Conditions: Episodic Migraine
Keywords: Migraine Aura
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 685
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of atogepant 60 mg once a day for the prevention of migraine in participants with episodic migraine.

Detailed description:

Arms:
arm 1: Participants received atogepant 60 mg, orally, once daily (QD) for up to 40 weeks.

Interventions: intervention 1: Atogepant
Intervention descriptions: intervention 1: Atogepant Tablets

Protocol document:
Prot_000.pdf: 
Allergan Confidential
Protocol 3101-309-002 Amendment 1
1
Title Page
ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information 
which is the property of Allergan
A PHASE 3, MULTICENTER, OPEN-LABEL 40-WEEK EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF ORAL ATOGEPANT 
FOR THE PREVENTION OF MIGRAINE IN PARTICIPANTS WITH EPISODIC MIGRAINE
Protocol Number:
3101-309-002
EudraCT Number (if applicable):
Not applicable
Phase:
3
Name of Study Intervention:
Atogepant
Sponsor:
Allergan Pharmaceuticals International Limited
Marlow International
The Parkway, Marlow SL7 1YL 
United Kingdom
US Agent
Allergan Sales LLC
2525 DuPont Drive
Irvine, California USA
92612
Emergency Telephone Number(s):
+1-866-438-8820
Serious Adverse Event Reporting 
Fax Number(s):
Back up fax number
+1-714-796-9504
+1-714-246-5295
Email
IR-Clinical-SAE@allergan.com
Allergan Medical Safety Physician
Contact Information:
Refer to the Study Contacts Page
Allergan Signatory:
 Neuroscience Development
Original Protocol Date
22 February 2019
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Protocol 3101-309-002 Amendment 1
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Amendment 1 Date:
15 September 2020
The following information can be found on FDA Form 1572 and/or study contacts page: Name 
and contact information of Allergan study personnel and Emergency Telephone Numbers; name, 
address, and statement of qualifications of each investigator; name of each subinvestigator 
working under the supervision of the investigator; name and address of the research facilities to 
be used; name and address of each reviewing IRB; US 21 CFR 312.23 section 6(iii)b.
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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:
!
Implement and conduct this study diligently and in strict compliance with the protocol, GCPs 
and all applicable laws and regulations.
!
Maintain all information supplied by Allergan 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 ........................................................................................ 13
1.1 Background....................................................................................................................... 13
1.2 Overview of Atogepant..................................................................................................... 13
1.3 Study Rationale................................................................................................................. 14
1.4 Rationale for Doses and Dose Regimens Selected ........................................................... 14
2
Study Objective and Clinical Hypotheses............................................................................... 14
2.1 Study Objective................................................................................................................. 14
2.2 Clinical Hypothesis........................................................................................................... 14
3
Study Design........................................................................................................................... 14
3.1 Structure............................................................................................................................ 14
3.2 Data Safety Monitoring Board.......................................................................................... 16
3.3 Adjudication Committee................................................................................................... 16
4
Study Population and Entry Criteria....................................................................................... 16
4.1 Number of Participants ..................................................................................................... 16
4.2 Inclusion Criteria .............................................................................................................. 16
4.3 Exclusion Criteria ............................................................................................................. 17
4.4 Permissible and Prohibited Medications/Treatments........................................................ 17
Permissible Medications/Treatments .................................................................... 17
Prohibited Medications/Treatments ...................................................................... 18
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods ......................................................................................... 19
Special Diet or Activities ...................................................................................... 20
4.5 Screen Failures.................................................................................................................. 20
5
Study Intervention................................................................................................................... 20
5.1 Study Intervention and Formulations................................................................................ 20
6
Control Intervention................................................................................................................ 21
6.1 Methods for Masking/Blinding......................................................................................... 21
6.2 Treatment Allocation Ratio............................................................................................... 21
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6.3 Method for Assignment to Treatment Groups .................................................................. 21
6.4 Treatment Regimen and Dosing ....................................................................................... 21
6.5 Safety Measures................................................................................................................ 22
Adverse Events ..................................................................................................... 22
Adverse Events of Special Interest ....................................................................... 22
Clinical Laboratory Determinations ..................................................................... 22
Vital Signs............................................................................................................. 23
Physical Examination............................................................................................ 24
Electrocardiograms ............................................................................................... 24
Columbia-Suicide Severity Rating Scale (C-SSRS)............................................. 24
6.6 Other Study Supplies ........................................................................................................ 25
6.7 Summary of Methods of Data Collection......................................................................... 25
7
Statistical Procedures.............................................................................................................. 25
7.1 Analysis Populations......................................................................................................... 25
7.2 Hypothesis and Methods of Analysis................................................................................ 25
Safety Analyses..................................................................................................... 25
7.3 Subgroup Analyses............................................................................................................ 26
7.4 Sample Size Calculation ................................................................................................... 26
7.5 Interim Analyses ............................................................................................................... 26
8
Study Visit Schedule and Procedures...................................................................................... 26
8.1 Participant Entry Procedures............................................................................................. 26
Overview of Entry Procedures.............................................................................. 26
Informed Consent and Participant Privacy ........................................................... 26
8.2 Washout Intervals/Run-in ................................................................................................. 27
8.3 Procedures for Final Study Entry...................................................................................... 27
8.4 Visits and Associated Procedures...................................................................................... 28
Open-label Treatment Period (40 Weeks)............................................................. 28
8.4.1.1 Visit 1 (Day 1)........................................................................................... 28
8.4.1.2 Visits 2 to Visit 11 (Week 4 to 40) ............................................................ 29
8.4.1.3 Visit 11/Early Termination (Week 40) ...................................................... 29
Safety Follow-up Period (4 Weeks)...................................................................... 30
8.4.2.1 Visit 12/End of Study (Week 44) Conducted Remotely ........................... 30
8.4.2.2 Visit 12/End of Study (Week 44) Conducted In-Person Prior to the 
COVID-19 Pandemic................................................................................ 30
8.5 Instructions for the Participants ........................................................................................ 30
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8.6 Unscheduled Visits............................................................................................................ 31
8.7 Compliance with Protocol................................................................................................. 31
8.8 Early Discontinuation of Participants............................................................................... 31
8.9 Withdrawal Criteria........................................................................................................... 32
8.10
Study Termination................................................................................................. 33
9
Adverse Events ....................................................................................................................... 33
9.1 Definitions......................................................................................................................... 33
Adverse Event....................................................................................................... 33
Serious Adverse Event .......................................................................................... 34
Intensity................................................................................................................. 35
Assessment of Causality ....................................................................................... 36
Follow-up of Adverse Events and Serious Adverse Events.................................. 36
9.2 Procedures for Reporting Adverse Events ........................................................................ 37
9.3 Procedures for Reporting a Serious Adverse Event.......................................................... 37
Regulatory Reporting Requirements for Serious Adverse Events........................ 37
9.4 Exposure to Study Intervention During Pregnancy .......................................................... 38
9.5 ALT or AST Elevations..................................................................................................... 38
Potential Hy’s Law Cases..................................................................................... 39
10 Administrative Items............................................................................................................... 40
10.1
Protection of Human Participants......................................................................... 40
Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations.............................................................................. 40
Compliance With IRB or IEC Regulations........................................................... 41
Compliance With Good Clinical Practice............................................................. 41
Compliance With Electronic Records; Electronic Signatures Regulations (US 
21CFR Part 11) ..................................................................................................... 41
10.2
Financial Disclosure.............................................................................................. 41
10.3
Changes to the Protocol ........................................................................................ 41
10.4
Data Protection...................................................................................................... 42
10.5
Participant Privacy................................................................................................ 42
10.6
Documentation...................................................................................................... 42
Source Documents ................................................................................................ 42
Case Report Form Completion ............................................................................. 43
Study Summary..................................................................................................... 44
Retention of Documentation................................................................................. 44
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10.7
Labeling, Packaging, and Return or Disposal of Study Intervention ................... 44
Labeling/Packaging............................................................................................... 44
Clinical Supply Inventory..................................................................................... 44
Return or Disposal of Study Intervention and/or Supplies................................... 45
10.8
Monitoring by the Sponsor ................................................................................... 45
10.9
Handling of Biological Specimens ....................................................................... 45
10.10
Publications........................................................................................................... 45
10.11
Coordinating Investigator ..................................................................................... 46
11 References............................................................................................................................... 47
12 Attachments ............................................................................................................................ 49
12.1
Examples of Prohibited Medications.................................................................... 49
12.2
Classification of Migraine Preventive Medications.............................................. 51
12.3
Glossary of Abbreviations..................................................................................... 52
12.4
Protocol Amendment 1 Summary......................................................................... 54
List of Tables
Table 1.
Schedule of Visits and Procedures for In-person Visits Conducted Prior to or 
During the COVID-19 Pandemic.....................................................................11
Table 2.
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the 
COVID-19 Pandemic...................................................................................... 12
Table 6-1.
Study Intervention........................................................................................... 22
Table 6–2.
Clinical Laboratory Parameters ...................................................................... 23
List of Figures
Figure 1.
Study Diagram ................................................................................................ 10
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Protocol Summary
Study Compound: Atogepant
Phase: 3
Study Objective:
To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily for the prevention of migraine 
over a 40-week duration. 
Clinical Hypotheses:
Atogepant 60 mg once daily is safe and well tolerated when administered over 40 weeks
Study Design
Structure: Multicenter, open-label, 40-week, long-term safety extension study conducted in the United States 
Duration: The study will consist of a 40-week treatment period, and a safety follow-up period of an additional 
4 weeks, for a total duration of 44 weeks.
Study Intervention: Atogepant 60 mg once daily
Control: Not applicable
Dosage/Dose Regimen: Atogepant 60 mg once daily will be administered for 40 weeks.
Randomization: Not applicable
Visit Schedule: Participants will directly rollover from Study 3101-301-002 (Phase 3 episodic migraine [EM]). As 
such, participants will have Visit 7 from Study 3101-301-002 function as the 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 End of Study (EOS) Visit will occur 4 weeks after the last dose of atogepant. During the COVID-19 
pandemic, Visit 12 (Follow-up/End of Study) should be conducted remotely for all participants.
Note, there may be participants who complete Visit 7 in the lead-in Study 3101-301-002 before extension 
Study 3101-309-002 has been initiated. Those participants should complete Visit 7/ET and Visit 8/EOS Visit 
(including discontinuation of IP) per the Study 3101-301-002 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, Visit 1 Study 3101-309-002 can be conducted on the same day as Visit 8/EOS Visit for
Study 3101-301-002 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 Study 3101-301-002 should be conducted on the same day as Visit 1 for 
Study 3101-309-002.
!
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 
Study 3101 301-002 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 3101-309-002 
Schedule of Visits and Procedures.
For details, please see Table 1, the Schedule of Visits and Procedures.
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Study Population Characteristics
Number of Participants/Sites: All participants who complete Study 3101-301-002, and meet all eligibility 
requirements, may participate in this study. Based on expected completion rates from Study 3101-301-002, it is 
estimated that approximately 750 participants will be enrolled from approximately 110 centers in the United States.
Condition/Disease: Migraine with aura or migraine without aura (ICHD-3 Section 1.1 or Section 1.2)
Inclusion Criteria:
!
Written informed consent and participant privacy information (eg, written authorization for use and release of 
health and research study information) obtained from the participant prior to initiation of any study-specific 
procedures.
!
Participants must be using a medically acceptable and effective method of birth control during the course of the 
entire study, as defined in Section 4.4.3.
!
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 3101-301-002 without significant 
protocol deviations (eg, noncompliance to protocol-required procedures) and who did not experience an 
adverse event (AE) that, in the investigator’s opinion, may indicate an unacceptable safety risk.
Key Exclusion Criteria:
!
Participants with clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease.
Response Measures
Safety – AEs, physical examinations, clinical laboratory determinations, vital sign measurements, electrocardiogram 
(ECG) parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS)
Efficacy – Not applicable
General Statistical Methods and Types of Analyses: 
The safety parameters will include AEs, clinical laboratory determinations, vital sign measurements, ECG 
parameters, and the C-SSRS. For each of the clinical laboratory determinations, vital sign measurements, and ECG 
parameters, the last non-missing safety assessment before the first dose of treatment will be used as the baseline for 
all analyses of that safety parameter. For all participants, baseline in lead-in study (Study 3101-301-002) will be 
used. Continuous variables will be summarized by the number of participants and mean, standard deviation (SD), 
median, minimum, and maximum values. Categorical variables will be summarized by number and percentage of 
participants.
Sample Size Calculation: 
As this is a safety extension study, all eligible participants from lead-in Study 3101-301-002 may be enrolled.
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Figure 1.
Study Diagram
ET = early termination; V = visit; Wk = week.
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Table 1.
Schedule of Visits and Procedures for In-person Visits Conducted Prior to or During the COVID-19 Pandemic
Study Period
Open-label Treatment Period (40 weeks)
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 1a
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10 Visit 11/ET
Visit 12/
EOSe
Day/Week
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)
Visit Windows
± 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
privacy
X
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Assess inclusion/exclusion criteria
X
Perform physical examination
X
X
X
Collect vital sign measurementsb
X
X
X
X
X
X
X
X
X
X
X
X
Perform ECG
X
X
X
X
Perform urine pregnancy testc
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory determinationsd
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study intervention (ie, atogepant)
X
X
X
X
X
X
X
X
X
X
Review of study intervention (ie, 
atogepant) compliance and accountability
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; ET = early termination; INR = international normalized 
ratio; IWRS = interactive web response system.
a
After providing informed consent for the current study, Visit 1 will be conducted on the same day as Study 3101-301-002 Visit 7; procedures collected as 
part of Study 3101-301-002 Visit 7 should not be repeated. Visit 1 must be conducted as an in-person visit.
b
Vital sign measurements: Weight, sitting and standing pulse rate, respiratory rate, sitting and standing blood pressure, and body temperature.
c
For women of child-bearing potential only, a urine pregnancy test will be performed at all visits.
d
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 screening (Visit 1).
e
During the COVID-19 pandemic, Visit 12 (Follow-up/End of Study) should be conducted remotely for all participants.
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Table 2.
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the COVID-19 Pandemic
Study Period
Open-label Treatment Period (40 weeks)a
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11/ET
Visit 12/
EOSc
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)
Visit Windows
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
± 3 days
+ 3 days
± 3 days
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
Provide urine pregnancy test and 
instructionsb
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
Dispense study intervention (ie, atogepant)
X
X
X
X
X
X
X
X
X
Review of study intervention (ie, atogepant) 
compliance and accountability
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; ET = early termination; IWRS = interactive web response 
system.
a
For participants who have a study visit replaced by a remote study visit, all missed in-person safety assessments (clinical laboratory determinations, vital 
signs, and ECGs) will be collected at the next in-person visit. To ensure participant safety, remote study visits can 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 be discontinued from the study.
b
For women of childbearing potential only, a urine pregnancy test must be performed within 48 hours prior to the remote visits. Investigators/site staff will 
provide participants with study-supplied urine pregnancy tests and corresponding written instructions to be used at home by participants for remote study 
visits. Sites are required to verbally review testing instructions with all participants.
c
During the COVID-19 pandemic, Visit 12 (Follow-up/End of Study) should be conducted remotely for all participants.
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1
Background and Clinical Rationale
1.1
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25 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). 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).
Migraine is typically characterized by attacks of throbbing, unilateral headache of moderate or 
severe pain intensity, associated with nausea, vomiting, and/or sensitivity to light (photophobia) 
and sound (phonophobia). In about 25% of individuals, the migraine headache is preceded by 
focal neurological dysfunction (aura). Improving diagnosis and optimizing treatments for 
migraine have been recognized as critically important to overcoming current barriers to reduce 
the global burden of migraine.
Because there are no biological markers for migraine, diagnosis is based on clinical history, 
examination, and the exclusion of other headache disorders. Physicians apply clinical criteria to 
guide diagnoses and subsequent treatment. 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 safety and 
tolerability of atogepant in participants with migraine.
1.2
Overview of Atogepant
Atogepant is a potent, selective oral CGRP receptor antagonist being developed for migraine 
prevention. Additional information on non-clinical pharmacology, toxicology, and PK properties 
of atogepant can be found in the IB. 
A Phase 2/3 clinical study was conducted, which compared atogepant 10 mg once daily, 
atogepant 30 mg once daily, atogepant 30 mg BID, atogepant 60 mg once daily and atogepant 
60 mg BID to placebo. 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 
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12-week treatment period, all atogepant doses demonstrated a statistically significant reduction 
compared with placebo in participants with EM.
1.3
Study Rationale
The purpose of this study is to evaluate the safety and tolerability of atogepant 60 mg once daily, 
when taken for 40 weeks for the prevention of EM.
1.4
Rationale for Doses and Dose Regimens Selected
The Phase 3 pivotal studies to evaluate atogepant will test a maximum dose of 60 mg once daily. 
For this reason, the same dose of 60 mg once daily has been selected for this study to evaluate 
the long-term safety and tolerability of atogepant for the prevention of EM.
2
Study Objective and Clinical Hypotheses 
2.1
Study Objective
To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily when 
administered over 40 weeks for the prevention of migraine in participants with EM.
2.2
Clinical Hypothesis
Atogepant 60 mg once daily is safe and well tolerated when administered over 40 weeks for the 
prevention of migraine in participants with EM.
3
Study Design
3.1
Structure
This is a multicenter, open-label, 40-week, long-term safety extension study conducted in the 
United States and will enroll approximately 750 participants from approximately 110 sites. 
Participants will be treated with atogepant 60 mg once daily.
The study will consist of a 40-week open-label treatment period, and a safety follow-up period of 
4 weeks. 
Participants will directly rollover from Study 3101-301-002 (Phase 3 EM). As such, participants 
will have Visit 7 from Study 3101-301-002 function as the 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.
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Note, there may be participants who complete Visit 7 in the lead-in Study 3101-301-002 before 
extension Study 3101-309-002 has been initiated. Those participants should complete Visit 7/ET 
and Visit 8/EOS Visit (including discontinuation of study intervention) per the Study 3101-301-
002 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, Visit 1 Study 3101-309-002 can be conducted on the same day as Visit 
8/EOS Visit for Study 3101-301-002 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 Study 3101-301-002 should be conducted on the same 
day as Visit 1 for Study 3101-309-002.
!
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 Study 3101-301-002 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 3101-309-002 Schedule of Visits 
and Procedures.
After Visit 1, study visits will occur every 4 weeks for the duration of the 40-week treatment 
period. Participants will return to the clinic for safety assessments at 4, 8, 12, 16, 20, 24, 28, 32, 
36 and 40 weeks relative to Visit 1 (Day 1). An EOS Visit will occur 4 weeks after the last dose 
of atogepant 60 mg once daily. During the COVID-19 pandemic, Visit 12 (Follow-up/End of 
Study) should be conducted remotely for all participants. For the schedule of visits and 
procedures conducted in-person, see Table 1. 
To eliminate immediate potential hazards to participants and study staff due to the COVID-19 
pandemic while ensuring participant safety and maintaining data integrity, the protocol has been
updated to allow investigators/appropriately designated study staff to perform study visits 
remotely. For the schedule of visits and procedures conducted remotely, see Table 2. 
The primary objective of the study is to assess the safety and tolerability of long-term atogepant 
treatment. The planned safety assessments include collection of AEs, clinical laboratory 
determinations, ECGs, vital sign measurements, physical examinations, and the C-SSRS. 
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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 Allergan, including modification or 
ET of a trial, if emerging data show unexpected and clinically significant AEs. 
Details of the DSMB memberships, standard operational procedures for data monitoring/review, 
frequency of review, and other pertinent details will be provided in a separate DSMB Charter.
3.3
Adjudication Committee
An Adjudication Charter will be established and will describe the process for the surveillance, 
monitoring, and adjudication by the 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
Approximately 750 participants will be treated with atogepant 60 mg once daily at
approximately 110 centers in the United States. 
4.2
Inclusion Criteria
1. Written informed consent and participant privacy information (eg, written authorization 
for use and release of health and research study information) obtained from the participant
prior to initiation of any study-specific procedures.
2. Participants must be using a medically acceptable and effective method of birth control 
during the course of the entire study, as defined in Section 4.4.3.
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 3101-301-002 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.
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4.3
Exclusion Criteria
1. Requirement for any medication, diet (ie, grapefruit juice), that is on the list of prohibited 
concomitant medications (see Section 4.4.2 and Attachment 12) that cannot be 
discontinued or switched to an allowable alternative medication. This includes 
concomitant medications with demonstrated efficacy for the prevention of migraine (eg, 
amitriptyline, topiramate, propranolol).
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.
3. An ECG with clinically significant abnormalities at Visit 1 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. Vital sign measurements that exceed these limits may be 
repeated only once.
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) since the last visit. 
6. Participants with clinically significant hematologic, endocrine, cardiovascular, pulmonary, 
renal, hepatic, gastrointestinal, or neurologic disease.
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
Permissible and Prohibited Medications/Treatments
Permissible Medications/Treatments
Medications that are not specifically prohibited in Section 4.4.2 are allowed, with the following 
clarifications and restrictions.
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The following medications for the acute treatment of migraine are allowed during the study:
!
Any triptan
!
Any ergot derivative
!
Any opioid
!
Any other form of analgesic (including acetaminophen)
!
Any NSAID agent
!
Any antiemetic agent
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
SSRI or SNRI will be permitted, provided that treatment is stable for at least 60 days prior to 
Visit 1 and continues without change in dose throughout the study.
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 
Allergan.
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) for 
