Conditions: Episodic Migraine
Keywords: Migraine Aura
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 910
Healthy volunteers: no

Brief summary:
To evaluate the safety and tolerability of atogepant 30 mg and 60 mg once a day for the prevention of migraine in participants with episodic migraine.

Detailed description:

Arms:
arm 1: Placebo-matching atogepant tablets orally once daily for 12 weeks. arm 2: Atogepant 10 mg tablet orally once daily and placebo-matching atogepant tablets orally once daily for 12 weeks. arm 3: Atogepant 30 mg tablet orally once daily and placebo-matching atogepant tablets orally once daily for 12 weeks. arm 4: Atogepant 60 mg tablet orally once daily and placebo-matching atogepant tablets orally once daily for 12 weeks.

Interventions: intervention 1: Atogepant intervention 2: Placebo
Intervention descriptions: intervention 1: Atogepant tablet intervention 2: Placebo-matching atogepant tablets

Protocol document:
Prot_000.pdf: 
 
   
 
 
 
 NCT 03777059  
 
Study ID: 3101-301-002 
 
 
Title: A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND TOLERABILITY OF ORAL ATOGEPANT 
FOR THE PREVENTION OF MIGRAINE IN PARTICIPANTS WITH 
EPISODIC MIGRAINE (ADVANCE) 
 
                    Protocol Date: May 16, 2020 


Allergan 
Protocol 3101-301-002, Amendment 3
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ALLERGAN 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF ORAL ATOGEPANT FOR THE 
PREVENTION OF MIGRAINE IN PARTICIPANTS WITH EPISODIC MIGRAINE
(ADVANCE)
Protocol Number:  
3101-301-002
Phase:
3
Name of Study intervention:
Atogepant
Sponsor:
US Agent
Allergan Pharmaceuticals International Limited
Marlow International
The Parkway, Marlow SL7 1YL
United Kingdom
Allergan (Sales, LLC)
2525 DuPont Drive
Irvine, California USA
92612
Emergency Telephone Number(s):
Serious Adverse Event Reporting:
Fax number:
Back up fax number:
Email
Allergan Medical Safety Physician
Contact Information:
Refer to the Study Contacts Page
Sponsor Signatory:
Vice President, Neuroscience Development
Original Protocol Date:
25 September 2018
Amendment 1 Date
30 November 2018
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Protocol 3101-301-002, Amendment 3
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Amendment 2 Date
25 February 2019
Amendment 3 Date
14 May 2020
Refer to the final page of this protocol for approval signature.
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, 
good clinical practices 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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Protocol 3101-301-002, Amendment 3
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Table of Contents
Title Page .................................................................................................................................. 1
Table of Contents ...................................................................................................................... 4
List of Tables............................................................................................................................. 9
List of Figures........................................................................................................................... 9
Protocol Summary .................................................................................................................. 10
1.
Background and Clinical Rationale................................................................................. 19
1.1
Background ............................................................................................................ 19
1.2
Overview of Atogepant .......................................................................................... 19
1.3
Study Rationale ...................................................................................................... 20
2.
Study Objectives and Clinical Hypotheses...................................................................... 21
2.1
Study Objectives .................................................................................................... 21
3.
Study Design.................................................................................................................... 21
3.1
Data Safety Monitoring Board............................................................................... 22
3.2
Adjudication Committee........................................................................................ 23
4.
Study Population and Entry Criteria................................................................................ 23
4.1
Number of Participants .......................................................................................... 23
4.2
Inclusion Criteria.................................................................................................... 23
4.3
Exclusion Criteria................................................................................................... 24
4.4
Permissible and Prohibited Medications/Treatments............................................. 27
4.4.1
Permissible Medications/Treatments.......................................................... 27
4.4.2
Prohibited Medications/Treatments............................................................ 27
4.4.3
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .............................................................................. 28
4.4.4
Special Diet or Activities............................................................................ 30
4.5
Screen Failures....................................................................................................... 30
5.
Study Interventions.......................................................................................................... 30
5.1
Study Interventions and Formulations ................................................................... 30
5.2
Control Intervention............................................................................................... 30
5.3
Methods for Masking/Blinding.............................................................................. 31
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5.4
Intervention Allocation Ratio................................................................................. 31
5.5
Method for Assignment to Intervention Groups/Randomization........................... 31
5.6
Study Intervention Regimen and Dosing ............................................................... 32
5.7
Storage of Study Interventions............................................................................... 32
6.
Response Measures and Summary of Data Collection Methods..................................... 33
6.1
Efficacy Measures.................................................................................................. 33
6.1.1
Migraine Day.............................................................................................. 33
6.1.2
Headache Day............................................................................................. 34
6.1.3
Acute Medication Use Day and Triptan Use Day...................................... 34
6.2
Health Outcomes Measures.................................................................................... 34
6.2.1
Activity Impairment in Migraine – Diary (AIM-D)................................... 34
6.2.2
Activity Level and Activity Limitation ...................................................... 35
6.2.10
Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1)
.................................................................................................................... 37
6.3
Pharmacokinetic Measures..................................................................................... 37
6.4
Future Biomedical Research .................................................................................. 38
6.5
Safety Measures ..................................................................................................... 39
6.5.1
Adverse Events........................................................................................... 39
6.5.2
Adverse Events of Special Interest............................................................. 39
6.5.3
Clinical Laboratory Determinations........................................................... 39
6.5.4
Vital Signs .................................................................................................. 40
6.5.5
Physical Examination................................................................................. 41
6.5.6
Electrocardiograms (ECG)......................................................................... 41
6.5.7
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................. 41
6.6
Other Study Supplies.............................................................................................. 42
6.7
Summary of Methods of Data Collection .............................................................. 42
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7.
Statistical Procedures....................................................................................................... 43
7.1
Analysis Populations.............................................................................................. 43
7.2
Collection and Derivation of Efficacy Assessments .............................................. 43
7.2.1
Primary Efficacy Variable .......................................................................... 44
7.2.2
Secondary Efficacy Variables..................................................................... 44
7.2.3
Additional Efficacy Variables..................................................................... 46
7.3
Hypothesis and Methods of Analysis..................................................................... 48
7.3.1
Primary Efficacy Analyses ......................................................................... 48
7.3.2
Secondary Efficacy Analyses ..................................................................... 50
7.3.3
Additional Efficacy Analyses..................................................................... 51
7.3.4
Safety Analyses .......................................................................................... 52
7.4
Off-treatment Hypothetical Estimand.................................................................... 52
7.4.1
Treatment Condition of Interest ................................................................. 52
7.4.2
Population................................................................................................... 52
7.4.3
Variable....................................................................................................... 52
7.4.4
Accounting of Intercurrent Events ............................................................. 53
7.4.5
Population-level Summary......................................................................... 53
7.4.6
Off-treatment Hypothetical Estimand Approach for the Secondary 
Endpoints ................................................................................................... 53
7.5
Subgroup Analyses................................................................................................. 53
7.6
Sample Size Calculation ........................................................................................ 54
7.7
Pharmacokinetics and Exposure-response Analyses.............................................. 55
7.8
Interim Analyses..................................................................................................... 55
8.
Study Visit Schedule and Procedures .............................................................................. 56
8.1
Participant Entry Procedures.................................................................................. 56
8.1.1
Overview of Entry Procedures ................................................................... 56
8.1.2
Informed Consent and Participant Privacy................................................. 56
8.1.3
Procedures for Duplicate Participant Identification – Verified Clinical Trials 
(VCT)......................................................................................................... 56
8.2
Washout Intervals................................................................................................... 57
8.3
Procedures for Final Study Entry........................................................................... 57
8.4
Visits and Associated Procedures........................................................................... 57
8.4.1
Visit 1 (Screening/Baseline) Day -35 to Day -28....................................... 57
8.4.2
Double-blind Treatment Phase (12 Weeks)................................................ 59
8.4.3
Follow-up Period (4 weeks) ....................................................................... 62
8.5
Instructions for the Participants ............................................................................. 63
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8.6
Unscheduled Visits................................................................................................. 63
8.7
Compliance with Protocol...................................................................................... 63
8.8
Early Discontinuation of Participants .................................................................... 64
8.9
Withdrawal Criteria................................................................................................ 64
8.10 Withdrawal from Future Biomedical Research...................................................... 65
8.11 Study Termination.................................................................................................. 65
9.
Adverse Events................................................................................................................ 65
9.1
Definitions.............................................................................................................. 65
9.1.1
Adverse Event (AE) ................................................................................... 65
9.1.2
Serious Adverse Event (SAE) .................................................................... 66
9.1.3
Intensity...................................................................................................... 68
9.1.4
Assessment of Causality............................................................................. 69
9.1.5
Follow-up of Adverse Events and Serious Adverse Events ....................... 69
9.2
Procedures for Reporting Adverse Events ............................................................. 70
9.3
Procedures for Reporting a Serious Adverse Event............................................... 70
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events ............. 70
9.4
Exposure to Study Intervention During Pregnancy ............................................... 71
9.5
ALT or AST Elevations.......................................................................................... 71
9.5.1
Potential Hy’s Law Cases........................................................................... 73
9.6
Procedures for Unmasking of Study Intervention.................................................. 73
10. Administrative Items ....................................................................................................... 74
10.1 Protection of Human Participants .......................................................................... 74
10.1.1
Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 74
10.1.2
Compliance with IRB or IEC Regulations................................................. 75
10.1.3
Compliance with Good Clinical Practice................................................... 75
10.1.4
Compliance with Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11).................................................................................. 75
10.2 Financial Disclosure............................................................................................... 75
10.3 Changes to the Protocol ......................................................................................... 75
10.4 Data Protection....................................................................................................... 76
10.5 Participant Confidentiality ..................................................................................... 76
10.5.1
Participant Privacy ..................................................................................... 76
10.6 Documentation....................................................................................................... 76
10.6.1
Source Documents...................................................................................... 76
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10.6.2
Case Report Form Completion................................................................... 78
10.6.3
Study Summary.......................................................................................... 78
10.6.4
Retention of Documentation ...................................................................... 78
10.7 Labeling, Packaging, and Return or Disposal of Study Interventions ................... 79
10.7.1
Labeling/Packaging.................................................................................... 79
10.7.2
Clinical Supply Inventory .......................................................................... 79
10.7.3
Return or Disposal of Study Intervention and/or Supplies......................... 79
10.8 Monitoring by the Sponsor..................................................................................... 79
10.9 Handling of Biological Specimens ........................................................................ 80
10.10 Publications............................................................................................................ 80
10.11 Coordinating Investigator....................................................................................... 80
11. References........................................................................................................................ 81
12. Attachments ..................................................................................................................... 83
12.1 International Classification of Headache Disorders, 3rd Edition............................ 83
12.2 Examples of Prohibited Medications ................................................................... 101
12.3 List of Migraine-preventive Medications with Proven Efficacy and Criteria for 
Determining Inadequate Response to a Prior Migraine-preventive Medication.. 103
12.3.1
List of Migraine-preventive Medications with Proven Efficacy.............. 103
12.3.2
Criteria for Determining Inadequate Response to a Prior Migraine 
Preventive Medication ............................................................................. 104
12.4 Glossary of Abbreviations.................................................................................... 105
12.5 Protocol Amendment 1 Summary........................................................................ 107
12.6 Protocol Amendment 2 Summary.........................................................................112
12.7 Protocol Amendment 3 Summary.........................................................................118
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List of Tables
Table 1
Schedule of Visits and Procedures for In-Person Visits Conducted Prior to or 
During the COVID-19 Pandemic.................................................................... 14
Table 2
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the 
COVID-19 Pandemic...................................................................................... 17
Table 5-1
Study Interventions ......................................................................................... 32
Table 6-1
Clinical Laboratory Parameters ...................................................................... 40
Table 7-1
Statistical Power for Primary and the First Three Secondary Endpoints........ 55
List of Figures
Figure 1
Study Diagram ................................................................................................ 13
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Protocol Summary
Study Compound: Atogepant
Phase: 3
Study Objectives:
To evaluate the safety and tolerability of atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg for the
prevention of migraine in participants with episodic migraine.
To prospectively test for superiority of atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg versus placebo 
for the prevention of migraine in participants with episodic migraine.
 
 
 
Study Design
Structure: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Duration: The study will consist of a 4-week screening and baseline period, a 12-week double-blind treatment 
period, and a follow-up period of 4 additional weeks, for a total duration of 20 weeks.
Study Intervention: Atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg tablets.
Control: Atogepant-matching placebo.
Dosage/Dose Regimen: Atogepant 10 mg, atogepant 30 mg, atogepant 60 mg, or placebo will each be 
administered once a day for 12 weeks duration.
Randomization/Stratification: Participants will be randomized to the following 4 arms in a 1:1:1:1 ratio:

Placebo (n = 218)

Atogepant 10 mg (n = 218)

Atogepant 30 mg (n = 218)

Atogepant 60 mg (n = 218)
Approximately 70% of randomized participants will have taken at least 1 prior migraine prevention medication, 
with proven efficacy (see Attachment 12.3). Randomization will be stratified based on prior exposure (yes/no) 
to a migraine prevention medication with proven efficacy (see Attachment 12.3).
Visit Schedule: Individual participant participation will begin with a 4-week screening/baseline period. 
Participants who complete the 4-week screening/baseline period and meet all entry criteria will be randomized 
at Visit 2 (Randomization Visit). The double-blind treatment period will last 12 weeks, with a follow-up period 
of 4 additional weeks.
There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), Visit 2 (Randomization), Visit 3 (Week 2), 
Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7 (Week 12), and Visit 8 (Follow-up). The Visit 8 
(Follow-up) must be completed for all participants who take at least one dose of study intervention, except for 
participants rolling over into Study 3101-309-002 (longterm safety extension study). For these participants
Visit 8 is not required, as the Follow-up Visit will be performed in the longterm safety study. For participants 
who screen fail for the longterm safety, the Follow-up Visit must be completed. For details, please see Table 1
(Schedule of Visits and Procedures for In-Person Visits Conducted Prior to or During the COVID-19 
Pandemic). 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 was updated to allow
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Incidence of treatment-emergent adverse events (TEAEs) will be tabulated by primary system organ class
(SOC) and by specific event within each primary SOC. Treatment-emergent adverse events will be analyzed 
after treatment start on Day 1 through the end of the study. 
Sample Size Calculation: A sample size of 218 randomized participants per treatment group will provide at least 
98% power to detect the treatment difference between each of the 3 atogepant doses (assumed equally effective) 
and placebo for the primary efficacy endpoint. This sample size was selected to provide sufficient power for 
each of the primary and first 3 secondary endpoints. The power calculations are based on the following 
assumptions: 1) the standard deviation and treatment difference from placebo will be similar to the average 
value across the migraine prevention studies for atogepant (Phase 2/3 Study CGP-MD-01), telcagepant 
(Ho 2014) and monoclonal antibodies (Dodick 2014a; Dodick 2014b; Bigal 2015). In particular, the assumed
treatment difference from placebo in change from baseline in mean monthly migraine days across the 12-week 
treatment period is –1.5 days, and the standard deviation is 3.5 days; and 2) the study statistical testing plan 
controls the overall type I error at 5%. The power calculations of the primary and secondary endpoints have 
taken the multiple comparisons into consideration by testing each dose versus placebo at a 0.0167 significance 
level, 2-sided.
Figure 1
Study Diagram
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Table 1
Schedule of Visits and Procedures for In-Person Visits Conducted Prior to or During the COVID-19 Pandemic
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1.
Background and Clinical Rationale
1.1
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25 to 55 years. Approximately one-third of patients with 
migraines have 3 or more migraine headaches per month, and over half report severe 
impairment or the need for bed rest (Lipton 2007). In the United States alone, work loss due 
to migraine is estimated to cost ~ $13 billion annually (Hu 1999). Prevalence is similar in 
Europe, with migraine headache affecting on average 17.6% of women and 8% of men 
(Stovner 2010). The Global Burden of Disease Survey 2010 (GBD2010) 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. Episodic migraine is a syndrome diagnosis 
applied to patients with migraine (with or without aura) who have 1 to 14 headache days per 
month. Chronic migraine 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 efficacy, safety and tolerability of atogepant in participants with EM.
1.2
Overview of Atogepant
Atogepant is a potent, selective oral CGRP receptor antagonist being developed for migraine 
prevention. CGRP is a neuropeptide implicated in the pathophysiology of migraine. CGRP 
levels in the cranial venous outflow (ie, external jugular vein) are increased during a 
migraine attack and exogenously administered CGRP has been shown to trigger 
migraine-like headache in people with migraine. The majority (80 to 90%) of trigeminal 
Aδ fibers that innervate the dura contain CGRP, suggesting that these fibers may be involved 
in sterile neurogenic inflammation and migraine pain transmission. Furthermore, the CGRP 
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receptor is present on human meningeal and cerebral blood vessels. These observations 
suggest that activation of the trigeminovascular system, with release of CGRP, may play a
key role in migraine pathogenesis and that inhibition of CGRP may yield a novel therapeutic
approach to treating migraine.
The ability of CGRP inhibition to induce pain relief in the acute treatment of migraine
was initially observed with an IV formulation of olcegepant (Olesen 2004), and replicated
by Merck & Co., Inc with an oral formulation of MK-0974 (telcagepant), a highly
selective CGRP receptor antagonist. In Phase 3 studies, telcagepant was superior to 
placebo in the primary endpoints of 2-hour pain freedom, 2-hour pain relief, and the 
absence of associated symptoms (photophobia, phonophobia, and nausea), as well as the key
secondary endpoint of 24-hour sustained pain freedom (Connor 2009). However, serum 
ALT increases were observed with telcagepant. For this reason, the development of these oral 
CGRP receptor antagonists was stopped.
A Phase 2/3 clinical study (Study CGP-MD-01) was conducted, which compared atogepant 
10 mg once a day, atogepant 30 mg once a day, atogepant 30 mg BID, atogepant 60 mg once 
a day and atogepant 60 mg BID to placebo in EM prevention. Overall, all the atogepant doses 
tested were well tolerated and the AE profile of all atogepant doses did not significantly 
differ from placebo. For the primary efficacy endpoint of change from baseline in mean 
monthly migraine days across the 12-week treatment period, all atogepant doses 
demonstrated a statistically significant reduction compared to placebo in patients with EM.
Additional information on non-clinical pharmacology, toxicology, and PK properties of 
atogepant can be found in the IB.
1.3
Study Rationale
Based on the results of the Phase 2/3 Study CGP-MD-01, the present study is being 
performed to prospectively assess the safety, tolerability and efficacy of atogepant 10 mg, 
atogepant 30 mg, and atogepant 60 mg compared with placebo in the prevention of EM. This 
randomized, double-blind, placebo-controlled Phase 3 study is designed to be a pivotal trial 
to confirm the efficacy of these doses and dose regimens and will be used to support 
registration applications.
 
 
 
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2.
Study Objectives and Clinical Hypotheses 
2.1
Study Objectives

To evaluate the safety and tolerability of atogepant 10 mg, atogepant 30 mg, and 
atogepant 60 mg for the prevention of migraine in participants with EM.

To prospectively test for superiority of atogepant 10 mg, atogepant 30 mg, and 
atogepant 60 mg versus placebo for the prevention of migraine in participants with 
EM.
 
 
3.
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
conducted at approximately 110 sites in the United States.
Approximately 872 participants will be randomized to one of 4 treatment arms (placebo, 
atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg) in a 1:1:1:1 ratio as follows:

Placebo (n = 218)

Atogepant 10 mg (n = 218)

Atogepant 30 mg (n = 218)

Atogepant 60 mg (n = 218)
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Approximately 70% of randomized participants will have taken at least 1 prior migraine 
prevention medication with proven efficacy (see Attachment 12.3). Randomization will be 
stratified based on prior exposure (yes/no) to a migraine prevention medication with proven 
efficacy (see Attachment 12.3).
Participant participation will begin with a 4-week screening/baseline period. Participants who 
complete the 4-week screening/baseline period and meet all entry criteria will be randomized 
to the double-blind treatment period of the study at Visit 2 (Randomization Visit). The 
double-blind treatment period will last 12 weeks, with a subsequent follow-up period of 
4 additional weeks. There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), 
Visit 2 (Randomization), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 
(Week 8), Visit 7/ET (Week 12), and Visit 8 (Follow-up). For details, please see Table 1
(Schedule of Visit and Procedures for In-Person Visits Conducted Prior to or During the 
COVID-19 Pandemic). 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 was updated to allow investigators/appropriately designated study staff 
to perform study visits remotely (as described in Table 2 Schedule of Visits and Procedures 
for Visits Conducted Remotely Due to the COVID-19 Pandemic).
Participants completing the double-blind treatment period in this study may be eligible to 
continue in Study 3101-309-002, a longterm extension safety study in participants with EM, 
if they are at a participating site. For these rollover participants, a Visit 8 is not required in 
the present study, as the Follow-up Visit will be performed in the longterm safety study. For 
participants who screen fail for the longterm safety study, the Follow-up Visit must be 
completed. If Visit 7 is conducted remotely due to the COVID-19 pandemic, the participant 
will not be eligible to roll over into Study 3101-309-002; therefore, Visit 8 (Follow-up/End of 
Study) should be conducted remotely as part of Study 3101-301-002.
3.1
Data Safety Monitoring Board
An independent DSMB will be established to review unblinded safety data and summary 
reports, identify any safety issues and trends, and make recommendations to Allergan, 
including modification or early termination of the trial, if emerging data show unexpected
and clinically significant AEs of treatment.
Details of the DSMB memberships, standard operational procedures for data 
monitoring/review, frequency of review, and other pertinent details will be provided in a 
separate DSMB Charter.
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3.2
Adjudication Committee
An Adjudication Charter will be established and will describe the process for the blinded 
surveillance, monitoring, and adjudication by the Clinical Adjudication Committee of events 
of post-treatment elevations of ALT and/or AST ≥ 3 × the ULN in the atogepant program. 
The purpose of this committee charter will be to provide a standardized process for the 
adjudication of data associated with these events in order to determine whether the elevation 
was related to atogepant.
4.
Study Population and Entry Criteria
4.1
Number of Participants
Approximately 872 participants will be randomized at approximately 110 sites in the United 
States.
4.2
Inclusion Criteria
The following are requirements for entry into the study: 
1. Written informed consent and participant privacy information (eg, written 
authorization for use and release of health and research study information) obtained 
from the participant prior to initiation of any study-specific procedures.
2. Male or female participants ages 18 to 80 years, inclusive, at Visit 1.
3. At least a 1-year history of migraine with or without aura consistent with a diagnosis 
according to the ICHD-3, 2018.
4. Age of the participant at the time of migraine onset < 50 years.
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4.3
Exclusion Criteria
The following are criteria for exclusion from participating in the study:
2. Has a history of migraine accompanied by diplopia or decreased level of 
consciousness or retinal migraine as defined by ICHD-3, 2018.
3. Has a current diagnosis of chronic migraine, new persistent daily headache, 
trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy 
as defined by ICHD-3, 2018.
6. History of an inadequate response to > 4 medications (2 of which have different 
mechanisms of action) prescribed for the prevention of migraine (see Attachment 
12.3 for classification of inadequate response to migraine-preventive medications).
12. Clinically significant cardiovascular or cerebrovascular disease 
 
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15. Any clinically significant hematologic, endocrine, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease:
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4.4
Permissible and Prohibited Medications/Treatments
4.4.1 Permissible Medications/Treatments
Medications that are not specifically prohibited in Section 4.4.2 are allowed, with the 
following clarifications and restrictions:
Therapy considered necessary for the participant's welfare may be given at the discretion of 
the investigator.
 
