002 Completers only. 
e. 
Review of inclusion/exclusion criteria includes the review of eDiary data and compliance during Screening/Baseline for De Novo EM Participants. 
f. 
Medical history will be collected for 3101 303 002 Completers who have a gap between the last visit of the lead in study and Visit 1 of this extension study and also for De 
Novo EM Participants. 
g. 
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. 
h. 
For WOCBP only, a urine pregnancy test will be performed at all visits. At the first study visit, discuss the method of contraception with WOCBP and document this method. 
Counsel participants on the importance of maintaining their agreed upon method of contraception throughout the study. 


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i. 
Clinical laboratory determinations include chemistry, hematology, coagulation parameters (INR), and urinalysis to be collected for all visits. Samples for serology and the 
urine drug screen will be collected only at Visit 1 for 3101 303 002 Completers and only at Visit 1 for De Novo EM Participants. 
j. 
Participants should begin using the eDiary as soon as it is dispensed and for the duration of the screening/baseline (for De Novo EM Participants) and treatment period (for all 
participants). Training for the eDiary will be provided for qualified participants during the first study visit (Visit 1 for De Novo EM Participants and Visit 1 for 
Study 3101 303 002 Completers). 
k. 
Daily eDiary data collection includes: headache frequency, duration, characteristics, symptoms, acute medication use, AIM D, Activity Level, and Activity Limitation. 
l. 
Participants must bring their eDiary to all visits (except Visit 15).  
m. At all visits except Visit 1, the "Since Last Visit" C SSRS will be completed for all participants. For Visit 1, the 'Screening/Baseline' assessment of the C SSRS will be 
completed for the participant's lifetime history and for the 6 months prior to screening. 
n. 
Clinicians will complete on eTablet. 
o. 
Participants will complete on eTablet. 
p. 
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol. 
q. 
eDiary will be collected on Visit 1 for screen failures (De Novo EM Participants only). 
 
 
 
 
 
 






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2. 
Statistical Hypotheses 
Since the primary objective of this study is to assess the safety and tolerability over 52 weeks of 
atogepant 60 mg once daily treatment, there is no statistical hypothesis specified for the study.


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3. 
Sample Size Determination 
The study sample size was driven by regulatory safety requirements for the duration and number 
of participants exposed rather than statistical considerations. At least 170 participants will be 
enrolled into this long-term, open label, safety extension study including at least 140 participants 
from the lead-in study (Study 3101-303-002) and approximately 30 De Novo EM Participants 
(from selected sites only) to meet a target of a minimum of 100 participants exposed to atogepant 
at 1 year. 


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4. 
Populations for Analysis 
The analysis populations will consist of participants as defined below. 
The Screened population will consist of all rollover participants with chronic migraine from 
lead-in 3101-303-002 study and De Novo EM participants, who signed informed consent for this 
extension study.  
The Safety population will consist of all participants who receive at least 1 dose of study 
intervention (atogepant) in this extension study. 
The mITT population will consist of all participants who received at least 1 dose of study 
intervention (atogepant) in this study, an evaluable baseline (in this study for De Novo EM 
Participants or in the lead-in study for the rollover participants), and had at least 1 evaluable 
post-baseline 4-week period of eDiary data in this extension study. 
The listing of serious adverse events and participants who died will be provided for the Screened 
population.  


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5. 
Statistical Analyses 
5.1. 
General Considerations 
• Efficacy endpoints will be analyzed descriptively based on the mITT population.  
• Safety endpoints will be performed using the Safety population. 
• Continuous variables will be summarized by number of participants with observed values 
(n), mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), minimum 
(min), and maximum (max). 
• Categorical variables will be summarized by number of participants with observed 
values, events (n), frequency count (n1), and percentage of participants with observed 
values.  
• Partial dates will be treated as missing in computation or in variable derivation unless 
specified otherwise, but will be listed in the data listings as they appear on the eCRF. 
• For monthly endpoints, baseline is defined as assessments during the last 28 days of 
baseline period in the lead-in study for 3101-303-002 rollover participants, and the last 
28 days of the screening/baseline period for De Novo EM Participants. For efficacy 
endpoints that are assessed at clinical visits, baseline is defined as the last non-missing 
efficacy assessment before the first dose of study intervention in the lead-in study 
(3101-303-002) for 3101-303-002 Completers, and the last non-missing efficacy 
assessment before the first dose of study for De Novo EM Participants. For each of the 
clinical, laboratory, vital sign, and ECG parameters, the baseline is defined as the 
baseline value in the lead-in study (3101-303-002) for 3101-303-002 Completers, and the 
last nonmissing safety assessment before the first dose of study drug for De Novo EM 
Participants. 
• The change from baseline values will be computed as the post-baseline value minus the 
baseline value. 
• Study intervention is treatment administered (atogepant 60 mg QD). 
• All statistical analysis will be performed using SAS version 9.4 or higher. 
• Medical Dictionary for Regulatory Activities (MedDRA), Version 27.0 or higher, will be 
used to code adverse events and medical history. 
• WHO Drug Global B3 (v.202403 or higher) will be used to code medications. 
 
5.2. 
Participant Dispositions 
The number of participants in the Safety and mITT populations will be summarized; the number 
of participants screened will be summarized overall.  