all participants and throughout the study (see Attachment 12.1):
!
Strong and moderate CYP3A4 inhibitors, including but not limited to: systemic (oral/IV) 
itraconazole, ketoconazole, fluconazole, erythromycin, clarithromycin, telithromycin, 
diltiazem, verapamil, aprepitant, cyclosporine, nefazodone, 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, gemfibrozil) 
!
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). See Attachment 12.2
!
CBD oil
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!
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, Myobloc®, 
Xeomin®, JeuveauTM) into areas of the head, face, or neck within 6 months prior to Visit 1 
and for the duration of the study
!
Injectable monoclonal antibodies blocking the CGRP pathway (eg, AimovigTM, 
EmgalityTM, Ajovy®) within 6 months prior to Visit 1 and for the duration of the study
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, Allergan should be notified before the 
prohibited medication/treatment is administered.
Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For purposes of this study, women will be considered of childbearing potential unless they are 
naturally postmenopausal (ie, no menses for 2 years) or permanently sterilized (ie, bilateral tubal 
ligation, bilateral tubal occlusion [eg, Essure® placement with HSG confirmation], bilateral 
salpingectomy, bilateral oophorectomy, or hysterectomy). For women of child-bearing 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, 
intravaginal, or transdermal (ie, pill, vaginal ring, patch)
!
Progestogen-only hormonal contraception (with inhibition of ovulation) that are oral, 
injectable,or implantable
!
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)
!
Male or female condom with or without spermicide (female and male condoms should not 
be used together)
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!
Cap, diaphragm or sponge with spermicide
!
A combination of male condom with either cap, diaphragm or sponge 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 Allergan 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 (2) follow the progress of the pregnancy. The 
investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to Allergan.
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 12-ounce can/bottle of beer, a 4-ounce glass of wine, or 1 ounce of liquor.
4.5
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently treated.
5
Study Intervention
5.1
Study Intervention and Formulations
Tablets containing atogepant 60 mg (Formulation Number: 11281X)
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6
Control Intervention 
Not applicable.
6.1
Methods for Masking/Blinding
This is an open-label study. 
6.2
Treatment Allocation Ratio
All participants will be treated with atogepant 60 mg once daily. 
6.3
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 their lead-in study participant number. This number will serve as 
the participant identification number on all study documents.
At Visit 1, eligible participants will receive atogepant 60 mg once daily.
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.
Atogepant bottles will be dispensed at the study visits summarized in the Schedule of Visits and 
Procedures. Returned atogepant bottles should not be re-dispensed to the participants.
6.4
Treatment Regimen and Dosing
Participants who meet all of the study entry criteria at Visit 1 will be treated with atogepant 
60 mg once daily. 
Atogepant to be used in this trial is listed in Table 6-1.
Participants will be instructed to take their atogepant at approximately the same time each day. 
Atogepant will be administered orally for 40 weeks, and participants will be followed for 
4 weeks following completion or discontinuation of the atogepant.
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Table 6-1.
Study Intervention
Drug/Dose
Study Intervention Frequency
Route of Administration
Atogepant 60 mg
Once daily
Oral
6.5
Safety Measures
Adverse Events
AEs will be collected from the time of consent through the last visit. For all AEs, the investigator 
must provide an assessment of the severity, causal relationship to the investigational product, 
start and stop date, 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, Allergan must be notified immediately to meet their reporting obligations 
to appropriate regulatory authorities.
Adverse Events of Special Interest 
Selected non-serious and SAEs are of special interest (AESI) 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 
!
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 AESI, ALT or AST elevations, and potential Hy’s law cases are 
outlined in Sections 9.5 and 9.5.1. These AEs or events determined to be SAEs must be reported 
appropriately via the designated eCRFs and safety forms.
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. The investigator will assess the 
clinical significance of any values outside the reference ranges provided by the central 
laboratory. Participants with abnormalities judged to be clinically significant, laboratory values 
that meet exclusionary criteria, or positive results on the urine drug screen at Visit 1 will be 
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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 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 6–2.
Table 6–2.
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 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. Those with a positive result on the Visit 1 urine drug 
screen for recreational (including marijuana regardless of legality) or illicit drugs or 
non-disclosed concomitant medications are not allowed to be repeated. For all other 
positive results, the urine drug screen may be repeated with permission from 
Allergan; 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.
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. Sitting and standing 
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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).
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.
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.
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 all visits the C-SSRS will be completed for ideation and behavior since last visit for all 
participants. The C-SSRS will be completed 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 
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not considered to be at risk. Participants who reply with “yes” to questions 4 or 5 in the suicidal 
ideation section or “yes” to any question in the suicidal behavior section of the C-SSRS at Visits 
2 through 10 must be withdrawn from the study and should receive appropriate follow-up as in 
routine clinical practice, including the ET (Visit 11) and the EOS (Visit 12) visits.
6.6
Other Study Supplies
The following will be provided by Allergan or Allergan 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 
6.7
Summary of Methods of Data Collection
An IWRS will be used to manage atogepant inventory. All office visit data for this study will be 
collected by eCRFs via an electronic data capture system. Source documents will be used at the 
sites and may include a participant’s medical record, hospital charts, clinic charts, the 
investigator’s participant study files, as well as the results of diagnostic tests such as laboratory 
tests, ECGs, etc. A centralized clinical laboratory will be used for the analysis of all blood and 
urine samples, and for ECG assessments. Additional information on the collection and handling 
of samples is detailed in the Laboratory Procedure Manual.
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 atogepant in this extension study. 
7.2
Hypothesis and Methods of Analysis
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 
as defined for the lead-in study (3101-301-002) will be used as the baseline in this extension 
study (3101-309-002).
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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.
Due to the COVID-19 pandemic, the study conduct and participants may be impacted. As per 
FDA guidance (FDA 2020), specific tables and listings will be generated to present the impact. 
In addition, analyses to further address the impact may be conducted.
7.3
Subgroup Analyses
No subgroup analysis is planned.
7.4
Sample Size Calculation
As this is a safety extension study from the lead-in Study 3101-301-002, all participants from the 
lead-in study who are eligible for this extension study will be enrolled. No separate sample size 
calculation was performed. Based on expected completion rate from the lead-in Study 3101-301-
002, approximately 750 participants will be enrolled into this long-term, open-label, safety 
extension study.
7.5
Interim Analyses
Interim data-cuts are planned to provide ongoing safety data to support global regulatory 
submissions. 
8
Study Visit Schedule and Procedures
See Table 1 for a schematic of the Schedule of Visits and Procedures conducted in-person, and
Table 2 for a schematic of the Schedule of Visits and Procedures conducted remotely due to the 
COVID-19 pandemic. See Figure 1 for a study visit flowchart.
8.1
Participant Entry Procedures
Overview of Entry Procedures
Prospective participants as defined by the criteria in Sections 4.2 and 4.3 (inclusion/exclusion 
criteria) will be considered for entry into this study.
Informed Consent and Participant Privacy
The study will be discussed with the participant, and a participant wishing to participate must 
give informed consent prior to any study-related procedures or change in treatment. The 
participant must also give authorization, and other written documentation in accordance with the 
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relevant country and local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment.
Participants will maintain their lead-in study participant identification number.
8.2
Washout Intervals/Run-in
This study will not include a washout period.
8.3
Procedures for Final Study Entry
At Visit 1 participants must meet all of the inclusion criteria and must not meet any of the 
exclusion criteria. 
Participants will directly rollover from Study 3101-301-002 (Phase 3 EM). As such, participants 
will have Visit 7 from Study 3101-301-002 function as the 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. 
Note, there may be participants who complete Visit 7 in the lead-in Study 3101-301-002 before 
extension Study 3101-309-002 has been initiated. Those participants should complete Visit 7/ET 
and Visit 8/EOS Visit (including discontinuation of study intervention) per the Study 3101-301-
002 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, Visit 1 Study 3101-309-002 can be conducted on the same day as Visit 
8/EOS Visit for Study 3101-301-002 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 Study 3101-301-002 should be conducted on the same day as Visit 1 
for Study 3101-309-002.
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 Study 3101-301-002 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 3101-309-002 Schedule of Visits and Procedures.
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8.4
Visits and Associated Procedures
There will be 12 scheduled clinic visits: 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/ET (Week 40), and Visit 12/EOS (Week 44). 
Refer to Table 1 for assessments to be performed at in-person study visits. Refer to Table 2 for 
assessments to be performed at study visits conducted remotely due to the COVID-19 pandemic.
For participants who have a study visit replaced by a remote study visit, all missed in-person
safety assessments (clinical laboratory determinations, vital signs, and ECGs) will be collected at 
the next in-person visit. To ensure participant safety, remote study visits can 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 be discontinued from the study.
 Open-label Treatment Period (40 Weeks)
8.4.1.1Visit 1 (Day 1)
!
Obtain informed consent and participant privacy.
!
Register participant in IWRS.
!
Review and record prior medications taken in the past 6 months, and all prior migraine 
headache medications and concomitant medications.
!
Assess inclusion/exclusion criteria.
!
Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, pulse rate, 
respiration rate, temperature, and weight).
!
Perform physical examination.
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect urine for drug screen.
!
Perform and transmit ECG 
!
Collect blood and urine for clinical laboratory determinations including: serology, INR, 
and urinalysis.
!
Review and assess AEs.
!
Review and update concomitant medications and concurrent procedures.
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!
Access IWRS and obtain the kit number for atogepant bottle and dispense atogepant 
bottle.
8.4.1.2Visits 2 to Visit 11 (Week 4 to 40)
Refer to Table 2 for assessments to be performed at study visits conducted remotely due to the 
COVID-19 pandemic.
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, 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 11 [Week 40] 
only).
!
Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.
!
Review and assess AEs.
!
Review and update concomitant medications and concurrent procedures.
!
Access IWRS to dispense atogepant bottle and enter accountability.
8.4.1.3Visit 11/Early Termination (Week 40)
Effort should be made by the site to not schedule Visit 11 earlier than 40 weeks after Day 1, to 
ensure participants complete the full 40 weeks of atogepant treatment.
!
Perform physical examination.
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, 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.
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!
Review and update concomitant medications and concurrent procedures.
!
Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.
!
Access IWRS to enter study visit and accountability.
Safety Follow-up Period (4 Weeks)
8.4.2.1 Visit 12/End of Study (Week 44) Conducted Remotely
During the COVID-19 pandemic, Visit 12 (Follow-up/End of Study) should be conducted 
remotely for all participants. Refer to Table 2 for assessments to be performed at study visits 
conducted remotely due to the COVID-19 pandemic.
8.4.2.2 Visit 12/End of Study (Week 44) Conducted In-Person Prior to the 
COVID-19 Pandemic
!
Perform physical examination.
!
Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, pulse rate, 
respiration rate, temperature, and weight). 
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.
!
Review and assess AEs.
!
Update concomitant medications and concurrent procedures.
!
Access IWRS to enter study visit.
8.5
Instructions for the Participants
Section 4.4.4 provides diet and activity instructions for participants enrolled in the study.
Prohibited medications should be reviewed with the participants. Participants will be instructed 
to return their atogepant bottle(s), both used and unused at each visit.
Participants should be instructed to take atogepant 60 mg once daily at approximately the same 
time each day (approximately 24 hours between doses). 
Participants should use appropriate contraceptive measures for the duration of their participation 
in the study (Section 4.4.3).
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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 (or Table 2 if 
conducted remotely due to the COVID-19 pandemic), 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
!
Non-compliance with study intervention (ie, atogepant)
!
Pregnancy
!
Protocol deviation
!
Site terminated by Allergan
!
Study terminated by Allergan
!
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 
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be seen for final study assessments. The final assessments will be defined as the evaluations 
scheduled for Visit 11/ET and Visit 12/EOS, 4 weeks post the last dose of atogepant.
8.9
Withdrawal Criteria
!
Participants with the following at Visit 1:
o
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 testing, or anti-hepatitis E IgM antibody.
o
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)
!
Participants with the following at any study visit:
o
Female participants who become pregnant (Section 9.4) 
o
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. 
o
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 10 must be withdrawn from the study.
o
A participant with a condition and/or a situation that, in the investigator's opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study may be 
withdrawn from treatment.
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All withdrawn participants should receive appropriate follow-up as in routine clinical practice, 
including the ET (Visit 11) and the EOS (Visit 12) assessments.
8.10
Study Termination
The study may be stopped at the study site at any time by the site investigator. Allergan 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
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 Visit 1, AEs 
will be assessed regardless of the administration of atogepant.
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 12), 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 for visits conducted in-person, or Table 2 for visits 
conducted remotely due to the COVID-19 pandemic), 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 
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AEs by asking each participant a general, non-directed question such as “How have you been 
feeling since the last visit?” Open-ended and non-leading 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.
Serious Adverse Event
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.
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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.
Allergan considers all cancer AEs as SAEs. In addition, Allergan 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 are 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 Allergan.
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 one of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
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Assessment of Causality
Assessment of Causality
!
The investigator is obligated to assess the relationship between atogepant and each 
occurrence of each AE or SAE.
!
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.
!
The investigator will use clinical judgment to determine the relationship.
!
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.
!
The investigator will also consult the investigator’s brochure in his/her assessment.
!
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.
!
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Allergan. 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 Allergan.
!
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.
!
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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 non-serious AEs of special interest (as defined 
in Section 6.5.2) 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 Allergan 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 
health care professionals.
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 
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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 Allergan 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 12) 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 Allergan as listed on the Allergan 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 Allergan and the IRB/IEC with any additional requested information (eg, autopsy reports 
and discharge summaries).
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to Allergan 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. 
!
Allergan 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. Allergan will comply with country-specific regulatory requirements relating 
to safety reporting to the regulatory authority, IRBs/ IECs, and investigators.
!
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Allergan policy and forwarded to investigators as necessary.
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!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs from Allergan) 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 12) 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 or elective 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
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. An extra blood serology sample must be 
collected and sent to the central laboratory for further diagnostic testing, at a later date, if needed.
In addition, the investigator will perform a complete history and examination to evaluate the 
participant for possible liver disease.
All AEs of special interest must be reported to Allergan within 24 hours of the time the 
investigator becomes aware of the event using the abnormal liver function reporting form and the 
AE eCRF. All new elements of history, physical examination, diagnostic testing results, and 
other relevant medical reports are to be reported for each AE of special interest.
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 
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quantitative RNA by polymerase chain reaction, anti-hepatitis E IgM, anti-hepatitis E IgG, 
Cytomegalovirus IgM antibody and Epstein-Barr Virus IgM antibody. The participant must be 
followed clinically and further medical evaluation (for other causes of acute hepatic injury) 
should be done per the judgment of the investigator and in conjunction with medical personnel at
Allergan. 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 Allergan 
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 Allergan 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.
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 
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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 
Allergan immediately when the above criteria have been met. A possible Hy’s law case must be 
faxed to Allergan on an abnormal liver function reporting form as soon as possible (within 24 
hours of learning of the possible Hy’s law case) to the fax number on the form or the SAE fax 
number, even if 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).
10.1
Protection of Human Participants
Compliance With Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations
Written informed consent is to be obtained from each participant, and/or from the participant's 
legally authorized representative, prior to any study-related activities or procedures in the study.
The following process will be followed:
!
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
!
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study center. 
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!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB. 
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Compliance With IRB or IEC Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) or 
applicable IEC regulations. The investigator must obtain approval from a properly constituted 
IRB/IEC prior to initiating the study and re-approval or review at least annually. Allergan is to 
be notified immediately if the responsible IRB/IEC has been disqualified or if proceedings 
leading to disqualification have begun. Copies of all IRB/IEC correspondence with the 
investigator should be provided to Allergan.
Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
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 Allergan with sufficient, accurate financial 
information as requested to allow Allergan 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 Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards to 
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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 Allergan will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Allergan 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 Allergan, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
10.5
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, and/or from the participant's legally authorized representative 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
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 
randomization (or medication kit) number
!
The study title and/or the protocol number of the study and the name of Allergan
!
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).
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 Allergan in a timely manner at the completion of the study, or as otherwise specified by 
Allergan and will be maintained in a central data repository.
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Study Summary
An investigator's summary will be provided to Allergan within a short time after the completion 
of the study, or as designated by Allergan. A summary is also to be provided to the responsible 
IRB/IEC.
Retention of Documentation
All study related correspondence, participant records, consent forms, participant privacy 
documentation, records of the distribution and use of all atogepant, and copies of eCRFs should 
be maintained on file.
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of atogepant. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirement(s) or if needed by Allergan.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
Allergan requires that it be notified in writing if the investigator wishes to relinquish ownership 
of the data so that mutually agreed-upon arrangements can be made for transfer of ownership to a 
suitably qualified, responsible person.
10.7
Labeling, Packaging, and Return or Disposal of Study Intervention
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.
Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the participants, the number of units 
returned to the investigator by the participant, and the number of units returned to Allergan 
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 
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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.
Return or Disposal of Study Intervention and/or Supplies
All atogepant and/or supplies will be returned to Allergan or Allergan designee for destruction.
10.8
Monitoring by the Sponsor
A representative of Allergan 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 Allergan 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 Allergan or Allergan’s designee for destruction. Allergan 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
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and Allergan 
personnel. Authorship will be established prior to the writing of the manuscript. As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the 
final report of the multicenter study except as agreed with Allergan.
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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
Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS. EFNS guidelines on the 
drug treatment of migraine – revised report of an EFNS task force. Eur J Neurol 2009 Sep; 
16(9):968-981.
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020 (Updated July 2, 2020).
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1-211.
Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in 
migraine. Expert Review of Clinical Pharmacology. Taylor & Francis; 2014 Mar;7(2):191-201.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United 
States. Arch Intern Med. 1999;159:813-818.
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. 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
peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 
2004;350:1104-1110.
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, Freita F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline 
update: pharmacologic treatment for episodic migraine prevention in adults. Neurology 
2012;78:1337-1345.
Steiner TJ, Paemeleire K, Jensen R, Valade D, Savi L, Lainez MJA, et al. European principles of 
management of common headache disorders in primary care. J Headache Pain 2007 Oct8
Suppl 1:S3-47.
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Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. J Headache Pain 
2013;14(1):1-2.
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010;11:289–299.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systemic analysis 
for the Global Burden of Disease Study 2010. Lancet 2013;14(9859):2163-2196.
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12 Attachments
12.1
Examples of Prohibited Medications
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) 
and throughout the study:
!
Strong OATP1B1 inhibitors eg, Gemfibrozil (Lopid™)
!
CBD oil
Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Anti-depressants/ 
Anti-anxiety
Barbiturates 
!
Amobarbital (Amytal™)
!
Aprobarbital (Alurate™)
!
Butalbital (Fiorinal™, Fioricet™)
!
Butabarbital (Busodium™, 
Butisol™)
!
Mephobarbital (Mebaral™)
!
Pentobarbital (Nembutal™)
!
Phenobarbital (Luminal™, 
Solfoton™)
!
Secobarbital (Seconal™)
Nefazodone (Serzone™) 
Anti-seizure
Carbamazepine (Atretol™, Carbatrol™, 
Epitol™, Equetro™, Tegretol™)
Oxcarbazepine (Trileptal™)
Phenytoin (Dilantin™, Phenytek™)
Primidone (Myidone™, Mysoline™)
Diabetes 
Pioglitazone (Actos™)
Troglitazone (Rezulin™, Resulin™)
Antiemetic
Aprepitant (Emend™)
Anti-hypertension
Diltiazem (Cardizem™)
Verapamil (Calan™, Calan SR™)
Glucocorticoid 
(Systemic)
Betamethasone (Celestone™)
Dexamethasone (Baycadron™, DexPak™)
Hydrocortisone (Cortef™)
Methylprednisolone (Medrol™)
Prednisolone (Prelone™)
Prednisone (Deltasone™)
Triamcinolone (Kenalog™)
Antibiotics
Rifabutin (Mycobutin™) 
Rifampicin/Rifampin (Rifadin™, Rifater™, 
Rimactane™) 
Erythromycin (Benzamycin™, 
EryTab™)
Clarithromycin (Biaxin™)
Telithromycin (Ketek™)
Anti-fungal
Fluconazole (Diflucan™, Trican™)
Itraconazole (Sporanox™)
Ketoconazole (Nizoral™)
Anti-HIV
Efavirenz (Stocrin™, Sustiva™) 
Nevirapine (Viramune™)
Indinavir (Crixivan™)
Nelfinavir (Viracept™) 
Ritonavir (Norvir™)
Saquinavir (Fortovase™, Invirase™)
Immune Suppressant
Cyclosporine - Oral/IV only (Neoral™, 
Sandimmune™)
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Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Others
St. John’s wort 
Enzalutamide (Xtandi™)
Modafinil (Provigil™)
Armodafinil (Nuvigil™)
Buprenorphine (Cizol™, Subutex™, 
Suboxone™)
Quinine
Drugs with narrow therapeutic margins with 
potential for CYP drug interactions
Warfarin (Coumadin™)
Digoxin (Digitek™, Lanoxin™, Digox™)
Cisapride (Prepulsid™, Propulsid™)
Pimozide (Orap™)
Drugs with demonstrated efficacy for the 
prevention of migraine
Topiramate (Topamax™)
Valproic acid, sodium valproate, divalproex sodium (Depakote™)
Amitriptyline (Elavil™)
Nortriptyline (Pamelor™)
Metoprolol (Lopressor™, Toprol™)
Atenolol (Tenormin™)
Nadolol (Corgard™)
Propranolol (Inderal™)
Timolol (Apo-Timol™)
Flunarizine (SibeliumTM)
Candesartan (AtacandTM)
Lisinopril (Zestril TM, PrinivilTM)
Desvenlafaxine (Pristiq™)
Venlafaxine (Effexor™)
The following medications or treatments are prohibited 6 months prior to Visit 1 and 
throughout the study:
!
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, Xeomin®, 
Myobloc®, JeuveauTM) into areas of the head, face, or neck.
!
Injectable monoclonal antibodies blocking the CGRP pathway (eg, AimovigTM, 
EmgalityTM, Ajovy®) 
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12.2
Classification of Migraine Preventive Medications
Below is a list of migraine preventive medications considered effective or probably effective 
sorted by mechanism of action. Of note, topiramate and valproic acid derivatives are considered 
separate categories. 
Pharmacologic Category
Drug Name
Antiepileptic
Valproic acid, sodium valproate, divalproex sodium
Topiramate
Tricyclic antidepressant
Amitriptyline
Nortriptyline
Beta-blockers
Metoprolol
Bisoprolol
Atenolol
Nadolol
Propranolol
Timolol
Calcium channel blocker
Flunarizine
Angiotensin receptor blocker (ARB)
Candesartan
Angiotensin-converting enzyme (ACE) inhibitor
Lisinopril
Serotonin-norepinephrine reuptake inhibitor (SNRI)
Desvenlafaxine
Venlafaxine
Miscellaneous
Country approved products for migraine prevention 
(eg, oxetrone, pizotifen)
Source: Evers 2009, Hoffmann 2014, Schürks 2008, Silberstein 2012, Steiner 2007.
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12.3
Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CBD
cannabidiol
CGRP
calcitonin gene-related peptide
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
EM
episodic migraine
EOS
end of study
ET
early termination
FDA
Food and Drug Administration
GBD 2010
Global Burden of Disease Survey 2010
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HSG
hysterosalpingogram
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone releasing system
IV
intravenous
IWRS
interactive web response system
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic anion transporting polypeptide 1B1
PK
pharmacokinetic
QTcF
QT interval corrected for heart rate using Fridericia formula (QTcF = 
QT/(RR)⅓)
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Term/Abbreviation
Definition
SAE
serious adverse event
SNRI
serotonin norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