4.4.2 Prohibited Medications/Treatments
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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.
4.4.3 Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For the 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 
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of childbearing potential who may participate in the study, the following methods of 
contraception, if properly used, are generally considered highly effective:

Combined (estrogen and progestogen containing) hormonal contraception such as oral, 
intravaginal, or transdermal (ie, pill, patch, vaginal ring)

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 women condom with or without spermicide (women 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 the participation in the study.
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If a woman becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the participant will be exited from the 
study after appropriate follow-up. The investigator will (1) notify the participant’s physician 
that the participant was being treated with an investigational drug atogepant and (2) follow 
the progress of the pregnancy. The investigator must document the outcome of the pregnancy 
and provide a copy of the documentation to Allergan.
4.4.4 Special Diet or Activities
4.5
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized to treatment. Rescreening of screen failures is permitted in certain 
situations, with permission from Allergan. However, participants with clinically significant 
laboratory values at Visit 1 (including ALT or AST > 1 × ULN, total bilirubin > 1 × ULN or 
serum albumin < 2.8 g/dL), or those with a positive result on the Visit 1 urine drug screen for 
recreational (including marijuana regardless of legality) or illicit drugs, or nondisclosed 
concomitant medications, are not allowed to be rescreened.
5.
Study Interventions
5.1
Study Interventions and Formulations
Tablets containing atogepant 10 mg (Formulation 
 ), atogepant 30 mg 
(Formulation
), and atogepant 60 mg (Formulation 
).
5.2
Control Intervention
Atogepant 10 mg matching placebo (Formulation 
), atogepant 30 mg matching 
placebo (Formulation 
), and atogepant 60 mg matching placebo 
(Formulation
).
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5.3
Methods for Masking/Blinding
A double-dummy design will be used to maintain study blind. Atogepant tablets and 
matching placebo will be provided in identical blister cards to maintain masking of the study.
All participants will be instructed to take study intervention once a day (3 tablets) at 
approximately the same time each day. Participants will therefore, receive either placebo, 
atogepant 10 mg, atogepant 30 mg, or atogepant 60 mg once a day.
5.4
Intervention Allocation Ratio
Participants will be randomized to the following 4 arms in a 1:1:1:1 ratio:

Placebo (n = 218)

Atogepant 10 mg (n = 218)

Atogepant 30 mg (n = 218)

Atogepant 60 mg (n = 218)
Approximately 70% of randomized participants will have taken at least 1 prior migraine 
prevention medication with proven efficacy (see Attachment 12.3). Randomization will be 
stratified based on prior exposure (yes/no) to a migraine prevention medication with proven 
efficacy (see Attachment 12.3).
5.5
Method for Assignment to Intervention Groups/Randomization
Prior to initiation of study intervention, each participant who provides informed consent 
and/or assent will be assigned a participant number that will serve as the participant
identification number on all study documents.
At randomization (Visit 2), eligible participants will be randomly assigned to 1 of 4
intervention arms in a 1:1:1:1 ratio to receive atogepant 10 mg, atogepant 30 mg, atogepant 
60 mg, or placebo once a day.
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, log in information and directions for the IWRS will be provided 
to each site.
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Study intervention will be labeled with study intervention kit numbers. The IWRS system 
will provide the site with the specific medication kit number(s) for each randomized 
participant at the time of randomization. Sites will dispense study intervention according to 
the IWRS instructions. Sites will also log onto the IWRS at subsequent visits to obtain a kit 
number for dispensing study intervention. Sites will receive the IWRS confirmation 
notifications for each transaction. All notifications are to be maintained with the study source 
documents.
Study intervention will be dispensed at the study visits summarized in the schedule of 
activities. Returned study intervention should not be re-dispensed to the participants.
For study visits conducted remotely due to the COVID-19 pandemic (Table 2), study 
intervention, can be shipped to participants via an overnight courier or provided curbside. 
Study medication to cover 1 additional remote study visit may be dispensed.
5.6
Study Intervention Regimen and Dosing
Treatments to be used in this trial are listed in (Table 5-1). Participants who meet all of the 
study entry criteria at Visit 2 will be randomized and provided with study intervention to be 
taken on an outpatient basis. Sites will subsequently dispense study intervention to 
participants at Visits 3, 4, 5, and 6. Participants will take their first dose study intervention at 
the clinic at Visit 2 and will be instructed to take their study intervention at approximately the 
same time each day. Details of PK samples with respect to timing of study intervention are 
provided in Section 6.3. Study intervention will be administered orally for 12 weeks, and 
participants will be followed for 4 weeks following discontinuation of the study intervention.
Table 5-1
Study Interventions
Drug/Dose
Study Intervention Product
Study Intervention 
Frequency
Route of Administration
Placebo
Placebo 10 mg/ Placebo 30 mg/
Placebo 60 mg
Once daily
Oral 
Atogepant 10 mg
Atogepant 10 mg/Placebo 30 mg/ 
Placebo 60 mg
Once daily
Oral
Atogepant 30 mg
Atogepant 30 mg/Placebo 10 mg/ 
Placebo 60 mg
Once daily
Oral 
Atogepant 60 mg
Atogepant 60 mg/Placebo 10 mg/ 
Placebo 30 mg
Once daily
Oral 
5.7
Storage of Study Interventions
The study intervention must be stored at room temperature in a securely locked cabinet. 
Further details regarding the storage of study intervention are in the Study Reference Manual.
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1) Headache characteristics:
i. Unilateral location
ii. Pulsating quality
iii. Moderate or severe pain intensity
iv. Aggravated by or causing avoidance of routine physical activity 
(eg, walking or climbing stairs)
2) Symptoms:
i. Nausea and/or vomiting
ii. Photophobia and phonophobia
iii. Typical aura (ie, visual, sensory, or speech/language) accompanying or
within 60 minutes before headache begins
E. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, 
migraine-specific medication (ie, triptan or ergot derivative) was used after the start 
of the headache, in which case no minimum duration will be specified.
6.1.2 Headache Day
A headache day is defined as any calendar day on which headache pain lasting 2 hours or 
longer occurs unless an acute headache medication (eg, ibuprofen, triptan) was used after the 
start of the headache, in which case no minimum duration will be specified. Calendar days 
begin at midnight and last until 11:59 PM (23:59).
6.1.3 Acute Medication Use Day and Triptan Use Day
An acute medication use day is defined as any day on which a participant reports, per eDiary, 
the intake of allowed medication(s) for the acute treatment of migraine. The allowed 
medications include the following categories of drugs: triptans, ergots, opioids, analgesics 
(including acetaminophen), NSAIDs (including aspirin), and antiemetics.
A triptan use day is defined as any day on which a participant reports intake of a triptan to 
treat a migraine per participant diary.
6.2
Health Outcomes Measures
6.2.1 Activity Impairment in Migraine – Diary (AIM-D)
The AIM-D is an 11-item daily diary measure that assesses the impact of migraine and is 
comprised of two domains that evaluate Performance of Daily Activities (7 items) and 
Physical Impairment (4 items). Participants are asked to rate the level of difficulty 
experienced in the past 24 hours with Performance of Daily Activities (ie, difficulty with 
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household chores, errands, leisure activities at home, leisure or social activities outside the 
home, strenuous physical activities, concentrating, and thinking clearly) and Physical 
Impairment (ie, difficulty walking, moving body, bending forward, moving head) using a 
6-point rating scale ranging from “Not difficult at all,” “A little difficult,” “Somewhat 
difficult,” “Very difficult,” “Extremely difficult,” and “I could not do it at all.” Three items 
include a response of “I did not…,” for example, “I did not have errands planned.” The 
AIM-D was developed as an electronic daily diary with the same set of questions 
administered in headache and non-headache versions. The Headache version is administered 
on days when a participant reports a headache and the Non-Headache version is administered 
on days when a participant does not report having a headache. The AIM-D instructs 
participants to answer each question based on the level of difficulty experienced in the past 
24 hours for both versions, with “during your headache” indicated for the AIM-D Headache 
version. In addition to the two domain scores, a total score using all 11 items can also be 
calculated. Each raw daily domain score, as well as the raw daily total score, are transformed 
to a 0-100 scale, with higher scores indicating greater impact of migraine (ie, higher disease 
burden).
6.2.2 Activity Level and Activity Limitation
Two items based on a 24-hour recall will be administered daily using Headache and 
Non-headache versions as additional health outcome measures and for evaluation of the 
AIM-D. The first item will be used to assess activity level within the past 24 hours with a 
5-level response scale ranging from “No activity – Spent all day lying down” to “Exercised –
Brisk walk, running, jogging, biking or other activity for 30 or more minutes.” The second 
item will be used to evaluate activity limitation with a 5-level response scale ranging from 
“Not at all limited – I could do everything” to “Extremely limited”.
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6.2.10Migraine Specific Quality of Life Questionnaire, Version 2.1
(MSQ v2.1)
The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality-of-life 
impairments attributed to migraine in the past 4 weeks. It is divided into three domains: Role 
Function-Restrictive assesses how migraines limit one’s daily social and work-related 
activities; Role Function-Preventive assesses how migraines prevent these activities; and the 
Emotional Function domain assesses the emotions associated with migraines. Participants
respond to items using a 6-point scale ranging from “none of the time” to “all of the time.” 
Raw dimension scores are computed as a sum of item responses and rescaled to a 
0 to 100 scale, where higher scores indicate better quality of life.
6.3
Pharmacokinetic Measures
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The date and time of collection of each PK sample will be recorded in the eCRF. In addition, 
for each of the PK samples collected (except the Visit 2 sample) the date and time of the dose 
of study intervention prior to the PK sample should be recorded. PK samples will be 
collected, stored (frozen) and shipped according to instructions provided in the Study 
Reference Manual.
The treatment codes will be provided to the bioanalytical lab using a secure process ensuring 
no one outside the bioanalytical team is unblinded, to allow only atogepant-treated 
participant PK samples to be analyzed. The bioanalytical method for the determination of 
individual plasma concentrations of atogepant and the performance of the assay during 
validation and sample analysis will be summarized in a separate bioanalytical report, 
including the results obtained from analysis of the PK samples. The bioanalytical report will 
be appended to the integrated clinical trial report.
6.4
Future Biomedical Research
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6.5
Safety Measures
6.5.1 Adverse Events
Subjective AEs will be collected from the time of consent through the last visit. For all AEs, 
the investigator must provide an assessment of the severity; causal relationship to study 
intervention; start and stop date, and seriousness of the event (eg, SAE); document all actions 
taken with regard to study 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.
6.5.2 Adverse Events of Special Interest
Selected nonserious and serious adverse events are of special interest and will require 
immediate reporting, recording, and follow-up. The following events will be closely
monitored:

Treatment-emergent suicidal ideations with intent, with or without a plan, (ie, Type 4 
or 5 on the C-SSRS) or any suicidal behaviors.

Treatment-emergent elevated ALT or AST lab value ≥ 3 × ULN.

Potential Hy’s law cases: elevated ALT or AST lab value that is ≥ 3 × ULN and an 
elevated total bilirubin lab value that is ≥ 2 × ULN and, at the same time, an alkaline 
phosphatase lab value that is < 2 × ULN.
Reporting requirements for ALT or AST elevations and potential Hy’s law cases are outlined 
in Section 9.5 and Section 9.5.1. Responses to the C-SSRS that meet the above criterion will 
be captured in the eTablet and monitored by Allergan. These AEs or events determined to be 
SAEs must be reported appropriately via the designated eCRFs and safety forms.
6.5.3 Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at the visits outlined in 
Table 1. Hematology, chemistry, coagulation parameters (INR), and urinalysis will be 
conducted at these visits. Serology and the urine drug screen will be conducted at Screening 
(Visit 1). The investigator will assess the clinical significance of any values outside the 
reference ranges provided by the central laboratory. Participants with abnormalities judged to 
be clinically significant at Screening (Visit 1) or with positive results on the urine drug screen 
will be excluded from the study. 
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Women of childbearing potential will be required to have a urine pregnancy test at all visits. 
A positive pregnancy test at Visit 1 or Visit 2 will exclude the participant from participation 
in the study.
Investigators may also perform unscheduled clinical laboratory determinations at any time 
for the purpose of participant safety. 
Participants are not required to fast overnight before coming in for their appointments.
The clinical laboratory parameters to be measured are shown in Table 6-1.
Table 6-1
Clinical Laboratory Parameters
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, lactate dehydrogenase, creatine kinase, total protein, 
albumin, calcium, phosphorus, uric acid, total cholesterol. The estimated 
glomerular filtration rate will be calculated by the central laboratory.
Hematology
Hemoglobin; hematocrit; red blood cell count; red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration); white blood cell count, including differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils); platelet count
Urinalysis
Urine dipstick for specific gravity, pH, protein, glucose, ketones, bilirubin, and 
blood; microscopic examination including red blood cells/high-power field, white 
blood cells/high-power field, and casts/low-power field.
Coagulation
International Normalized Ratio
Serology
At Visit 1 only: anti-hepatitis A IgM antibody, hepatitis B surface antigen, 
anti-hepatitis C antibody, or 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. Urine drug screens positive for recreational (including 
marijuana regardless of legality) or illicit drugs or non-disclosed concomitant 
medications are not allowed to be repeated. All other positive urine drug screens
may be repeated with permission from 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 randomization.
A central laboratory will be used to evaluate all urine and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory.
6.5.4 Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, body weight, and height (at Visit 1 only), will be performed at 
every visit. Sitting and standing BP and pulse rate will be determined as follows: BP and 
pulse measurements will be performed after the participant sits quietly for 5 minutes, 
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followed by a second set of measurements taken after the participant stands for at least 
3 minutes (but no longer than 10 minutes).
6.5.5 Physical Examination
A complete physical examination will be performed at the visits outlined in Table 1. A 
professionally trained physician or healthcare professional licensed to perform physical
examinations will examine the participant for any detectable abnormalities of the following 
body systems: general appearance; neck (including thyroid); head, eyes, ears, nose, and 
throat; lungs; heart/cardiovascular; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic; skin; and other. The neurologic examination should be conducted to detect the 
presence of any significant sensory/motor abnormalities.
6.5.6 Electrocardiograms (ECG)
A 12-lead ECG will be performed at the visits outlined in Table 1. All ECGs should be
performed after the participant has been supine for at least 5 minutes. All ECGs performed
will be saved as a source document. ECGs will be transmitted electronically to the central 
ECG laboratory for analysis according to the instructions provided by the laboratory to be 
centrally read by a cardiologist. The overall interpretation of the clinical significance of the 
ECG will be determined by the investigator and recorded in the participant’s eCRF.
6.5.7 Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation 
and behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 
2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods [not 
plan] without intent to act), 4 (active suicidal ideation with some intent to act, without 
specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-SSRS also 
captures information about the intensity of ideation, specifically the frequency, duration, 
controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or 
behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). More than 
1 classification can be selected provided they represent separate episodes. For actual attempts 
only, the actual or potential lethality is classified for the initial, most lethal, and most recent 
attempts. The C-SSRS will be completed at all study visits. At Visit 1 (Screening), the 
C-SSRS will be completed for the participant’s lifetime history and for the 6 months prior to 
screening. At all other visits the C-SSRS will be completed for ideation and behavior since 
the previous visit. The C-SSRS will be completed on the eTablet by the investigator or 
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designee with current and valid training in administering the assessment. A participant
should not be released from the study center until the results of C-SSRS are reviewed and it 
is confirmed that the participant is not considered to be at risk. Participants who reply with 
“yes” to questions 4 or 5 in the suicidal ideation section or “yes” to any question in the 
suicidal behavior section of the C-SSRS at Visits 3 through 6 must be withdrawn from the 
study and should receive appropriate follow-up as in routine clinical practice, including the 
Early Termination Visit 7 and the Follow-up Visit 8. These participants must continue to 
complete their daily eDiary through Visit 8 Follow-up.
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 onsite urine pregnancy test

All supplies needed for PK and future biomedical research sample collections

Shipping materials for shipment of laboratory samples to central laboratory

All supplies needed for ECG assessment including ECG machine

Electronic diaries

Electronic tablet(s)
6.7
Summary of Methods of Data Collection
An IWRS will be used to randomize participants and manage study intervention inventory. 
All office visit data (ie, non-diary data) for this study will be collected by either the eTablet 
(eg, questionnaires for participant reported outcomes) or eCRFs via an electronic data 
capture system. Source documents will be used at the sites and may include a participant’s 
medical record, hospital charts, clinic charts, the investigator’s participant study files, as well 
as the results of diagnostic tests such as laboratory tests, ECGs, etc. A centralized clinical 
laboratory will be used for the analysis of all blood and urine samples, and for ECG 
assessments. Additional information on the collection and handling of samples is detailed in 
the Laboratory Procedure Manual.
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Participants will use an eDiary daily to record the daily total duration of headache, headache 
characteristics, associated symptoms, the worst pain severity, acute medication use, AIM-D, 
Activity Level, and Activity Limitation both in the screening/baseline period and double-
blind treatment period until Visit 8. Training for the eDiary will be provided for qualified 
participants during the Screening/Baseline Visit (Visit 1).
7.
Statistical Procedures
7.1
Analysis Populations
The ITT population will consist of all randomized participants. All efficacy analyses will be 
performed using the mITT population, consisting of all randomized participants who 
received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data 
and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of 
eDiary data during the double-blind treatment period. All safety analyses will be performed 
using the safety population, consisting of all participants who received at least 1 dose of 
study intervention.
The primary efficacy analysis population 
 
 includes all randomized participants who received at least 1 dose of 
study treatment, had an evaluable baseline period of eDiary data and had at least 1 evaluable 
post-baseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the double-
blind treatment period and follow-up period, regardless of whether on study treatment or off 
study treatment.
7.2
Collection and Derivation of Efficacy Assessments
On a daily basis during the 28-day baseline period and throughout the study, participants are
to record into an eDiary information on the daily total duration of headache, headache 
specific characteristics and symptoms, the worst pain severity, and use of any acute headache 
pain medication. Participants will be able to report headache data, including absence of 
headache, for the day of the eDiary report and for the day immediately prior to the day of the 
eDiary report, as long as information reported is for a time subsequent to the participant’s
most recent report. This is defined as a one-day “missing-recall” window.
Following randomization on Day 1, there are 4 visits at 2-week intervals, followed by 2 visits 
at 4-week intervals; altogether encompassing a 12-week double-blind treatment phase of the 
study and a 4-week follow-up phase. In practice, there may or may not be exact 2-week or 
4-week durations between two consecutive visits and the visits might not align with each 
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28-day period recorded in the eDiary (ie, Weeks 1 to 4, 5 to 8 and 9 to 12, corresponding to 
Days 1 to 28, 29 to 56, and 57 to 84). Therefore, for data analysis purposes, the number of 
migraine days during the last 28 days prior to the randomization date, will serve as the 
“baseline”, and change from baseline will be calculated for consecutive 28-day periods 
beginning with the date of first dose of study intervention.
In order to be randomized, a participant should be in the baseline phase for at least 28 days 
and must report eDiary data for at least 20 days (including missing recall) during the 28-day 
baseline period. If less than 28 days of baseline data are reported, the number of headache 
days and other such counting variables for “baseline” will be prorated to standardize the
count to a 28-day equivalent. Subsequent to treatment start, the number of headache days will 
be counted in successive and non-overlapping 4-week (ie, 28-day) windows. Headaches that 
continue into a subsequent 4-week period will be counted (with recorded severity and 
duration) as occurring in each period.
If any postbaseline eDiary window for a participant has at least 14 but less than 28 days of 
reported data, the prorated approach will be used. If a participant reports less than 14 days of 
headache data, the participant’s observed counts in that particular 28-day eDiary window will 
be set to missing for that window. These prorating rules will be applied to all efficacy 
analyses of eDiary data unless otherwise stated.
7.2.1 Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in mean monthly migraine days 
across the 12-week treatment period. Baseline is defined as the number of migraine days 
during the last 28 days of the baseline phase, ie, Day –28 to –1.
7.2.2 Secondary Efficacy Variables
The secondary efficacy variables for the United States and the EU:

Change from baseline in mean monthly headache days across the 12-week treatment 
period.

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period.

At least a 50% reduction in 3-month average of monthly migraine days.
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
Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at 
Week 12

Change from baseline in mean monthly Performance of Daily Activities domain score 
of the AIM-D across the 12-week treatment period.

Change from baseline in mean monthly Physical Impairment domain score of the 
AIM-D across the 12-week treatment period.
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7.2.3 Additional Efficacy Variables
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7.3
Hypothesis and Methods of Analysis
For efficacy analyses, data will be analyzed according to participants’ randomization 
assignments, regardless of actual treatment received.
For safety data analyses, the participants will be analyzed according to actual treatment 
received (rather than as randomized).
7.3.1 Primary Efficacy Analyses
The primary efficacy endpoint is the change from baseline in mean monthly migraine days 
across the 12-week treatment period. The primary null hypothesis is that atogepant treatment 
doses (atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg once a day) are each equally 
effective to placebo in mean change from baseline in mean monthly migraine days across the 
12-week treatment period. The alternative hypothesis is that at least 1 of the 3 doses of 
atogepant has a different effect than placebo.
The primary comparison between treatment groups will be done by a mixed-effects model for 
repeated measures (MMRM) of the change from baseline. The statistical model will include 
treatment group, visit, prior exposure (yes/no) to a migraine prevention medication with 
proven efficacy, and treatment group by visit interaction as categorical fixed effects. It will 
also include the baseline score and baseline-by-visit interaction as covariates. An 
unstructured covariance matrix will be used to model the covariance of within-participant
repeated measurements. The Kenward-Roger approximation (Kenward 1997) will be used to
estimate the denominator degrees of freedom. The analysis will be performed based on all 
postbaseline values using only the observed cases without imputation of missing values. 
Pairwise contrasts in the MMRM model will be used to make the pairwise comparisons of 
each atogepant dose to placebo. 
 
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 Only data collected during the double-blind period will be 
included in the analysis. Participants are always analyzed based on the treatment group 
assigned by randomization.
7.3.1.1 Sensitivity Analyses in Missing Data Handling
Multiple sensitivity analyses for missing data handling will be conducted and are 
summarized below. Details of the sensitivity analyses will be provided in the statistical 
analysis plan.
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
The response variable for the ANCOVA model is the change from baseline in 3-month 
average of monthly migraine days for each participant. The ANCOVA model includes terms 
for treatment, prior exposure (yes/no) to a migraine prevention medication with proven 
efficacy, and baseline score. The treatment difference for atogepant doses versus placebo will 
be estimated and reported along with the corresponding 95% CI and nominal p-value for 
superiority testing. This analysis is also termed as “supportive analysis”.
Within-group Imputation Based on Observed Data 
A sensitivity analysis will be performed based on imputation using participants from the 
same treatment group with observed data under the MAR assumption.  Missing data for 
participants who prematurely discontinued are assumed to copy the profile of participants in 
the same treatment group with observed data.
Copy-reference Approach
The Copy-reference Approach will be performed on the primary endpoint to assess the 
robustness of the MMRM analysis to possible violation of the missing-at-random (MAR)
assumption. This sensitivity analysis is one type of pattern-mixture models (PMM), under 
which data could be missing-not-at-random (MNAR), with repeated analyses combined via 
the reference based multiple imputation (MI) procedure. Participants who discontinued in the 
Atogepant groups are assumed to have no treatment effect after the discontinuation. 
Participants are assumed to copy the profile of placebo arm and missing values are imputed 
based on the distribution estimated from the placebo group under the MAR using copy-
reference approach.
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MMRM Based on Primary Measures Collected during the Double-blind and Follow-up 
Periods
The details for this analysis are provided in Section 7.4. 
 
 
7.3.1.2 Sensitivity Analysis for Possible Violation of Normality 
Assumption
The normality test is performed on the residuals which are generated by the same MMRM as 
used for the primary efficacy analysis. The residuals are scaled by the inverse Cholesky root 
of its estimated variance-covariance matrix. The Kolmogorov-Smirnov test for normality is 
applied to the de-correlated and scaled residuals and normality test is rejected if p-value from 
the Kolmogorov-Smirnov test is less than 0.01. 
If the normality test is rejected, the sensitivity analysis uses MI in conjunction with robust 
regression to assess the robustness of the primary MMRM analysis to the possible violation 
of normality assumption. This method has been described and referred as ADAP [R] in 
Mehrotra 2012.  The detail of the sensitivity analyses will be provided in the statistical 
analysis plan.
7.3.2 Secondary Efficacy Analyses
The secondary efficacy variables are identified in Section 7.2.2.
The secondary endpoints for headache days, acute medication use days, MSQ v2.1 Role 
Function-Restrictive domain score, Performance of Daily Activities domain score of the 
AIM-D, and Physical Impairment domain score of the AIM-D will be analyzed in the same 
manner as that used to analyze the primary endpoint.
The 50% responder, defined as a participant with at least a 50% reduction from baseline in
the 3-month average of monthly migraine days, will be assessed for each individual. A 
logistic regression model will be used to analyze the 50% responders across the 12-week 
treatment period. This model assumes a binary distribution for the response and uses a logit 
link. The analysis model will include treatment group, prior exposure (yes/no) to a migraine 
prevention medication with proven efficacy,  and baseline monthly migraine days. The 
treatment difference in terms of odds ratio between each atogepant dose group and placebo 
will be estimated and tested from this model. 
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The overall type I error rate for multiple comparisons across two atogepant doses and the 
primary and secondary efficacy endpoints will be controlled at the 0.05 level using a 
graphical approach by Bretz 2009. The primary endpoint will serve as the gatekeeper for the
secondary endpoints. A complete graph and details of the graphical multiple comparison 
procedure will be presented in the statistical analysis plan of this study.
7.3.3 Additional Efficacy Analyses
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7.3.4 Safety Analyses
MedDRA nomenclature will be used to code TEAEs. Incidence will be tabulated by primary 
SOC and by specific event within each primary SOC. TEAEs will be analyzed after treatment
start on Day 1 through the end of the study. TEAEs will also be summarized separately for 
the double-blind treatment and follow-up phases of the study.
7.4
Off-treatment Hypothetical Estimand 
This section defines an estimand, termed as off-treatment hypothetical estimand, 
 
 
7.4.1 Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-blind treatment 
period. In addition, permissible and prohibited mediations are described below:

Participants are allowed to take acute migraine medications (Protocol Section 4.4.1) to 
keep the participants in the study.  