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Screen-failure participants (i.e., participants who consent to participate in the study but are not 
subsequently treated) and the associated reasons for failure to enter into the open-label treatment 
period will be tabulated for all screened participants. The number and percentage of participants 
who enter the open-label treatment period, complete the open-label treatment period and of 
participants who prematurely discontinue during the open-label period will be tabulated by 
3101-303-002 rollover CM participants, De Novo EM Participants, and overall for Safety 
population. The reasons for premature discontinuation from the open-label treatment period as 
recorded on the disposition page of the electronic case report forms (eCRFs) will be summarized 
(number and percentage). The percentage is relevant to the total number of participants in the 
Safety population. Similar disposition information will be presented for the safety follow-up 
period. All participants in the all screened population who prematurely discontinue during the 
open-label treatment period or the safety follow-up period will be listed by discontinuation 
reason. 
The number of participants in the Safety population will be summarized by lead-in study 
treatments (placebo, Atogepant 60 mg QD, Atogepant 30 mg BID), enrollment category 
(3101-303-002 completer (3101-303-002 Visit 7 completer, Visit 8 completer, Completer with 
Gap prior to start) and De Novo EM participants), and overall.  
5.3. 
Efficacy Endpoint Analyses and Health Outcome Measures 
5.3.1. 
Definition of Endpoints 
Since the primary objective of this open-label extension study is to assess the safety and 
tolerability over 52 weeks of atogepant treatment, efficacy endpoints are not classified as 
primary, secondary, or additional. 
Efficacy endpoints are listed below, and will be analyzed descriptively. 
• Change from baseline in monthly migraine days at each monthly period (i.e., each 
consecutive 4-week period) 
• Change from baseline in monthly headache days at each monthly period 
• Change from baseline in monthly acute medication use days at each monthly period 
≥ 25%, ≥ 30%, ≥ 50%, ≥ 75%, and 100% improvement (decrease) in monthly migraine 
days at each monthly period 
• Change from baseline in monthly triptan use days at each monthly period 
• Change from baseline in monthly moderate/severe headache days at each monthly period 
• Change from baseline in monthly severe headache days at each monthly period 


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• Change from baseline in monthly cumulative headache hours at each monthly period 
• At least a 5-point improvement (decrease) from baseline in total HIT-6 score at each 
monthly period 
• Change from baseline in the HIT-6 total score at each monthly period 
• Rating of "much better" or "very much better" at Weeks 12, 24, 36, 48, and 52 assessed 
by the PGIC 
• Change from baseline in percent work time missed, percent impairment while working, 
percent overall impairment, and percent activity impairment due to migraine at each 
monthly period as assessed by the WPAI:MIGRAINE 
• Change from baseline in EQ-5D-5L descriptive system index score at each monthly 
period 
• Change from baseline in the EQ-5D-5L VAS score at each monthly period 
• Participants reporting "satisfied" or "extremely satisfied" with study medication for 
migraine prevention at each monthly period 
• Change from baseline in monthly Performance of Daily Activities domain score of the 
AIM-D at each monthly period 
• Change from baseline in monthly Physical Impairment domain score of the AIM-D at 
each monthly period  
• Change from baseline in monthly AIM-D total score at each monthly period 
• Change from baseline in monthly activity level at each monthly period 
• Change from baseline in monthly activity limitation at each monthly period 
• Change from baseline in MIDAS absenteeism score (Questions 1, 3, and 5) at Weeks 12, 
24, 36, 48, and 52 
• Change from baseline in MIDAS presenteeism score (Questions 2 and 4) at Weeks 12, 
24, 36, 48, and 52 
• Change from baseline in the MIDAS total score at Weeks 12, 24, 36, 48, and 52 
• Change from baseline in PGI-S at each monthly period 
• Change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at 
Weeks 12, 24, 36, 48, 52, and 56 
• Change from baseline in the MSQ v2.1 Role Function-Preventive domain score at 
Weeks 12, 24, 36, 48, 52, and 56 
• Change from baseline in the MSQ v2.1 Emotional Function domain score at Weeks 12, 
24, 36, 48, 52, and 56 
 
All efficacy endpoints listed above will be summarized descriptively. In addition, for the primary 
endpoint of the lead-in 3101-303-002 study (Change from baseline in monthly migraine days at 


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each monthly period) and for the key secondary endpoints of the lead-in 3101-303-002 study 
(Change from baseline in monthly headache days at each monthly period, Change from baseline 
in monthly acute medication use days at each monthly period, ≥ 50% improvement (decrease) in 
monthly migraine days at each monthly period, change from baseline in MSQ v2.1 Role 
Function  Restrictive Domain at each monthly period, change from baseline in monthly 
Performance of Daily Activities domain score of the AIM-D at each monthly period, change 
from baseline in the Physical Impairment domain score of the AIM-D at each monthly period, 
change from baseline in the HIT-6 total score at each monthly period), point estimates and 95% 
CIs will be provided. The 95% CI for the continuous endpoints will be based on a mixed-effects 
model for repeated measures (MMRM). The model will include visit (derived as month) as a 
categorical fixed effect, and the baseline score, baseline-by-visit interaction as covariates. 
Restricted maximum likelihood method will be used. An unstructured covariance matrix will be 
used to model the covariance of within-participant repeated measurements. If the model does not 
converge, then simplified covariance structures will be used to fit the model in the following 
order: (1) Toeplitz and (2) compound symmetry. The Kenward Roger approximation 
(Kenward 1997) will be used to estimate the denominator degrees of freedom. Each treatment 
effect will be estimated by the least square mean along with the corresponding standard error and 
95% confidence interval. The analysis will be performed based on all post-baseline values using 
only the observed cases without imputation of missing values.  The 95% CI for percent 
improvement (decrease) in monthly migraine days at each monthly period will be based on the 
normal approximation to the binomial. 
On a daily basis during the open-label 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 headache pain medication. Participants 
will be able to report headache data, including absence of headache, for the day of the eDiary 
report and for the day immediately prior to the day of the eDiary report. 
For analysis purpose, change from baseline will be calculated for consecutive 28-day periods 
beginning with study Day 1 (i.e., Weeks 1-4, 5-8 and 9-12, corresponding to Days 1-28, 29-56 
and 57-84, etc.), where Day 1 is the first dose date of the open-label study treatment. 
5.3.2. 
Main Analytical Approach 
Descriptive statistics will be provided by visit for all efficacy endpoints based on the mITT 
population using the observed case (OC) approach. No inferential statistical analyses will be 
performed for the efficacy endpoints except where noted above. 