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12.4
Protocol Amendment 1 Summary
Title: A Phase 3, Multicenter, Open-label, 40-Week Extension Study to Evaluate the Long-term
Safety and Tolerability of Oral Atogepant for the Prevention of Migraine in Participants With 
Episodic Migraine
Protocol 3101-309-002
Date of Amendment: 15 September 2020
Amendment Summary
This amendment includes changes made to Protocol 3101-309-002 dated 22 February 2019. The 
protocol was amended to: 
!
Add Table 2 for study visits to be conducted remotely to eliminate immediate potential 
hazards to participants and study staff due to the COVID-19 pandemic, while ensuring 
participant safety and maintaining data integrity
!
Clarified requirements around the use of remote visits, in particular for Visits 1 and 12. 
The table below provides details related to content changes that were made in the protocol, and a 
brief rationale for these changes. Minor editorial and document formatting revisions have not 
been summarized.
Section
Revision
Rationale
Throughout
Added in following requirements:
!
Visit 1 must be conducted as an in-person 
visit.
!
During the COVID-19 pandemic, Visit 12 
(Follow up/End of Study) should be 
conducted remotely for all participants.
!
To ensure participant safety, remote study 
visits can 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 be discontinued from the 
study.
To clarify requirements in 
line with remote visits 
during the COVID-19 
pandemic
Protocol Title Page
Added “Amendment 1 Date”
To reflect the approval date 
of Amendment 1
Table 1
Modified title of Schedule of Visits and Procedures to 
“Schedule of Visits and Procedures for In-person Visits 
Conducted Prior to or During the COVID-19 
To clarify that this Schedule 
only applies for in-person 
visits; remote visits are 
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Pandemic”, plus added in relevant information on 
remote visits.
described in Table 2.
Removal of requirement to measure height at Visit 1.
Correction of error.
Table 2
Addition of “Schedule of Visits and Procedures for 
Visits Conducted Remotely Due to the COVID 19 
Pandemic” to describe remote study visits.
To eliminate immediate 
potential hazards to 
participants and study staff 
due to the COVID-19 
pandemic while ensuring 
participant safety and 
maintaining data integrity.
Section 7.2.1
Safety Analyses
Addition of a statement that specific tables and listings 
will be generated to present the impact of the 
COVID-19 pandemic on study conduct and 
participants. Analyses to further address the impact 
may be conducted.
Added in line with FDA 
guidance.
Section 8.4.1.1
Visit 1
Removal of requirement to measure height at Visit 1.
Correction of error.
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The following information can be found on FDA Form 1572 and/or study contacts page: Name 
and contact information of Allergan study personnel and Emergency Telephone Numbers; name, 
address, and statement of qualifications of each investigator; name of each subinvestigator 
working under the supervision of the investigator; name and address of the research facilities to 
be used; name and address of each reviewing IRB; US 21 CFR 312.23 section 6(iii)b.
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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:
!
Implement and conduct this study diligently and in strict compliance with the protocol, GCPs 
and all applicable laws and regulations.
!
Maintain all information supplied by Allergan 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
Table of Contents ............................................................................................................................ 4
List of Tables................................................................................................................................... 7
List of Figures................................................................................................................................. 7
Protocol Summary .......................................................................................................................... 8
1
Background and Clinical Rationale ........................................................................................ 12
1.1 Background....................................................................................................................... 12
1.2 Overview of Atogepant..................................................................................................... 12
1.3 Study Rationale................................................................................................................. 13
1.4 Rationale for Doses and Dose Regimens Selected ........................................................... 13
2
Study Objective and Clinical Hypotheses............................................................................... 13
2.1 Study Objective................................................................................................................. 13
2.2 Clinical Hypothesis........................................................................................................... 13
3
Study Design........................................................................................................................... 13
3.1 Structure............................................................................................................................ 13
3.2 Data Safety Monitoring Board.......................................................................................... 14
3.3 Adjudication Committee................................................................................................... 15
4
Study Population and Entry Criteria ....................................................................................... 15
4.1 Number of Participants ..................................................................................................... 15
4.2 Inclusion Criteria .............................................................................................................. 15
4.3 Exclusion Criteria ............................................................................................................. 16
4.4 Permissible and Prohibited Medications/Treatments........................................................ 16
Permissible Medications/Treatments .................................................................... 16
4.4.1
Prohibited Medications/Treatments ...................................................................... 17
4.4.2
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
4.4.3
Contraceptive Methods ......................................................................................... 18
Special Diet or Activities ...................................................................................... 19
4.4.4
4.5 Screen Failures.................................................................................................................. 20
5
Study Intervention................................................................................................................... 20
5.1 Study Intervention and Formulations................................................................................ 20
6
Control Intervention................................................................................................................ 20
6.1 Methods for Masking/Blinding......................................................................................... 20
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6.2 Treatment Allocation Ratio............................................................................................... 20
6.3 Method for Assignment to Treatment Groups .................................................................. 20
6.4 Treatment Regimen and Dosing ....................................................................................... 21
6.5 Safety Measures................................................................................................................ 21
Adverse Events ..................................................................................................... 21
6.5.1
Adverse Events of Special Interest ....................................................................... 21
6.5.2
Clinical Laboratory Determinations ..................................................................... 22
6.5.3
Vital Signs............................................................................................................. 23
6.5.4
Physical Examination............................................................................................ 23
6.5.5
Electrocardiograms ............................................................................................... 24
6.5.6
Columbia-Suicide Severity Rating Scale (C-SSRS)............................................. 24
6.5.7
6.6 Other Study Supplies ........................................................................................................ 24
6.7 Summary of Methods of Data Collection ......................................................................... 25
7
Statistical Procedures.............................................................................................................. 25
7.1 Analysis Populations......................................................................................................... 25
7.2 Hypothesis and Methods of Analysis................................................................................ 25
7.3 Safety Analyses................................................................................................................. 25
7.4 Subgroup Analyses............................................................................................................ 25
7.5 Sample Size Calculation ................................................................................................... 26
7.6 Interim Analyses ............................................................................................................... 26
8
Study Visit Schedule and Procedures...................................................................................... 26
8.1 Participant Entry Procedures............................................................................................. 26
Overview of Entry Procedures.............................................................................. 26
8.1.1
Informed Consent and Participant Privacy ........................................................... 26
8.1.2
8.2 Washout Intervals/Run-in ................................................................................................. 26
8.3 Procedures for Final Study Entry...................................................................................... 26
8.4 Visits and Associated Procedures...................................................................................... 27
Open-label Treatment Period (40 Weeks) ............................................................. 27
8.4.1
8.4.1.1 Visit 1 (Day 1)........................................................................................... 27
8.4.1.2 Visits 2 to Visit 11 (Week 4 to 40) ............................................................ 28
8.4.1.3 Visit 11/Early Termination (Week 40) ...................................................... 29
Safety Follow-up Period (4 Weeks) ...................................................................... 29
8.4.2
8.4.2.1 Visit 12/EOS (Week 44)............................................................................ 29
8.5 Instructions for the Participants ........................................................................................ 30
8.6 Unscheduled Visits............................................................................................................ 30
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8.7 Compliance with Protocol................................................................................................. 30
8.8 Early Discontinuation of Participants ............................................................................... 31
8.9 Withdrawal Criteria........................................................................................................... 31
8.10
Study Termination................................................................................................. 32
9
Adverse Events ....................................................................................................................... 32
9.1 Definitions......................................................................................................................... 33
Adverse Event....................................................................................................... 33
9.1.1
Serious Adverse Event .......................................................................................... 34
9.1.2
Intensity................................................................................................................. 35
9.1.3
Assessment of Causality ....................................................................................... 36
9.1.4
Follow-up of Adverse Events and Serious Adverse Events.................................. 36
9.1.5
9.2 Procedures for Reporting Adverse Events ........................................................................ 37
9.3 Procedures for Reporting a Serious Adverse Event .......................................................... 37
Regulatory Reporting Requirements for Serious Adverse Events ........................ 37
9.3.1
9.4 Exposure to Study Intervention During Pregnancy .......................................................... 38
9.5 ALT or AST Elevations..................................................................................................... 38
Potential Hy’s Law Cases ..................................................................................... 39
9.5.1
10 Administrative Items............................................................................................................... 40
10.1
Protection of Human Participants ......................................................................... 40
Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
10.1.1
Relevant Country Regulations .............................................................................. 40
Compliance With IRB or IEC Regulations........................................................... 41
10.1.2
Compliance With Good Clinical Practice ............................................................. 41
10.1.3
Compliance With Electronic Records; Electronic Signatures Regulations (US 
10.1.4
21CFR Part 11) ..................................................................................................... 41
10.2
Financial Disclosure.............................................................................................. 41
10.3
Changes to the Protocol ........................................................................................ 42
10.4
Data Protection...................................................................................................... 42
10.5
Participant Privacy................................................................................................ 42
10.6
Documentation...................................................................................................... 42
Source Documents ................................................................................................ 42
10.6.1
Case Report Form Completion ............................................................................. 43
10.6.2
Study Summary..................................................................................................... 44
10.6.3
Retention of Documentation................................................................................. 44
10.6.4
10.7
Labeling, Packaging, and Return or Disposal of Study Intervention ................... 44
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Labeling/Packaging............................................................................................... 44
10.7.1
Clinical Supply Inventory..................................................................................... 45
10.7.2
Return or Disposal of Study Intervention and/or Supplies ................................... 45
10.7.3
10.8
Monitoring by the Sponsor ................................................................................... 45
10.9
Handling of Biological Specimens ....................................................................... 45
10.10
Publications........................................................................................................... 46
10.11
Coordinating Investigator ..................................................................................... 46
11 References............................................................................................................................... 47
12 Attachments ............................................................................................................................ 49
12.1
Examples of Prohibited Medications .................................................................... 49
12.2
Classification of Migraine Preventive Medications.............................................. 51
12.3
Glossary of Abbreviations..................................................................................... 52
List of Tables
Table 1.
Schedule of Visits and Procedures ...................................................................11
Table 6-1.
Study Intervention........................................................................................... 21
Table 6–2.
Clinical Laboratory Parameters ...................................................................... 23
List of Figures
Figure 1.
Study Diagram ................................................................................................ 10
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Protocol Summary
Study Compound: Atogepant
Phase: 3
Study Objective:
To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily for the prevention of migraine 
over a 40-week duration. 
Clinical Hypotheses:
Atogepant 60 mg once daily is safe and well tolerated when administered over 40 weeks
Study Design
Structure: Multicenter, open-label, 40-week, long-term safety extension study conducted in the United States 
Duration: The study will consist of a 40-week treatment period, and a safety follow-up period of an additional 
4 weeks, for a total duration of 44 weeks.
Study Intervention: Atogepant 60 mg once daily
Control: Not applicable
Dosage/Dose Regimen: Atogepant 60 mg once daily will be administered for 40 weeks.
Randomization: Not applicable
Visit Schedule: Participants will directly rollover from Study 3101-301-002 (Phase 3 episodic migraine [EM]). As 
such, participants will have Visit 7 from Study 3101-301-002 function as the 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 End of Study (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 3101-301-002 before extension Study 
3101-309-002 has been initiated. Those patients should complete Visit 7/ET and Visit 8/EOS Visit (including 
discontinuation of IP) per the Study 3101-301-002 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, Visit 1 Study 3101-309-002 can be conducted on the same day as Visit 8/EOS Visit for Study 3101-301-
002 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 Study 3101-301-002 should be conducted on the same day as Visit 1 for 
Study 3101-309-002.
!
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 Study 3101-
301-002 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 3101-309-002 Schedule of 
Visits and Procedures.
For details, please see Table 1, the Schedule of Visits and Procedures.
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Study Population Characteristics
Number of Participants/Sites: All participants who complete Study 3101-301-002, and meet all eligibility 
requirements, may participate in this study. Based on expected completion rates from Study 3101-301-002, it is 
estimated that approximately 750 participants will be enrolled from approximately 110 centers in the United States.
Condition/Disease: Migraine with aura or migraine without aura (ICHD-3 Section 1.1 or Section 1.2)
Inclusion Criteria:
!
Written informed consent and participant privacy information (eg, written authorization for use and release of 
health and research study information) obtained from the participant prior to initiation of any study-specific 
procedures.
!
Participants must be using a medically acceptable and effective method of birth control during the course of the 
entire study, as defined in Section 4.4.3.
!
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 3101-301-002 without significant 
protocol deviations (eg, noncompliance to protocol-required procedures) and who did not experience an 
adverse event (AE) that, in the investigator’s opinion, may indicate an unacceptable safety risk.
Key Exclusion Criteria:
!
Participants with clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease.
Response Measures
Safety – AEs, physical examinations, clinical laboratory determinations, vital sign measurements, electrocardiogram 
(ECG) parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS)
Efficacy – Not applicable
General Statistical Methods and Types of Analyses: 
The safety parameters will include AEs, clinical laboratory determinations, vital sign measurements, ECG 
parameters, and the C-SSRS. For each of the clinical laboratory determinations, vital sign measurements, and ECG 
parameters, the last non-missing safety assessment before the first dose of treatment will be used as the baseline for 
all analyses of that safety parameter. For all participants, baseline in lead-in study (Study 3101-301-002) will be 
used. Continuous variables will be summarized by the number of participants and mean, standard deviation (SD), 
median, minimum, and maximum values. Categorical variables will be summarized by number and percentage of 
participants.
Sample Size Calculation: 
As this is a safety extension study, all eligible participants from lead-in Study 3101-301-002 may be enrolled.
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Figure 1.
Study Diagram
ET = early termination; V = visit; Wk = week.
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Table 1.
Schedule of Visits and Procedures
Study Period
Open-label Treatment Period (40 weeks)
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 1a
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10 Visit 11/ET
Visit 12/
EOS
Day/Week
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)
Visit Windows
± 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
privacy
X
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Assess inclusion/exclusion criteria
X
Perform physical examination
X
X
X
Collect vital sign measurementsb
X
X
X
X
X
X
X
X
X
X
X
X
Perform ECG
X
X
X
X
Perform urine pregnancy testc
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory determinationsd
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study intervention (ie, atogepant)
Xe
X
X
X
X
X
X
X
X
X
Review of study intervention (ie, 
atogepant) compliance and accountability
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EM = episodic migraine; EOS = end of study; ET = early 
termination; INR = international normalized ratio; IWRS = interactive web response system; WOCBP = women of childbearing potential
a
After providing informed consent for the current study, Visit 1 will be conducted on the same day as Study 3101-301-002 Visit 7; procedures collected as 
part of Study 3101-301-002 Visit 7 should not be repeated.
b
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.
c
For women of child-bearing potential only, a urine pregnancy test will be performed at all visits.
d
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 screening (Visit 1).
e
The first dose of atogepant must be taken in the office.
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1
Background and Clinical Rationale
1.1
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25 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). 
The Global Burden of Disease Survey 2010 (GBD 2010) estimated the global prevalence of 
migraine to be 14.7%, making it the third most common disease in the world in both males 
and females. Migraine was ranked seventh highest among specific causes of disability 
globally (Steiner 2013).
Migraine is typically characterized by attacks of throbbing, unilateral headache of moderate 
or severe pain intensity, associated with nausea, vomiting, and/or sensitivity to light 
(photophobia) and sound (phonophobia). In about 25% of individuals, the migraine headache
is preceded by focal neurological dysfunction (aura). Improving diagnosis and optimizing 
treatments for migraine have been recognized as critically important to overcoming current 
barriers to reduce the global burden of migraine.
Because there are no biological markers for migraine, diagnosis is based on clinical history, 
examination, and the exclusion of other headache disorders. Physicians apply clinical criteria 
to guide diagnoses and subsequent treatment. 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 safety and 
tolerability of atogepant in participants with migraine.
1.2
Overview of Atogepant
Atogepant is a potent, selective oral CGRP receptor antagonist being developed for migraine 
prevention. Additional information on non-clinical pharmacology, toxicology, and PK 
properties of atogepant can be found in the IB. 
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A Phase 2/3 clinical study was conducted, which compared atogepant 10 mg once daily, 
atogepant 30 mg once daily, atogepant 30 mg BID, atogepant 60 mg once daily and atogepant 
60 mg BID to placebo. 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 participants with EM.
1.3
Study Rationale
The purpose of this study is to evaluate the safety and tolerability of atogepant 60 mg once 
daily, when taken for 40 weeks for the prevention of EM.
1.4
Rationale for Doses and Dose Regimens Selected
The Phase 3 pivotal studies to evaluate atogepant will test a maximum dose of 60 mg once 
daily. For this reason, the same dose of 60 mg once daily has been selected for this study to 
evaluate the long-term safety and tolerability of atogepant for the prevention of EM.
2
Study Objective and Clinical Hypotheses 
2.1
Study Objective
To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily when 
administered over 40 weeks for the prevention of migraine in participants with EM.
2.2
Clinical Hypothesis
Atogepant 60 mg once daily is safe and well tolerated when administered over 40 weeks for 
the prevention of migraine in participants with EM.
3
Study Design
3.1
Structure
This is a multicenter, open-label, 40-week, long-term safety extension study conducted in the 
United States and will enroll approximately 750 participants from approximately 110 sites. 
Participants will be treated with atogepant 60 mg once daily.
The study will consist of a 40-week open-label treatment period, and a safety follow-up 
period of 4 weeks. 
Participants will directly rollover from Study 3101-301-002 (Phase 3 EM). As such, 
participants will have Visit 7 from Study 3101-301-002 function as the Visit 1 for this study 
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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 3101-301-002 
before extension Study 3101-309-002 has been initiated. Those participants should complete 
Visit 7/ET and Visit 8/EOS Visit (including discontinuation of study intervention) per the 
Study 3101-301-002 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, Visit 1 Study 3101-309-002 can be conducted on the 
same day as Visit 8/EOS Visit for Study 3101-301-002 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 Study 3101-301-002 should be conducted on the 
same day as Visit 1 for Study 3101-309-002.
!
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 Study 3101-301-002 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 3101-309-
002 Schedule of Visits and Procedures.
After Visit 1, study visits will occur every 4 weeks for the duration of the 40-week treatment 
period. Participants will return to the clinic for safety assessments at 4, 8, 12, 16, 20, 24, 28, 
32, 36 and 40 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 safety and tolerability of long-term 
atogepant treatment. The planned safety assessments include collection of AEs, 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 Allergan, including 
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modification or ET of a trial, if emerging data show unexpected and clinically significant 
AEs. 
Details of the DSMB memberships, standard operational procedures for data 
monitoring/review, frequency of review, and other pertinent details will be provided in a 
separate DSMB Charter.
3.3
Adjudication Committee
An Adjudication Charter will be established and will describe the process for the 
surveillance, monitoring, and adjudication by the 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
Approximately 750 participants will be treated with atogepant 60 mg once daily at
approximately 110 centers in the United States. 
4.2
Inclusion Criteria
1. Written informed consent and participant privacy information (eg, written 
authorization for use and release of health and research study information) obtained 
from the participant prior to initiation of any study-specific procedures.
2. Participants must be using a medically acceptable and effective method of birth control 
during the course of the entire study, as defined in Section 4.4.3.
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 3101-301-002 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.
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4.3
Exclusion Criteria
1. Requirement for any medication, diet (ie, grapefruit juice), that is on the list of 
prohibited concomitant medications (see Section 4.4.2 and Attachment 12) that cannot 
be discontinued or switched to an allowable alternative medication. This includes 
concomitant medications with demonstrated efficacy for the prevention of migraine 
(eg, amitriptyline, topiramate, propranolol).
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.
3. An ECG with clinically significant abnormalities at Visit 1 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. Vital sign measurements that exceed these limits may be 
repeated only once.
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) since the last visit. 
6. Participants with clinically significant hematologic, endocrine, cardiovascular, 
pulmonary, renal, hepatic, gastrointestinal, or neurologic disease.
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
Permissible and Prohibited Medications/Treatments
Permissible Medications/Treatments
4.4.1
Medications that are not specifically prohibited in Section 4.4.2 are allowed, with the 
following clarifications and restrictions.
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The following medications for the acute treatment of migraine are allowed during the study:
!
Any triptan
!
Any ergot derivative
!
Any opioid
!
Any other form of analgesic (including acetaminophen)
!
Any NSAID agent
!
Any antiemetic agent
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
SSRI or SNRI will be permitted, provided that treatment is stable for at least 60 days prior to 
Visit 1 and continues without change in dose throughout the study.
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 Allergan.
Prohibited Medications/Treatments
4.4.2
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) 
for all participants and throughout the study (see Attachment 12.1):
!
Strong and moderate CYP3A4 inhibitors, including but not limited to: systemic 
(oral/IV) itraconazole, ketoconazole, fluconazole, erythromycin, clarithromycin, 
telithromycin, diltiazem, verapamil, aprepitant, cyclosporine, nefazodone, 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, gemfibrozil) 
!
Drugs with narrow therapeutic margins with theoretical potential for CYP drug 
interactions (eg, warfarin)
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!
Medications with demonstrated efficacy for the prevention of migraine (eg, 
amitriptyline, topiramate, propranolol). See Attachment 12.2
!
CBD oil
!
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, 
Myobloc®, Xeomin®, JeuveauTM) into areas of the head, face, or neck within 6 
months prior to Visit 1 and for the duration of the study
!
Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig TM, 
EmgalityTM, Ajovy®) within 6 months prior to Visit 1 and for the duration of the study
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration. When possible, Allergan should be notified 
before the prohibited medication/treatment is administered.
Definition of Women of (Non-)Childbearing Potential and/or 
4.4.3
Acceptable Contraceptive Methods
For purposes of this study, women will be considered of childbearing potential unless they 