The protocol prohibits patients from starting any new migraine preventive treatments 
(Protocol Section 4.4.2) during the study (including the double-blind treatment period
and the follow-up period).
7.4.2
Population
The target population is patients suffering from migraine with aura or migraine without aura 
satisfying the inclusion and exclusion criteria as specified in Section 4.
The analysis population is defined to be all randomized participants who received at least 
1 dose of study treatment, had an evaluable baseline period of eDiary data and had at least 
1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data, 
regardless of whether on study treatment or off study treatment.
7.4.3 Variable
The variable is the same as the primary efficacy endpoint defined in Section 7.2.1, which is 
the change from baseline in the participant’s mean monthly (4-weeks) migraine days across 
the 12-week treatment period as derived from the eDiary data.
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7.4.4 Accounting of Intercurrent Events
Intercurrent events and their handling rules are as follows:

Participants who started a new migraine prophylaxis treatment during the double-blind 
or safety follow-up period will have their data during the safety follow-up period after 
starting the new migraine prophylaxis treatment excluded from the analysis.

Participants who discontinue study treatment due to all reasons other than starting a 
new migraine prophylaxis treatment will have their data collected after discontinuation 
of study treatment, and those off-treatment data will be included in the analysis.
Detailed methods and procedures will be documented in the statistical analysis plan prior to
study completion.
7.4.5 Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between each atogepant group and placebo.
Participants are always analyzed based on their treatment assignment by randomization. To 
obtain the estimate of treatment effect defined in the off-treatment hypothetical estimand, a 
MMRM similar to the primary analysis specified in Section 7.3.1 will be performed on 
observed data including both on-treatment and off-treatment monthly migraine days.
7.4.6 Off-treatment Hypothetical Estimand Approach for the Secondary 
Endpoints
Continuous secondary endpoints will be handled using the same estimand approach defined 
above for the primary endpoint.
The secondary endpoint of 50% responders will be derived using both on-treatment and off-
treatment observed data as defined in the primary endpoint above. The population-level 
summary for this endpoint is the odds ratio for each atogepant group relative to placebo.
7.5
Subgroup Analyses
Subgroup analysis based on prior exposure (yes/no) to a migraine prevention medication with 
proven efficacy will be performed for the following efficacy endpoints:
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
Change from baseline in mean monthly migraine days across the 12-week treatment 
period.

Change from baseline in mean monthly headache days across the 12-week treatment 
period.

Change from baseline in mean monthly acute medications use days across the 
12-week treatment period.

≥ 50% reduction in 3-month average of monthly migraine days

≥ 75% reduction in 3-month average of monthly migraine days

100% reduction in 3-month average of monthly migraine days
Subgroup analyses for primary efficacy endpoint based on demographic factors (age, sex, 
race) will be provided in the integrated summary of efficacy to facilitate the comparison 
across pivotal studies.
7.6
Sample Size Calculation
A total sample size of 218 participants will be randomized per treatment group and that will 
provide at least 98% power to detect the treatment difference between each of the 3 atogepant 
doses (assumed equally effective) and placebo for the primary efficacy endpoint. The sample 
size of this study was selected to provide sufficient power for the primary efficacy endpoint 
and the first 3 secondary endpoints as shown in Table 7-1. The power calculations are based
on the following assumptions:
1) The treatment difference from placebo will be similar to the average value across the 
migraine prevention studies for atogepant (Phase 2/3 Study CGP-MD-01), telcagepant 
(Ho 2014) and monoclonal antibodies (Dodick 2014a; Dodick 2014b; Bigal 2015). The
standard deviation of each endpoint was estimated from an internal study that randomized 
approximately 800 participants. In particular, the assumed treatment difference from placebo 
in change from baseline in mean monthly migraine days across the 12-week treatment period 
is -1.5 days, and the standard deviation is 3.5 days. Detailed treatment difference and 
standard deviation assumptions are listed in Table 7-1.
2) The study statistical testing plan controls the overall type I error at 5%. The power 
calculations of the primary and secondary endpoints have taken the multiple comparisons 
into consideration by testing each dose versus placebo at a 0.0167 significance level, 2-sided. 
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A detailed graphical multiple comparison procedure will be presented in the statistical 
analysis plan.
Table 7-1
Statistical Power for Primary and the First Three Secondary Endpoints
Hypothesis 
Testing
Endpoint
Treatment 
Difference 
from Placebo
Standard 
Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across the 
12-week treatment period
–1.5
3.5a
98%
Secondary 1
Change from baseline in mean 
monthly headache days across the 
12-week treatment period
–1.5
3.8a
95%b
Secondary 2
Change from baseline in mean 
monthly acute medication use days
across the 12-week treatment period
–1.2
3.2a
93%b
Secondary 3
≥50% reduction in 3-month average 
of monthly migraine days
33% Placebo 
rate
50% Atogepant 
rate
89%b
a
Standard deviations observed in an internal study that randomized approximately 800 participants
b
Statistical power for secondary endpoints are conditional on success of prior endpoints (assuming 
independence among the endpoints) in the sequence for the comparisons of each dose versus placebo.
7.7
Pharmacokinetics and Exposure-response Analyses
A graphical evaluation of the PK and PD data of atogepant will be performed for the 
identification of possible trends. The pharmacokinetics will be evaluated using the existing 
population PK model, updated with data from this study. Individual predictions of atogepant 
exposure (including but not limited to steady state AUC0-Tau and Cmin) will be evaluated 
graphically for potential relationships with efficacy and/or safety endpoints. If graphical 
evaluation identifies possible trends, exploratory PK/PD analyses will be performed for the 
evaluation and quantification of potential relationships via nonlinear mixed effects modeling. 
Efficacy endpoints to be evaluated will include migraine days and responder rates. A 
standalone pharmacometric analysis plan will be written, and the analyses results will be 
reported separately from the integrated clinical study report.
7.8
Interim Analyses
No interim analysis is planned.
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8.
Study Visit Schedule and Procedures
Please see Table 1 for a schematic of the schedule of visits and procedures (for in-person 
visits conducted prior to or during the COVID-19 pandemic) and Figure 1 for a study visit
flowchart. Refer to Table 2 for assessments to be performed at study visits conducted 
remotely due to the COVID-19 pandemic.
8.1
Participant Entry Procedures
8.1.1 Overview of Entry Procedures
Prospective participants as defined by the criteria in Sections 4.2 and 4.3 (inclusion/exclusion 
criteria) will be considered for entry into this study.
8.1.2 Informed Consent and Participant Privacy
The study will be discussed with the participant and those wishing to enter the study 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 
local privacy requirements (where applicable) prior to any study-related procedures or 
change in treatment.
Each participant who provides informed consent and/or assent will be assigned a participant
identification number that will be used on participant documentation throughout the study.
The investigator or qualified designee will explain the PK and future biomedical research 
substudy consents to the participant and answer all of his/her questions. Participants will sign 
separate consent forms to participate in the PK substudy and future biomedical research 
before performing any procedure related to the substudies, respectively.
8.1.3 Procedures for Duplicate Participant Identification – Verified 
Clinical Trials (VCT)
A central vendor will be used to verify participants current and past research study status in 
order to mitigate safety concerns associated with duplicate enrollment and protocol 
deviations associated with multiple trial enrollment. The use of this central vendor will be 
mandatory for US sites. Following proper informed consent and after issuing a participant
number, each participant will be checked in the VCT database, indicated in the Schedule of 
Visits and Procedures (Table 1). Partial identifiers will be utilized. Participants who are 
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identified as verification failures by VCT should not be enrolled without documented 
approval from Allergan.
8.2
Washout Intervals
This study will not include a washout period.
8.3
Procedures for Final Study Entry
At the Screening and Randomization Visits (Visits 1 and 2), participants must meet all of the 
inclusion criteria and must not meet any of the exclusion criteria. Rescreening of participants
may be considered with permission from Allergan (Section 4.5). Also, all women of 
childbearing potential must have negative results on the urine pregnancy test at the Screening 
and Randomization Visits (Visits 1 and 2, prior to the first administration of study 
intervention).
Prior to randomization, it must be confirmed that the participant had 4 to 14 migraine days 
and < 15 headache days during the 28-day baseline period (see Section 6.1.1 for definition)
and completed the eDiary for at least 20 of the 28 days.
See Section 5.5 for the method for assignment to treatment groups/randomization.
8.4
Visits and Associated Procedures
There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), Visit 2 (Randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ET (Week 12), 
and Visit 8 (Follow-up). For details, please see Table 1 Schedule of Visits and Procedures for 
In-Person Visits Conducted Prior to or During the COVID-19 Pandemic. Refer to Table 2 for 
assessments to be performed at study visits conducted remotely due to the COVID-19 
pandemic.
8.4.1 Visit 1 (Screening/Baseline) Day -35 to Day -28
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8.4.2 Double-blind Treatment Phase (12 Weeks)
8.4.2.1 Visit 2 (Randomization) Day 1
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8.4.2.2 Visits 3 to 6 (Weeks 2 to 8)
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8.4.2.3 Visit 7/Early Termination (Week 12)
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8.4.3 Follow-up Period (4 weeks)
8.4.3.1 Visit 8 (End of Study) Week 16 Conducted Remotely (Due to the 
COVID-19 Pandemic)
During the COVID-19 pandemic, Visit 8 (Follow-up/End of Study) should be conducted 
remotely for all participants in all cases.
 
8.4.3.2 Visit 8 (End of Study) Week 16 Conducted During In-Person Visit 
(Prior to the COVID-19 Pandemic)
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8.5
Instructions for the Participants
8.6
Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to 
ensure the safety and wellbeing 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 
they changed the dose/regimen of any existing concomitant medications or initiated the use 
of any new concomitant medications since the last visit to ensure compliance with the 
protocol. 
Study intervention compliance during any period will be closely monitored by counting the 
number of tablets dispensed and returned. Every effort will be made to collect all unused 
study intervention.
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8.8
Early Discontinuation of Participants
A premature discontinuation will occur when a participant who signed the ICF and has been 
randomized ceases participation in the study, regardless of circumstances, before completion 
of the study. Participants can be prematurely discontinued from the study for one of the 
following reasons:

AE

Lack of efficacy

Lost to follow-up

Non-compliance with study intervention

Other

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 
Allergan and will be documented on the appropriate case report form. All randomized 
participants who prematurely discontinue from the study, regardless of cause, should be seen 
for final study assessments. The final assessments will be defined as completion of the 
evaluations scheduled for Visit 7/ET and Visit 8 Follow-up, 4 weeks post the last dose of 
study intervention. These participants must continue to complete their eDiary through Visit 8 
Follow-up.
8.9
Withdrawal Criteria
Women who become pregnant (Section 9.4) and participants who meet study intervention
discontinuation criteria related to abnormal liver function tests (Section 9.5) and advised not 
to be rechallenged will be withdrawn from the study and should refrain from taking study 
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intervention. The participant should return to the clinic for early termination procedures 
(Visit 7) and the Follow-up Visit 8. Participants who reply with “yes” to questions 4 or 5 in 
the suicidal ideation section or “yes” to any question in the suicidal behavior section of the 
C-SSRS at Visits 3 through 6 must be withdrawn from the study and should receive 
appropriate follow-up as in routine clinical practice, including the Early Termination Visit 7
and the Follow-up Visit 8. These participants must continue to complete their daily eDiary 
through Visit 8 Follow-up.
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 must be withdrawn from 
treatment.
8.10
Withdrawal from Future Biomedical Research
A participant who initially consents can withdraw that consent at any time and have his or her 
sample destroyed, including any by-products of the sample whenever possible. If a 
participant withdraws consent, their physical sample will be destroyed and no new health 
information identifying the participant will be gathered after that date. However, once the 
genetic data is anonymized and placed into the biorepository database after study database 
lock, the information cannot be withdrawn.
8.11
Study Termination
The study may be stopped at his/her 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
9.1.1 Adverse Event (AE)
An AE is any untoward medical occurrence in a patient or clinical study participant 
associated with the use of study intervention, whether or not considered related to the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
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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.
Allergan considers all cancer AEs as SAEs. Allergan considers any spontaneous abortion as 
an SAE. Elective abortions can be SAEs or AEs depending on the reason for the elective 
abortion (eg, fetal death, still birth, congenital anomalies, ectopic pregnancy, which would 
make the elective abortion an SAE).
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
participant requires hospitalization is not reportable as an SAE.
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the participant’s entry into 
the study. If it has not been documented at the time of the participant’s entry into the study, 
then it should be documented as an SAE and reported to Allergan.
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9.1.3 Intensity
The intensity assessment for a clinical AE must be completed using the following definitions 
as guidelines:
MILD
A type of adverse event 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 adverse event 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 adverse event 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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9.1.4 Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 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 study intervention 
administration will be considered and investigated.

The investigator will also consult the IB 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. 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.

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.
9.1.5 Follow-up of Adverse Events and Serious Adverse Events

After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs/SAEs (and nonserious AEs of special
interest, as defined in Section 6.5.2) 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).
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
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 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
Any AE must be recorded on the appropriate eCRF.
All AEs that are related to study intervention and are unexpected (not listed as 
treatment-related in the current IB) must be reported to the governing IRB/IEC as required by 
the IRB/IEC, local regulations, and the governing health authorities. Any AE that is marked 
‘ongoing’ at the exit visit must be followed-up as appropriate.
9.3
Procedures for Reporting a Serious Adverse Event
Any SAE occurring during the study period (beginning with informed consent) until the 
Follow-up Visit (Visit 8) or 30 days after the last dose of study intervention if the Follow-up 
Visit is not done must be immediately reported but no later than 24 hours after learning of an 
SAE. 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).
9.3.1 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 under clinical investigation are met.
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
Allergan has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. 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’s policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other
specific safety information (eg, summary or listing of SAEs) from Allergan will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.4
Exposure to Study Intervention During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until the Follow-up Visit (Visit 8) or 
30 days after the last dose of study intervention if the Follow-up Visit is not done. Study 
center personnel must report every pregnancy on the pregnancy form within 24 hours of 
learning of the pregnancy to the SAE/pregnancy fax number, 
 even if no 
AE has occurred. The pregnancy must be followed to term and the outcome reported by 
completing a follow-up pregnancy form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 
SAEs. Elective abortions can be SAEs or AEs depending on the reason for the elective 
abortion (eg, fetal death, still birth, congenital anomalies, ectopic pregnancy, which would 
make the elective abortion an SAE). For pregnancy-related SAEs, in addition to the 
pregnancy form, a separate SAE form must be filed as described in Section 9.3 with the 
appropriate serious criterion (eg, hospitalization) indicated.
9.5
ALT or AST Elevations
A treatment-emergent ALT ≥ 3 × ULN and/or AST ≥ 3 × ULN is considered an AE of special
interest. Any participant with this laboratory result after study intervention was taken must 
have repeat testing within 48 to 72 hours to confirm the abnormality. For this repeat testing, 
the following laboratory tests must be drawn: hematology and chemistry panels, INR, serum 
acetaminophen level, urine drugs of abuse screen, and blood alcohol level. An extra blood 
serology sample must be collected and sent to the central laboratory for further diagnostic 
testing at a later date if needed. In addition, the investigator will perform a complete history 
and examination to evaluate the participant for possible liver disease.
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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 
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.
Study intervention must be discontinued if any of the following criteria are met:

ALT orAST ≥ 3 × ULN and the participant is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (> 5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN

ALT or AST ≥ 3 × ULN and INR > 1.5

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
The participant may be rechallenged with study intervention only after consultation with the 
Allergan Medical Monitor. For participants who are not rechallenged with study intervention, 
they should be discontinued from the study and complete an ET visit (Visit 7/ET 
assessments) and 4-week Follow-up Visit. 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 × ULN. All ALT/AST elevations must be followed 
until ALT and AST return to < 1.5 × ULN and there is full clinical resolution.
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9.5.1 Potential Hy’s Law Cases
Sites must report every participant who meets the following potential Hy’s law criteria if this 
occurs within the time the participant signs the ICF until 30 days after the last dose of study 
intervention:

ALT or AST ≥ 3 x ULN AND

Total bilirubin ≥ 2 x ULN AND

Alkaline phosphatase < 2 x ULN
Study site personnel must report every participant who meets these criteria. Typically, all 
3 analytes will be obtained from the same sample, but they may come from multiple samples
taken within a 24-hour period. This requirement applies from the time the participant signs 
the ICF for the study until 30 days after the final protocol-defined study visit or the last 
known dose of study intervention (if the final visit does not occur).
A laboratory alert for possible Hy’s law cases will be in place, and must notify investigators 
and 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 
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.
9.6
Procedures for Unmasking of Study Intervention
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
study intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Allergan Medical Monitor 
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prior to unblinding a participant’s study intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s study intervention assignment is 
unblinded, the Allergan Medical Monitor must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the source 
documentation.
10.
Administrative Items
10.1
Protection of Human Participants
10.1.1Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each participant prior to any study-related 
activities or procedures in the study, and/or from the participant's legally authorized 
representative.
The following process will be followed:

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
HIPAA requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
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10.1.2Compliance 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.
10.1.3Compliance with Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
10.1.4Compliance with Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature.
10.3
Changes to the Protocol
The investigator must not implement any deviation from or changes of 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).
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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 Confidentiality
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study intervention may ultimately be marketed, but 
the participant’s name will not be disclosed in these documents. The participant's name may 
be disclosed to the sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information.
10.5.1Participant Privacy
Written authorization and other documentation in accordance with 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
10.6.1Source Documents
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10.6.2Case Report Form Completion
The investigator is responsible for ensuring that data are properly recorded on each 
participant's eCRF and related documents. An investigator who has signed the protocol 
signature page should personally sign for the case report forms (as indicated in the case 
report forms) to ensure that the observations and findings are recorded on the case report 
forms 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.
10.6.3Study 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.
10.6.4Retention of Documentation
All study related correspondence, participant records, consent forms, participant privacy 
documentation, records of the distribution and use of all study interventions, 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 the study intervention. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirement(s) 
or if needed by 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.
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10.7
Labeling, Packaging, and Return or Disposal of Study Interventions
10.7.1Labeling/Packaging
10.7.2Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of intervention units 
received from Allergan, dispensed or administered to the participants, the number of units 
returned to the investigator by the participant (if applicable), and the number of units 
returned to Allergan during and at the completion of the study. A detailed inventory must be 
completed for the study intervention. The study intervention must be dispensed or 
administered only by an appropriately qualified person to participants in the study. The 
medication is to be used in accordance with the protocol for participants who are under the 
direct supervision of a study investigator.
10.7.3Return or Disposal of Study Intervention and/or Supplies
All clinical study intervention 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.
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10.9
Handling of Biological Specimens
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
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, 
tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic 
migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 
Lancet Neurol 2015;14:1081–1090.
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586-604.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled
trial of telcagepant for the acute treatment of migraine. Neurology 2009;73(12):970-977.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M. Safety and 
efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of 
frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory 
phase 2 trial. Lancet Neurol 2014a;13:1100-1107.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and 
efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the 
prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.
Lancet Neurol 2014b;13:885-892.
Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS; European Federation of 
Neurological Societies. EFNS guideline on the drug treatment of migraine – revised report of 
an EFNS task force. Eur J Neurol 2009;16: 968–998.
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
Ho TW, Connor KM, Zhang Y, Pearlman E, Kopperhaver J, Fan X et al. Randomized 
controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. 
Neurology 2014;83:958–966.
Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in 
migraine. Expert Rev Clin Pharmacol 2014;7:191-201.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the 
United States. Arch Intern Med 1999;159:813-818.
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Katsarava Z, Buse DC, Manack AN, and Lipton RB. Defining the differences between 
episodic migraine and chronic migraine. Curr Pain Headache Rep 2012:16:86–92.
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997;53:983–997. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology 2007;68:343-349.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 
2012;68(4):1250-1259.
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. Curr Treat 
Options Neurol 2008;10:20-29.
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. Prophylactic drugs with good evidence of efficacy from the European Headache 
Federation (EHF), in conjunction with Lifting the Burden, the global campaign against 
headache. 2007. J Headache Pain. 2007;8(S1).
Steiner TJ, Stovner LJ, and Birbeck GL. Migraine: the seventh disabler. J Headache Pain 
2013;14:1-2.
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, and Naghavi M. Years lived with disability (YLDs) for 1160 sequelae of 
289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease 
Study 2010. Lancet 2013;380:2163–2196.
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12.
Attachments
12.1
International Classification of Headache Disorders, 3rd Edition
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1.
Migraine
1.1
Migraine without aura
1.2
Migraine with aura
1.2.1
Migraine with typical aura
1.2.1.1
Typical aura with headache
1.2.1.2
Typical aura without headache
1.2.2
Migraine with brainstem aura
1.2.3
Hemiplegic migraine
1.2.3.1
Familial hemiplegic migraine
(FHM)
1.2.3.1.1
Familial hemiplegic 
migraine type 1 (FHM1)
1.2.3.1.2
Familial hemiplegic 
migraine type 2 (FHM2)
1.2.3.1.3
Familial hemiplegic 
migraine type 3 (FHM3)
1.2.3.1.4
Familial hemiplegic 
migraine, other loci
1.2.3.2
Sporadic hemiplegic migraine
(SHM)
1.2.4
Retinal migraine
1.3
Chronic migraine
1.4
Complications of migraine
1.4.1
Status migrainosus
1.4.2
Persistent aura without infarction
1.4.3
Migrainous infarction
1.4.4
Migraine aura-triggered seizure
1.5
Probable migraine
1.5.1
Probable migraine without aura
1.5.2
Probable migraine with aura
1.6
Episodic syndromes that may be associated
with migraine
1.6.1
Recurrent gastrointestinal
disturbance
1.6.1.1
Cyclical vomiting syndrome
1.6.1.2
Abdominal migraine
1.6.2
Benign paroxysmal vertigo
1.6.3
Benign paroxysmal torticollis
Coded elsewhere:
Migraine-like headache secondary to another 
disorder (symptomatic migraine) is coded as a 
secondary headache attributed to that disorder.
General comment
Primary or secondary headache or both? Three 
rules apply to migraine-like headache, according 
to circumstances.
1. When a new headache with the 
characteristics of migraine occurs for the 
ﬁrst time in close temporal relation to another 
disorder known to cause headache, or fulﬁls 
other criteria for causation by that disorder, 
the new headache is coded as a secondary 
headache attributed to the causative
disorder.
2. When pre-existing migraine becomes chronic in
close temporal relation to such a causative disorder, 
both the initial migraine diagnosis and the 
secondary
diagnosis 
should 
be 
given. 
8.2 
Medication-overuse headache is a particularly 
important example of this: both the migraine 
diagnosis (episodic or chronic) and the diagnosis
8.2 Medication-overuse headache should be given 
when medication overuse is present.
3. When pre-existing migraine is made signiﬁcantly 
worse (usually meaning a twofold or greater
increase in frequency and/or severity) in close 
temporal relation to such a causative disorder, both 
the initial migraine diagnosis and the secondary 
headache diagnosis should be given, provided that
there is good evidence that the disorder can cause
headache.
Introduction
Migraine is a common disabling primary headache 
disorder. 
Many 
epidemiological 
studies 
have 
documented its high prevalence and socio-economic and 
personal impacts. In the Global Burden of Disease Study 
2010 (GBD2010), it was ranked as the third most 
prevalent disorder in the world. In GBD2015, it was 
ranked the third-highest cause of disability worldwide in 
both males and females under the age of 50 years.
Migraine has two major types: 1.1 Migraine without 
aura is a clinical syndrome characterized by headache 
with speciﬁc features and associated symptoms; 1.2 
Migraine with aura is primarily characterized by the 
transient focal neurological symptoms that usually 
precede or sometimes accompany the headache. Some 
patients also experience a prodromal phase, occurring 
hours or days before the headache, and/or a postdromal 
phase following headache resolution. Prodromal and 
postdromal 
symptoms 
include 
hyperactivity, 
hypoactivity, depression, cravings for particular foods, 
repetitive yawning, fatigue and neck stiffness and/or 
pain.
When a patient fulﬁls criteria for more than one type, 
subtype or subform of migraine, all should be 
diagnosed and coded. For example, a patient who has 
frequent attacks with aura but also some attacks 
without aura should be coded as 1.2 Migraine with
aura and 1.1 Migraine without aura. However, since
the diagnostic criteria for 1.3 Chronic migraine 
subsume attacks of all types, subtypes or subforms, 
additional coding is unnecessary for episodic subtypes 
of migraine.
1.1 Migraine without aura
Previously used terms: Common migraine; hemicrania 
simplex
Description: Recurrent headache disorder manifesting 
in attacks lasting 4–72 hours Typical characteristics of 
the headache are unilateral location, pulsating quality, 
moderate or severe intensity, aggravation by routine 
physical activity and association with nausea and/or 
photophobia and phonophobia.
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Diagnostic criteria:
A.
At least ﬁve attacks1 fulﬁlling criteria B–D
B.
Headache attacks lasting 4–72 hours 
(when untreated or unsuccessfully
treated)2,3
C.
Headache has at least two of the 
following four characteristics:
1.
unilateral location
2.
pulsating quality
3.
moderate or severe pain intensity
4.
aggravation by or causing avoidance of 
routine physical activity (e.g. walking 
or climbing stairs)
D.
During
headache
at
least
one
of
the
following:
1.
nausea and/or vomiting
2.
photophobia and phonophobia
E.
Not better accounted for by another 
ICHD-3 diagnosis.
Notes:
1. One or a few migraine attacks may be 
difficult to distinguish from symptomatic 
migraine-like attacks. Furthermore, the nature 
of a single or a few attacks may be difficult to 
understand. Therefore, at least ﬁve attacks are 
required. Individuals who otherwise meet 
criteria for 1.1 Migraine without aura but 
have had fewer than ﬁve attacks should be 
coded 1.5.1 Probable migraine without aura.
2. When the patient falls asleep during a 
migraine attack and wakes up without it, 
duration of the attack is reckoned until the
time of awakening.
3. In children
and adolescents (aged under 
18 years), attacks may last 2–72 hours (the 
evidence for untreated durations of less than 
two 
hours 
in 
children 
has 
not 
been
substantiated).
Comments: Migraine headache in children and
adolescents (aged under 18 years) is more often
bilateral than is the case in adults; unilateral pain
usually emerges in late adolescence or early adult
life. Migraine headache is usually frontotemporal. 
Occipital headache in children is rare and calls for 
diagnostic caution. A subset of otherwise typical 
patients have facial location of pain, which is called 
‘facial migraine’ in the literature; there is no evidence 
that these patients form a separate subgroup of 
migraine patients. Prodromal symptoms may begin 
hours or a day or two before the other symptoms of a 
migraine attack without aura. They include various 
combinations of fatigue, diffculty in concentrating, 
neck stiffness, sensitivity to light and/or sound, nausea, 
blurred vision, yawning and pallor. Postdromal 
symptoms, most commonly feeling tired or weary, 
difficulty with concentration and neck stiffness, may 
follow resolution of the headache, persisting for up to 
48 hours; these are less well studied.
Migraine attacks can be associated with cranial 
autonomic symptoms and symptoms of cutaneous 
allodynia.
In young children, photophobia and phonophobia 
may be inferred from their behaviour.
A minority (<10%) of women have attacks of migraine 
in association with the majority of their menstrual 
cycles; most of such attacks are without aura. Attacks 
during 
menstruation 
tend 
to 
be 
longer 
and 
accompanied by more severe nausea than attacks 
outside the menstrual cycle. ICHD-3 offers criteria for 
A1.1.1 Pure menstrual migraine without aura, A1.1.2 
Menstrually related migraine without aura and A1.1.3 
Non-menstrual migraine without aura, but in the 
Appendix because of uncertainty over whether they 
should be regarded as separate entities. Criteria are 
also offered for A1.2.0.1 Pure menstrual migraine 
with aura, A1.2.0.2 Menstrually related migraine with 
aura and A1.2.0.3 Non-menstrual migraine with aura 
to 
encourage 
better 
characterization 
of 
these 
uncommon subforms if they are separate entities.
Very frequent migraine attacks are distinguished as 1.3 
Chronic migraine. When there is associatedmedication
overuse, both of the diagnoses 1.3 Chronic migraine 
and 8.2 Medication-overuse headache should be
applied. 1.1 Migraine without aura is the disease most
prone to accelerate with frequent use of symptomatic
medication. Regional cerebral blood ﬂow imaging
shows no changes suggestive of cortical spreading
depression (CSD) during attacks of 1.1 Migraine
without aura, although blood ﬂow changes in the
brainstem may occur, as may cortical changes 
secondary topain activation. This contrasts with the
pathognomonic spreading oligaemiaof1.2Migraine
withaura.Whilethebulkofthe literature suggests that 
CSD does not occur in 1.1 Migraine without aura, 
some recent studies disagree. Furthermore, it has been
suggested that glial waves or other cortical 
phenomena may be involved in 1.1 Migraine without 
aura. The messenger molecules nitric oxide (NO), 
serotonin (5-hydroxytryptamine;5-HT) and calcitonin 
gene-related peptide (CGRP) are involved. While the 
disease was previously regarded as primarily vascular, 
the importance of sensitization of pain pathways, and
the possibility that attacks may originate in the central
nervous system, have gainedincreasing attention over 
the last decades.
At the same time, the circuitry of migraine pain,
the trigeminovascular system, and several aspects 
of its neurotransmission peripherally and in the
trigeminal nucleus caudalis, central
mesencephalic grey and thalamus, have been
recognized. Highly receptor- speciﬁc acute 
medications including 5-HT1B/D receptor agonists 
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(triptans), 5-HT1F receptor agonists and CGRP
receptor antagonists have demonstrated efficacy
in the acute treatment of migraine attacks. 
Because of their highreceptor-speciﬁcity, their
mechanisms of action provide new insight into 
migraine mechanisms. It is now clear that 1.1
Migraine without aura is a neurobiological 
disorder, while clinical as well as basic
neuroscience studies continue to advance our 
knowledge of migraine mechanisms.
1.2 Migraine with aura
Previously used terms: Classic or classical migraine; 
ophthalmic, hemiparaesthetic, hemiplegic or aphasic 
migraine;
migraine
accompagnee;
complicated
migraine.
Description: Recurrent attacks, lasting minutes, of 
unilateral fully reversible visual, sensory or other 
central nervous system symptoms that usually 
develop gradually and are usually followed by 
headache and associated migraine symptoms.
Diagnostic criteria:
A.
At least two attacks fulﬁlling criteria B and C
B.
One or more of the following fully reversible 
aura symptoms:
1.
visual
2.
sensory
3.
speech and/or language
4.
motor
5.
brainstem
6.
retinal
C.
At least three of the following six
characteristics:
1.
at least one aura symptom spreads gradually 
over ≥5 minutes
2.
two or more aura symptoms occur in
succession
3.
each individual aura symptom lasts 5–60 
minutes1
4.
at least one aura symptom is unilateral2
5.
at least one aura symptom is positive3
6.
the aura is accompanied, or followed 
within 60 minutes, by headache
D.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. When, for example, three symptoms occur 
during an aura, the acceptable maximal duration 
is 3 x 60 minutes. Motor symptoms may last up
to 72 hours.
2. Aphasia is always regarded as a unilateral 
symptom; dysarthria may or may notbe.
3. Scintillations and pins and needles are positive 
symptoms of aura.
Comments: Many patients who have migraine 
attacks with aura also have attacks without aura; 
they should be coded as both 1.2 Migraine with 
aura and 1.1 Migraine without aura.
Field testing has compared the diagnostic criteria for 
1.2 Migraine with aura in the main body of ICHD-3 
beta with those for A1.2 Migraine with aura in the 
Appendix. 
The 
latter 
performed 
better 
in 
distinguishing migraine with aura from transient 
ischaemic attacks. These are now adopted in 
ICHD-3, which no longer has Appendix criteria for 
this disorder.
The aura is the complex of neurological symptoms 
that occurs usually before the headache of 1.2 
Migraine with aura, but it may begin after the 
headache phase has commenced or continue into the 
headache phase.
Visual aura is the most common type of aura, 
occurring in over 90% of patients with 1.2 Migraine 
with aura, at least in some attacks. It often presents 
as a fortiﬁcation spectrum: a zigzag ﬁgure near the 
point of ﬁxation that may gradually spread right or 
left and assume a laterally convex shape with an 
angulated scintillating edge, leaving absolute or 
variable degrees of relative scotoma in its wake. In 
other cases, scotoma without positive phenomena 
may occur; this is often perceived as being of acute 
onset but, on scrutiny, usually enlarges gradually. In 
children and adolescents,less typical bilateral visual 
symptoms occur that may represent an aura. A 
visual aura rating scale with high speciﬁcity and 
sensitivity has been developed and validated.
Next in frequency are sensory disturbances, in the 
form of pins and needles moving slowly from the 
point of origin and affecting a greater or smaller part 
of one side of the body, face and/or tongue. 
Numbness may occur in its wake, but numbness 
may also be the only symptom.
Less frequent are speech disturbances, usually 
aphasic but often hard to categorize.
Systematic studies have demonstrated that many 
patients with visual aura occasionally have 
symptoms in the extremities and/or speech 
symptoms. Conversely, patients with symptoms in 
the extremities and/or speech or language symptoms 
almost always also experience visual aura symptoms 
at least during some attacks. A distinction between 
migraine with visual aura, migraine with 
hemiparaesthetic aura and migraine with speech 
and/or language aura is probably artiﬁcial, and 
therefore not recognized in this classiﬁcation: they 
are all coded as 1.2.1 Migraine with typical aura.
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When aura symptoms are multiple, they usually 
follow one another in succession, beginning with 
visual, then sensory, then aphasic; but the reverse 
and other orders have been noted. The accepted 
duration for most aura symptoms is one hour, but 
motor symptoms are often longer lasting.
Patients with aura symptoms arising from the 
brainstem are coded as 1.2.2 Migraine with brainstem
aura, but they almost always have additional typical 
aura symptoms. When the aura includes motor 
weakness, the disorder should be coded as 1.2.3 
Hemiplegic migraine or one of its subforms. 1.2.3 
Hemiplegic migraine is classiﬁed as a separate 
subtype because of genetic and pathophysiological
differences from 1.2.1 Migraine with typical aura. 
Patients with 1.2.3 Hemiplegic migraine often have 
brainstem symptoms in addition.
Patients often ﬁnd it hard to describe their aura
symptoms, in which case they should be instructed to 
time and record them prospectively. The clinical 
picture then becomes clearer. Common mistakes are 
incorrect reports of lateralization, of sudden rather 
than gradual onset and of monocular rather than 
homonymous visual disturbances, as well as of 
duration of aura and mistaking sensory loss for 
weakness. After an initial consultation, use of an
aura diary may clarify the diagnosis.
Migraine aura is sometimes associated with a 
headache that does not fulﬁll criteria for 1.1 Migraine
without aura, but this is still regarded as a migraine 
headache because of its relation to the aura. In other 
cases, migraine aura may occur without headache.
Before or simultaneously with the onset of aura 
symptoms, regional cerebral blood ﬂow is decreased 
in the cortex corresponding to the clinically affected 
area and often over a wider area. Blood ﬂow 
reduction usually starts posteriorly and spreads 
anteriorly, and is usually above the ischaemic 
threshold. After one to several hours, gradual 
transition into hyperaemia occurs in the same region. 
Cortical spreading depression of Leao is the likely
underlying mechanism.
The previously deﬁned syndromes, migraine with 
prolonged aura and migraine with acute-onset aura, 
have been abandoned. It is not rare for aura to last 
more than one hour but, in most such cases, patients 
have at least two of the other characteristics of
criterion C. Even when most of a patient’s attacks do 
not fulﬁl criterion C, it is usual that other attacks 
fulﬁl criteria for one of the recognized subtypes or 
subforms of 1.2 Migraine with aura, and this should 
be the diagnosis. The few other cases should be coded 
to 1.5.2 Probable migraine with aura, specifying the 
atypical feature (prolonged aura or acute-onset aura) in 
parenthesis. The diagnosis is usually evident after a 
careful history alone, although there are rare secondary 
mimics including carotid dissection, arteriovenous 
malformation and seizure.
Prodromal symptoms may begin hours or a day or two 
before the other symptoms of a migraine attack with 
aura. They include various combinations of fatigue, 
difﬁculty in concentrating, neck stiﬀness, sensitivity to
light and/or sound, nausea, blurred vision, yawning 
and pallor. The term ‘prodrome’, which has replaced 
‘premonitory phase’ or ‘premonitory symptoms’, 
does not include aura. Postdromal symptoms, most 
commonly feeling tired or weary, difficulty with 
concentration
and neck stiffness, may follow 
resolution of the headache, persisting for up to 48 
hours; these are less well studied.
1.2.1 Migraine with typical aura
Description: Migraine with aura, in which aura 
consists 
of 
visual 
and/or 
sensory 
and/or 
speech/language 
symptoms, 
but 
no 
motor 
weakness, and is characterized by gradual 
development, duration of each symptom no longer 
than one hour, a mix of positive and negative 
features and complete reversibility
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine 
with aura and criterion B below
B.
Aura with both of the following:
1.
fully reversible visual, sensory and/or 
speech/ language symptoms
2.
no motor, brainstem or retinal
symptoms.
1.2.1.1 Typical aura with headache
Description: Migraine with typical aura in which 
aura 
is 
accompanied 
or 
followed 
within 
60 minutes by headache with or without migraine 
characteristics.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine 
with typical aura and criterion B below
B.
Headache, with or without migraine
characteristics, accompanies or follows the
aura within 60 minutes.
1.2.1.2 Typical aura without headache
Description: Migraine with typical aura in which 
aura is neither accompanied nor followed by 
headache of any sort.
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Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine 
with typical aura and criterion B below
B.
No headache accompanies or follows the 
aura within 60 minutes.
Comments: In some patients, a typical aura is 
always followed by migraine headache, but many 
patients have, in addition, attacks with aura 
followed by a less distinct headache or even 
without headache. A number of patients have, 
exclusively, 1.2.1.2 Typical aura without
headache.
In the absence of headache fulﬁlling criteria for 
1.1 Migraine without aura, the precise diagnosis
of aura and its distinction from mimics that may 
signal serious disease (e.g. transient ischaemic 
attack) becomes more difﬁcult and often requires 
investigation. When aura occurs for the ﬁrst time 
after age 40, when symptoms are exclusively 
negative (e.g. hemianopia) or when aura is 
prolonged or very short, other causes, particularly 
transient ischaemic attacks, should be ruled out.
1.2.2 Migraine with brainstem aura
Previously used terms: Basilar artery migraine; 
basilar migraine; basilar-type migraine.
Description: Migraine with aura symptoms clearly 
originating from the brainstem, but no motor 
weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura with both of the following:
1.
at least two of the following fully 
reversible brainstem symptoms:
a.
dysarthria1
b.
vertigo2
c.
tinnitus
d.
hypacusis3
e.
diplopia4
f.
ataxia not attributable to sensory
deﬁcit
g.
decreased level of consciousness
(GCS ≤13)5
2.
no motor6 or retinal symptoms.
Notes:
1. Dysarthria should be distinguished from aphasia.
2. Vertigo does not embrace and should be 
distinguished from dizziness.
3. This criterion is not fulﬁlled by sensations of ear 
fullness.
4. Diplopia does not embrace (or exclude) blurred 
vision.
5. The Glasgow Coma Scale (GCS) score may 
have 
been 
assessed 
during 
admission; 
alternatively, deficits clearly described by the 
patient allow GCS estimation.
6. When motor symptoms are present, code as 1.2.3
Hemiplegic migraine.
Comments: Originally the terms basilar artery 
migraine or basilar migraine were used but, since 
involvement of the basilar artery is unlikely, the 