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5.3.3. 
Key Efficacy Measures 
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 (e.g., walking or 
climbing stairs) 
B. At least one of the following: 
i. Nausea and/or vomiting 
ii. Photophobia and phonophobia 
iii. Typical aura (i.e., 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 (i.e., 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 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 (e.g., walking or 
climbing stairs) 
2) Symptoms: 
i. Nausea and/or vomiting 
ii. Photophobia and phonophobia 
iii. Typical aura (i.e., 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 (i.e., triptan or ergot derivative) was used after the start of the headache, 
in which case no minimum duration will be specified. 
A headache day is defined as any calendar day on which headache pain lasting 2 hours or longer 
occurs unless an acute headache medication (e.g., ibuprofen, triptan) was used after the start of 
the headache, in which case no minimum duration will be specified. Note that antiemetics will 
  
 


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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). 
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 eDiary. 
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 patient on a scale from mild to 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. 
5.3.4. 
Health Outcome Measures 
5.3.4.1. 
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). 
5.3.4.2. 
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, missed household 
work days, days at work or school plus days of household work where productivity was reduced 
by half or more, and missed non-work activity days due to headaches in the last 3 months. 
  
 


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5.3.4.3. 
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." 
5.3.4.4. 
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 one-week recall and contains six 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. 
5.3.4.5. 
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. 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 EQ VAS records the respondent's self-rated health on a vertical, visual 
analogue scale where the endpoints are labeled "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). 
5.3.4.6. 
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." 


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5.3.4.7. 
Patient Satisfaction with Study Medication 
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). 
5.3.4.8. 
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, and 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 
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). 
5.3.4.9. 
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 
scale 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 scale ranging from "Not at all limited  
I could do everything" to "Extremely limited." 


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5.3.4.10. 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 three 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. 
The detailed algorithms for derivation of the above health outcome measures are presented in 
Section 6.4.3. 
5.4. 
Safety Analyses 
The safety analysis will be performed using descriptive statistics as described in Section 5.1 
based upon the Safety population. 
5.4.1. 
Extent of Exposure 
The study will consist of a 52-week treatment period and a 4-week safety follow up period; total 
study duration is 56 weeks. 
Exposure to extension study treatment for the Safety population during the open-label treatment 
period will be summarized for treatment duration, calculated as the number of days from the date 
of the first dose of extension study treatment to the date of the last dose taken, inclusive. 
The number and percentage of participants with each treatment duration of ≥ 1 day, ≥ 28 days, 
≥ 56 days, ≥ 84 days, ≥ 90 days, ≥ 112 days, ≥ 140 days, ≥ 168 days, ≥ 180 days, ≥ 196 days, 
≥ 224 days, ≥ 252 days, ≥ 270 days, ≥ 280 days, and ≥ 360 will be summarized. 
Participant-years, defined as exposure to the study treatment in years, will be summarized for the 
Safety population. 
5.4.2. 
Treatment Compliance 
Dosing compliance for the open-label treatment period is defined as the total number of open-
label study treatments actually taken by a participant during that period divided by the number of 
open-label study treatments that were expected to be taken by a participant during the same 
period multiplied by 100. The total number of tablets actually taken during a specific period will 
be calculated from the study treatment record. Descriptive statistics for treatment compliance 
together with the compliance categories (< 80%, 80% - 120%, > 120%) will be summarized for 


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open-label study treatment period between 2 consecutive visits, as well as for the whole open-
label treatment period of the study based on the Safety population. 
5.4.3. 
Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 27.0 or higher. 
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 open-
label study treatment. An AE that occurs more than 30 days after the last dose of open-label 
study treatment or the safety follow-up visit (Visit 15) in this extension study whichever comes 
later will not be counted as a TEAE. Per case report form instructions, a new AE record will be 
created for any AE that worsens; therefore, TEAEs can be identified as those AEs captured in 
Study 3101-306-002 with recorded onset date on or after the date of the first dose of open-label 
study treatment and within 30 days after the last dose of open-label study treatment or Visit 15 
whichever comes later.  
An AE is a TESAE if it is a TEAE that additionally meets any SAE criterion below (as specified 
in the protocol Section 9.1.2): 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other situations that the medical or scientific judgment considers to be serious. 
 
TEAEs that started after the date of last dose of open-label study treatment will be considered as 
newly emergent TEAEs (NEAEs). 
TEAEs that started on or after the date of first dose of open-label study treatment will be 
summarized. 
Overall summary of AEs will be provided on a per-participant basis for categories of TEAEs, 
treatment-related TEAEs, TESAEs, treatment-related TESAEs, TEAEs leading to study 
intervention discontinuation, and deaths. 