are naturally postmenopausal (ie, no menses for 2 years) or permanently sterilized (ie, 
bilateral tubal ligation, bilateral tubal occlusion [eg, Essure® placement with HSG 
confirmation], bilateral salpingectomy, bilateral oophorectomy, or hysterectomy). For women 
of child-bearing 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, intravaginal, or transdermal (i.e. pill, vaginal ring, patch)
!
Progestogen-only hormonal contraception (with inhibition of ovulation) that are oral, 
injectable,or implantable
!
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)
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Acceptable birth control methods which may not be considered as highly effective:
!
Progestogen-only oral hormonal contraception (where inhibition of ovulation is not 
the primary mode of action)
!
Male or female condom with or without spermicide (female and male condoms 
should not be used together)
!
Cap, diaphragm or sponge with spermicide
!
A combination of male condom with either cap, diaphragm or sponge 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 Allergan 
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 (2) follow the progress of the 
pregnancy. The investigator must document the outcome of the pregnancy and provide a 
copy of the documentation to Allergan.
Special Diet or Activities
4.4.4
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 12-ounce can/bottle of beer, a 4-ounce glass of wine, or 1 ounce of 
liquor.
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4.5
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently treated.
5
Study Intervention
5.1
Study Intervention and Formulations
Tablets containing atogepant 60 mg (Formulation Number: 11281X)
6
Control Intervention 
Not applicable.
6.1
Methods for Masking/Blinding
This is an open-label study. 
6.2
Treatment Allocation Ratio
All participants will be treated with atogepant 60 mg once daily. 
6.3
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 their lead-in study participant number. This number 
will serve as the participant identification number on all study documents.
At Visit 1, eligible participants will receive atogepant 60 mg once daily.
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.
Atogepant bottles will be dispensed at the study visits summarized in the Schedule of Visits 
and Procedures. Returned atogepant bottles should not be re-dispensed to the participants.
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6.4
Treatment Regimen and Dosing
Participants who meet all of the study entry criteria at Visit 1 will be treated with atogepant 
60 mg once daily. 
Atogepant to be used in this trial is listed in Table 6-1.
Participants will be instructed to take their atogepant at approximately the same time each 
day. Atogepant will be administered orally for 40 weeks, and participants will be followed 
for 4 weeks following completion or discontinuation of the atogepant.
Table 6-1.
Study Intervention
Drug/Dose
Study Intervention Frequency
Route of Administration
Atogepant 60 mg
Once daily
Oral
6.5
Safety Measures
Adverse Events
6.5.1
AEs will be collected from the time of consent through the last visit. For all AEs, the 
investigator must provide an assessment of the severity, causal relationship to the 
investigational product, start and stop date, 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, Allergan must be notified immediately 
to meet their reporting obligations to appropriate regulatory authorities.
Adverse Events of Special Interest 
6.5.2
Selected non-serious and SAEs are of special interest (AESI) 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 
!
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.
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Reporting requirements for AESI, ALT or AST elevations, and potential Hy’s law cases are 
outlined in Sections 9.5 and 9.5.1. These AEs or events determined to be SAEs must be 
reported appropriately via the designated eCRFs and safety forms.
Clinical Laboratory Determinations
6.5.3
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. The investigator will 
assess the clinical significance of any values outside the reference ranges provided by the 
central laboratory. Participants with abnormalities judged to be clinically significant, 
laboratory values that meet exclusionary criteria, or positive results on the urine drug screen 
at Visit 1 will be 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 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 6–2.
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Table 6–2.
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 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. Those with a positive result on the Visit 1 urine drug 
screen for recreational (including marijuana regardless of legality) or illicit drugs or 
non-disclosed concomitant medications are not allowed to be repeated. For all other 
positive results, the urine drug screen may be repeated with permission from 
Allergan; 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.
Vital Signs
6.5.4
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, and weight will be performed at every visit. Sitting and 
standing BP and pulse rate will be determined as follows. BP and pulse measurements will be 
performed after the participant sits quietly for 5 minutes, followed by a second set of 
measurements taken after the participant stands for at least 3 minutes (but no longer than 10 
minutes).
Physical Examination
6.5.5
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; 
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lymphatic; skin; and other. The neurologic examination should be conducted to detect the 
presence of any significant sensory/motor abnormalities.
Electrocardiograms
6.5.6
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.
Columbia-Suicide Severity Rating Scale (C-SSRS)
6.5.7
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 all visits the C-SSRS will be completed for 
ideation and behavior since last visit for all participants. The C-SSRS will be completed by 
the investigator or designee with current and valid training in administering the assessment. A 
participant should not be released from the study center until the results of C-SSRS are 
reviewed and it is confirmed that the participant is not considered to be at risk. Participants 
who reply with “yes” to questions 4 or 5 in the suicidal ideation section or “yes” to any 
question in the suicidal behavior section of the C-SSRS at Visits 2 through 10 must be 
withdrawn from the study and should receive appropriate follow-up as in routine clinical 
practice, including the ET (Visit 11) and the EOS (Visit 12) visits.
6.6
Other Study Supplies
The following will be provided by Allergan or Allergan designee:
!
All supplies needed for blood and urine sampling (central laboratory analysis)
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!
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 
6.7
Summary of Methods of Data Collection
An IWRS will be used to manage atogepant inventory. All office visit data for this study will 
be collected by eCRFs via an electronic data capture system. Source documents will be used 
at the sites and may include a participant’s medical record, hospital charts, clinic charts, the 
investigator’s participant study files, as well as the results of diagnostic tests such as 
laboratory tests, ECGs, etc. A centralized clinical laboratory will be used for the analysis of 
all blood and urine samples, and for ECG assessments. Additional information on the 
collection and handling of samples is detailed in the Laboratory Procedure Manual.
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 atogepant in this extension study. 
7.2
Hypothesis and Methods of Analysis
7.3
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 as defined for the lead-in study (3101-301-002) will be used as the baseline in this 
extension study (3101-309-002).
Continuous variables will be summarized by the number of participants, and mean, SD, 
median, minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of participants.
7.4
Subgroup Analyses
No subgroup analysis is planned.
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7.5
Sample Size Calculation
As this is a safety extension study from the lead-in Study 3101-301-002, all participants from 
the lead-in study who are eligible for this extension study will be enrolled. No separate 
sample size calculation was performed. Based on expected completion rate from the lead-in 
Study 3101-301-002, approximately 750 participants will be enrolled into this long-term, 
open-label, safety extension study.
7.6
Interim Analyses
Interim data-cuts are planned to provide ongoing safety data to support global regulatory 
submissions. 
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
Overview of Entry Procedures
8.1.1
Prospective participants as defined by the criteria in Sections 4.2 and 4.3 (inclusion/exclusion 
criteria) will be considered for entry into this study.
Informed Consent and Participant Privacy
8.1.2
The study will be discussed with the participant, and a participant wishing to participate must 
give informed consent prior to any study-related procedures or change in treatment. The 
participant must also give authorization, and other written documentation in accordance with 
the relevant country and local privacy requirements (where applicable) prior to any 
study-related procedures or change in treatment.
Participants will maintain their lead-in study participant identification number.
8.2
Washout Intervals/Run-in
This study will not include a washout period.
8.3
Procedures for Final Study Entry
At Visit 1 participants must meet all of the inclusion criteria and must not meet any of the 
exclusion criteria. 
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Participants will directly rollover from Study 3101-301-002 (Phase 3 EM). As such, 
participants will have Visit 7 from Study 3101-301-002 function as the 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. 
Note, there may be participants who complete Visit 7 in the lead-in Study 3101-301-002 
before extension Study 3101-309-002 has been initiated. Those participants should complete 
Visit 7/ET and Visit 8/EOS Visit (including discontinuation of study intervention) per the 
Study 3101-301-002 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, Visit 1 Study 3101-309-002 can be conducted on the 
same day as Visit 8/EOS Visit for Study 3101-301-002 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 Study 3101-301-002 should be conducted on the same day 
as Visit 1 for Study 3101-309-002.
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 Study 3101-301-002 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 3101-309-002 Schedule of Visits and 
Procedures.
8.4
Visits and Associated Procedures
There will be 12 scheduled clinic visits: 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/ET (Week 40), and Visit 12/EOS (Week 44). 
 Open-label Treatment Period (40 Weeks)
8.4.1
8.4.1.1Visit 1 (Day 1)
!
Obtain informed consent and participant privacy.
!
Register participant in IWRS.
!
Review and record prior medications taken in the past 6 months, and all prior 
migraine headache medications and concomitant medications.
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!
Assess inclusion/exclusion criteria.
!
Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, pulse 
rate, respiration rate, temperature, height, and weight).
!
Perform physical examination.
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect urine for drug screen.
!
Perform and transmit ECG 
!
Collect blood and urine for clinical laboratory determinations including: serology, 
INR, and urinalysis.
!
Review and assess AEs.
!
Review and update concomitant medications and concurrent procedures.
!
Access IWRS and obtain the kit number for atogepant bottle and dispense atogepant 
bottle.
8.4.1.2Visits 2 to Visit 11 (Week 4 to 40)
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, 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 11
[Week 40] only).
!
Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.
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!
Review and assess AEs.
!
Review and update concomitant medications and concurrent procedures.
!
Access IWRS to dispense atogepant bottle and enter accountability.
8.4.1.3Visit 11/Early Termination (Week 40)
Effort should be made by the site to not schedule Visit 11 earlier than 40 weeks after Day 1, 
to ensure participants complete the full 40 weeks of atogepant treatment.
!
Perform physical examination.
!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, 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.
!
Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.
!
Access IWRS to enter study visit and accountability.
Safety Follow-up Period (4 Weeks)
8.4.2
8.4.2.1 Visit 12/EOS (Week 44)
!
Perform physical examination.
!
Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).
!
Collect vital sign measurements (sitting and standing systolic and diastolic BP, pulse 
rate, respiration rate, temperature, and weight). 
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!
Perform urine pregnancy test for women of child-bearing potential.
!
Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.
!
Review and assess AEs.
!
Update concomitant medications and concurrent procedures.
!
Access IWRS to enter study visit.
8.5
Instructions for the Participants
Section 4.4.4 provides diet and activity instructions for participants enrolled in the study.
Prohibited medications should be reviewed with the participants. Participants will be 
instructed to return their atogepant bottle(s), both used and unused at each visit.
Participants should be instructed to take atogepant 60 mg once daily at approximately the 
same time each day (approximately 24 hours between doses). For dosing on Day 1 (Visit 1), 
the first dose is to be taken at the study site.
Participants should use appropriate contraceptive measures for the duration of their 
participation in the study (Section 4.4.3)
8.6
Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to 
ensure the safety and well-being of the participants during the study period. Unscheduled 
visit eCRFs should be completed for each unscheduled visit.
8.7
Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1, and the 
timing of the visits should occur as close as possible to the day specified. At each visit, the 
participant will be asked if the participant changed the dose/regimen of any existing 
concomitant medications or initiated the use of any new concomitant medications since the 
last visit, to ensure compliance with the protocol. 
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.
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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
!
Non-compliance with study intervention (ie, atogepant)
!
Pregnancy
!
Protocol deviation
!
Site terminated by Allergan
!
Study terminated by Allergan
!
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 
the evaluations scheduled for Visit 11/ET and Visit 12/EOS, 4 weeks post the last dose of 
atogepant.
8.9
Withdrawal Criteria
!
Participants with the following at Visit 1:
o
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 
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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 testing, or anti-hepatitis E IgM antibody.
o
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)
!
Participants with the following at any study visit:
o
Female participants who become pregnant (Section 9.4) 
o
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. 
o
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 10 must be withdrawn from the study.
o
A participant with a condition and/or a situation that, in the investigator's opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study may be 
withdrawn from treatment.
All withdrawn participants should receive appropriate follow-up as in routine clinical 
practice, including the ET (Visit 11) and the EOS (Visit 12) assessments.
8.10
Study Termination
The study may be stopped at the study site at any time by the site investigator. Allergan 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.
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9.1
Definitions
Adverse Event
9.1.1
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 Visit 1, AEs 
will be assessed regardless of the administration of atogepant.
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 12), 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 queryin g 
for AEs by asking each participant a general, non-directed question such as “How have you 
been feeling since the last visit?” Open-ended and non-leading 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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Serious Adverse Event
9.1.2
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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Allergan considers all cancer AEs as SAEs. In addition, Allergan 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 are 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 Allergan.
Intensity
9.1.3
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 one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
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Assessment of Causality
9.1.4
Assessment of Causality
!
The investigator is obligated to assess the relationship between atogepant and each 
occurrence of each AE or SAE.
!
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.
!
The investigator will use clinical judgment to determine the relationship.
!
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.
!
The investigator will also consult the investigator’s brochure in his/her assessment.
!
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.
!
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Allergan. 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 Allergan.
!
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.
!
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of Adverse Events and Serious Adverse Events
9.1.5
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs/SAEs and non-serious AEs of special 
interest (as defined in Section 6.5.2) 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 Allergan 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 health care professionals.
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 
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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 Allergan 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 12) 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 Allergan as listed on the Allergan 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 Allergan and the IRB/IEC with any additional requested information 
(eg, autopsy reports and discharge summaries).
Regulatory Reporting Requirements for Serious Adverse Events
9.3.1
!
Prompt notification by the investigator to Allergan 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. 
!
Allergan 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. Allergan will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/ IECs, and investigators.
!
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Allergan 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 Allergan) will review 
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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 12) 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 or elective 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 
SAEs. 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. An extra blood 
serology sample must be collected and sent to the central laboratory for further diagnostic 
testing, at a later date, if needed. In addition, the investigator will perform a complete history
and examination to evaluate the participant for possible liver disease.
All AEs of special interest must be reported to Allergan within 24 hours of the time the 
investigator becomes aware of the event using the abnormal liver function reporting form and 
the AE eCRF. All new elements of history, physical examination, diagnostic testing results, 
and other relevant medical reports are to be reported for each AE of special interest.
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 
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be followed clinically and further medical evaluation (for other causes of acute hepatic 
injury) should be done per the judgment of the investigator and in conjunction with medical 
personnel at Allergan. 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 Allergan 
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 Allergan 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.
Potential Hy’s Law Cases
9.5.1
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 
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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 Allergan immediately when the above criteria have been met. A possible Hy’s law case 
must be faxed to Allergan on an abnormal liver function reporting form as soon as possible 
(within 24 hours of learning of the possible Hy’s law case) to the fax number on the form or 
the SAE fax number, even if 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).
10.1
Protection of Human Participants
Compliance With Informed Consent Regulations (US 21 CFR 
10.1.1
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each participant, and/or from the 
participant's legally authorized representative, prior to any study-related activities or 
procedures in the study.
The following process will be followed:
!
The investigator or his/her representative will explain the nature of the study to the
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
!
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed consent 
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that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study center. 
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB. 
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Compliance With IRB or IEC Regulations
10.1.2
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations. The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually. 
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun. Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan.
Compliance With Good Clinical Practice
10.1.3
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
Compliance With Electronic Records; Electronic Signatures 
10.1.4
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 Allergan with sufficient, accurate financial 
information as requested to allow Allergan 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.
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10.3
Changes to the Protocol
The investigator must not implement any deviation from or changes to the protocol without 
approval by Allergan 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 Allergan will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Allergan 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 Allergan, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.5
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, and/or from the participant's legally authorized representative 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
Source Documents
10.6.1
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.
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The following information should be entered into the participant's medical record:
!
Participant’s name
!
Participant’s contact information
!
The date that the participant entered the study, participant number, and participant 
randomization (or medication kit) number
!
The study title and/or the protocol number of the study and the name of Allergan
!
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).
Case Report Form Completion
10.6.2
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 
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eCRFs are to be submitted to Allergan in a timely manner at the completion of the study, or 
as otherwise specified by Allergan and will be maintained in a central data repository.
Study Summary
10.6.3
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan. A summary is also to be provided to 
the responsible IRB/IEC.
Retention of Documentation
10.6.4
All study related correspondence, participant records, consent forms, participant privacy 
documentation, records of the distribution and use of all atogepant, and copies of eCRFs 
should be maintained on file.
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of atogepant. These documents should be retained for 
a longer period, however, if required by the applicable regulatory requirement(s) or if needed 
by Allergan.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person.
10.7
Labeling, Packaging, and Return or Disposal of Study Intervention
Labeling/Packaging
10.7.1
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.
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Clinical Supply Inventory
10.7.2
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the participants, the number of units 
returned to the investigator by the participant, and the number of units returned to Allergan 
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.
Return or Disposal of Study Intervention and/or Supplies
10.7.3
All atogepant and/or supplies will be returned to Allergan or Allergan designee for 
destruction.
10.8
Monitoring by the Sponsor
A representative of Allergan 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 Allergan 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 Allergan or Allergan’s designee for destruction. Allergan 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.
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10.10 Publications
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.
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
Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS. EFNS guidelines on the 
drug treatment of migraine – revised report of an EFNS task force. Eur J Neurol 2009 Sep; 
16(9):968-981.
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 
2018;38(1):1-211.
Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in 
migraine. Expert Review of Clinical Pharmacology. Taylor & Francis; 2014
Mar;7(2):191-201.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the 
United States. Arch Intern Med. 1999;159:813-818.
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. 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 peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.
N Engl J Med. 2004;350:1104-1110.
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, Freita F, Dodick DW, Argoff C, Ashman E. Evidence-based 
guideline update: pharmacologic treatment for episodic migraine prevention in adults. 
Neurology 2012;78:1337-1345.
Steiner TJ, Paemeleire K, Jensen R, Valade D, Savi L, Lainez MJA, et al. European principles 
of management of common headache disorders in primary care. J Headache Pain 2007 Oct8
Suppl 1:S3-47.
Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. J Headache Pain 
2013;14(1):1-2.
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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.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systemic 
analysis for the Global Burden of Disease Study 2010. Lancet 2013;14(9859):2163-2196.
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12 Attachments
12.1
Examples of Prohibited Medications
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) 
and throughout the study:
!
Strong OATP1B1 inhibitors e.g, Gemfibrozil (Lopid™)
!
CBD oil
Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Anti-depressants/ 
Anti-anxiety
Barbiturates 
!
Amobarbital (Amytal™)
!
Aprobarbital (Alurate™)
!
Butalbital (Fiorinal™, Fioricet™)
!
Butabarbital (Busodium™, 
Butisol™)
!
Mephobarbital (Mebaral™)
!
Pentobarbital (Nembutal™)
!
Phenobarbital (Luminal™, 
Solfoton™)
!
Secobarbital (Seconal™)
Nefazodone (Serzone™) 
Anti-seizure
Carbamazepine (Atretol™, Carbatrol™, 
Epitol™, Equetro™, Tegretol™)
Oxcarbazepine (Trileptal™)
Phenytoin (Dilantin™, Phenytek™)
Primidone (Myidone™, Mysoline™)
Diabetes 
Pioglitazone (Actos™)
Troglitazone (Rezulin™, Resulin™)
Antiemetic
Aprepitant (Emend™)
Anti-hypertension
Diltiazem (Cardizem™)
Verapamil (Calan™, Calan SR™)
Glucocorticoid 
(Systemic)
Betamethasone (Celestone™)
Dexamethasone (Baycadron™, DexPak™)
Hydrocortisone (Cortef™)
Methylprednisolone (Medrol™)
Prednisolone (Prelone™)
Prednisone (Deltasone™)
Triamcinolone (Kenalog™)
Antibiotics
Rifabutin (Mycobutin™) 
Rifampicin/Rifampin (Rifadin™, Rifater™, 
Rimactane™) 
Erythromycin (Benzamycin™, 
EryTab™)
Clarithromycin (Biaxin™)
Telithromycin (Ketek™)
Anti-fungal
Fluconazole (Diflucan™, Trican™)
Itraconazole (Sporanox™)
Ketoconazole (Nizoral™)
Anti-HIV
Efavirenz (Stocrin™, Sustiva™) 
Nevirapine (Viramune™)
Indinavir (Crixivan™)
Nelfinavir (Viracept™) 
Ritonavir (Norvir™)
Saquinavir (Fortovase™, Invirase™)
Immune Suppressant
Cyclosporine - Oral/IV only (Neoral™, 
Sandimmune™)
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Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Others
St. John’s wort 
Enzalutamide (Xtandi™)
Modafinil (Provigil™)
Armodafinil (Nuvigil™)
Buprenorphine (Cizol™, Subutex™, 
Suboxone™)
Quinine
Drugs with narrow therapeutic margins with 
potential for CYP drug interactions
Warfarin (Coumadin™)
Digoxin (Digitek™, Lanoxin™, Digox™)
Cisapride (Prepulsid™, Propulsid™)
Pimozide (Orap™)
Drugs with demonstrated efficacy for the 
prevention of migraine
Topiramate (Topamax™)
Valproic acid, sodium valproate, divalproex sodium (Depakote™)
Amitriptyline (Elavil™)
Nortriptyline (Pamelor™)
Metoprolol (Lopressor™, Toprol™)
Atenolol (Tenormin™)
Nadolol (Corgard™)
Propranolol (Inderal™)
Timolol (Apo-Timol™)
Flunarizine (SibeliumTM)
Candesartan (AtacandTM)
Lisinopril (Zestril TM, PrinivilTM)
Desvenlafaxine (Pristiq™)
Venlafaxine (Effexor™)
The following medications or treatments are prohibited 6 months prior to Visit 1 and 
throughout the study:
!
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, 
Xeomin®, Myobloc®, JeuveauTM) into areas of the head, face, or neck.
!
Injectable monoclonal antibodies blocking the CGRP pathway (eg, AimovigTM, 
EmgalityTM, Ajovy®) 
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12.2
Classification of Migraine Preventive Medications
Below is a list of migraine preventive medications considered effective or probably effective 
sorted by mechanism of action. Of note, topiramate and valproic acid derivatives are 
considered separate categories. 
Pharmacologic Category
Drug Name
Antiepileptic
Valproic acid, sodium valproate, divalproex sodium
Topiramate
Tricyclic antidepressant
Amitriptyline
Nortriptyline
Beta-blockers
Metoprolol
Bisoprolol
Atenolol
Nadolol
Propranolol
Timolol
Calcium channel blocker
Flunarizine
Angiotensin receptor blocker (ARB)
Candesartan
Angiotensin-converting enzyme (ACE) inhibitor
Lisinopril
Serotonin-norepinephrine reuptake inhibitor (SNRI)
Desvenlafaxine
Venlafaxine
Miscellaneous
Country approved products for migraine prevention 
(eg, oxetrone, pizotifen)
Source: Evers 2009, Hoffmann 2014, Schürks 2008, Silberstein 2012, Steiner 2007.
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12.3
Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CBD
cannabidiol
CGRP
calcitonin gene-related peptide
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
EM
episodic migraine
EOS
end of study
ET
early termination
FDA
Food and Drug Administration
GBD 2010
Global Burden of Disease Survey 2010
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HSG
hysterosalpingogram
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone releasing system
IV
intravenous
IWRS
interactive web response system
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic anion transporting polypeptide 1B1
PK
pharmacokinetic
QTcF
QT interval corrected for heart rate using Fridericia formula (QTcF = 
QT/(RR)⅓)
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Term/Abbreviation
Definition
SAE
serious adverse event
SNRI
serotonin norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
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SAP_001.pdf: 
Allergan PLC
Page 1
Atogepant
3101-309-002 Statistical Analysis Plan 
1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
A Phase 3, Multicenter, Open-label 40-week Extension Study to Evaluate the 
Long-Term Safety and Tolerability of Oral Atogepant for the Prevention of 
Migraine in Participants with Episodic Migraine
Final SAP Date: 25 JULY 2019
Amendment 1: 30 APR 2021
Protocol Number:
3101-309-002
Development Phase:
3
Product Name:
AGN-241689
Sponsor Name and Legal 
Registered Address:
Allergan Pharmaceuticals International Limited
Marlow International
The Parkway, Marlow SL7 1YL
United Kingdom
Confidentiality Statement
This document is the property of Allergan, Inc. and may not!in full or part!be passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, Inc.
NCT03939312