term migraine with brainstem aura is preferred.
There are typical aura symptoms in addition to 
the brainstem symptoms during most attacks. 
Many patients who have attacks with brainstem 
aura also report other attacks with typical aura 
and should be coded for both 1.2.1 Migraine
with
typical
aura
and 1.2.2 Migraine with 
brainstem aura.
Many of the symptoms listed under criterion B1 
may occur with anxiety and hyperventilation, 
and are therefore subject to misinterpretation.
1.2.3 Hemiplegic1 migraine
Description:
Migraine with aura including 
motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine 
with aura and criterion B below
B.
Aura consisting of both of the following:
1.
fully reversible motor weakness2
2.
fully reversible visual, sensory and/or 
speech/ language symptoms.
Notes:
1. The term plegic means paralysis in most 
languages, 
but 
most 
attacks 
are 
characterized by motor weakness.
2. Motor symptoms generally last less than 
72 hours but, in some patients, motor 
weakness may persist for weeks.
Comment: It may be difficult to distinguish 
weakness from sensory loss.
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1.2.3.1 Familial hemiplegic migraine (FHM)
Description: Migraine with aura including 
motor weakness, and at least one ﬁrst- or 
second-degree relative
has 
migraine 
aura 
including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 
Hemiplegic migraine
B.
At least one ﬁrst-
or second-degree 
relative has had attacks fulﬁlling criteria
for 1.2.3 Hemiplegic migraine.
Comments: New genetic data have allowed a more
precise deﬁnition of 1.2.3.1 Familial hemiplegic 
migraine than was previously possible. Speciﬁc 
genetic subforms have been identiﬁed: in FHM1 
there are mutations in the CACNA1A gene (coding 
for a calcium channel) on chromosome 19; in 
FHM2 there are mutations in the ATP1A2 gene 
(coding for a K/Na-ATPase) on chromosome 1; and 
in FHM3 there are mutations in the SCN1A gene 
(coding for a sodium channel) on chromosome 2. 
There may be other loci not yet identiﬁed. When
genetic testing is done, the genetic subform (if
discovered) should be speciﬁed at the ﬁfth digit.
It has been shown that 1.2.3.1 Familial hemiplegic 
migraine very often presents with brainstem 
symptoms in addition to the typical aura symptoms, 
and that headache almost always occurs. Rarely, 
during FHM attacks, disturbances of consciousness 
(sometimes including coma), confusion, fever and 
cerebrospinal ﬂuid (CSF) pleocytosis can occur.
1.2.3.1 Familial hemiplegic migraine may be mistaken 
for epilepsy and treated (unsuccessfully) as such. 
FHM attacks can be triggered by (mild) head trauma. 
In approximately 50% of FHM families, chronic 
progressive cerebellar ataxia occurs independently of 
the migraine attacks.
1.2.3.1.1 Familial hemiplegic migraine type 1
(FHM1)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the CACNA1A gene has
been demonstrated.
1.2.3.1.2 Familial hemiplegic migraine type 2
(FHM2)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the ATP1A2 gene has been 
demonstrated.
1.2.3.1.3 Familial hemiplegic migraine type 3
(FHM3)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
A mutation on the SCN1A gene has been 
demonstrated.
1.2.3.1.4 Familial hemiplegic migraine, other loci
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial 
hemiplegic migraine
B.
Genetic testing has demonstrated no
mutationon the CACNA1A, ATP1A2 or 
SCN1A genes.
1.2.3.2 Sporadic hemiplegic migraine (SHM)
Description: Migraine with aura including motor 
weakness, and no ﬁrst- or second-degree relative 
has migraine aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 
Hemiplegic migraine
B.
No ﬁrst- or second-degree relative fulﬁls 
criteria for 1.2.3 Hemiplegic migraine.
Comments: Epidemiological studies have shown 
that sporadic cases occur with approximately the 
same prevalence as familial cases.
The attacks in 1.2.3.2 Sporadic hemiplegic 
migraine have the same clinical characteristics as 
those in 1.2.3.1 Familial hemiplegic migraine.
Some apparently sporadic cases have known 
FHM mutations and, in some, a ﬁrst- or second-
degree 
relative 
later 
develops 
hemiplegic 
migraine,
thus
completing
fulﬁlment
of
the
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criteria for 1.2.3.1 Familial hemiplegic migraine 
and requiring a change of diagnosis.
Sporadic cases usually require neuroimaging and 
other tests to rule out other causes. A lumbar 
puncture may be necessary to rule out 7.3.5 
Syndrome of transient headache and neurological
deﬁcits with cerebrospinal ﬂuid lymphocytosis
(HaNDL).
1.2.4 Retinal migraine
Description: Repeated attacks of monocular 
visual 
disturbance, 
including 
scintillations, 
scotomata or blindness, associated with migraine 
headache.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine 
with aura and criterion B below
B.
Aura characterized by both of the following:
1.
fully reversible, monocular, positive 
and/or negative visual phenomena (e.g. 
scintillations, scotomata or blindness) 
conﬁrmed during an attack by either or
both of the following:
a.
clinical visual ﬁeld examination
b.
the patient’s drawing of a 
monocular ﬁeld defect (made after 
clear instruction)
2.
at least two of the following:
a.
spreading gradually over ≥5
minutes
b.
symptoms last 5–60 minutes
c.
accompanied, or followed within 60 
minutes, by headache
C.
Not better accounted for by another ICHD-3 
diagnosis, and other causes of amaurosis fugax 
have been excluded.
Comments: Some patients who complain of 
monocular 
visual 
disturbance 
in 
fact 
have 
hemianopia. Some cases without headache have 
been reported, but migraine as the underlying 
aetiology cannot be ascertained.
1.2.4 Retinal migraine is an extremely rare cause of 
transient monocular visual loss. Cases of permanent 
monocular visual loss associated with migraine have 
been described. Appropriate investigations are 
required to exclude other causes of transient 
monocular blindness.
1.3 Chronic migraine
Description: Headache occurring on 15 or more 
days/ month for more than three months, which, 
on at least eight days/month, has the features of
migraineheadache.
Diagnostic criteria:
A.
Headache (migraine-like or tension-type-like1) 
on ≥15 days/month for >3 months, and 
fulﬁlling criteria B and C
B.
Occurring in a patient who has had at least 
ﬁve attacks fulﬁlling criteria B–D for 1.1
Migraine without aura and/or criteria B and C 
for 1.2 Migraine with aura
C.
On ≥8 days/month for >3 months, fulﬁlling 
any of the following2:
1.
criteria C and D for 1.1 Migraine without
aura
2.
criteria B and C for 1.2 Migraine with
aura
3.
believed by the patient to be migraine at 
onset and relieved by a triptan or ergot
derivative
D.
Not better accounted for by another ICHD-3 
diagnosis.3–5
Notes:
1. The reason for singling out 1.3 Chronic migraine
from types of episodic migraine is that it is 
impossible to distinguish the individual episodes 
of headache in patients with such frequent or 
continuous headaches. In fact, the characteristics 
of the headache may change not only from day 
to day but even within the same day. Such 
patients 
are 
extremely 
diﬃcult 
to 
keep 
medication-free in order to observe the natural 
history of the headache. In this situation, attacks 
with and those without aura are both counted, as 
are both migraine-like and tension-type-like 
headaches (but not secondary headaches).
2. Characterization 
of 
frequently 
recurring 
headache generally requires a headache diary
to record information on pain and associated 
symptoms day by day for at least one month.
3. Because tension-type-like headache is within the 
diagnostic criteria for 1.3 Chronic migraine, this 
diagnosis excludes the diagnosis of 2. Tension-
type headache or its types.
4.
4.10 New daily persistent headache may have
features suggestive of 1.3 Chronic migraine. The
latter disorder evolves over time from 1.1
Migraine without aura and/ or 1.2 Migraine with 
aura; therefore, when these criteria A–C are 
fulﬁlled by headache that, unambiguously, is 
daily and unremitting from <24 hours after its
ﬁrst onset, code as 4.10 New daily persistent
headache. When the manner of onset is not
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remembered or is otherwise uncertain, code as
1.3 Chronic migraine.
5.
The 
most 
common 
cause 
of 
symptoms 
suggestive of chronic migraine is medication
overuse, as deﬁned under8.2Medication-overuse
headache. Around 50% of patients apparently 
with 1.3 Chronic migraine revert to an episodic 
migraine type after drug withdrawal; such 
patients are in a sense wrongly diagnosed as 1.3 
Chronic migraine. Equally, many patients 
apparently overusing medication do not improve 
after drug withdrawal; the diagnosis of 8.2 
Medication-overuse
headache 
may 
be 
inappropriate for these (assuming that chronicity 
induced by drug overuse is always reversible). 
For these reasons, and because of the general 
rule to apply all relevant diagnoses, patients 
meeting criteria for 1.3 Chronic migraine and 
for 8.2 Medication-overuse headache should be 
coded for both. After drug withdrawal, migraine 
will either revert to an episodic type or remain 
chronic and should be re-diagnosed accordingly; 
in the latter case, the diagnosis of 8.2 
Medication-overuse headache may be rescinded.
1.4 Complications of migraine
Comment: Code separately for both the migraine 
type, subtype or subform and for the complication.
1.4.1 Status migrainosus
Description: A debilitating migraine attack 
lasting for more than 72 hours.
Diagnostic criteria:
A.
A headache attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.1 Migraine 
without aura and/or 1.2 Migraine with 
aura, and typical of previous attacks
except for its duration and severity
C.
Both of the following characteristics:
1.
unremitting for >72 hours1
2.
pain and/or associated
symptoms are debilitating2
D.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. Remissions of up to 12 hours due to 
medication or sleep are accepted.
2. Milder cases, not meeting criterion C2, are
coded 1.5.1 Probable migraine without aura.
Comment: Headache with the features of 1.4.1 
Status migrainosus may often be caused by 
medication overuse. When headache in these 
circumstances 
meets 
the 
criteria 
for 
8.2 
Medication-overuse headache, code for this disorder 
and the relevant type or subtype of migraine but not 
for 1.4.1 Status migrainosus. When overuse of 
medication is of shorter duration than three months, 
code for the appropriate migraine type or subtype(s)
only.
1.4.2 Persistent aura without infarction
Description: Aura symptoms persisting for one 
week or more without evidence of infarction on 
neuroimaging.
Diagnostic criteria:
A.
Aura fulﬁlling criterion B
B.
Occurring in a patient with 1.2 Migraine 
with aura and typical of previous auras 
except that one or more aura symptoms 
persists for ≥1 week
C.
Neuroimaging shows no evidence of
infarction
D.
Not better accounted for by another 
ICHD-3 diagnosis.
Comments: Persistent aura symptoms are rare but 
well documented. They are often bilateral and 
may last for months or years. The one-week 
minimum in criterion B is based on the opinion 
of experts and should be formally studied.
Diagnostic work-up must distinguish 1.4.2
Persistent aura without infarction from 1.4.3 
Migrainous infarction and exclude symptomatic 
aura due to cerebral infarction of other causes. 
Attacks with prolonged aura lasting less than one 
week and not fulﬁlling criteria for 1.2.1 Migraine 
with typical aura are coded 1.5.2 Probable 
migraine with aura.
1.4.3 Migrainous infarction
Description: One or more migraine aura 
symptoms occurring in association with an 
ischaemic brain lesion in the appropriate territory 
demonstrated by neuroimaging, with onset during 
the course of a typical migraine with aura attack.
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Diagnostic criteria:
A.
A migraine attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.2 Migraine 
with aura and typical of previous attacks 
except that one or more aura symptoms 
persists for >60 minutes1
C.
Neuroimaging demonstrates ischaemic 
infarction in a relevant area
D.
Not better accounted for by another ICHD-3 
diagnosis.
Note:
1. There may be additional symptoms 
attributable to the infarction.
Comments: Ischaemic stroke in a migraine 
sufferer may be categorized as cerebral infarction 
of other cause coexisting with 1. Migraine, 
cerebral infarction of other cause presenting with 
symptoms resembling 1.2 Migraine with aura, or 
cerebral infarction occurring during the course of 
a typical attack of 1.2 Migraine with aura. Only 
the last fulﬁls criteria for 1.4.3 Migrainous
infarction.
1.4.3 Migrainous infarction mostly occurs in the
posterior circulation and in younger women. A 
twofold increased risk of ischaemic stroke in 
patients with 1.2 Migraine with aura has been 
demonstrated in several population-based studies. 
However, it should be noted that these infarctions 
are not migrainous infarctions. The mechanisms 
of the increased risk of ischaemic stroke in 
migraine sufferers remain unclear; likewise, the 
relationship between increased risk and frequency 
of aura and the nature of aura symptoms denoting 
the increase in risk are unknown. Most studies 
have shown a lack of association between 1.1 
Migraine without aura and ischaemic stroke.
1.4.4 Migraine aura-triggered seizure
Description: A seizure triggered by an attack of 
migraine with aura.
Diagnostic criteria:
A.
A seizure fulﬁlling diagnostic criteria for 
one type of epileptic attack, and criterion B
below
B.
Occurring in a patient with 1.2 Migraine
with aura, and during or within one hour 
after an attack of migraine with aura
C.
Not better accounted for by another ICHD-3 
diagnosis.
Comment: Migraine and epilepsy are prototypical 
examples of paroxysmal brain disorders. While
migraine-like headaches are quite frequently seen in 
the epileptic post-ictal period, sometimes a seizure 
occurs during or following a migraine attack. This 
phenomenon, sometimes referred to as migralepsy, 
is a rare event, originally described in patients with 
1.2 Migraine with aura. Evidence of an association 
with 1.1 Migraine without aura is lacking.
1.5 Probable migraine
Previously used term: Migrainous disorder.
Coded 
elsewhere: 
Migraine-like 
headache 
secondary 
to 
another 
disorder 
(symptomatic 
migraine) is coded according to that disorder.
Description: Migraine-like attacks missing one of 
the features required to fulﬁl all criteria for a type or 
subtype of migraine coded above, and not fulﬁlling 
criteria for another headache disorder.
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A-D
for 1.1 Migraine without aura, or all but one of
criteria A–C for 1.2 Migraine with aura
B.
Not fulﬁlling ICHD-3 criteria for any other 
headache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
Comment: In making a headache diagnosis, attacks 
that fulﬁl criteria for both 2. Tension-type headache 
and 1.5 Probable migraine are coded as the former 
in accordance with the general rule that a deﬁnite 
diagnosis always trumps a probable diagnosis. 
However, in patients who already have a migraine 
diagnosis, and where the issue is to count the 
number of attacks they are having (e.g. as an 
outcome measure in a drug trial), attacks fulﬁlling 
criteria for 1.5 Probable migraine should be counted 
as migraine. The reason for this is that mild 
migraine attacks, or attacks treated early, often do 
not achieve all characteristics necessary for a 
migraine attack diagnosis but nevertheless respond 
to speciﬁc migraine treatments.
1.5.1 Probable migraine without aura Diagnostic
criteria:
A.
Attacks fulﬁlling all but one of criteria A-D
for 1.1 Migraine without aura
B.
Not fulﬁlling ICHD-3 criteria for any 
other headache disorder
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C.
Not better accounted for by another 
ICHD-3 diagnosis.
1.5.2 Probable migraine with aura
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–C for
1.2 Migraine with aura or any of its subtypes
B.
Not fulﬁlling ICHD-3 criteria for any 
other headache disorder
C.
Not better accounted for by another 
ICHD-3 diagnosis.
1.6 Episodic syndromes that may be associated with
migraine
Previously used terms: Childhood periodic 
syndromes; periodic syndromes of childhood.
Comments: This group of disorders occurs in 
patients who also have 1.1 Migraine without 
aura or 1.2 Migraine with aura, or who have an 
increased likelihood to develop either of these 
disorders. Although historically noted to occur 
in childhood, they may also occur in adults.
Additional conditions that may also occur in 
these patients include episodes of motion 
sickness and periodic sleep disorders including 
sleep walking, sleep talking, night terrors and 
bruxism.
1.6.1 Recurrent gastrointestinal disturbance
Previously used terms: Chronic abdominal pain; 
functional 
abdominal 
pain; 
functional 
dyspepsia; irritable bowel syndrome; functional 
abdominal pain syndrome.
Description: Recurrent episodic attacks of 
abdominal pain and/or discomfort, nausea 
and/or 
vomiting, 
occurring 
infrequently, 
chronically or at predictable intervals, that may 
be associated with migraine.
Diagnostic criteria:
A.
At least ﬁve attacks with distinct episodes 
of abdominal pain and/or discomfort and/or 
nausea and/or vomiting
B.
Normal gastrointestinal examination and 
evaluation
C.
Not attributed to another disorder.
1.6.1.1 Cyclic vomiting syndrome
Description: Recurrent episodic attacks of intense 
nausea and vomiting, usually stereotypical in the 
individual and with predictable timing of episodes. 
Attacks may be associated with pallor and lethargy. 
There is complete resolution of symptoms between
attacks.
Diagnostic criteria:
A.
At least ﬁve attacks of intense nausea and 
vomiting, fulﬁlling criteria B and C
B.
Stereotypical in the individual patient and 
recurring with predictable periodicity
C.
All of the following:
1.
nausea and vomiting occur at least four 
times per hour
2.
attacks last for ≥1 hour, up to 
10 days
3.
attacks occur ≥1 week apart
D.
Complete freedom from symptoms between 
attacks
E.
Not attributed to another disorder.1
Note:
1. In particular, history and physical 
examination do not show signs of 
gastrointestinal disease.
Comments:1.6.1.1 Cyclic vomiting syndrome is 
typically a self-limiting episodic condition 
occurring in childhood, with periods of complete 
normality between episodes. The cyclic nature is 
the hallmark, and attacks are predictable.
This disorder was ﬁrst included as a childhood 
periodic syndrome in ICHD-II. The clinical 
features of this syndrome resemble those found in 
association with migraine headaches, and 
multiple threads of research over the last years 
have suggested that 1.6.1.1 Cyclic vomiting 
syndrome is a condition related to migraine.
1.6.1.2 Abdominal migraine
Description: An idiopathic disorder seen mainly 
in children as recurrent attacks of moderate to 
severe midline abdominal pain, associated with 
vasomotor symptoms, nausea and vomiting, 
lasting 2–72 hours and with normality between 
episodes. Headache does not occur during these 
episodes.
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Diagnostic criteria:
A.
At least ﬁve attacks of abdominal pain, 
fulﬁlling criteria B–D
B.
Pain has at least two of the following three 
characteristics:
1.
midline location, periumbilical or 
poorly localized
2.
dull or ‘just sore’ quality
3.
moderate or severe intensity
C.
At least two of the following four associated 
symptoms or signs:
1.
anorexia
2.
nausea
3.
vomiting
4.
pallor
D.
Attacks last 2–72 hours when untreated or
unsuccessfully treated
E.
Complete freedom from symptoms between 
attacks
F.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination 
do not show signs of gastrointestinal or renal 
disease, or such disease has been ruled out by 
appropriate investigations.
Comments: Pain of 1.6.1.2 Abdominal migraine is 
severe enough to interfere with normal daily 
activities.
In young children, the presence of headache is 
often overlooked. A careful history of presence or 
absence of headache must be taken and, when 
headache or head pain during attacks is identiﬁed, 
a diagnosis of 1.1 Migraine without aura should 
be considered.
Children may ﬁnd it difficult to distinguish 
anorexia from nausea. Pallor is often accompanied 
by dark shadows under the eyes. In a few patients, 
ﬂushing is the predominant vasomotor 
phenomenon.
Most children with abdominal migraine will 
develop migraine headache later in life.
1.6.2 Benign paroxysmal vertigo
Description: A disorder characterized by 
recurrent brief attacks of vertigo, occurring 
without warning and resolving spontaneously, in 
otherwise healthy children.
Diagnostic criteria:
A.
At least ﬁve attacks fulﬁlling criteria B and C
B.
Vertigo1 occurring without warning, maximal 
at onset and resolving spontaneously after 
minutes to hours without loss of
consciousness
C.
At least one of the following ﬁve associated 
symptoms or signs:
1.
nystagmus
2.
ataxia
3.
vomiting
4.
pallor
5.
fearfulness
D.
Normal neurological examination and 
audiometric and vestibular functions between
attacks
E.
Not attributed to another disorder.2
Notes:
1. Young children with vertigo may not be able to 
describe 
vertiginous 
symptoms. 
Parental 
observation of episodic periods of unsteadiness 
may be interpreted as vertigo in young children.
2. In particular, posterior fossa tumours, seizures 
and vestibular disorders have been excluded.
Comment: The relationship between 1.6.2 Benign
paroxysmal vertigo and A1.6.6 Vestibular migraine 
(see Appendix) needs to be further examined.
1.6.3 Benign paroxysmal torticollis
Description: Recurrent episodes of head tilt to one 
side, perhaps with slight rotation, which remit 
spontaneously. The condition occurs in infants and 
small children, with onset in the ﬁrst year.
Diagnostic criteria:
A.
Recurrent attacks1 in a young child, fulﬁlling 
criteria B and C
B.
Tilt of the head to either side, with or without 
slight rotation, remitting spontaneously after 
minutes to days
C.
At least one of the following ﬁve associated 
symptoms or signs:
1.
pallor
2.
irritability
3.
malaise
4.
vomiting
5.
ataxia2
D.
Normal neurological examination between
attacks
E.
Not attributed to another disorder.3
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Notes:
1. Attacks tend to recur monthly.
2. Ataxia is more likely in older children 
within the affected age group.
3. The 
differential 
diagnosis 
includes 
gastro-oesophageal reﬂux, idiopathic torsional 
dystonia and complex partial seizure, but 
particular attention must be paid to the posterior 
fossa 
and 
craniocervical 
junction 
where 
congenital or acquired lesions may produce
torticollis.
Comments: The child’s head can be returned to 
the neutral position during attacks: some 
resistance may be encountered but can be 
overcome.
These observations need further validation by 
patient diaries, structured interviews and 
longitudinal data collection.
1.6.3 Benign paroxysmal torticollis may evolve into
1.6.2 Benign paroxysmal vertigo or 1.2 
Migraine with aura (particularly 1.2.2 Migraine 
with brainstem aura) or cease without further 
symptoms.
Bibliography
1 Migraine in general
Arruda MA, Guidetti V, Galli F, et al. Primary 
headaches in childhood – a population-based 
study. Cephalalgia 2010; 30: 1056–1064.
Diener HC and Silberstein SD. Medication 
overuse headache. In: Olesen J, Goadsby PJ, 
Ramadan NM, et al. (eds) The headaches, 3rd 
edition. Philadelphia: Lippincott Williams & 
Wilkins, 2006, pp.971–979.
GBD 2015 Disease and Injury Incidence and 
Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived 
with disability for 310 diseases and injuries, 
1990– 2015: a systematic analysis for the Global 
Burden of Disease Study 2015. Lancet 2016; 
388: 1545–1602.
Gelfand AA, Fullerton HJ and Goadsby PJ. Child 
neurology: migraine with aura in children. 
Neurology 2010; 75(5): e16–e19.
Goadsby PJ. Migraine pathophysiology. Headache
2005; 45(Suppl 1): S14–S24.
Goadsby PJ. Recent advances in the diagnosis 
and management of migraine. BMJ 2006; 332:
25–29.
Katsarava Z, Manack A, Yoon MS, et al. Chronic 
migraine: 
classiﬁcation 
and 
comparisons. 
Cephalalgia 2011; 31: 520–529.
Lipton RB, Bigal ME, Steiner TJ, et al. 
Classiﬁcation of primary headaches. Neurology 
2004; 63: 427–435.
Martelletti P, Haimanot RT, Lainez MJ, et al. The 
Global Campaign (GC) to Reduce the Burden of 
Headache Worldwide. The International Team for 
Specialist Education (ITSE). J Headache Pain 
2005; 6: 261–263.
Silberstein SD. Migraine. Lancet 2004; 363: 381-391.
Vetvik KG, Macgregor EA, Lundqvist C, et al. 
Prevalence of menstrual migraine: a population-based 
study. 
Cephalalgia 
2014; 
34: 280-288.
Vetvik KG, Benth JSˇ , MacGregor EA, et al. 
Menstrual versus non-menstrual attacks of migraine 
without aura in women with and without menstrual 
migraine. Cephalalgia 2015; 35: 1261–1268.
Vos T, Flaxman AD, Naghavi M, et al. Years lived 
with disability (YLD) for 1160 sequelae of 289 
diseases and injuries 1990–2010: a systematic analysis 
for the global burden of disease study 2010. Lancet 
2012; 380: 2163–2196.
1.2 Migraine with aura
Cao Y, Welch KM, Aurora S, et al. Functional 
MRI-BOLD of visually triggered headache in patients
with migraine. Arch Neurol 1999; 56: 548–554.
Charles A and Brennan K. Cortical spreading 
depression – new insights and persistent questions. 
Cephalalgia 2009; 29: 1115–1124.
Cologno D, Torelli P and Manzoni GC. Migraine with 
aura: a review of 81 patients at 10–20 years’ follow-
up. Cephalalgia 1998; 18: 690–696.
Cutrer FM, Sorensen AG, WeisskoﬀRM, et al.
Perfusion-weighted 
imaging 
defects 
during 
spontaneous migrainous aura. Ann Neurol 1998; 43: 
25–31.
Eriksen MK, Thomsen LL, Andersen I, et al. Clinical
characteristics of 362 patients with familial migraine
with aura. Cephalalgia 2004; 24: 564–575.
Eriksen MK, Thomsen LL and Olesen J. The Visual 
Aura Rating Scale (VARS) for migraine aura 
diagnosis. Cephalalgia 2005; 25: 801–810.
Giﬃn NJ, Lipton RB, Silberstein SD, et al. The 
migraine postdrome: an electronic diary study. 
Neurology 2016; 87: 309–313.
Hadjikhani N, Sanchez del Rio M, Wu O, et al. 
Mechanisms of migraine aura revealed by functional 
MRI in human visual cortex. PNAS 2001; 98: 
4687-4692.
Hansen JM, Lipton R, Dodick D, et al. Migraine head-
ache is present in the aura phase – a prospective study. 
Neurology 2012; 79: 2044–2049.
Jensen K, Tfelt-Hansen P, Lauritzen M, et al. Classic 
migraine. A prospective recording of symptoms. Acta 
Neurol Scand 1986; 73: 359–362.
Approval Date: 15-May-2020 16:33:54 (GMT)