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The number and percentage of participants reporting TEAEs will be tabulated by system organ 
class (SOC) and preferred term (PT), and further categorized by severity. If more than 1 AE is 
coded to the same preferred term for the same participants, the participant will be counted only 
once for that preferred term using the greatest severity for the summarization by severity. 
The number and percentage of participants reporting treatment-related TEAEs will be tabulated 
by SOC and PT. 
The number and percentage of participants reporting treatment-related TEAEs will be tabulated 
by SOC, PT, and the following AE onset time intervals: < 3 months, ≥ 3 and < 6 months, ≥ 6 and 
< 9 months, ≥ 9 and < 12 months, ≥ 12 months, where a month is defined as 30 days for analysis 
purposes.  
The number and percentage of participants reporting NEAEs will be tabulated by SOC and PT. 
The number and percentage of participants who have TEAEs leading to study intervention 
discontinuation will be summarized by SOC and PT. 
The incidence of common (≥ 2% of participants [after rounding] in either CM completer cohort 
or De Novo EM cohort) TEAEs will be summarized by PT and sorted by decreasing frequency 
in total. 
The incidence of common (≥ 5% of participants [after rounding] in either CM completer cohort 
or De Novo EM cohort) TEAEs will be summarized by PT and sorted by decreasing frequency 
in total. 
The number and percentage of participants who have TESAE will be tabulated by SOC and PT. 
The number and percentage of participants reporting treatment-related TESAEs will be tabulated 
by SOC and PT. 
In addition, separate tabular displays will be presented for participants who died, participants 
with SAEs, and participants with TEAEs leading to study intervention discontinuation. 
5.4.4. 
Additional Safety Assessments  
5.4.4.1. 
Clinical Laboratory Parameters 
Descriptive statistics for values and changes from the baseline in standard (SI) units at each 
assessment time point will be presented for the following laboratory parameters: 


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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 
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 
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 Table 6-1. A description of reporting the laboratory values in conventional units in 
participant narratives (along with the standard reporting in SI units) is presented at the end of 
Table 6-2. 
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 Section 6.3.7.2. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be 
tabulated. 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 open-label 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 values will be provided. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided. 
The number and percentage of participants with an adjudicated case (i.e., ALT ≥ 3 × ULN and/or 
AST ≥ 3 × ULN) will be summarized by relationship of ALT or AST elevation to study 
treatment. 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. 
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 treatment, and confounding factor(s). Additional listings will be provided for 


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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. 
Potential Hy's Law criteria is defined by a postbaseline elevation of alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) ≥ 3 × ULN, along with total bilirubin (TBL) 
≥ 2 × ULN and a non-elevated alkaline phosphatase (ALP) < 2 × ULN, all based on blood draws 
collected within a 24-hour period. Participants who meet the potential Hy's Law criteria from the 
first dose of study treatment to the end of study will be summarized. Supportive tabular displays 
will also be provided. 
The number and percentage of participants meeting each of the postbaseline hepatic laboratory 
abnormalities criteria listed in Table 6-4 will be summarized. 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. 
5.4.4.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures [sitting and standing], 
pulse rate [sitting and standing], respiratory rate, temperature, weight, body mass index (BMI), 
orthostatic systolic blood pressure, orthostatic diastolic blood pressure, and orthostatic pulse rate) 
and their changes from baseline at each assessment timepoint will be presented. 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 that will be detailed in Section 6.3.7.4. 
The number and percentage of participants who have PCS postbaseline vital sign values will be 
tabulated. For criteria related with systolic blood pressure, diastolic blood pressure, pulse rate 
and weight, the denominator will be the number of participants who have available baseline and 
at least 1 postbaseline assessment. For criteria related with orthostatic measures, the denominator 
will be the number of participants who have available non-PCS baseline 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 PCS values will be provided. 


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In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline vital sign values will be provided. 
5.4.4.3. 
Electrocardiogram 
Descriptive statistics for ECG parameters (i.e., heart rate, PR interval, QRS interval, RR interval, 
QT interval, and QTc interval) and changes from baseline values at each assessment timepoint 
will be presented. The QTc will be calculated using the Fridericia correction. 
ECG parameter values are considered PCS if ECG values meet either the actual value or change 
from baseline PCS high criteria listed in Table 6-5. The number and percentage of participants 
with PCS postbaseline values will be tabulated. 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 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. 
To evaluate ECG postbaseline values of clinical interest, the number and percentage of 
participants with post-treatment QTcF > 450 msec, > 480 msec, and > 500 msec will be 
tabulated. 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 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 open-label treatment period in the investigator's overall 
interpretation of the ECG will be presented 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. 
5.4.4.4. 
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 for the Safety population. The 


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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 open-label treatment period, and in 
the safety follow-up period will also be presented. Supportive listings will be provided and will 
include the PID number, 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. 
5.5. 
Other Analyses 
5.5.1. 
Subgroup Analyses 
Efficacy Subgroup Analyses 
For all efficacy and health outcome endpoints, subgroup analyses will be performed by 
3101-303-002 Completers or De Novo EM Participants and overall. 
For the following efficacy endpoints, separate figures will be presented by 3101-303-002 
Completers or De Novo EM Participants. The figures for over time change during the 12-Week 
Double-Blind treatment period and the 52-Week Open-label treatment period for 3101-303-002 
CM Completers in mITT population will also be presented, for the following efficacy endpoints. 
• Change from baseline in monthly migraine days at each monthly period 
• Change from baseline in monthly headache days at each monthly period 
• Change from baseline in monthly acute medication use days at each monthly period 
 
Safety Subgroup Analyses 
For all safety endpoints, subgroup analyses will be performed by 3101-303-002 Completers or 
De Novo EM Participants and overall. 
5.6. 
Interim Analyses 
No interim analysis is planned for this study. 