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Page 2
Atogepant
3101-309-002 Statistical Analysis Plan 
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
TABLE OF CONTENTS..................................................................................................................2
2.1
List of Tables......................................................................................................................4
2.2
List of Figures.....................................................................................................................4
3.0
LIST OF ABBREVIATIONS...........................................................................................................5
4.0
INTRODUCTION ............................................................................................................................6
5.0
OBJECTIVES.................................................................................................................................10
6.0
ANALYSIS POPULATIONS.........................................................................................................11
6.1
Screened Population .........................................................................................................11
6.2
Safety Population..............................................................................................................11
7.0
PARTICIPANT DISPOSITION .....................................................................................................12
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................13
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................14
9.1
Extent of Exposure ...........................................................................................................14
9.2
Measurement of Treatment Compliance...........................................................................14
10.0
EFFICACY ANALYSES ...............................................................................................................15
11.0
SAFETY ANALYSES....................................................................................................................16
11.1
Adverse Events .................................................................................................................16
11.2
Clinical Laboratory Parameters ........................................................................................17
11.3
Vital Signs ........................................................................................................................21
11.4
Electrocardiogram.............................................................................................................22
11.5
Columbia-Suicide Severity Rating Scale..........................................................................24
12.0
COVID-19 Related Analyses..........................................................................................................25
13.0
HEALTH OUTCOMES ANALYSES............................................................................................26
14.0
SUBGROUP ANALYSES .............................................................................................................27
15.0
INTERIM ANALYSIS ...................................................................................................................28
16.0
DETERMINATION OF SAMPLE SIZE .......................................................................................29
17.0
STATISTICAL SOFTWARE.........................................................................................................30
18.0
DATA HANDLING CONVENTIONS ..........................................................................................31
18.1
Visit Time Windows.........................................................................................................31
18.2
Derived Variables .............................................................................................................31
18.3
Repeated or Unscheduled Assessments of Safety Parameters..........................................32