Allergan 
Protocol 3101-301-002, Amendment 3
96
Kallela M, Wessman M, Farkkila M, et al. Clinical 
characteristics of migraine in a population-based twin 
sample: similarities and diﬀerences between migraine 
with and without aura. Cephalalgia 1999; 19: 151–158.
Kelman L. The premonitory symptoms (prodrome): 
a tertiary care study of 893 migraineurs. Headache 
2004; 44: 865–872.
Lauritzen M. Pathophysiology of the migraine aura. 
The spreading depression theory. Brain 1994; 117(Pt 
1): 199–210.
Leao AAP. Spreading depression of activity in the 
cerebral cortex. J Neurophysiol 1944; 7: 359–390.
Lebedeva ER, Gurary NM, Gilev DV, et al. 
Prospective testing of ICHD-3 beta diagnostic 
criteria for migraine with aura and migraine with 
typical aura in patients with transient ischemic 
attacks. Cephalalgia. Epub ahead of print 1 January 
2017. DOI: 10.1177/0333102417702121.
Li D, Christensen AF and Olesen J. Field-testing of 
the ICHD-3 beta/proposed ICD-11 diagnostic 
criteria for migraine with aura. Cephalalgia 2015; 
35: 748–756.
Olesen J, Friberg L, Olsen TS, et al. Timing and 
topography of cerebral blood ﬂow, aura, and 
headache during migraine attacks. Ann Neurol 1990; 
28: 791–798.
Queiroz LP, Friedman DI, Rapoport AM, et al. 
Characteristics of migraine visual aura in Southern 
Brazil and Northern USA. Cephalalgia 2011; 31: 
1652–1658.
Rasmussen BK and Olesen J. Migraine with aura 
and migraine without aura: an epidemiological 
study. Cephalalgia 1992; 12: 221–228 (discussion 
186).
Salhofer-Polanyi S, Frantal S, Brannath W, et al. 
Prospective analysis of factors related to migraine 
aura – The PAMINA Study. Headache 2012; 52: 
1236–1245.
Schoonman GG, Evers DJ, Terwindt GM, et al. The 
prevalence of premonitory symptoms in migraine: a 
questionnaire study in 461 patients. Cephalalgia 
2006; 26: 1209–1213.
Ulrich V, Gervil M, Kyvik KO, et al. Evidence of a 
genetic 
factor 
in 
migraine 
with 
aura: 
A 
population-based Danish twin study. Ann Neurol 
1999; 45: 242–246.
1.2.1 Migraine with typical aura
Eriksen 
MK, 
Thomsen 
LL 
and 
Olesen 
J. 
Implications of clinical subtypes of migraine with 
aura.Headache 2006; 46: 286–297.
Hansen JM, Goadsby PJ and Charles AC. Variability
of clinical features in attacks of migraine with aura. 
Cephalalgia 2016; 36: 216-224.
Matharu MJ and Goadsby PJ. Post-traumatic chronic 
paroxysmal hemicrania (CPH) with aura. Neurology 
2001; 56: 273–275.
Morrison DP. Abnormal perceptual experiences in 
migraine. Cephalalgia 1990; 10: 273–277.
Silberstein SD, Niknam R, Rozen TD, et al. Cluster 
headache with aura. Neurology 2000; 54: 219–221.
Viana M, Linde M, Sances G, et al. Migraine aura 
symptoms: 
duration, 
succession 
and 
temporal 
relationship to headache. Cephalalgia 2016; 36: 
413-421.
Wijman CA, Wolf PA, Kase CS, et al. Migrainous 
visual accompaniments are not rare in late life: the 
Framingham Study. Stroke 1998; 29: 1539–1543.
1.2.2 Migraine with brainstem aura
Ambrosini A, D’Onofrio M, Grieco GS, et al. 
Familial basilar migraine associated with a new 
mutation in the ATP1A2 gene. Neurology 2005; 65: 
1826–1828.
Bickerstaff ER. Basilar artery migraine. Lancet 1961; 
i:15–17.
Caplan LR. Migraine and vertebrobasilar ischemia. 
Neurology 1991; 41: 55–61.
Eriksen MK, Thomsen LL and Olesen J. Implications 
of clinical subtypes of migraine with aura. Headache 
2006; 46: 286–297.
Kirchmann M, Thomsen LL and Olesen J. Basilar-
type migraine: clinical, epidemiologic, and genetic 
features. Neurology 2006; 66: 880–886.
Lempert T, Neuhauser H and Daroff RB. Vertigo 
as a symptom of migraine. Ann NY Acad Sci 2009;
1164: 242–251.
Li D, Christensen AF and Olesen J. Field-testing of 
the ICHD-3 beta/proposed ICD-11 diagnostic criteria 
for migraine with aura. Cephalalgia 2015;
35: 
748-756.
Sturzenegger MH and Meienberg O. Basilar artery 
migraine: a follow-up study of 82 cases. Headache 
1985; 25: 408–415.
Swanson JW and Vick NA. Basilar artery migraine 
12 
patients, 
with 
an 
attack 
recorded 
electroencephalographically. Neurology 1978; 28: 
782–786.
Thomsen LL, Eriksen MK, Roemer SF, et al. A 
population-based 
study 
of 
familial 
hemiplegic 
migraine suggests revised diagnostic criteria. Brain 
2002; 125: 1379–1391.
Thomsen LL, Ostergaard E, Olesen J, et al. Evidence 
for a separate type of migraine with aura: sporadic 
hemiplegic migraine. Neurology 2003; 60: 595–601.
1.2.3 Hemiplegic migraine
Ambrosini A, D’Onofrio M, Grieco GS, et al. 
Familial basilar migraine associated with a new 
mutation in the ATP1A2 gene. Neurology 2005; 
65: 1826–1828.
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Allergan 
Protocol 3101-301-002, Amendment 3
97
De Fusco M, Marconi R, Silvestri L, et al. 
Haploinsuffciency of ATP1A2 encoding the 
Naþ/Kþ pump a2 subunit associated with familial 
hemiplegic migraine type 2. Nat Genet 2003; 
33:192–196.
De Vries B, Frants RR, Ferrari M, et al.
Molecular genetics of migraine. Hum Genet 
2009; 126: 115–132.
Dichgans M, Freilinger T, Eckstein G, et al. 
Mutation in the neuronal voltage-gated sodium 
channel SCN1A in familial hemiplegic migraine. 
Lancet 2005; 366: 371–377.
Dreier JP, Jurkat-Rott K, Petzold GC, et al. 
Opening of the blood–brain barrier preceding 
cortical edema in a severe attack of FHM type II. 
Neurology 2005; 64: 2145–2147.
Eriksen MK, Thomsen LL and Olesen J. 
Implications of clinical subtypes of migraine with 
aura.Headache 2006; 46: 286–297.
Hansen JM, Schytz HW, Larsen VA, et al. 
Hemiplegic migraine aura begins with cerebral 
hypoperfusion: imaging in the acute phase. 
Headache 2011; 51: 1289–1296.
Hansen JM, Thomsen LL, Olesen J, et al. 
Coexisting 
typical 
migraine 
in 
familial 
hemiplegic migraine. Neurology 2010; 74: 
594-600.
Iizuka T, Takahashi Y, Sato M, et al. 
Neurovascular changes in prolonged migraine 
aura in FHM with a novel ATP1A2 gene 
mutation. J Neurol Neurosurg Psychiatry 2012; 
83: 205–212.
Jurkat-Rott K, Freilinger T, Dreier JP, et al. 
Variability of familial hemiplegic migraine with 
novel A1A2 Naþ/Kþ-ATPase variants. Neurology 
2004; 62:1857–1861.
Kirchmann M, Thomsen LL and Olesen J. Basilar-
type migraine: clinical, epidemiologic, and genetic 
features. Neurology 2006; 66: 880-886.
Leo L, Gherardini L, Barone V, et al. Increased 
susceptibility to cortical spreading depression in the 
mouse model of familial hemiplegic migraine type 2. 
PloS Genet 2011; 7: e1002129.
Thomsen LL, Eriksen MK,Roeme SF, et al. A 
population-based 
study 
of 
familial 
hemiplegic 
migraine suggests revised diagnostic criteria. Brain 
2002; 125: 1379–1391.
Thomsen LL, Kirchmann M, Bjornsson A, et al. The 
genetic spectrum of a population-based sample of 
familial hemiplegic migraine. Brain 2007; 130: 346–
356.
Thomsen LL, Ostergaard E, Olesen J, et al. Evidence 
for a separate type of migraine with aura: sporadic 
hemiplegic migraine. Neurology 2003; 60: 595–601.
Vanmolkot KRJ, Kors EE, Turk U, et al. Two de 
novo mutations in the Na,K-ATPase gene ATP1A2 
associated with pure familial hemiplegic migraine. 
Eur J Hum Genet 2006; 14: 555–560.
1.2.4 Retinal migraine
Carroll D. Retinal migraine. Headache 1970; 10: 
9-13. Chronicle EP and Mulleners WM. Visual system 
dysfunction in migraine: a review of clinical and 
psychophysical ﬁndings. Cephalalgia 1996; 16: 525–
535.
Grosberg BM, Solomon S, Friedman DI, et al. Retinal 
migraine reappraised. Cephalalgia 2006; 26: 1275–
1286.
Hedges TR. Isolated ophthalmic migraine in the 
diﬀerential diagnosis of cerebroocular ischemia. 
Stroke 1976; 7: 379–381.
Hill DL, Daroff RB, Ducros A, et al. Most cases
labeled as ‘‘retinal migraine’’ are not migraine. J 
Neuroophthalmol 2007; 27: 3–8.
Martin TJ and Corbett JJ. Disorders of the eye. In: 
Silberstein SD, Lipton RB and Dalessio DJ (eds) 
Wolff’s headache and other head pain. New York: 
Oxford University Press, 2001, pp.459–474.
Troost T and Zagami AS. Ophthalmoplegic migraine 
and retinal migraine. In: Olesen J, Tfelt-Hansen P and 
Welch KMA (eds) The headaches, 2nd edition. 
Philadelphia: Lippincott Williams & Wilkins, 2000, 
pp.511–516.
1.3 Chronic migraine
Aurora SK. Is chronic migraine one end of a spectrum 
of migraine or a separate entity? Cephalalgia 2009; 
29: 597–605.
Bigal ME and Lipton RB. Concepts and mechanisms 
of migraine chroniﬁcation. Headache 2008; 48: 7–15.
Bigal M, Rapoport A, Sheftell F, et al. The 
International Classiﬁcation of Headache Disorders 
revised criteria for chronic migraine – ﬁeld testing in a 
headache specialty clinic. Cephalalgia 2007; 27: 230–
234.
Bigal ME, Serrano D, Reed M, et al. Chronic 
migraine in the population: burden, diagnosis, and 
satisfaction with treatment. Neurology 2008; 71: 
559-566.
Bigal ME, Sheftell FD, Rapoprt AM, et al. Chronic 
daily
headache
in
a
tertiary
care
population:
correlation between the International Headache 
Society diagnostic criteria and proposed revisions of
criteria for chronic daily headache. Cephalalgia 
2002; 22: 432–438.
Bloudek LM, Stokes M, Buse DC, et al. Cost of 
health-
care for patients with migraine in ﬁve 
European countries: results from the International 
Burden of Migraine Study (IBMS). J Headache Pain 
2012; 13: 361-378.
Buse DC, Manack AN, Fanning KM, et al. Chronic 
migraine prevalence, disability, and sociodemographic 
factors. 
Results 
from 
the 
American 
Migraine 
Prevalence and Prevention Study. Headache 2012; 52:
1456-1470.
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Protocol 3101-301-002, Amendment 3
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Buse D, Manack A, Serrano D, et al. Headache 
impact of chronic and episodic migraine: results 
from the American Migraine Prevalence and 
Prevention study. Headache 2012; 52: 3–17.
Diamond S. A view of chronic daily headache.
Headache Q 2000; 11: 177.
Diener HC, Dodick DW, Goadsby PJ, et al. Chronic 
migraine – classiﬁcation, characteristics and 
treatment. Nat Rev Neurol 2012; 8: 162–171.
Goadsby PJ and Hargreaves R. Refractory migraine 
and chronic migraine: pathophysiological 
mechanisms. Headache 2008; 48: 799–804.
Katsarava Z, Manack A, Yoon MS, et al. Chronic 
migraine: classiﬁcation and comparisons. 
Cephalalgia 2011; 31: 520–529.
Manzoni GC, Bonavita V, Bussone G, et al.; 
ANIRCEF (Associazione Neurologica Italiana 
Ricerca Cefalee). Chronic migraine classiﬁcation: 
current knowledge and future perspectives. J 
Headache Pain 2001; 12: 585–592.
Mathew NT, Stubits E and Nigam MP. Transformed 
or evolutive migraine. Headache 1987; 27: 102–106. 
Natoli JL, Manack A, Dean B, et al. Global 
prevalence of chronic migraine: a systematic review. 
Cephalalgia 2010; 30: 599–609.
Scher AI, Stewart WF, Liberman J, et al. Prevalence 
of frequent headache in a population sample.
Headache 1998; 38: 497–506.
Scher AI, Stewart WF, Ricci JA, et al. Factors 
associated with the onset and remission of chronic 
daily headache in a population-based study. Pain 
2003; 106: 81–89.
Silberstein SD, Lipton RB and Sliwinski M. 
Classiﬁcation of daily and near-daily headaches: 
ﬁeld trial of revised IHS criteria. Neurology 1996; 
47: 871–875.
Silberstein SD, Lipton RB, Solomon S, et al. 
Classiﬁcation of daily and near-daily headaches: 
proposed revisions to the IHS criteria. Headache 
1994; 34: 1–7.
Stewart WF, Scher AI and Lipton RB. Stressful life 
events and risk of chronic daily headache: results 
from the frequent headache epidemiology study. 
Cephalalgia 2001; 21: 279. Abstract no: OR32.
Yalın OO, Uluduz D, O¨zge A, et al. Phenotypic 
features of chronic migraine. J Headache Pain 2016; 
17: 26.
Zeeberg P, Olesen J and Jensen R. Probable 
medication-overuse headache: the effect of a 
2-month drug- free period. Neurology 2006; 66: 
1894–1898.
Zeeberg P, Olesen J and Jensen R. Medication 
overuse headache and chronic migraine in a 
specialized headache centre: ﬁeld-testing proposed 
new appendix criteria. Cephalalgia 2009; 29: 
214-220.
1.4.1 Status migrainosus
Akhtar ND, Murray MA and Rothner AD. Status 
migrainosus in children and adolescents. Semin 
Pediatr Neurol 2001; 8: 27–33.
Beltramone M and Donnet A. Status migrainosus and 
migraine aura status in a French tertiary-care center: 
An 11-year retrospective analysis. Cephalalgia 2014; 
34: 633–637.
Couch JR and Diamond S. Status migrainosus. 
Causative and therapeutic aspects. Headache 1983; 
23: 94–101.
Cure J and Rothrock J. Prolonged status migrainosus 
complicated by cerebellar infarction. Headache 2007; 
47: 1091–1092.
Gentile S, Rainero I, Daniele D, et al. Reversible MRI 
abnormalities in a patient with recurrent status 
migrainosus. Cephalalgia 2009; 29: 687-690.
Lanfranconi S, Corti S, Bersano A, et al. Aphasic and 
visual aura with increased vasogenic leakage: an 
atypical migrainosus status. J Neurol Sci 2009; 285:
227–229.
Perucca P, Terzaghi M and Manni R. Status 
epilepticus migrainosus: clinical, electrophysiologic, 
and imaging characteristics. Neurology 2010; 75: 
373–374.
Raskin NH. Treatment of status migrainosus: the 
American experience. Headache 1990; 30(Suppl 2): 
550–553.
1.4.2 Persistent aura without infarction
Ambrosini A, de Noordhout AM and Schoenen J. 
Neuromuscular transmission in migraine patients with 
prolonged aura. Acta Neurol Belg 2001; 101: 166–
170.
Bento MS and Esperanca P. Migraine with prolonged 
aura. Headache 2000; 40: 52–53.
Chen WT, Fuh JL, Lu SR, et al. Persistent migrainous 
visual phenomena might be responsive to lamotrigine. 
Headache 2001; 41: 823–825.
Chen WT, Lin YY, Fuh JL, et al. Sustained visual 
cortex hyperexcitability in migraine with persistent 
visual aura. Brain 2011; 134(Pt 8): 2387-2395.
Evans RW and Lay CL. A persistent migraine aura.
Headache 2000; 40: 696–698.
Haan J, Sluis P, Sluis IH, et al. Acetazolamide 
treatment for migraine aura status. Neurology 2000; 
55: 1588–1589.
Haas DC. Prolonged migraine aura status. Ann Neurol 
1982; 11: 197–199.
Lebedeva ER, Gurary NM, Gilev DV, et al. 
Prospective testing of ICHD-3 beta diagnostic criteria 
for migraine with aura and migraine with typical aura 
in patients with transient ischemic attacks. 
Cephalalgia. Epub ahead of print 1 January 2017. 
DOI: 10.1177/0333102417702121.
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Liu GT, Schatz NJ, Galetta SK, et al. Persistent 
positive 
visual 
phenomena 
in 
migraine. 
Neurology 1995; 45: 664–668.
Luda E, Bo E, Sicuro L, et al. Sustained visual 
aura: a totally new variation of migraine. 
Headache 1991; 31: 582–583.
Relja G, Granato A, Ukmar M, et al. Persistent 
aura without infarction: description of the ﬁrst 
case studied with both brain SPECT and 
perfusion MRI. Cephalalgia 2005; 25: 56–59.
Rothrock JF. Successful treatment of persistent 
migraine 
aura 
with 
divalproex
sodium. 
Neurology 1997; 48: 261–262.
San-Juan OD and Zermeno PF. Migraine with 
persistent aura in a Mexican patient: case report and 
review of the literature. Cephalalgia 2007; 27: 456–
460.
Smith M, Cros D and Sheen V. Hyperperfusion 
with vasogenic leakage by fMRI in migraine with 
pro- longed aura. Neurology 2002; 58: 1308–
1310.
Wang YF, Fuh JL, Chen WT, et al. The visual 
aura rating scale as an outcome predictor for 
persistent 
visual
aura
without
infarction.
Cephalalgia 2008; 28: 1298–1304.
1.4.3 Migrainous infarction
Bono G, Minonzio G, Mauri M, et al. 
Complications of migraine: migrainous 
infarction. Clin Exp Hypertens 2006; 28:
233-242.
Bousser MG, Conard J, Kittner S, et al. 
Recommendations on the risk of ischemic stroke 
associated 
with 
use 
of 
combined
oral 
contraceptives and hormone replacement therapy 
in women with migraine. The International 
Headache Society Task Force on Combined Oral 
Contraceptives 
& 
Hormone 
Replacement 
Therapy. Cephalalgia 2000; 20: 155–156.
Chang CL, Donaghy M and Poulter N. Migraine 
and stroke in young women: case–control study. 
The World Health Organization Collaborative 
Study of Cardiovascular Disease and Steroid 
Hormone Contraception. BMJ 1999; 318: 13–18.
Connor CCR. Complicated migraine. A study of 
permanent neurological and
visual defects. 
Lancet 1962; ii: 1072–1075.
Laurell K, Artto V, Bendtsen L, et al. Migrainous 
infarction: a Nordic multicenter study. Eur J
Neurol 2011; 18: 1220–1226.
MacGregor EA and Guillebaud J. Combined oral 
contraceptives, migraine and ischemic stroke. 
Clinical and Scientiﬁc Committee of the Faculty 
of Family Planning and Reproductive Health 
Care and the Family Planning Association. Br J 
Fam Plann 1998; 24: 55–60.
Olesen 
J, 
Friberg 
L, 
Olsen 
TS, 
et 
al. 
Ischaemia-induced (symptomatic) migraine attacks 
may be more frequent than migraine induced ischemic
insults. Brain 1993; 116: 187–202.
Rothrock JF, Walicke P, Swenson MR, et al.
Migrainous stroke. Arch Neurol 1988; 45: 63–67.
Schulz UG, Blamire AM, Davies P, et al. Normal 
cortical energy metabolism in migrainous stroke: A 
31P-MR spectroscopy study. Stroke 2009; 40: 
3740-3744.
Tietjen GE. The relationship of migraine and stroke.
Neuroepidemiology 2000; 19: 13–19.
Tzourio C, Kittner SJ, Bousser MG, et al. Migraine 
and stroke in young women. Cephalalgia 2000; 20: 
190–199.
Vollbracht S, Robbins MS and Kister I. Classiﬁcation 
challenge in migrainous infarction. Headache 2014; 
54: 170–171.
Wolf ME, Szabo K, Griebe M, et al. Clinical and MRI 
characteristics 
of 
acute 
migrainous 
infarction. 
Neurology 2011; 76: 1911–1917.
1.4.4 Migraine aura-triggered seizure
Belcastro V Striano P, Kasteleijn-Nolst Trenite DGet 
al. 
Migralepsy, 
hemicrania 
epileptica, 
postictal 
headache and ‘‘ictal epileptic headache’’: a proposal 
for 
terminology 
and 
classiﬁcation 
revision. 
J 
Headache Pain 2011; 12: 289–294. 
Davies PT and Panayiotopoulos CP. Migraine 
triggered seizures and epilepsy triggered headache
and migraine attacks: a need for re-assessment. J 
Headache Pain 2011; 12: 287–288.
Friedenberg S and Dodick DW. Migraine-associated 
seizure: a case of reversible MRI abnormalities and 
persistent 
nondominant 
hemisphere 
syndrome. 
Headache 2000; 40: 487–490.
Maggioni F, Mampreso E, Ruﬀatti S, et al. 
Migralepsy: is the current deﬁnition too narrow? 
Headache 2008; 48: 1129–1132.
Marks DA and Ehrenberg BL. Migraine-related 
seizures in adults with epilepsy, with EEG correlation. 
Neurology 1993; 43: 2476–2483.
Merlino G, Valente MR, D’Anna S, et al. Seizures
with prolonged EEG abnormalities during an attack
of migraine
without
aura.
Headache
2007;
47:
919-922.
Parisi 
P 
and 
Kasteleijn-Nolst 
Trenite` 
DGA. 
‘‘Migralepsy’’: a call for revision of the deﬁnition. 
Epilepsia 2010; 51: 932–933.
Rogawski 
MA. 
Common 
pathophysiologic 
mechanisms in migraine and epilepsy. Arch Neurol 
2008; 65: 709–714.
Sances G, Guaschino E, Perucca P, et al. 
Migralepsy: a call for revision of the deﬁnition.
Epilepsia 2009; 50: 2487–2496.
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Ter Berg HW. Migraine-associated seizure: a case of 
reversible MRI abnormalities and persistent non-
dominant hemisphere syndrome. Headache 2001; 
41: 326–328.
Velioglu SK and Ozmenoglu M. Migraine-related 
seizures in an epileptic population. Cephalalgia 
1999; 19: 797–801.
Verrotti A, Coppola G, Di Fonzo A, et al. Should 
‘‘migralepsy’’ be considered an obsolete concept? A 
multicenter retrospective clinical/EEG study and 
review of the literature. Epilepsy Behav 2011; 21: 
52–59.
1.5 Probable migraine
Granella F, Alessandro RD, Manzoni GC, et al. 
International Headache Society classiﬁcation: inter-
observer reliability in the diagnosis of primary 
headaches. Cephalalgia 1994; 14: 16–20.
Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis 
of migraine: empirical analysis of a large clinical 
sample of atypical migraine (IHS 1.7) patients and 
proposed revision of the IHS criteria. Cephalalgia 
2001, 21: 584–595.
Rasmussen
BK,
Jensen R and Olesen J.
A
population-
based analysis of the diagnostic 
criteria of the International Headache Society.
Cephalalgia 1991; 11: 129–134.
Russell MB and Olesen J. Migrainous disorder and 
its relation to migraine without aura and migraine 
with 
aura. 
A 
genetic 
epidemiological study. 
Cephalalgia 1996; 16: 431–435.
1.6.1 Recurrent gastrointestinal disturbance
Abu-Arafeh I and Russel G. Prevalence and clinical 
features of abdominal migraine compared with those 
of migraine headache. Arch Dis Child 1995; 72:
413–417.
Al-Twaijri WA and Shevell MI. Pediatric migraine 
equivalents: occurrence and clinical features in 
practice. Pediatr Neurol 2002; 26: 365–368.
Dignan F, Abu-Arafeh I and Russell G. The 
prognosis of childhood abdominal migraine. Arch 
Dis Child 2001; 84: 415–418.
Drossman DA and Dumitrascu DL. Rome III: new 
standard for functional gastrointestinal disorders. 
J Gastrointestin Liver Dis 2006; 15: 237–241.
Farquar HA. Abdominal migraine in children. BMJ 
1956; i: 1082–1085.
Fleisher DR. Cyclic vomiting syndrome and migraine. 
J Pediatr 1999; 134: 533–535.
Haan J, Kors EE and Ferrari MD. Familial cyclic 
vomiting syndrome. Cephalalgia 2002; 22: 552-554.
Li BU. Cyclic vomiting syndrome: age-old syndrome 
and new insights. Semin Pediatr Neurol 2001; 8:
13-21.
Li BUK, Lefevre F, Chelimsky GG, et al. North 
American Society for Pediatric Gastroenterology, 
Hepatology, and Nutrition consensus statement on the 
diagnosis and management of cyclic vomiting 
syndrome. J Pediatr Gastroenterol Nutr 2008; 47: 
379–393.
Rashed H, Abell TL, Familoni BO, et al. Autonomic 
function in cyclic vomiting syndrome and classic 
migraine. Dig Dis Sci 1999; 44(Suppl 8): 74S-78S.
Russell G, Abu-Arafeh I and Symon DN. Abdominal 
migraine: evidence for existence and treatment 
options. Paediatr Drugs 2002; 4: 1-8.Thiessen PN. 
Recurrent abdominal pain. Pediatr Rev 2002; 23: 
39-46.
Welch KM. Scientiﬁc basis of migraine: speculation 
on the relationship to cyclic vomiting. Dig Dis Sci
1999; 44(Suppl 8): 26S–30S.
1.6.2 Benign paroxysmal vertigo
Drigo P, Carli G and Laverda AM. Benign 
paroxysmal vertigo of childhood. Brain Dev 
2001; 23: 38–41.
Dunn DW and Snyder CH. Benign paroxysmal 
vertigo of childhood. Am J Dis Child 1976; 130: 
1099–1100.
Fenichel GM. Migraine as a cause of benign
paroxysmal vertigo of childhood. J Pediatr 1967; 
71:114–115.
1.6.3 Benign paroxysmal torticollis
Drigo P, Carli G and Laverda AM. Benign 
paroxysmal torticollis of infancy. Brain Dev 
2000; 22: 169–172. 
Giffin NJ, Benton S and Goadsby PJ. Benign 
paroxysmal torticollis of infancy: four new cases 
and linkage to CACNA1A mutation. Dev Med 
Child Neurol 2002; 44: 490–493.
Rosman NP, Douglass LM, Sharif UM, et al. The 
neurology of benign paroxysmal torticollis of 
infancy: report of 10 new cases and review of the 
literature. J Child Neurol 2009; 24: 155-160.
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12.2
Examples of Prohibited Medications
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12.3.2Criteria for Determining Inadequate Response to a Prior Migraine 
Preventive Medication 
Failure of a migraine-preventive medication can be assessed on the basis of efficacy or 
tolerability and is based on investigator judgment. The criteria below should be used to 
determine eligibility related to the number of prior failed migraine-preventive medications 
with unique mechanisms of action.
For efficacy:

Failure is defined as a < 50% reduction in migraine days per month per investigator 
judgment and participant interview.

Medications must have been started within the past 7 years.
For tolerability:

Failure is defined as discontinuation of a drug treatment due to adverse effects. 

In assessing failure of a migraine preventive drug on the basis of inadequate 
tolerability, the entire medical history can be considered. For example, a participant 
who tried and discontinued topiramate 10 years ago for cognitive clouding should be 
considered to have failed this treatment.
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12.4
Glossary of Abbreviations
Term/ Abbreviation
Definition
ACE
angiotensin-converting enzyme
AE
adverse event
AIM-D
Activity Impairment in Migraine – Diary
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
ASC-12
Allodynia Symptom Checklist
AST
aspartate aminotransferase
AUC0-Tau
area under the concentration-time curve over the dosing interval
BID
twice-daily
BP
blood pressure
CBD
cannabidiol
CFR
Code of Federal Regulations
CGRP
calcitonin gene-related peptide
Cmin
minimum plasma drug concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
CYP3A4
cytochrome P450 3A4
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
EMA
European Medicines Agency
ET
early termination
eTablet
electronic tablet
EU
European Union
FDA
Food and Drug Administration
GBD2010
Global Burden of Disease Survey 2010
GCP
Good Clinical Practices
GI
gastrointestinal
GLP
Good Laboratory Practice
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HSG
hysterosalpingogram
IB
investigators brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders criteria, 3rd
edition
IEC
Independent Ethics Committee
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Term/ Abbreviation
Definition
IgG
immunoglobulin G
IgM
immunoglobulin M
IHS
International Headache Society
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IWRS
interactive web response system
MAR
missing-at-random
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MNAR
missing-not-at-random
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, version 2.1
NA
not applicable
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic-anion-transporting polypeptide 1B1
PD
pharmacodynamic
PK
pharmacokinetic
PMM
pattern-mixture model
PRO
Patient-Reported Outcome
QTcF
QT interval corrected for heart rate using the Fridericia formula
SAE
serious adverse event
SAP
statistical analysis plan
SNRI
serotonin–norepinephrine reuptake inhibitors
SOC
system organ class
SSRI
selective serotonin reuptake inhibitors
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VAS
visual analogue scale
VCT
Verified Clinical Trials
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SAP_001.pdf: 
 
   
 
 
 
    NCT 03777059 
 
Study ID: 3101-301-002 
 
 
Title: A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND TOLERABILITY OF ORAL ATOGEPANT 
FOR THE PREVENTION OF MIGRAINE IN PARTICIPANTS WITH 
EPISODIC MIGRAINE (ADVANCE) 
 
                Statistical Analysis Plan Date: June 25, 2020 


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Title Page
STATISTICAL ANALYSIS PLAN
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND TOLERABILITY OF ORAL ATOGEPANT FOR THE 
PREVENTION OF MIGRAINE IN PARTICIPANTS WITH EPISODIC MIGRAINE 
(ADVANCE)
Final SAP Date: 13 MAR 2019
Amendment 1: 25 JUN 2020
Protocol Number:
3101-301-002
Development Phase:
3
Product Name:
AGN-241689
Study Statistician:
Sponsor Name and Legal Registered 
Address:
Allergan Pharmaceuticals International Limited
Marlow International
The Parkway, Marlow SL7 1YL
United Kingdom


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Table of Contents
1
Title Page ................................................................................................................................. 1
2
Table of Contents..................................................................................................................... 2
List of Tables................................................................................................................................... 4
List of Figures................................................................................................................................. 5
3
List of Abbreviations and Definition of Terms........................................................................ 6
4
Introduction.............................................................................................................................. 7
5
Study Objectives.................................................................................................................... 14
6
Analysis Populations ............................................................................................................. 14
7
Participant Disposition........................................................................................................... 14
8
Demographic and Other Baseline Characteristics ................................................................. 15
9
Extent of Exposure and Treatment Compliance .................................................................... 16
9.1
Extent of Exposure....................................................................................................... 16
9.2
Measurement of Treatment Compliance...................................................................... 17
10 Efficacy Analyses .................................................................................................................. 17
10.1 Efficacy and Health Outcome Measures...................................................................... 17
10.1.1 Efficacy Measures............................................................................................ 17
10.1.2 Health Outcome Measures............................................................................... 19
10.2 Primary Efficacy Endpoints ......................................................................................... 21
10.2.1 Primary Analysis 
21
10.2.2 Sensitivity Analysis for Possible Violation of Normality Assumption ............ 22
10.2.3 Sensitivity Analyses in Missing Data Handling............................................... 23
10.3 Secondary Efficacy Endpoints ..................................................................................... 25
10.5 Off-treatment Hypothetical Estimand.......................................................................... 33
10.5.1 Treatment Condition of Interest ....................................................................... 33
10.5.2 Population ........................................................................................................ 34
10.5.3 Variable ............................................................................................................ 34
10.5.4 Accounting of Intercurrent Events................................................................... 34
10.5.5 Population-level Summary............................................................................... 35
10.5.6 Off-treatment Hypothetical Estimand Approach for the Secondary Endpoints35
11
Safety Analyses...................................................................................................................... 36


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11.1 Adverse Events............................................................................................................. 36
11.2 Clinical Laboratory Assessments................................................................................. 37
11.3 Vital Signs.................................................................................................................... 41
11.4 Electrocardiograms ...................................................................................................... 42
11.5 Columbia-Suicide Severity Rating Scale..................................................................... 43
12 Health Outcome Analyses...................................................................................................... 44
13 Subgroup Analyses ................................................................................................................ 44
14 Interim Analysis..................................................................................................................... 45
15 Determination of Sample Size............................................................................................... 46
16 Statistical Software................................................................................................................ 47
17 Data Handling Convention .................................................................................................... 48
17.1 Visit Time windows...................................................................................................... 48
17.2 Derived Efficacy and Health Outcome endpoints........................................................ 52
17.2.1 Derivation of Efficacy Endpoints Based on eDiary Data ................................ 52
17.2.2 Derivation of Health Outcome Endpoints........................................................ 54
17.3 Repeated or Unscheduled Assessments of Safety Parameters ..................................... 58
17.4 Missing Date of the Last Dose of Study treatment ...................................................... 59
17.5 Missing Severity Assessment for Adverse Events ....................................................... 59
17.6 Missing Causal Relationship to Study treatment for Adverse Events.......................... 59
17.7 Missing Date Information for Adverse Events ............................................................ 59
17.8 Missing Date Information for Prior or Concomitant Medications............................... 60
17.8.1 Incomplete Start Date....................................................................................... 60
17.8.5 Incomplete Stop Date....................................................................................... 61
17.9 Character Values of Clinical Laboratory Parameters................................................... 62
17.10 Identifying Prior Exposure (yes/no) to a Migraine Prevention Medications with Proven 
Efficacy Based on Prior Medications Reported in eCRF............................................. 62
17.11 Identifying Participants Who Took a New Migraine Prophylaxis Treatment with 
Proven Efficacy Based on Concomitant Medications Reported in eCRF for the 
Intercurrent Events Specified in the Off-Treatment Hypothetical Estimand............... 72
18 COVID-19 Related Analyses................................................................................................. 73
18.1 Efficacy Evaluation...................................................................................................... 73
18.2 Safety and other evaluations ........................................................................................ 74
19 Changes to Analyses Specified in Protocol ........................................................................... 76


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20 References.............................................................................................................................. 77
APPENDIX I.
Reporting Selected Laboratory Parameters in Conventional Unit .... 78
APPENDIX II.
Summary of Changes for Amendment 1 ........................................... 80
List of Tables
Table 3–1
Abbreviations and Definitions of Terms................................................................. 6
Table 4–1
Schedule of Visits and Procedures for In-Person Visits Conducted Prior to or 
During the COVID-19 Pandemic............................................................................ 9
Table 4–2
Schedule of Visits and Procedures for Visits Conducted Remotely Due to the 
COVID-19 Pandemic............................................................................................ 12
Table 10–1
Multiple Comparisons Procedure Definitions ...................................................... 28
Table 11–1
Criteria for Potentially Clinically Significant Laboratory Values......................... 38
Table 11–2
Criteria for Hepatic Laboratory Abnormalities..................................................... 40
Table 11–3
Criteria for Potentially Clinically Significant Vital Signs .................................... 42
Table 11-4
Criteria for Potentially Clinically Significant Electrocardiograms....................... 43
Table 15–1
Statistical Power for Primary and the First Three Secondary Endpoints.............. 46
Table 17–1
Efficacy Analysis Visit Definitions for eDiary Data............................................. 48
Table 17–2
Efficacy Analysis Visit Definitions in the Estimand Approach for eDiary Data.. 48
Table 17–3
Efficacy Analysis Visit Definitions for eDiary Data in the First Monthly Period 48
Table 17–4
Efficacy Analysis Visit Definitions for eDiary Data............................................. 49
Table 17–5
Efficacy Analysis Visit Definitions for MSQ v2.1 ............................................... 49
Table 17–6
Efficacy Analysis Visit Definitions in the Off-treatment Estimand for MSQ v2.1
............................................................................................................................... 49


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Table 17–11
Safety Analysis Visit Definitions.......................................................................... 51
Table 17–12
Item Values for MSQ Item Responses.................................................................. 55
Table 17–13
Item Values for HIT-6 Item Responses................................................................. 57
Table 17–14
List of Migraine-preventive Medications with Proven Efficacy .......................... 63
Table 18–1
Summary of Collection Devices for Primary and Key secondary endpoints ....... 74
Table 20–1
List of Selected Parameters to be Reported in Conventional Units...................... 78
Table 20–2
Presenting Laboratory Data Using SI and Conventional Units in Narratives ...... 79
List of Figures
Figure 4-1
Study Design........................................................................................................... 8
Figure 10-1
Multiple Comparisons Procedure ......................................................................... 29


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List of Abbreviations and Definition of Terms
Table 3–1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
AE
adverse event
AIM-D
Activity Impairment in Migraine - Diary
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
C-SSRS
Columbia–Suicide Severity Rating Scale
DB
double-blind
eCRF
electronic case report form
ePRO
electronic patient report outcome
ECG
electrocardiogram, electrocardiographic
ET
early termination
INR
international normalized ratio
ITT
intent-to-treat
IWRS
interactive web response system
mITT
modified intent-to-treat
MedDRA
Medication Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
MSQ
Migraine Specific Quality of Life Questionnaire
PCS
potentially clinically significant
PDRS
protocol deviation requirement specification 
PID
participant identification
PT
preferred term
Q1
first quartile (25th percentile of the data)
Q3
third quartile (75th percentile of the data)
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
SOC
standard of care
TBL
total bilirubin
TEAE
treatment-emergent adverse event
WHO
World Health Organization


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4
Introduction
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the protocol
amendment #3 (dated 14 May 2020) of Study 3101-301-002. Specifications of tables, figures, 
and data listings are contained in a separate document. 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
conducted in the United States and will enroll approximately 872 participants from 
approximately 110 sites. Participants will be randomized to one of four treatment arms (placebo,
atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg) in a 1:1:1:1 ratio. Approximately 70% 
of randomized participants will have taken at least 1 prior migraine prevention medication with 
proven efficacy. Randomization will be stratified based on prior exposure (yes/no) to a migraine 
prevention medication with proven efficacy.
The study will consist of a 4-week screening and baseline period, a 12-week double-blind 
treatment period, and a follow up period of 4 additional weeks, for a total duration of 20 weeks. 
Participant participation will begin with a 4-week screening/baseline period. Participants who 
complete the 4-week screening/baseline period and meet all entry criteria will be randomized to 
the double-blind treatment period of the study at Visit 2 (Randomization Visit). The double-blind 
treatment period will last 12 weeks, with a subsequent follow-up period of 4 additional weeks. 
There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), Visit 2 (Randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ET (Week 12), and 
Visit 8 (Follow-up). The Visit 8 (Follow-up) must be completed for all participants who take at 
least one dose of study intervention, except for participants rolling over into Study 3101-309-002 
(long-term safety extension study). For these participants Visit 8 is not required, as the Follow-up 
Visit will be performed in the long-term safety study. For participants who screen fail for the 
long-term safety, the Follow-up Visit must be completed.
Per study design (Protocol Sections 8.4.3.2 and 8.8), eDiary data will be collected for 
participants who early terminated from the double-blind treatment period during the 4 weeks 
between V7 (Early termination visit) and V8 (Follow-up Visit).
After the last patient first visit on January 31,2020, COVID-19 pandemic emerged. The Section 0
is added to specify analyses for evaluating the impact of COVID-19.


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Figure 4-1
Study Design


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following factors: 1) Randomization stratification factor (prior exposure [yes/no] to a migraine 
prevention medication with proven efficacy) from IWRS; 2) Prior exposure to migraine 
prevention medication with proven efficacy based on prior medication collected from eCRF, 
which will be termed as “actual strata” in the SAP. The list of participants with incorrect 
randomization stratum will be provided.
Screen-failure participants (i.e., participants screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the all screened participants. The 
number and percentage of participants who enter the double-blind treatment period, complete the 
double-blind treatment period and of participants who prematurely discontinue during the same 
period will be presented for each treatment group and pooled across treatment groups for all 
randomized participants. The reasons for premature discontinuation from the double-blind
treatment period as recorded on the termination pages of the electronic case report forms will be 
summarized (number and percentage) by treatment group. The percentage is relevant to the total 
number of randomized participants. Similar disposition information to the double-blind treatment 
period will be presented for the follow-up period. All randomized participants who prematurely 
discontinue during the double-blind treatment period or the follow-up period will be listed by 
discontinuation reason.  The number of participants who signed informed consent for Safety 
Extension Study 3101-309-002 will be provided. 
8
Demographic and Other Baseline Characteristics
Demographic parameters (age; age group [< 20, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥ 70]; 
race; race group [white, all other races]; ethnicity; sex), baseline characteristics (weight; height; 
and body mass index, calculated as weight [kg]/(height [m])2 will be summarized descriptively 
by treatment group for the Safety and mITT Populations, and Off-treatment Hypothetical 
Estimand Population. Continuous variables will be summarized by number of participants and 
mean, 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 in each system organ class and 
preferred term will be summarized by treatment group for the Safety Population. 
Migraine history, including diagnosis, duration of disorder, use of migraine prevention 
medication in the past, average number of migraine or headache days per month in the last 3 


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months, acute medications taken to treat migraine headaches, and advice on lifestyle alterations
will be reported in total and by treatment group for the Safety Population.
Prior medication is defined as any medication taken before the first dose of double-blind study 
treatment. Concomitant medication is defined as any medication taken on or after the date of the 
first dose of the double-blind study treatment.
Prior medication use will be summarized by the number and proportion of participants in each 
treatment group receiving each medication within each therapeutic class for the Safety 
Population. Concomitant medication use will be summarized by the number and percentage of 
participants in each treatment group receiving each medication within each therapeutic class for 
the double-blind treatment period and follow-up period for the Safety Population. If a participant
took a specific medication multiple times or took multiple medications within a specific 
therapeutic class, that participant would be counted only once for the coded drug name or 
therapeutic class. Any prior and concomitant medications will be included in listings. 
The World Health Organization (WHO) Drug Dictionary Enhanced, March 2017 or newer, will 
be used to classify prior and concomitant medications by therapeutic class and drug name.
Protocol deviations will be defined in Protocol Deviation Requirement Specification (PDRS), 
including significant classification. The number and percentage of participants with significant 
protocol deviations will be summarized by treatment group for all categories specified in PDRS 
for all randomized participants.
Baseline efficacy parameters (monthly migraine days, monthly headache days, monthly acute 
medication use days, Migraine Specific Quality of Life Questionnaire [MSQ] v2.1 Role Function 
Restrictive domain score, Performance of Daily Activities domain score of the AIM-D, and 
Physical Impairment domain score of the AIM-D) will be summarized by treatment group for 
mITT Population and Off-treatment Hypothetical Estimand Population.   
9
Extent of Exposure and Treatment Compliance
9.1 Extent of Exposure
Exposure to double-blind study treatment for the Safety Population during the treatment period 
will be summarized for treatment duration, calculated as the number of days from the date of the 
first dose of double-blind study treatment taken to the date of the last dose taken, inclusive. The 
number and percentage of participants with each treatment duration of ≥ 1 day, ≥ 7 days, 
≥14 days, ≥ 21 days, ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥49 days, ≥ 56 days, ≥ 63 days, ≥ 70 
days, ≥ 77 days, ≥ 84 days will be summarized by treatment group respectively. Descriptive 


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statistics (number of participants, mean, SD, median, Q1, Q3, minimum, and maximum) will
also be summarized by treatment group.
Participant-years, defined as exposure to the study treatment in years, will be summarized by 
treatment group for the Safety Population.
9.2 Measurement of Treatment Compliance
Dosing compliance for a specified period is defined as the total number of double-blind study 
medications actually taken by a participant during that period divided by the number of 
double-blind study medications that were expected to be taken during the same period multiplied 
by 100. The total number of tablets actually taken during a specific period will be calculated 
from the study medication record. The prescribed number of tablets during a specific period will 
be calculated as following: 3 tablets/day × the number of days during the period. Descriptive 
statistics for double-blind study medication dosing compliance together with the compliance 
categories (< 80%, 80% - 120%, > 120%) will be summarized by treatment group for each 
period between 2 consecutive visits, as well as for the period from the first dose of the double-
blind study interventions actually taken to the last dose of double-blind study intervention 
actually taken for the Safety Population.
10 Efficacy Analyses
10.1 Efficacy and Health Outcome Measures
10.1.1Efficacy Measures
A migraine day is defined as any calendar day on which a headache occurs which meets criteria 
A, B, and C OR meets criteria D and E, as listed below, as per participant eDiary. Calendar days 
begin at midnight and last until 11:59 PM (23:59). 
A. Headache has at least two of the following four characteristics:
i.
Unilateral location
ii.
Pulsating quality
iii.
Moderate or severe pain intensity
iv.
Aggravated by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs)
B. At least one of the following:
i.
Nausea and/or vomiting 
ii.
Photophobia and phonophobia 


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


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A triptan use day is defined as any day on which a participant reports intake of a triptan to treat a 
migraine per participant diary.
Headache day pain intensity is defined as the worst pain intensity on any headache day where 
headache pain intensity will be subjectively rated by the patient on a scale from mild to severe:

Mild pain (=1)

Moderate pain (=2)

Severe pain (=3)
If participants experience no headache in a day, then the corresponding pain intensity of that day 
will be set as missing.
10.1.2Health Outcome Measures
The AIM-D is an 11-item daily diary measure that assesses the impact of migraine and is 
comprised of two domains that evaluate performance of daily activities (7 items) and physical 
impairment (4 items). Participants are asked to rate the level of difficulty experienced in the past 
24 hours with performance of daily activities (i.e., difficulty with household chores, errands, 
leisure activities at home, leisure or social activities outside the home, strenuous physical 
activities, concentrating, and thinking clearly) and physical impairment (i.e., difficulty walking, 
moving body, bending forward, moving head) using a 6-point rating scale ranging from “Not 
difficult at all,” “A little difficult,” “Somewhat difficult,” “Very difficult,” “Extremely difficult,” 
and “I could not do it at all.” Three items include a response of “I did not…,” for example, “I did 
not have errands planned.” The AIM-D was developed as an electronic daily diary with the same 
set of questions administered in headache and non-headache versions. The Headache version is 
administered on days when a participant reports a headache and the Non-Headache version is 
administered on days when a participant does not report having a headache. The AIM-D instructs 
participants to answer each question based on the level of difficulty experienced in the past 
24 hours for both versions, with “during your headache” indicated for the AIM-D Headache 
version. In addition to the two domain scores, a total score using all 11 items can also be 
calculated. Each raw daily domain score, as well as the raw daily total score, are transformed to a 
0-100 scale, with higher scores indicating greater impact of migraine (i.e., higher disease 
burden).
Two items based on a 24-hour recall will be administered daily using Headache and 
Non-headache versions as additional health outcome measures and for evaluation of the AIM-D. 
The first item will be used to assess activity level within the past 24 hours with a 5-level 
response scale ranging from “No activity – Spent all day lying down” to “Exercised – Brisk 


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walk, running, jogging, biking or other activity for 30 or more minutes.” The second item will be 
used to evaluate activity limitation with a 5-level response scale ranging from “Not at all limited 
– I could do everything” to “Extremely limited”.
The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality-of-life 
impairments attributed to migraine in the past 4 weeks. It is divided into three domains: Role 
Function Restrictive assesses how migraines limit one’s daily social and work-related activities; 
Role Function Preventive assesses how migraines prevent these activities; and the Emotional 
Function domain assesses the emotions associated with migraines. Participants respond to items 
using a 6-point scale ranging from “none of the time” to “all of the time.” Raw dimension scores 
are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores 
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10.2 Primary Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline in mean monthly migraine days
across the 12-week treatment period. The primary null hypothesis is that atogepant treatment 
doses (atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg once a day) are each equally 
effective to placebo in mean change from baseline in mean monthly migraine days across the 12-
week treatment period. The alternative hypothesis is that at least 1 of the 3 doses of atogepant 
has a different effect than placebo. Baseline is defined as the number of migraine days during the
last 28 days prior to the randomization date.
10.2.1Primary Analysis 
The endpoint will be analyzed using a mixed model for repeated measures (MMRM). The 
response variable is the change from baseline to each postbaseline month in monthly migraine
days. The model will include treatment group, visit (derived as month), prior exposure (yes/no) 
to a migraine prevention medication with proven efficacy, and treatment group by visit 
interaction as categorical fixed effects. It will also include the baseline score and baseline-by-
visit interaction as covariates. The stratum “prior exposure (Yes/No)” will use the actual 
stratification factor from prior medication collected by eCRF. The analysis will be performed 
based on evaluable postbaseline data using only the observed cases without missing data 
imputation. Only data collected during the double-blind period will be included in the analysis.
Participants are always analyzed based on the treatment group assigned by randomization. 
Restricted maximum likelihood method will be used. The within-patient correlation will be 
modeled using the unstructured covariance matrix. If the model does not converge, then the
Toeplitz covariance structure will be used. if the model with the Toeplitz covariance structure 
does not converge, then the compound symmetry covariance structure will be used. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Contrasts will be constructed to obtain the average treatment effects across the 12-week 
treatment period to compare each atogepant treatment group versus the placebo group. Each


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treatment effect and treatment comparisons will be estimated by the LS Means and their 
differences in LS Means, along with their SE and 95% confidence intervals, and the p-value 
corresponding to the between-treatment group difference. The sample SAS code is given as 
follows
The impact of dropouts on the primary efficacy measure will be explored graphically by plotting 
the response profiles by the dropout reason. Plot of mean change from baseline in the number of 
migraine days versus visit (month) based on the observed cases will be provided in each 
treatment group by major reason of early termination, such as, adverse events, lack of efficacy, 
withdrawal of consent, lost to follow-up, etc. Similar plot for completers in each treatment group 
will be provided as a reference.
10.2.2Sensitivity Analysis for Possible Violation of Normality Assumption


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10.2.3Sensitivity Analyses in Missing Data Handling
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
The response variable for the ANCOVA model is the change from baseline in the 3-month 
average of the monthly migraine days for each participant. The ANCOVA model includes terms 
for treatment, prior exposure (yes/no) to a migraine prevention medication with proven efficacy, 
and baseline score. The treatment difference for atogepant doses versus placebo will be estimated 
and reported along with the corresponding 95% CI and nominal p-value for superiority testing. 
This analysis was recommended by FDA at the End of Phase 2 meeting and termed as supportive 
analysis. There are no missing data based on this derivation because patients who discontinued 
the treatment are assumed to maintain the same mean (observed while on treatment) for 
3 months (12 weeks).
Within-group Imputation Based on Observed Data 
Sensitivity analysis will be performed based on imputation using participants from the same 
treatment group with observed data under the MAR assumption. The details of imputation are as 
follows




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MMRM Based on Primary Measures Collected during the Double-blind and Follow-up 
Periods
The details for this analysis are provided in Section 10.5. 
 
 
10.3 Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the United States and the EU are as follows:

Change from baseline in mean monthly headache days across the 12-week treatment 
period.

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period.

≥50% reduction in 3-month average of monthly migraine days 

Change from baseline in MSQ v2.1 Role Function Restrictive domain score at Week 12.

Change from baseline in mean monthly Performance of Daily Activities domain score of 
the AIM-D across the 12-week treatment period.

Change from baseline in mean monthly Physical Impairment domain score of the AIM -D 
across the 12-week treatment period.
The secondary endpoints for headache days, acute medication use days, Performance of Daily 
Activities domain score of the AIM-D, and Physical Impairment domain score of the AIM-D
will be analyzed in the same manner as that used to analyze the primary endpoint. For MSQ v2.1 
Role Function Restrictive domain score, the analysis will be performed similarly to the primary 
MMRM, with focus on the pairwise contrasts of each dose group to placebo at Week 12. Week 


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16 (follow-up visit) data for MSQ v2.1 Role Function Restrictive domain score will not be 
included in MMRM analysis, and only summary statistics for Week 16 will be provided. The
corresponding sample SAS code is given as follows
The 50% responder, defined as a participant with at least a 50% reduction from baseline in the 3-
month average of monthly migraine days, will be assessed for each individual. A logistic 
regression model will be used to analyze the 50% responders across the 12-week treatment 
period. This model assumes a binary distribution for the response and uses a logit link. The 
analysis model will include treatment group, prior exposure (yes/no) to a migraine prevention 
medication with proven efficacy, and baseline monthly migraine days. The treatment difference 
in terms of odds ratio between each atogepant dose group and placebo will be estimated and 
tested from this model. The sample SAS is given as follows


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10.4 Additional Endpoints 


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10.5 Off-treatment Hypothetical Estimand 
This section defines an estimand
Per study design (Protocol Sections 8.4.3.1 and 8.8), eDiary data will be collected for 
participants who early terminated from the double-blind treatment period during the 4 weeks 
between V7 (Early termination visit) and V8 (Follow-up Visit), i.e., participants who prematurely 
discontinued (before Week 12) will continue to complete eDiary efficacy assessments while off-
treatment.
10.5.1Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-blind treatment period. 
In addition, permissible and prohibited mediations are described below:

Participants are allowed to take acute migraine medications (Protocol Section 4.4.1) to 
keep the participants in the study.  

The protocol prohibits patients from starting any new migraine preventive treatments 
(Protocol Section 4.4.2) during the study (including the double-blind treatment period and 
the follow-up period).


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10.5.2Population
The target population is patients suffering from migraine with aura or migraine without aura 
satisfying the inclusion and exclusion criteria as specified in Section 4 of protocol.
The analysis population for off-treatment hypothetical estimand is defined to be all randomized 
participants who received at least 1 dose of study treatment, had an evaluable baseline period of 
eDiary data and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 
12) of eDiary data, regardless of whether on study treatment or off study treatment. 
On 
study treatment is from the first dose till the last dose of study intervention. As the analysis-visit 
mapping window (Table 17–2) is defined for the entire postbaseline period (not limited to the 
double-blind treatment period for participants who prematurely discontinued), the number of 
participants in the analysis population for off-treatment hypothetical estimand is expected to be 
greater than or equal to the number of participants in the mITT Population.  
10.5.3 Variable
The variable is the same as the primary efficacy endpoint defined in Section 10.2, which is the 
change from baseline in the participant’s mean monthly (4-weeks) migraine days across the 
12-week treatment period as derived from the eDiary data.
10.5.4 Accounting of Intercurrent Events
Intercurrent events and their handling rules are as follows:

Participants who started a new migraine prophylaxis treatment during the double-blind 
or safety follow-up period will have their data during the follow-up period after 
starting the new migraine prophylaxis treatment excluded from the analysis.