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6. 
Supporting Documentation 
Additional specifications on study population's demographics and baseline characteristics, as 
well as pre-defined safety criteria can be found in Appendix 3. 
6.1. 
Appendix 1: List of Abbreviations 
Abbreviation/Term 
Definition 
AE 
adverse event 
AIM-D 
activity impairment in migraine – diary 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CM 
chronic migraine 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ECG 
electrocardiogram, electrocardiographic 
EM 
episodic migraine 
EOS 
end of study 
EQ 5D 5L 
European Quality of Life - 5 Dimensional 
ET 
early termination 
HIT-6 
Headache Impact Test 
INR 
international normalized ratio 
IWRS 
interactive web response system 
LLN 
lower limit of normal value 
MedDRA 
Medication Dictionary for Regulatory Activities 
MIDAS 
Migraine Disability Assessment 
mITT 
modified intent-to-treat 
MSQ v2.1 
Migraine Specific Quality of Life Questionnaire, Version 2.1 
PCS 
potentially clinically significant 
PGIC 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression - Severity 
PID 
participant identification 
PRO 
patient reported outcome 
PT 
preferred term 
Q1 
first quartile (25th percentile of the data) 
Q3 
third quartile (75th percentile of the data) 
QD 
once daily 
QTc 
QT interval corrected for heart rate 


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Abbreviation/Term 
Definition 
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 
SI 
Le Système International d'Unités (International System of Units) 
SOC 
standard of care 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal value 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
WPAI:MIGRAINE 
Work Productivity and Activity Impairment Questionnaire: Migraine V2.0 
 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses 
Add the following efficacy endpoint: 
Change from baseline in monthly acute medication use days at each monthly period 
≥ 30% improvement (decrease) in monthly migraine days at each monthly period. 
6.3. 
Appendix 3: Supporting Study Information 
6.3.1. 
Demographic 
Demographic parameters (age; age group [< 20, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥ 70]; 
< 40 years, ≥ 40 - < 65 years, ≥ 65 years; < 75 years, ≥ 75 years; race group [Asian, all other 
races]; ethnicity; sex) will be summarized descriptively by 3101-303-002 Completers from the 
lead-in study, De Novo EM Participants, and overall for the Safety and mITT populations. 
6.3.2. 
Baseline and Disease Characteristics 
Baseline characteristics (weight; height; and BMI, calculated as weight [kg]/(height [m])2, and 
BMI category [underweight [ < 18.5], normal [>  18.5 - < 25], overweight [>  25 - < 30], and 
obese [>  30]) will be summarized descriptively for the Safety and mITT populations.  
Baseline efficacy parameters (e.g., monthly migraine days, monthly headache days, and monthly 
acute medication use days) will be summarized by 3101-303-002 Completers from the lead-in 
study, De Novo EM Participants, and overall for mITT population. 


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For monthly endpoints, baseline is the baseline value in the lead-in study (3101-303-002) for 
3103-303-002 Completers or the last 28 days of the screening/baseline period for De Novo EM 
Participants. For efficacy endpoints that are assessed at clinical visits, baseline is the last 
nonmissing efficacy assessment before the first dose of study intervention in the lead-in 
study (3101-303-002) for 3103-303-002 Completers or the last nonmissing efficacy assessment 
before the first dose of study drug for De Novo EM Participants. 
6.3.3. 
Protocol Deviations 
For each of the following significant protocol deviation categories and across all categories, the 
number and percentage of randomized subjects with at least one protocol deviation will be 
summarized overall and by 3101-303-002 Completers from the lead-in study, De Novo EM 
Participants, and overall for Safety population. A listing of subjects with significant protocol 
deviations will be provided. 
• Participant entered into the study even though did not met inclusion criteria; 
• Participant entered into the study even though met exclusion criteria; 
• Participant developed withdrawal criteria during the study but was not withdrawn; 
• Participant received wrong treatment or incorrect dose; 
• Participant received excluded concomitant treatment. 
6.3.4. 
Medical History 
Abnormalities in participants' medical and surgical history will be coded using the Medical 
Dictionary for Regulatory Activities, version 27.0 or newer. The number and percentage of 
participants with abnormalities in medical and surgical histories from the lead-in study in each 
system organ class (SOC) and preferred term (PT) will be summarized 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 by 3101-303-002 Completers from the lead-in study and De Novo EM 
Participants for the Safety population. 
6.3.5. 
Prior/Concomitant/Follow-up medications 
Prior medication is defined as any medication taken before the date of the first dose of lead-in 
study treatment for participants who rolled over from the lead-in study and collected in this 
study, or before the first dose of study treatment in this study for De Novo EM participants. 


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Concomitant medication for this study is defined as any medication taken on or after the date of 
the first dose of open-label study treatment. 
The number and percentage of participants will be tabulated by 3101-303-002 Completers from 
the lead-in study and De Novo EM Participants and by Anatomical Therapeutic Chemical (ATC) 
4 class and preferred term (PT) for both prior medications and concomitant medications in the 
Safety population. Concomitant medications will be summarized by period, for the open-label 
treatment period and the safety follow-up period, respectively. 
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 medication data will be coded using the World Health Organization (WHO) Drug Global B3 
version March 2024 or higher. 
6.3.6. 
Adverse Events of Special Interest 
Per the 3101-306-002 Protocol Section 6.1.2, selected non-serious and serious adverse events are 
of special interest and will require immediate reporting, recording, and follow-up. The following 
events will be closely monitored: 
• Treatment-emergent suicidal ideations with intent, with or without a plan, (i.e., Type 4 or 5 
on the C-SSRS) or any suicidal behaviors. 
• Treatment-emergent elevated ALT or AST lab value ≥ 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. 
 
The summaries of above are described in the corresponding SAP Section 5.4.4.1 and 
Section 5.4.4.4. 
6.3.7. 
Potentially Clinically Significant Criteria for Safety Endpoints 
Laboratory values in conventional unit, the potentially clinically significant criteria for clinical 
laboratory parameters, Hepatic laboratory abnormalities, vital signs and ECG parameters are 
provided in the following sections. 