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Atogepant
3101-309-002 Statistical Analysis Plan 
18.4
Missing Date of the Last Dose of STudy Treatment.........................................................32
18.5
Missing Severity Assessment for Adverse Events............................................................32
18.6
Missing Causal Relationship to stuyd drug for Adverse Events.......................................32
18.7
Missing Date Information for Adverse Events .................................................................32
18.8
Missing Date Information for Prior or Concomitant Medications....................................34
18.8.1
Incomplete Start Date.........................................................................................34
18.8.2
Incomplete Stop Date .........................................................................................35
18.9
Character Values of Clinical Laboratory Parameters........................................................36
19.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................37
20.0
APPENDICES ................................................................................................................................38
APPENDIX I.
REPORTING SELECTED LABORATORY PARAMETERS IN 
CONVENTIONAL UNIT ................................................................................................39


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3101-309-002 Statistical Analysis Plan 
2.1
LIST OF TABLES
Table 4-1
Schedule of Visits and Procedures for In-person Visits Conducted Prior to or 
During the COVID-19 Pandemic ................................................................................8
Table 4-2
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the 
COVID-19 Pandemic ..................................................................................................9
Table 11-1
Criteria for Potentially Clinically Significant Laboratory Values .............................19
Table 11-2
Criteria for Hepatic Laboratory Abnormalities..........................................................20
Table 11-3
Criteria for Potentially Clinically Significant Vital Signs .........................................22
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms............................23
Table 18.1–1.
Safety Analysis Visit Definitions ..............................................................................31
Table 18.9–1
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters .................................................................................................................36
Table19.I–1
List of Selected Parameters to be Reported in Conventional Units...........................39
Table19.I–2
Presenting Laboratory Data Using SI and Conventional Units in Narratives............40
2.2
LIST OF FIGURES
Figure 4–1
Study Design Diagram.................................................................................................7