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6.3.7.1. 
Laboratory values in Conventional Unit 
6.3.7.1.1. Background 
All laboratory parameters are reported in the International System (SI) units as standard practice. 
In addition, selected laboratory parameters (listed in Table 6-1) will be reported in conventional 
units to facilitate interpretation and reporting for the CSR and future labeling. 
6.3.7.1.2. List of Parameters Reported in Conventional Unit  
The list of selected parameters required to be reported in conventional unit is provided in 
Table 6-1. 
Table 6-1 
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 
µIU/mL 
1 
19 
Uric Acid 
mg/dL 
1 
20 
Hemoglobin 
g/dL 
1 
 
6.3.7.1.3. Analysis and Reporting Format in Conventional Units 
1) For individual clinical study reports for the central nervous system (CNS) projects, the 
descriptive statistics for the selected laboratory parameters (Table 6-1) will be reported in 
conventional units using the similar layout for the summary table in SI unit. 


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2) Participant narratives generated by the statistical programming team will also include the 
values in conventional units for the selected lab parameters (Table 6-1). 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 6-2 for lab parameter 
'Bilirubin, Total,' for which 'µmol/L' is the SI unit and 'mg/dL' is the conventional unit. 
 
Table 6-2 
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 (µmol/L 
(mg/dL))  
0 (0) 
18.81 (1.1) 
6.84 (0.4) 
5.13 (0.3) 
5.13 (0.3) 
 


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6.3.7.2. 
Potentially Clinically Significant Criteria for Clinical Laboratory Parameters 
Table 6-3 
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters 
 
 
 
PCS Criteria 
Category 
Parameter 
SI Unit 
PCS Low 
PCS High 
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 
— 
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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6.3.7.3. 
Criteria for Hepatic Laboratory Abnormalities 
Table 6-4 
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 Elevationsa 
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 1.5 × ULN 
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 2 × ULN 
Potential Hy's Lawa 
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) 
a. 
Elevations are from the same day. 
 


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6.3.7.4. 
Potentially Clinically Significant Criteria for Vital Signs 
Table 6-5 
Potentially Clinically Significant Criteria for 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 
 
6.3.7.5. 
Potentially Clinically Significant Criteria for ECG parameters 
Table 6-6 
Potentially Clinically Significant Criteria for ECG parameters 
Parameter 
Unit 
Criterion 
QRS interval 
msec 
≥ 150 
PR interval 
msec 
≥ 250 
QTcF interval 
msec 
> 500 
QTcF interval 
msec 
Increase from baseline > 60 
QTcF  QT interval corrected for heart rate using the Fridericia formula 
 
6.4. 
Data handling convention 
Day 1 is defined as day for the date of the first dose of open-label study treatment. There is no 
Day 0 or Week 0. Treatment day is relative to the date of the first dose of open-label study dose. 


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6.4.1. 
Analysis Window 
The analysis visit windows for monthly efficacy endpoints based on daily eDiary data are 
defined as follows: 
Table 6-7 
Efficacy Analysis Visit Definitions for eDiary Data (Monthly)  
Analysis Phase 
Analysis Visit (Derived) 
eDiary Window 
Pretreatment 
Baseline 
Baseline from lead-in study for 3101-303-002 
Completer 
Last 28 days prior to treatment start date for De Novo 
EM Participant 
Open-label Treatment 
Period 
Weeks 1 – 4 
Treatment Day [1, 28] 
Weeks 5 – 8 
Treatment Day [29, 56] 
Weeks 9 – 12 
Treatment Day [57, 84] 
Weeks 13 - 16 
Treatment Day [85,112] 
Weeks 17 - 20 
Treatment Day [113,140] 
Weeks 21 - 24 
Treatment Day [141,168] 
Weeks 25 - 28 
Treatment Day [169,196] 
Weeks 29 - 32 
Treatment Day [197,224] 
Weeks 33 - 36 
Treatment Day [225,252] 
Weeks 37 - 40 
Treatment Day [253,280] 
Weeks 41 - 44 
Treatment Day [281,308] 
Weeks 45 - 48 
Treatment Day [309,336] 
Weeks 49 - 52 
Treatment Day [337, minimum (the end of open-label 
treatment period, 364)] 
 


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The analysis visit windows for MSQ v2.1, PGIC, and MIDAS are defined as follows: 
Table 6-8 
Efficacy Analysis Visit Definitions for MSQ v2.1, PGIC, and MIDAS 
Analysis Phase 
Analysis Visit 
(Derived) 
Scheduled Study 
Visit (eCRF) 
Window 
Pretreatment* 
Baseline 
Visit 1 
for De Novo EM 
Participant only 
Baseline from lead-in study for 3101-303-002 
Completer 
Treatment Day ≤ 1 for De Novo EM Participant 
Open-label 
Treatment 
Period 
Week 12 
Visit 4 
Treatment Day [1, 126] for 3101-303-002 
Completer 
Treatment Day [2, 126] for De Novo EM 
Participant 
Week 24 
Visit 7 
Treatment Day [127, 210] 
Week 36 
Visit 10 
Treatment Day [211, 294] 
 
Week 48 
Visit 13 
Treatment Day [295, 350] 
 
Week 52 
Visit 14/ET 
Treatment Day >= 351 and within open-label 
treatment period 
Safety Follow-
up Period** 
Week 56 
(Follow-up) 
Visit 15 
Treatment Day [the end of open-label treatment 
period +1, the last study visit] 
ET  early termination 
* 
Only for MSQ v2.1 and MIDAS. 
** Only for MSQ v2.1. 
 


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The analysis visit windows for HIT-6, EQ-5D-5L, PGI-S, Patient Satisfaction with Study 
Medication, and WPAI:MIGRAINE are defined as follows: 
Table 6-9 
Efficacy Analysis Visit Definitions for HIT-6, EQ-5D-5L, PGI-S, Patient 
Satisfaction with Study Medication, and WPAI:MIGRAINE 
Analysis Phase 
Analysis Visit 
(Derived) 
Scheduled Study 
Visit (eCRF) 
Window 
Pretreatment* 
Baseline 
Visit 1 
for De Novo EM 
Participant only 
Baseline from lead-in study for 3101-303-002 
Completer 
Treatment Day ≤ 1 for De Novo EM Participant 
Open-label 
Treatment 
Period 
Week 4 
Visit 2 
Treatment Day [1, 42] for 3101-303-002 Completer 
Treatment Day [2, 42] for De Novo EM Participant 
Week 8 
Visit 3 
Treatment Day [43, 70] 
Week 12 
Visit 4 
Treatment Day [71, 98] 
Week 16 
Visit 5 
Treatment Day [99, 126] 
Week 20 
Visit 6 
Treatment Day [127, 154] 
Week 24 
Visit 7 
Treatment Day [155, 182] 
Week 28 
Visit 8 
Treatment Day [183, 210] 
Week 32 
Visit 9 
Treatment Day [211, 238] 
Week 36 
Visit 10 
Treatment Day [239, 266] 
 
Week 40 
Visit 11 
Treatment Day [267, 294] 
 
Week 44 
Visit 12 
Treatment Day [295, 322] 
 
Week 48 
Visit 13 
Treatment Day [323, 350] 
 
Week 52 
Visit 14/ET 
Treatment Day >= 351 and within open-label 
treatment period 
Safety Follow-
up Period** 
Week 56 
(Follow-up) 
Visit 15 
Treatment Day [the end of open-label treatment 
period +1, the last study visit] 
ET  early termination 
* 
Only for HIT 6,  EQ 5D 5L and PGI S. 
** Only for HIT 6 and EQ 5D 5L. 
 


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The analysis visit windows for safety endpoints are defined as follows: 
Table 6-10 
Safety Analysis Visit Definitions 
Analysis Phase 
Analysis Visit 
(Derived) 
Scheduled Study 
Visit (eCRF) 
Window 
Pretreatment 
Baseline 
Visit 1 
for De Novo EM 
Participant only 
Baseline from lead-in study for 3101-303-002 
Completer 
Treatment Day ≤ 1 for De Novo EM Participant 
Open-label 
Treatment 
Period 
Week 4 
Visit 2 
Treatment Day [1, 42] for 3101-303-002 Completer 
Treatment Day [2, 42] for De Novo EM Participant 
Week 8 
Visit 3 
Treatment Day [43,70] 
Week 12 
Visit 4 
Treatment Day [71,98] 
 
Week 16 
Visit 5 
Treatment Day [99,126] 
 
Week 20 
Visit 6 
Treatment Day [127,154] 
 
Week 24 
Visit 7 
Treatment Day [155,182] 
 
Week 28 
Visit 8 
Treatment Day [183,210] 
 
Week 32 
Visit 9 
Treatment Day [211,238] 
 
Week 36 
Visit 10 
Treatment Day [239,266] 
 
Week 40 
Visit 11 
Treatment Day [267,294] 
 
Week 44 
Visit 12 
Treatment Day [295,322] 
 
Week 48 
Visit 13 
Treatment Day [323,350] 
 
Week 52 
Visit 14/ET 
Treatment Day >= 351 and within open-label 
treatment period 
 
End of treatment 
 
Last available assessment during open-label 
treatment period 
Safety Follow-
up Period 
Week 56 (Safety 
follow-up) 
Visit 15 
Treatment Day [the end of open-label treatment 
period +1, the last study visit] 
End of study 
 
Last available assessment after treatment start date, 
i.e., occurs at final visit (expected Day 392) or ET 
ET  early termination 
Safety follow up visit will be presented in analysis tables for clinical laboratory values and vital signs. 
End of Open label Treatment is defined as the last available assessment during open label treatment period. End of Open label 
Treatment results will be presented in analysis tables for clinical laboratory values, electrocardiograms and vital signs.  
End of Study is defined as the last available assessment during the study, including open label and safety follow up period. End 
of Study results will be presented in analysis tables for safety parameters, including but not limited to clinical laboratory values, 
and vital signs. 
 
For endpoints collected by visit, the last visit with a non-missing value will be used for analysis, 
if a participant has 2 or more visits within the same window. 


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6.4.2. 
Derived Efficacy Data 
6.4.2.1. 
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 open-label treatment period, 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 dairy" 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 at any time from 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 "todays 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" 
 
The date (COLLDAT) and time of the daily headache diary will be used for merging "today's 
diary" and "yesterday's diary" for 3101-303-002 rollover CM participants to align with the 
eDiary data derivation in 3101-303-002 study. The collection date (COLLDAT) is the date the 
daily headache diary is for, and collection time (COLLTIM) is triggered by the opening of the 
daily headache diary. Due to the eCOA vendor no longer collecting collection time in the EM 
cohort, the start date (STDAT) and time (STTIM) of the daily headache diary, which is the date 
and time when the daily headache diary is opened, will be used for merging "today's diary" and 
"yesterday's diary" for De Novo EM participants. 