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Atogepant
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LIST OF ABBREVIATIONS
Term/Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CM
chronic migraine
C-SSRS 
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
EM
episodic migraine
EOS
end of study
ET
early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
LLN
low limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
OL
open-label
PCS
potentially clinically significant
PID
participant identification
PK
pharmacokinetic
PT
preferred term
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis software
SD
standard deviation
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event
ULN
upper limit of normal
V
Visit
WHO
World Health Organization
WK
Week


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Atogepant
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INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the safety data as outlined and/or specified in the final protocol 
of Study 3101-309-002 (dated 22 Feb 2019) and protocol amendment 1 (dated 15 Sept 
2020). Specifications of tables, figures, and data listings are contained in a separate 
document.
Study 3101-309-002 is a Phase 3, multicenter, open-label, 40-week, long-term safety 
extension study conducted in the United States and will enroll approximately 
750 participants from the United States. Participants will be treated with atogepant 60 mg 
once daily.
The study will consist of a 40-week open-label treatment period, and a safety follow-up
period of 4 weeks.
Participants will directly rollover from Study 3101-301-002 (Phase 3 EM). As such,
participants will have Visit 7 from Study 3101-301-002 function as the 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 3101-301-002
before extension Study 3101-309-002 has been initiated. Those participants should 
complete Visit 7/ET and Visit 8/EOS Visit (including discontinuation of study 
intervention) per the Study 3101-301-002 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, Visit 1 Study 3101-309-002 can be conducted on 
the same day as Visit 8/EOS Visit for Study 3101-301-002 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 Study 3101-301-002 should be conducted on the 
same day as Visit 1 for Study 3101-309-002.
∀
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 Study 3101-301-002 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 3101-309-
002 Schedule of Visits and Procedures.


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After Visit 1, study visits will occur every 4 weeks for the duration of the 40-week 
treatment period. Participants will return to the clinic for safety assessments at 4, 8, 12, 
16, 20, 24, 28, 32, 36 and 40 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 4-1 Study Design Diagram, and Figure 4-1 Schedule of Visits and Procedures.
To eliminate immediate potential hazards to participants and study staff due to the 
COVID-19 pandemic while ensuring participant safety and maintaining data integrity, the 
protocol has been updated to allow investigators/appropriately designated study staff to 
perform study visits remotely in protocol amendment 1. For the schedule of visits and 
procedures conducted remotely, see Table 4-2. 
Figure 4–1
Study Design Diagram
ET = early termination; V = visit; Wk = week. 


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Table 4-1
Schedule of Visits and Procedures for In-person Visits Conducted Prior to or During the COVID-19 Pandemic
Study Period
Open-label Treatment Period (40 weeks)
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 1a Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10 Visit 11/ET
Visit 12/
EOSe
Day/Week
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)
Visit Windows
± 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 participan
privacy
X
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Assess inclusion/exclusion criteria
X
Perform physical examination
X
X
X
Collect vital sign measurementsb
X
X
X
X
X
X
X
X
X
X
X
X
Perform ECG
X
X
X
X
Perform urine pregnancy testc
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory determinationsd
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study intervention (ie, 
atogepant)
X
X
X
X
X
X
X
X
X
X
Review of study intervention (ie, 
atogepant) compliance and 
accountability
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; ET = early termination; INR = international normalized ratio; IWRS 
= interactive web response system.
a
After providing informed consent for the current study, Visit 1 will be conducted on the same day as Study 3101-301-002 Visit 7; procedures collected as part of 
Study 3101-301-002 Visit 7 should not be repeated. Visit 1 must be conducted as an in-person visit.
b
Vital sign measurements: Weight, sitting and standing pulse rate, respiratory rate, sitting and standing blood pressure, and body temperature.
c
For women of child-bearing potential only, a urine pregnancy test will be performed at all visits.
d
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 screening (Visit 1).
e
During the COVID-19 pandemic, Visit 12 (Follow-up/End of Study) should be conducted remotely for all participants.


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Table 4-2
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the COVID-19 Pandemic
Study Period
Open-label Treatment Period (40 weeks)a
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10 Visit 11/ET
Visit 12/
EOSc
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)
Visit Windows
± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days ± 3 days
± 3 days
+ 3 days
± 3 days
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
Provide urine pregnancy test and 
instructionsb
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
Dispense study intervention (ie, atogepant
X
X
X
X
X
X
X
X
X
Review of study intervention (ie, 
atogepant) compliance and accountability
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; ET = early termination; IWRS = interactive web 
response system.
a
For participants who have a study visit replaced by a remote study visit, all missed in-person safety assessments (clinical laboratory determinations, 
vital signs, and ECGs) will be collected at the next in-person visit. To ensure participant safety, remote study visits can 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 be discontinued from the 
study.
b
For women of childbearing potential only, a urine pregnancy test must be performed within 48 hours prior to the remote visits. Investigators/site 
staff will provide participants with study-supplied urine pregnancy tests and corresponding written instructions to be used at home by participants 
for remote study visits. Sites are required to verbally review testing instructions with all participants.
c
During the COVID-19 pandemic, Visit 12 (Follow-up/End of Study) should be conducted remotely for all participants.


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5.0
OBJECTIVES
The study objective is to evaluate the safety and tolerability of treatment with atogepant 
60 mg once daily for the prevention of migraine over a 40-week duration.


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6.0
ANALYSIS POPULATIONS
6.1
SCREENED POPULATION
The Screened Population consists of all participants who signed an informed consent 
form to enroll in this study.
6.2
SAFETY POPULATION
The Safety Population consists of all participants who received at least 1 dose of 
atogepant in this extension study.


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7.0
PARTICIPANT DISPOSITION
Screen-failures and the associated reasons for failure will be tabulated for all screened 
participants.
The number of participants in the 2 study populations (Screened, Safety) will be
summarized overall.
The number of participants in the safety population will be summarized by lead-in study 
treatments (placebo, Atogepant 10 mg, Atogepant 30 mg, Atogepant 60 mg) and 
enrollment category (3101-301-002 Visit 7 Completer, 3101-301-002 Visit 8 Completer, 
3101-301-002 Study Completer) and overall.
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 same period will be presented for the Safety Population. The 
reasons for premature discontinuation from the open-label treatment period will be 
summarized (number and percentage). Similar disposition information to the treatment 
period will be presented for the safety follow-up period. All participants who prematurely 
discontinue during the open-label treatment period or the safety follow-up period will be 
listed by discontinuation reason.


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8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (age; age group[<20, 20-29, 30-39, 40-49, 50-59, 60-69, 
and >=70]; race; race group [white, non-white]; ethnicity; sex), baseline characteristics 
(weight; height; and body mass index, calculated as weight [kg]/(height [m])2 will be 
summarized descriptively for the Safety Population. For all participants in 3101-309-002, 
demographics and other baseline characteristics from the lead-in study (Study 
3101-301-002) will be used. Continuous variables will be summarized by number of 
participants and mean, standard deviation (SD), median, first quartile (Q1), third quartile 
(Q3), minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of participants.
Abnormalities in participants’ medical and surgical history will be coded using the 
Medical Dictionary for Regulatory Activities, version 22.0 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 and preferred term 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 from the lead-in study will be reported for the Safety Population.
Prior medication is defined as any medication taken before the date of the first dose of 
lead-in study treatment. Concomitant medication 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 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 for the open-label treatment period and 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 World Health Organization (WHO) Drug Dictionary Enhanced,
March 2019 or newer, will be used to classify prior and concomitant medications by 
therapeutic class and drug name.
Protocol deviations will be defined in Protocol Deviation Requirement Specification, 
including significant deviation classification. The number and percentage of participants 
with significant protocol deviations will be summarized for the Safety Population.


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to study treatment for the Safety Population during the treatment period will be 
summarized for treatment duration, calculated as the number of days from the date of the 
first dose of open-label study treatment taken to the date of the last dose taken, inclusive. 
The number and percentage of participants with each treatment duration of ≥ 1 day, 
≥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 will be summarized. 
Descriptive statistics (number of participants, mean, SD, median, Q1, Q3, minimum, and 
maximum) will also be summarized. 
Participant-years, defined as exposure to the study treatment in years, will be summarized 
for the Safety Population.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for a specified period is defined as the total number of study 
medications actually taken by a participant during that period divided by the number of 
open-label study medications that were expected to be taken during the same period 
multiplied by 100. The total number of tablets actually taken during the treatment period 
will be calculated from the study medication record. Descriptive statistics for open-label 
study medication dosing compliance together with the compliance categories (<80%, 
80% - 120%, >120%) will be summarized for open-label study treatment period between 
2 consecutive visits, as well as for the period from the first dose of the open-label study 
interventions actually taken to the last dose of open-label study intervention actually 
taken for the Safety Population.


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10.0
EFFICACY ANALYSES
No efficacy analysis is planned. 


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11.0
SAFETY ANALYSES
The safety analysis will be performed using the Safety Population. The safety parameters 
will include adverse events (AEs), clinical laboratory, vital sign, electrocardiographic 
(ECG), and C-SSRS. For each of the clinical laboratory, vital sign, and ECG parameters, 
the last non-missing safety assessment before the first dose of treatment from lead-in 
study (Study 3101-301-002) will be used as the baseline. Continuous variables will be 
summarized by number of participants and mean, SD, median, Q1, Q3, minimum, and 
maximum values. Categorical variables will be summarized by number and percentage of 
participants.
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 22.0 or newer.
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 
double-blinded dose of the lead-in study treatment. An AE that occurs more than 30 days 
after the last dose of study treatment in this study or safety follow-up visit (Visit 12)
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 with recorded onset date on or after the date of the first dose of 
lead-in study treatment and within 30 days after the last dose of open-label study 
treatment or Visit 12 whichever comes later. An AE will be considered as a treatment-
emergent SAE (TESAE) if it is a TEAE that also meets SAE criteria. TEAEs that started 
after the date of last dose of open-label study treatment will be considered as newly 
emergent. Only TEAEs that started on or after the date of first dose of open-label study 
treatment will be summarized for this study.
Overall summary of AEs will be provided on a per-participant basis for categories of 
TEAEs, treatment-related TEAEs, deaths, TESAEs, and TEAEs leading to study 
intervention discontinuation.
The number and percentage of participants reporting TEAEs will be tabulated by system 
organ class and preferred term, and further categorized by severity and causal 
relationship to the study treatment. If more than 1 AE is coded to the same preferred term 
for the same participants, the participant will be counted only once for that preferred term 
using the greatest severity and strictest causality for the summarization by severity and 
causal relationship.
The number and percentage of participants reporting newly emergent TEAEs will be 
tabulated by system organ class and preferred term.


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The number and percentage of participants who have TEAEs leading to premature 
discontinuation of the study intervention will be summarized by system organ class, 
preferred term.
The incidence of common (≥ 2% [after rounding] of participants) TEAEs will be 
summarized by preferred term.
The number and percentage of participants who have TESAE will be tabulated by system 
organ class and preferred term.
In addition, separate tabular displays will be presented for participants who died, 
participants with SAEs, and participants with TEAEs leading to study intervention 
discontinuation.
All AE reports in this study will be summarized or listed.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in SI units) at baseline, postbaseline, 
and changes from baseline values at each postbaseline timepoint will be presented for the 
following laboratory parameters.
In addition, descriptive statistics for values and changes from the baseline values in
conventional units at each assessment time point will be presented for selected clinical 
laboratory parameters listed in Appendix I. A description of reporting the lab values in 
conventional units in patient narratives (along with the standard reporting in SI units) is 
presented at the end of Appendix I.
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
Chemistry:
Sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen, creatinine, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, creatine kinase, 
total protein, albumin, calcium, phosphorus, uric acid, 
total cholesterol, estimated glomerular filtration rate
Urinalysis:
Specific gravity, pH


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Clinical laboratory test values will be considered potentially clinically significant (PCS) 
if they meet either the lower-limit or higher-limit PCS criteria listed in Table 11-1 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. The numerator will be the total number of participants with available 
non-PCS baseline values and at least 1 PCS postbaseline value during the study. A 
supportive tabular display of participants with PCS postbaseline values will be provided, 
including the participant identification (PID) number, baseline and all postbaseline 
(including non-PCS) values.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
Potential Hy’s Law criteria within a 24-hour window is defined by a postbaseline 
elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 x 
ULN, along with total bilirubin (TBL) ≥ 2 x ULN and a non-elevated alkaline 
phosphatase (ALP) < 2 x 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.


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Table 11-1
Criteria for Potentially Clinically Significant Laboratory Values
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 
mL/min/1.73
m2
—
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).
The number and percentage of participants meeting each of the following criteria for 
postbaseline hepatic laboratory abnormalities listed in Table 11-2 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.