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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 duplicate 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. 
The monthly migraine days is defined 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. For each postbaseline 
4-week treatment period, a minimum of 14 days' eDiary data during that period is required for 
the migraine days to be evaluable. 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, 13-16, 17-20, 21-24, 25-28, 29-32, 33-36, 37-40, 41-44, 
45-48, 49-52). 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 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 participant reports 'Yes' to the 
intake of 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. 
6.4.3. 
Derivation of Health Outcome Endpoints 
AIM-D Related Endpoints Derivation 
As described in SAP Section 5.3.4.8 (copied from protocol Section 6.3.1), 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. 


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• Monthly Performance of Daily Activities domain score of the AIM-D 
• Monthly Physical Impairment domain score of the AIM-D 
• Monthly Total Score of the AIM-D 
 
Step 1: Calculate AIM-D daily domain 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 6-11. 
Table 6-11 
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. 
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. 


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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:  
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−7)∗100
35
 
• Role Function-Preventive:  
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−4)∗100
20
 
• Emotional Function:           
(𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−3)∗100
15
 
HIT-6 Total Score Derivation 
For HIT-6 total score, pre-coded item values and final item values for each item response are 
shown in Table 6-12. 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 6-12 
Item Values for HIT-6 Item Response 
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. 
• Q5  migraine affected productivity while working. 
• Q6  migraine affected regular daily activity. 
 


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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)))×(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. 
EQ-5D-5L 
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 participants 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). 
The EQ-5D-5L will be completed by the participants at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, 52, and 56.  
6.4.4. 
Repeated or Unscheduled Assessments of Safety Parameters 
Baseline is defined as the last assessment made before the first dose of study treatment. If 
end-of-study assessments are repeated or if unscheduled visits occur, the last non-missing 
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. 
6.4.5. 
Missing Date of the Last Dose of Study Treatment 
When the date of the last dose of the open-label study treatment is missing, all efforts should be 
made to obtain the date from the Investigator. If it is still missing after all efforts have been 
made, the last available study treatment date will be used in the calculation of treatment duration. 
  
 


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6.4.6. 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of open-label study 
treatment, a severity of mild will be assigned. If severity is missing for an AE that started on or 
after the date of the first dose of open-label study treatment, a severity 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. 
6.4.7. 
Missing Causal Relationship to Study treatment for Adverse Events 
If the causal relationship to the open-label study treatment is missing for an AE that started on or 
after the date of the first dose of open-label study treatment, a causality of yes will be assigned. 
The imputed values for causal relationship to open-label treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
6.4.8. 
Missing Date Imputation 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., 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 open-label study 
treatment, the month and day of the first dose of open-label 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 open-label 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 open-label 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 open-label study treatment, the day of the first dose of open-label 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 
open-label 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 open-label 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 open-
label 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 open-label 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 open-label study treatment, the date of 
the first dose of open-label study treatment will be assigned to the missing start date 
• If the stop date is before the date of the first dose of open-label study treatment, the stop 
date will be assigned to the missing start date 
6.4.9. 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (i.e., 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. 
6.4.9.1. 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 open-label study 
treatment, the month and day of the first dose of open-label 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 open-label 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 open-label 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 open-label study treatment, the day of the first dose of open-label 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 
open-label 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 open-label 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 
open-label 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 open-label study treatment, the first day of 
the month will be assigned to the missing day. 
6.4.9.2. 
 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, 
replace it with the last visit date in the imputations described below. 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. 


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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. 
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. 
6.4.10. 
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. 


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7. 
Covid-19 Related Analyses 
7.1. 
Efficacy Evaluation 
For the endpoints are collected via eDiary, minimal disruption is expected for these endpoints 
because participants are expected to complete eDiary at home and submit the responses every 
day. 
The health outcome measures will be collected using eTablet as electronic patient reported 
outcomes (ePRO) at site. To evaluate the missing rate for these efficacy endpoints, the number of 
participants who missed at least one visit due to COVID-19 will be summarized at each visit in 
the efficacy analysis population. 
7.2. 
Safety and Other Evaluations 
This section specifies analyses related to COVID-19 pandemic from the following aspects: 
• Disposition 
• Study visits and study procedures 
• Protocol deviation  
• Treatment interruption due to COVID-19 
• TEAEs related with COVID-19 infection and supplemental signs and symptoms 
• COVID-19 status (COVID-19 testing results or contact with a COVID-19 positive 
person) 
• COVID-19 vaccination 
 
The Safety Population will be used for the planned COVID-19 related analyses, except where 
noted below. 
The number of participants impacted by COVID-19 during the study will be summarized. In 
addition, the number of participants impacted by COVID-19 and their corresponding disposition 
status in the open-label 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. Furthermore, the number of participants who missed at least one assessment due to 
COVID-19 will be summarized by assessment category (laboratory, C-SSRS, urine pregnancy 
test, vital signs, ECG, and ePRO) and overall. Similar summaries will be provided by visit. 


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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 COVID-19 will be tabulated 
by preferred terms, and related supplemental signs and symptoms will be listed. COVID-19 
status, i.e., testing results or contact with a COVID-19 positive person, will be summarized. 
The number and percentage of participants who received a COVID-19 vaccine will be tabulated 
by Anatomical Therapeutic Chemical (ATC) 4 class and preferred term (PT) in participants 
received COVID-19 vaccine in Safety Population during this study. The number and percentage 
of participants with TEAEs and serious TEAEs related to COVID-19 vaccine will be 
summarized in Safety Population and participants received COVID-19 vaccine in Safety 
Population during this study. Supporting listings for the described analyses above will be 
provided. 


CONFIDENTIAL 
Atogepant 
Statistical Analysis Plan 3101-306-002 
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8. 
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