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Table 11-2
Criteria for Hepatic Laboratory Abnormalities
Laboratory Parameter
Categories
ALT
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT or AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Bilirubin Total
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Alkaline Phosphatase
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN


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Laboratory Parameter
Categories
Concurrent Elevations1
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 1.5 × ULN
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 2 × ULN
Potential Hy’s Law within 24-hour window1
Postbaseline assessment of the following laboratory 
parameters based on blood draws collected within a 24-hour 
period:
∀ALT or AST ≥ 3 × ULN
∀TBL ≥ 2 × ULN
∀ALP < 2 × ULN
e-DISH
Postbaseline assessment of the following laboratory 
parameters at any time:
∀Maximum ALT or AST ≥ 3 ×ULN
∀Maximum TBL ≥ 2 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; 
ALP = alkaline phosphatase; ULN = upper limit of normal (value provided by the laboratory).
1 Elevations are from the same day
The number and percentage of participants with an adjudicated case (i.e., ALT ≥ 3 x 
ULN and/or AST ≥ 3 x ULN) will be summarized and by relationship of ALT or AST 
elevation to study medication. The percentages will be calculated relative to the number 
of participants with at least 1 adjudicated case. The numerator will be the number of 
participants with at least 1 adjudicated case in the specific category of relationship. If a 
participant has more than 1 adjudicated case, he or she will be counted in the most 
relevant category of relationship.
Participants with an adjudicated case (i.e. ALT ≥ 3 x ULN or AST ≥ 3 x ULN) will be 
listed with their ALT and AST assessments, adjudication dates, relationship of ALT or 
AST elevation to study medication, and confounding factor(s). Additional listings will be 
provided for participants who meet ALT ≥ 3 x ULN or AST ≥ 3 x ULN and/or potential 
Hy’s law and have one of the following categories: at least 1 abnormal liver biochemistry 
risk factor, at least 1 liver disease sign and symptom, at least 1 liver diagnostic test 
performed, consultation with a specialist for liver evaluation, liver lab tests performed, 
and drug screen performed, respectively.
11.3
VITAL SIGNS
Descriptive statistics for vital signs (systolic and diastolic blood pressures [sitting and 
standing], pulse rate [sitting and standing], respiratory rate, temperature, weight, 
orthostatic systolic blood pressure, orthostatic diastolic blood pressure, and orthostatic 
pulse rate) values at baseline, postbaseline, and changes from baseline values at each 
postbaseline timepoint will be presented. 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.


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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 Table 11-3.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 participants with PCS 
postbaseline values will be provided. In addition, a tabular display showing all AEs that 
occurred in participants who had PCS postbaseline vital sign values will be provided.
Table 11-3
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteria
Observed Value
Change from Baseline
Systolic blood pressure, mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic blood pressure, mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
Orthostatic SBP change, mm Hg
Low
≤ -20
—
Orthostatic DBP change, mm Hg
Low
≤ -15
—
Orthostatic Pulse rate change, 
bpm
High
≥ 25
—
SBP = Systolic blood pressure, DBP = Diastolic blood pressure, bpm = beats per minute.
11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (ie, heart rate, PR interval, QRS interval, QT 
interval, and QTc interval) at baseline, postbaseline, and changes from baseline values at 
each postbaseline timepoint will be presented.


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ECG parameter values are considered PCS if ECG values meet either the actual value or 
change from baseline PCS high criteria listed in Table 11-4.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 ms, >480 ms, or >500 ms will be tabulated 
by treatment group. A supportive listing of participants with postbaseline clinical interest 
will be provided. A listing of all AEs for participants with postbaseline clinical interest 
will also be provided.
The number and percentage of participants with an increase > 30 msec but ≤ 60 msec, 
and with an increase > 60 msec in QTcF will be tabulated. Participants will be counted 
only once for the most severe category. A supportive listing of participants with 
postbaseline QTcF increases > 30 msec will be provided, including the PID number, 
study center, and all QTc values (including changes from baseline). A listing of all AEs 
for participants with postbaseline QTcF increases > 30 msec will also be provided.
A shift table from baseline to the end of 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.
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Criterion
QRS interval
msec
≥150
PR interval
msec
≥ 250
QTc (QTcB or QTcF) interval
msec
> 500
QTc (QTcB or QTcF) interval
msec
Increase from baseline > 60
QTc = QT interval corrected for heart rate. 
QTcB = QT interval corrected for heart rate using the Bazett formula.
QTcF = QT interval corrected for heart rate using the Fridericia formula.


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11.5
COLUMBIA-SUICIDE SEVERITY RATING SCALE
For C-SSRS, the number and percentage of participants with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS will be summarized for the Safety Population. The 
distribution of responses for most severe suicidal ideation and most severe suicidal 
behavior in the participant’s lifetime history, in the 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, study center number, lifetime history, and postbaseline 
values. Intensity of suicidal ideation and suicidal behavior type will also be included in 
these listings.


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12.0
COVID-19 RELATED ANALYSES
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 and supplemental signs and symptoms
∀
COVID-19 status (COVID-19 testing results or contact with a COVID-19 positive 
person)
Safety population will be used for the planned analyses described above. The number of 
participants impacted by COVID-19 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 tabulated, respectively. 
The number of participants with study visits impacted by COVID-19 will be summarized 
by the classification of study visits (missed, clinical visits in person, remote [auto/video]). 
Furthermore, the number of participants who missed at least one entire visit due to 
COVID-19 will be summarized; the number of participants who missed at least one 
assessment due to COVID-19 will be summarized by assessment procedures (laboratory, 
C-SSRS, urine pregnancy test, vital signs and ECG) and visit. The number of 
participants with remote assessments of C-SSRS and pregnancy test will be summarized 
by visit. 
The number of participants with significant protocol deviation due to COVID-19 will be 
provided. The number of participants with study drug disruption due to COVID-19 will 
be provided as well. The number of participants with TEAEs related to 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. 
Supporting listings for the described analyses above will be provided.  


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13.0
HEALTH OUTCOMES ANALYSES
Not Applicable.


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14.0
SUBGROUP ANALYSES
No subgroup analysis is planned.


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15.0
INTERIM ANALYSIS
Interim data-cuts are planned to provide ongoing safety data to support global regulatory 
submissions.


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16.0
DETERMINATION OF SAMPLE SIZE
As this is a safety extension study from the lead-in Study 3101-301-002, all participants 
from the lead-in study who are eligible for this extension study will be enrolled. No 
separate sample size calculation was performed. Based on expected completion rate from 
the lead-in Study 3101-301-002, approximately 750 participants will be enrolled into this 
long-term, open-label, safety extension study.


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17.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 or newer of SAS.


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18.0
DATA HANDLING CONVENTIONS
18.1
VISIT TIME WINDOWS
The analysis visit windows for safety endpoints are defined as follows:  
Table 18.1–1.
Safety Analysis Visit Definitions
Analysis Visit
(Derived)
Scheduled Visit Daya
Window
Baseline
Baseline from lead-in study
Week 4
Day 28 (Visit 2)
Treatment Day [1, 42]
Week 8
Day 56 (Visit 3)
Treatment Day [43, 70]
Week 12
Day 84 (Visit 4)
Treatment Day [71, 98]
Week 16
Day 112 (Visit 5)
Treatment Day [99, 126]
Week 20
Day 140 (Visit 6)
Treatment Day [127, 154]
Week 24
Day 168 (Visit 7)
Treatment Day [155, 182]
Week 28
Day 196 (Visit 8)
Treatment Day [183, 210]
Week 32
Day 224 (Visit 9)
Treatment Day [211, 238]
Week 36
Day 252 (Visit 10)
Treatment Day [239, 266]
Week 40
Day 280 (Visit 11)
Treatment Day [267, the last open-label visit]
End of open-label 
treatment period
Last available assessment during open-label
treatment period
Safety Follow-up/EOS
Day 308 (Visit 12)
Treatment Day [the last open-label visit +1, 
the last study visit]
End of Study
Last available assessment Day after treatment 
start date, i.e. occurs at final visit (expected 
Day 280) or ET
a Relative to the date of the first dose of study treatment. Day 1 = the date of the first dose of study treatment. There is 
no Day 0 or Week 0.
End of Treatment is defined as the last available assessment during open-label treatment period, i.e. on or before the 
treatment end date. End of Treatment results will be presented in analysis tables for clinical laboratory values, 
electrocardiogram 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 
electrocardiograms, clinical laboratory values, and vital signs. 
ET = early termination. EOS=end of study.
18.2
DERIVED VARIABLES
Not applicable.


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18.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
Baseline is defined as the last assessment made before the first dose of lead-in study 
treatment. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
nonmissing postbaseline assessment will be used as the end-of-study assessment for 
generating summary statistics. However, all postbaseline assessments will be used for 
PCS value determinations, and all assessments will be presented in the data listings.
18.4
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT
When the date of the last dose of 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 medication date will be used in the calculation of 
treatment duration.
18.5
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, an intensity 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, an intensity of 
severe will be assigned. The imputed values for severity assessment will be used for the
incidence summary; the values will be shown as missing in the data listings.
18.6
MISSING CAUSAL RELATIONSHIP TO STUYD DRUG 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 study 
treatment will be used for the incidence summary; the values will be shown as missing in 
the data listings.
18.7
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (ie, partly missing).
Missing month and day
∀
If the year of the incomplete start date is the same as the year of the first dose of 
open-label study treatment, the month and day of the first dose of open-label study 
treatment will be assigned to the missing fields


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∀
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
∀
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


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18.8
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS
For prior or concomitant medications, including rescue medications, incomplete 
(ie, partly missing) start dates and/or stop dates will be imputed. When the start date and 
the stop date are both incomplete for a participant, the start date will be imputed first.
18.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date.
Missing month and day
∀
If the year of the incomplete start date is the same as the year of the first dose of 
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
∀
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.


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∀
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
18.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of 
open-label study treatment is missing, impute it as descripted in Section 18.4. If the 
imputed stop date is before the start date (imputed or nonimputed start date), the imputed 
stop date will be equal to the start date.
Missing month and day
∀
If the year of the incomplete stop date is the same as the year of the last dose of 
open-label study treatment, the month and day of the last dose of open-label 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 open-label 
study treatment, December 31 will be assigned to the missing fields
∀
If the year of the incomplete stop date is after the year of the last dose of 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 stop date are the same as the month and year 
of the last dose of open-label study treatment, the day of the last dose of open-label 
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 open-label 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 open-label 
study treatment, the last day of the month will be assigned to the missing day


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∀
If either the year of the incomplete stop date is after the year of the date of the last 
dose of open-label 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 open-label study 
treatment, the first day of the month will be assigned to the missing day
18.9
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, however, as reported in the database will be presented in the 
data listings.
Table 18.9–1 shows examples of how some possible laboratory results should be coded 
for the analysis.
Table 18.9–1
Examples of Coding Special Character Values for Clinical 
Laboratory Parameters
Laboratory Test,
SI Unit
Possible Laboratory Results
Coded Value for Analysis
CHEMISTRY
ALT, U/L
< 5
5
AST, U/L
< 5
5
Bilirubin, total, μmol/L
< 2
2
URINALYSIS
Glucose, mmol/L
= OR > 55, ≥ 55, > 0
Positive
≤ 0, negative
Negative
pH
> 8.0, ≥ 8.0
8.0
≥ 8.5
8.5
Protein
= OR > 3.0, ≥ 3.0, > 0
Positive
≤ 0
Negative
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités
(International System of Units).


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19.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
None


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20.0
APPENDICES


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APPENDIX I.
REPORTING SELECTED LABORATORY PARAMETERS 
IN CONVENTIONAL UNIT
All clinical laboratory parameters will be reported in the International System (SI) units 
as standard practice. In addition, descriptive statistics for values and changes from 
baseline in conventional units at all assessed visits will be reported for selected laboratory 
parameters as listed in Table19.I–1 below. 
Table19.I–1
List of Selected Parameters to be Reported in Conventional Units
Number
Laboratory Parameter
Conventional Unit
Decimal Places
1
Alanine Aminotransferase (SGPT)
U/L
0
2
Albumin
g/dL
1
3
Alkaline Phosphatase
U/L
0
4
Aspartate Aminotransferase (SGOT)
U/L
0
5
Bilirubin, Direct (Conjugated)
mg/dL
1
6
Bilirubin, Indirect (Unconjugated)
mg/dL
1
7
Bilirubin, Total
mg/dL
1
8
Blood Urea Nitrogen
mg/dL
0
9
Calcium
mg/dL
1
10
Cholesterol, HDL
mg/dL
0
11
Cholesterol, LDL
mg/dL
0
12
Cholesterol, LDL direct and calculated 
(combined)
(This lab parameter could be the same as #11) 
mg/dL
0
13
Cholesterol, Total
mg/dL
0
14
Creatine Kinase
U/L
0
15
Creatinine
mg/dL
1
16
Glucose
mg/dL
0
17
Insulin
uIU/mL
1
18
Triglycerides
mg/dL
0
19
Uric Acid
mg/dL
1
20
Hemoglobin
g/dL
1


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Patient narratives will also include the values in conventional units for the selected lab 
parameters (Table19.I–1). That will be accomplished by presenting the values in 
conventional units within the parentheses next to the values in SI units. As shown in 
Table19.I–2 below for ‘Bilirubin, Total’ parameter, for which ‘umol/L’ is the SI unit and 
‘mg/dL’ is the conventional unit. 
Table19.I–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 (umol/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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Summary of Changes from Original to Amendment 1
Date
Section
Description
August 6, 2019
11.2
Added eGFR in Chemistry 
to be consistent with the 
protocol.
August 6, 2019
17.1
Updated visit window 
definitions to ease ISS 
preparation.
October 2, 2019
11.3
Deleted Vital Signs of 
Clinical Interest since it 
would be summarized in 
ISS.
October 2, 2019
11.1
Clarified the definition of 
newly emergent adverse 
event.
October 15, 2019
9.1
Added more categories for 
ISS purpose.
October 17, 2019
11.1
Added another sentence to 
accommodate AE captured 
at the shared visits for both 
lead-in study and extension 
study.
October 22, 2019
11.4
Added ECG of clinical 
interest to align with all 
other Atogepant studies.
December 4, 2019
11.1
Updated to include only
“study intervention 
discontinuation”
December 4, 2019
7.0
Clarified the “Screened 
Population” for disposition
January 3, 2020
11.2
Updated PCS High for 
Urinalysis in Table 11-1
February 13, 2020
11.2
Deleted the shift table for 
lab parameters
February 25, 2020
11.2
Updated eGFR’s PCS 
lower limit in Table 11-1
since central lab did not 
provide the lower level of 
normal
February 25, 2020
Appendix I
Updated the unit for 
Albumin and Hemoglobin 


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Date
Section
Description
for CDISC compliance 
purpose
April 22, 2020
11.3
Clarified the denominator 
of PCS table for vital signs
May 6, 2020
7.0
Deleted “by study center” 
since it is not necessary
April 26, 2021
Title Page
Added Amendment 1 Date, 
and removed statistician 
name
April 26, 2021
4.0 
Added protocol amendment 
1 information; indicated 
Schedule of assessments is 
updated and remote 
assessment schedule is 
provided. 
April 26, 2021
Table 4.1 and Table 4.2
Updated Table 4.1 to align 
with protocol amendment 
1; Added Table 4.2 of 
“Schedule of Visits and 
Procedures for Visits 
Conducted Remotely Due 
to the COVID 19 
Pandemic” to describe 
remote study visits.
April 26, 2021
9.2
The overall period for 
compliance calculation is 
clarified
April 26, 2021
11.2
Deleted the criteria for 
potential Hy’s law without 
window. Clarified the 
criteria for e-DISH in Table 
11-2
April 26, 2021
Section 12
Added the section to 
describe COVID-19 related 
analyses.