Participants who discontinue study treatment due to all reasons other than starting a 
new migraine prophylaxis treatment will have their data collected after discontinuation 
of study treatment, and those off-treatment data will be included in the analysis.
If a participant provides less than 14 days of efficacy data during a monthly period regardless in 
the double-blind treatment period or the follow-up period, then he/she is considered to have 
missing data during that monthly period. When a participant provides at least 14 days of efficacy 


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data during a monthly period, he/she is considered to have efficacy data during that monthly 
period.
As the protocol prohibits participants from starting any new prophylaxis treatment until the study 
is completed. Only a limited number of participants as protocol deviators might take new 
prophylaxis treatment during the study. The criteria for identifying the participants who started a 
new migraine prophylaxis treatment are described in Section 17.11.
10.5.5 Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between each atogepant group and placebo.
Participants are always analyzed based on their treatment assignment by randomization. To 
obtain the estimate of treatment effect defined in the off-treatment hypothetical estimand, an 
MMRM similar to the primary analysis specified in Section 10.2.1 will be performed on 
observed data collected from both double-blind treatment period and follow-up period. The 
model terms include treatment group, visit (derived as month), prior exposure (yes/no) to a 
migraine prevention medication with proven efficacy, treatment- by-visit interaction, the baseline 
score and baseline-by-visit interaction.
10.5.6 Off-treatment Hypothetical Estimand Approach for the Secondary 
Endpoints
Continuous secondary endpoints based on eDiary data will be handled using the same estimand 
approach defined above for the primary endpoint.
The secondary endpoint of 50% responders are derived at least a 50% reduction from baseline in 
the 3-month average of monthly migraine days using data collected from the double-blind period 
and follow-up period. Data after participants started a new prophylaxis treatment during the 
follow-up period will be excluded. The population-level summary for this endpoint is the odds 
ratio from a logistic regression for each atogepant group relative to placebo with baseline 
monthly migraine days as a covariate, prior exposure (yes/no) to a migraine prevention 
medication with proven efficacy and treatment group as fixed factors.
The graphical approach to control the overall Type I error rate described in Section 10.3 will be 
provided for primary and key secondary endpoints in the analysis population for off-treatment 
hypothetical estimand.


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11 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 clinical laboratory, vital sign, and ECG, the last non-missing safety assessment 
before the first dose of treatment will be used as the baseline for all analyses of that safety 
parameter. Continuous variables will be summarized by 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 dose of 
double-blind study treatment. An AE that occurs more than 30 days after the last dose of double-
blind study treatment or Visit 8 whichever comes later will not be counted as a TEAE. Per case 
report form instructions, a new AE record will be created for any AE that worsens; therefore,
TEAEs can be identified as those AEs captured in Study 3101-301-002 with recorded onset date 
on or after the date of the first dose of double-blind study treatment and within 30 days after the 
last dose of double-blind study treatment or Visit 8 whichever comes later. 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 study treatment will be considered as newly 
emergent.  
Only AEs captured in Study 3101-301-002 will be considered for TEAEs in this study. For 
participants rolling over into Study 3101-309-002 (extension study) who start the first dose on 
Visit 1 or beyond, AEs captured in Study 3101-309-002 will be summarized in that study 
although some AEs might occur within 30 days after the last dose from Study 3101-301-002.
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 treatment discontinuation.
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term, and further categorized by severity to the 
study treatment. 


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The number and percentage of participants reporting treatment-related TEAEs in each treatment 
group will be tabulated by system organ class and preferred term.
The number and percentage of participants reporting newly emergent TEAEs in each treatment 
group will be tabulated by system organ class and preferred term.
The number and percentage of participants who have TEAEs leading to treatment 
discontinuation will be summarized by system organ class, preferred term and treatment group.
The incidence of common (≥ 2% of participants in any treatment group) TEAEs will be 
summarized by preferred term, and treatment group. A similar 5% table will be provided as well. 
The number and percentage of participants who have TESAE in each treatment group will be 
tabulated by system organ class and preferred term.
In addition, separate tabular displays will be presented for patients who died, participants with 
SAEs, and participants with TEAEs leading to treatment discontinuation.
11.2 Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline, postbaseline, and 
changes from baseline values at each postbaseline timepoint will be presented by treatment 
group for the following laboratory parameters:
Hematology:
Hemoglobin, hematocrit, red blood cell count, red blood cell 
indices (mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration), 
white blood cell count, 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, eGFR
Urinalysis:
Specific gravity, pH
In addition, descriptive statistics for values and changes from the baseline values in conventional 
units at each assessment time point will be presented for selected clinical laboratory parameters 


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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.
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 normal range for 
eGFR was not collected in the lab. Therefore, eGFR<60 mL/min/1.73m2 is defined in Table 11–2
to classify renal function as the category of “Moderate eGFR Decrease or Worse” based on FDA 
guidance on PK studies in Patients with impaired renal function. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated by treatment 
group. The percentages will be calculated relative to the number of participants with available 
non-PCS baseline values and at least 1 postbaseline assessment for the double-blind treatment 
period. The numerator will be the total number of participants with available non-PCS baseline 
values and at least 1 PCS postbaseline value during the study. A supportive tabular display of 
participants with PCS postbaseline values will be provided, including the PID number, baseline 
and all postbaseline (including non-PCS) values.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
Shift tables from baseline to end of the double-blind treatment period for clinical laboratory 
parameters will be presented by treatment group for the following categories: low, normal, and 
high, which are provided by the laboratory vendor.
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline 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. Potential Hy’s Law criteria without time 
window is defined by maximum of post baseline elevation of ALT or AST ≥ 3 x ULN, along with 
maximum of post baseline elevation of TBL ≥ 2 x ULN. Patients who meet the potential Hy’s 
Law criteria from the first dose of study drug to the end of study will be summarized. Supportive 
tabular displays will also be provided.
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


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Table 11–1
Criteria for Potentially Clinically Significant Laboratory Values
PCS Criteria
Category
Parameter
SI Unit
PCS Low
PCS High
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.6 × ULN
Creatinine
μmol/L
—
> 1.5 × ULN
Creatine kinase
U/L
—
> 2.0 × ULN
Estimated glomerular filtration rate
mL/min/1.73m2
< 60
—
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 2.0 × ULN
Lactate dehydrogenase (LDH)
U/L
—
> 3.0 × ULN
Phosphorus
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Triglycerides
mmol/L
—
> 2.0 × 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).
eGFR<60 mL/min/1.73m2 indicates moderate eGFR decrease or worse.
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 by 
treatment group. The percentages will be calculated relative to the number of participants with at 
least 1 available postbaseline assessment. The numerator will be the total number of participants 
having at least 1 postbaseline value that meets the specific category during the study. A 
supportive listing will also be provided.


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Table 11–2
Criteria for Hepatic Laboratory Abnormalities
Laboratory Parameter
Categories
ALT
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT or AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Bilirubin Total
≥1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Alkaline Phosphatase
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Concurrent Elevations1
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 1.5 × ULN
ALT or AST >= 3 × ULN and Bilirubin Total ≥ 2 × ULN
Potential Hy’s Law1
ALT or AST ≥ 3 × ULN and Bilirubin Total ≥ 2 × ULN and ALP 
< 2 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ALP = alkaline phosphatase; 
ULN = upper limit of normal (value provided by the laboratory).
1 Elevations are from the same day


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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 by treatment group and by relationship of ALT or AST 
elevation to study medication. The percentages will be calculated relative to the number of 
participants with at least 1 adjudicated case. The numerator will be the number of participants 
with at least 1 adjudicated case in the specific category of relationship. If a participant has more 
than 1 adjudicated case, he or she will be counted in the most relevant category of relationship.
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. A listing of 
urine pregnancy test results will be provided for female participants of child-bearing potential 
with at least one positive result. 
11.3 Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressures [sitting and standing], 
pulse rate [sitting and standing], respiratory rate, temperature, weight, orthostatic systolic blood 
pressure, orthostatic diastolic blood pressure, and orthostatic pulse rate) values at baseline, 
postbaseline, and changes from baseline values at each postbaseline timepoint will be presented 
by treatment group. Orthostatic vital sign values (orthostatic systolic and diastolic blood 
pressures, and orthostatic pulse rate) are defined as the corresponding standing measurement 
minus sitting measurement of systolic and diastolic blood pressures and pulse rate respectively.
Vital sign values will be considered PCS if they meet both the observed value criterion and the 
change from baseline value criterion, if both criteria are available, or meet either the observed 
value criterion or the change from baseline value criterion that will be detailed in Table 11–3. 
The number and percentage of participants who have PCS postbaseline vital sign values will be 
tabulated by treatment group. 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 


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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 Electrocardiograms
Descriptive statistics for ECG parameters (i.e., heart rate, PR interval, QRS interval, RR interval,
QT interval, and QTc interval) at baseline, postbaseline, and changes from baseline values at 
each postbaseline timepoint will be presented by treatment group.
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 by study treatment. 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.


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AddTableTitle
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.
To evaluate ECG postbaseline values of clinical interest, the number and percentage of 
participants with post-treatment QTcF > 450 msec, > 480 msec, and > 500 msec will be 
tabulated by treatment group.
The number and percentage of participants with an increase > 30 msec but ≤ 60 msec, and with 
an increase > 60 msec in QTcF will be tabulated. Participants will be counted only once for the 
most severe category. A supportive listing of participants with postbaseline QTcF increases 
> 30 msec will be provided, including the PID number, study center, and all QTc values 
(including changes from baseline). A listing of all AEs for participants with postbaseline QTcF 
increases > 30 msec will also be provided.
A shift table from baseline to the end of double-blind treatment period in the investigator’s 
overall interpretation of the ECG will be presented by treatment group for the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant. A 
tabular display of participants with postbaseline clinically significant ECG abnormalities 
according to the investigator’s overall interpretation will be provided.
11.5 Columbia-Suicide Severity Rating Scale
For C-SSRS, the number and percentage of participants with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS will be summarized by treatment group for the Safety 
Population. The distribution of responses for most severe suicidal ideation and most severe 
suicidal behavior in the participant’s lifetime history, in the past 6 months, in the double-blind
treatment period, and in the follow-up period will also be presented by treatment group. 
Supportive listings will be provided and will include the PID number, study center number, 
treatment group, lifetime history, and postbaseline values. Intensity of suicidal ideation and 
suicidal behavior type will also be included in these listings.  


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12 Health Outcome Analyses
Health outcomes which are planned to be reported in CSR main body are provided in 
Section 10.4.  Other health outcome analyses are documented in health economics and outcomes 
research SAP.  
13 Subgroup Analyses
Subgroup analysis based on prior exposure (yes/no) to a migraine prevention medication with 
proven efficacy will be performed for the following efficacy endpoints

Change from baseline in mean monthly migraine days across the 12-week treatment 
period

Change from baseline in mean monthly headache days across the 12-week treatment 
period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

≥ 50% reduction in 3-month average of monthly migraine days

≥ 75% reduction in 3-month average of monthly migraine days

100% reduction in 3-month average of monthly migraine days
Subgroup analyses for primary efficacy endpoint based on demographic factors (age, sex, race) 
will be provided in the integrated summary of efficacy to facilitate the comparison across pivotal 
studies.


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14 Interim Analysis
No interim analysis is planned.


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15 Determination of Sample Size
A total sample size of 218 participants will be randomized per treatment group and that will 
provide at least 98% power to detect the treatment difference between each of the 3 atogepant 
doses (assumed equally effective) and placebo for the primary efficacy endpoint. The sample size 
of this study was selected to provide sufficient power for the primary efficacy endpoint and first 
3 secondary endpoints as shown in Table 15–1. The power calculations are performed by using
nQuery Advisor 7.0 and based on the following assumptions:
1) The treatment difference from placebo will be similar to the average value across the migraine 
prevention studies for atogepant (Phase 2/3 Study CGP-MD-01), telcagepant (Ho 2014) and 
monoclonal antibodies (Dodick 2014a; Dodick 2014b; Bigal 2015). The standard deviation of 
each endpoint was estimated from an internal study that randomized approximately 
800 participants. In particular, the assumed treatment difference from placebo in change from 
baseline in mean monthly migraine days across the 12-week treatment period is 
assumed -1.5 days, and the standard deviation is 3.5 days. Detailed treatment difference and 
standard deviation assumptions are listed in Table 15–1.
2) The study statistical testing plan controls the overall type 1 error at 5%. The power 
calculations of the primary and secondary endpoints have taken the multiple comparisons into 
consideration by testing each dose versus placebo at a 0.0167 significance level, 2-sided. Once 
the primary endpoint for each dose is significant at 0.0167 (2-sided), the secondary endpoints
will be tested sequentially. 
Table 15–1
Statistical Power for Primary and the First Three Secondary Endpoints
Hypothesis 
Testing
Endpoint
Treatment 
Difference from 
Placebo
Standard 
Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across the 
12-week treatment period
–1.5
3.5a
98%
Secondary 1
Change from baseline in mean 
monthly headache days across the 12-
week treatment period
–1.5
3.8a
95%b
Secondary 2
Change from baseline in mean 
monthly acute medication use days 
across the 12-week treatment period
–1.2
3.2a
93%b
Secondary 3
Proportion of participants with at least 
a 50% reduction in mean monthly 
migraine days across the 12-week 
treatment period
33% Placebo rate
50% Atogepant 
rate
89%b
a
Standard deviations observed in an internal study that randomized approximately 800 participants
b
Statistical power for secondary endpoints are conditional on success of prior endpoints (assuming independence 
among the endpoints) in the sequence for the comparisons of each dose versus placebo.


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16 Statistical Software
Statistical analyses will be performed using 
 SAS.


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17 Data Handling Convention
17.1 Visit Time windows
For analysis purposes, Day 1 is defined on the date of the first dose of double-blind study 
intervention. On-treatment Period is defined to from the first dose till the last dose.


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17.2 Derived Efficacy and Health Outcome endpoints
17.2.1 Derivation of Efficacy Endpoints Based on eDiary Data 
For analysis purposes, four weeks (28 days) will be considered as one month. On a daily basis 
during the 4-week baseline period and throughout the double-blind treatment period, participants 
are to record eDiary information on the duration of headache, headache specific characteristics 
and symptoms, the pain severity, and use of any acute headache pain medication. 
 


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17.2.2 Derivation of Health Outcome Endpoints 
If a participant reported multiple records on the same day and records are inconsistent, then the 
records on the date with discrepancy will be excluded from endpoint derivation and thus 
excluded from the analyses. The corresponding records will be flagged in the analysis datasets.
AIM-D Related Endpoints Derivation
As described in SAP Section 10.1.2 (copied from protocol Section 6.2.1), the AIM-D was 
developed as a daily eDiary with a recall period 24 hours. By design, it is collected in the today 
diary only. The scoring of the following endpoints is completed in 2 steps.

Monthly Performance of Daily Activities domain score of the AIM-D

Monthly Physical Impairment domain score of the AIM -D

Monthly AIM -D total score
Step 1: Calculate AIM-D daily domain score and total score
Daily performance of daily activities score will be calculated based on the summation of items 
1-5 and 10 and 11, ranging from 0-35. A daily performance of daily activities domain score will 
be calculated if 4 or more item scores have non-missing responses. When the response category 
“I did not have <errands, leisure or social, strenuous activities> planned” (items 2, 4, and 5), is 
selected, the response will be considered missing. The corresponding performance of daily 
activities domain score will be calculated by summing the non-missing item scores and dividing 
by the number of non-missing items and then multiplying by 7, provided that 4 or more item 
scores are available; otherwise it will be set to missing. The raw daily score will be transformed 
to a 0-100 scale by multiplying by 100 and dividing by the highest raw score (35).
Daily physical impairment scores will be calculated based on the summation of items 6-9, 
ranging from 0-20. A daily physical Impairment score will be calculated if 2 or more item scores 
have non-missing responses. The corresponding physical Impairment score will be calculated by 
summing the non-missing item scores and dividing by the number of non-missing items and then 
multiplying by 4, provided that 2 or more item scores are available; otherwise it will be set to 
missing. The raw daily score will be transformed to a 0-100 scale by multiplying by 100 and 
dividing by the highest raw score (20).
A daily total score will be calculated based on the summation of items 1-11, ranging from 0-55. 
A Total Score will be calculated if 6 or more items scores have non-missing responses.  When the 
response category “I did not have <errands, leisure or social, strenuous activities> planned” 
(items 2, 4, and 5), is selected, the response will be considered missing. The corresponding Total 


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Score will be calculated by summing the non-missing item scores and dividing by the number of 
non-missing items and then multiplying by 11, provided that 6 or more item scores are available; 
otherwise it will be set to missing. The raw score will be transformed to a 0-100 scale by 
multiplying by 100 and dividing by the highest raw score (55).
Step 2: Calculate Monthly Scores and Baseline Score
Monthly scores will be calculated using the average daily scores only if there are at least 14
non-missing daily scores in the corresponding monthly (28-day) period. The corresponding 
monthly scores will be calculated by summing the non-missing daily domain scores and dividing 
by the number of non-missing daily domain, provided that 14 or more daily scores are available; 
otherwise it will be set to missing.  
Monthly activity level score will be calculated by summing the non-missing daily scores and 
dividing by the number of these scores, provided that 14 or more daily scores are available in the 
corresponding monthly (28-day) period; otherwise it will be set to missing.  Same rule will be 
applied to the calculation of monthly activity limitation score.
MSQ Related Endpoints Derivation
MSQ v2.1 consists of 14 items with a 4-week recall period. The scoring of the MSQ is 
completed in following 3 steps. 
Step 1: Final item value assignment.
Precoded item values and final item values for each MSQ item response are shown in 
Table 17–12.
Table 17–12
Item Values for MSQ Item Responses
Response Categories
Precoded Item Value
Final Item Value
None of the time
1
6
A little bit of the time
2
5
Some of the time
3
4
A good bit of the time
4
3
Most of the time
5
2
All of the time
6
1
Step 2: Computation of raw domain(dimension) scores


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Once a final item value has been assigned to each item, a raw score can be computed for 
each MSQ domain. Role Function Restrictive domain includes Items 1 - 7, Role Function 
Preventive domain includes Items 8 - 11, and Emotional Function domain includes Items 
12 - 14. The raw score for each domain is the algebraic sum of the final item values for 
all items in that domain. 
Missing data handling: if a respondent answered at least half of the items in a domain (or 
half plus one in the case of scales with an odd number of items), a missing item value can 
be estimated using the average of the other completed items within the same dimension.
In detail, for MSQ v2.1 Role Function Restrictive domain, the 7 individual item 
responses using final item value will be summed, resulting in the raw domain score 
ranging from 7 to 42 with higher scores indicating better quality of life. If there are 
missing item responses, the raw domain score will be calculated by summing the non-
missing item responses using final item value and dividing by the number of non-missing 
items and then multiplying by 7 provided that 4 or more items in the domain are 
completed; otherwise it will be set to missing. For MSQ v2.1 Role Function Preventive
and Emotional domains, the raw domain scores will be calculated similarly using final 
item value respectively. If there are missing item responses, the corresponding raw 
domain score will be calculated by summing the non-missing item responses using final 
item value and dividing by the number of non-missing items and then multiplying by the 
number of questions in that domain provided that 2 or more domain items are completed; 
otherwise it will be set to missing. 
Step 3: Linear transformation to a 0 to 100 scale.
The transformation formula for each MSQ 2.1 domain are listed below

Role Function -Restrictive: 
( ! "#$%&')∗)**
+,

Role Function-Preventive: 
( ! "#$%&-)∗)**
.*

Emotional Function:           
( ! "#$%&+)∗)**
),


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17.3 Repeated or Unscheduled Assessments of Safety Parameters
Baseline is defined as the last assessment made before the first dose of double-blind study
treatment. If a participant has 2 or more visits within the same window, the last visit with a non-
missing value will be used for summary over time unless specified otherwise. If end-of-study 
assessments are repeated or if unscheduled visits occur, the last non-missing postbaseline 
assessment will be used as the end-of-study assessment for generating summary statistics. 
However, all postbaseline assessments will be used for PCS value determinations, and all 
assessments will be presented in the data listings.


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17.4 Missing Date of the Last Dose of Study treatment
When the date of the last dose of the double-blind 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. 
17.5 Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of double-blind 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 double-blind 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.
17.6 Missing Causal Relationship to Study treatment for Adverse Events
If the causal relationship to the double-blind study treatment is missing for an AE that started on 
or after the date of the first dose of double-blind study treatment, a causality of yes will be 
assigned. The imputed values for causal relationship to double-blind treatment will be used for 
the incidence summary; the values will be shown as missing in the data listings.
17.7 Missing Date Information for Adverse Events
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., partly missing).
17.7.1 Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of double-blind
study treatment, the month and day of the first dose of double-blind 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 double-blind
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 double-blind study 
treatment, January 1 will be assigned to the missing fields
17.7.2 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


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17.7.3 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 double-blind study treatment, the day of the first dose of double-blind 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 
double-blind 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 double-blind 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 
double-blind 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 double-blind 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 double-blind study treatment, the date of 
the first dose of double-blind study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of double-blind study treatment, the stop 
date will be assigned to the missing start date
17.8 Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including rescue medications, incomplete (i.e., partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
17.8.1 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.
17.8.2 Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of double-blind
study treatment, the month and day of the first dose of double-blind 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 double-blind
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 double-blind study 
treatment, January 1 will be assigned to the missing fields
17.8.3 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
17.8.4 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 double-blind study treatment, the day of the first dose of double-blind 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 
double-blind 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 double-blind 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 
double-blind 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 double-blind study treatment, the 
first day of the month will be assigned to the missing day
17.8.5 Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
replace it with the last visit date in the imputations described below. If the imputed stop date is 
before the start date (imputed or nonimputed start date), the imputed stop date will be equal to 
the start date.
17.8.6 Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
treatment, the month and day of the last dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete stop date is before the year of the last dose of study treatment, 
December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study treatment, 
January 1 will be assigned to the missing fields


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17.8.7 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
17.8.8 Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
last dose of study treatment, the day of the last dose of study treatment will be assigned to the 
missing day

If either the year of the incomplete stop date is before the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
before the month of the date of the last dose of study treatment, the last day of the month will 
be assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
after the month of the date of the last dose of study treatment, the first day of the month will 
be assigned to the missing day
17.9 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.
17.10 Identifying Prior Exposure (yes/no) to a Migraine Prevention 
Medications with Proven Efficacy Based on Prior Medications Reported 
in eCRF
According to Appendix 12.3.1 in the protocol, a list of migraine-preventive medications with 
proven efficacy was identified by clinical team and coding team as shown in Table 17–14.  
If a participant has taken medications before the screening visit with preferred names in 
Table 17–14, and the prior medications are classified as “Migraine Prevention Medication” in the 
prior and concomitant medications eCRF, then the prior exposure to migraine prevention 
medications with proven efficacy will be “Yes” for this participant, otherwise, it is set as “No.”


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Table 17–14
List of Migraine-preventive Medications with Proven Efficacy


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17.11 Identifying Participants Who Took a New Migraine Prophylaxis 
Treatment with Proven Efficacy Based on Concomitant Medications 
Reported in eCRF for the Intercurrent Events Specified in the Off-
Treatment Hypothetical Estimand
To identify the participants who started a new migraine prophylaxis treatment as specified in 
Section 10.5.4 (Accounting of Intercurrent Events), the following criteria are used:
A participant has taken prophylaxis medications during the double-blind or follow-up period 
with preferred names in the Table 17–14, and the concomitant medications are classified as 
“Migraine Prevention Medication” in concomitant medications eCRF. 


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18 COVID-19 Related Analyses
To eliminate immediate potential hazards to participants and study staff due to the COVID-19 
pandemic while ensuring participant safety and maintaining data integrity, the protocol 
clarification letter and corresponding protocol amendment were sent to sites during the pandemic 
to allow remote visits (as described in the protocol Table 2 Schedule of Visits and Procedures for 
Visits Conducted Remotely Due to the COVID-19 Pandemic).
This section specifies analyses for evaluating the impact of COVID-19. 
18.1 Efficacy Evaluation
Efficacy Endpoints
Table 18–1 describes the collection devices for primary and key secondary endpoints. The 
primary endpoint and 5 key secondary endpoints are collected via eDiary according to protocol 
design. Minimal disruption is expected for these endpoints because participants are expected to 
complete eDiary at home and submit the responses every day. 
The endpoint, MSQ v2.1 Role Function Restrictive domain score at Week 12, will be collected 
using eTablet as one electronic patient reported outcome (ePRO) at site. The remote collection 
for this endpoint was in production starting from April 20,2020. Participants are required to 
complete the ePRO measures remotely at Visit 7 (Week 12) according to remote-visit procedure
(Table 4–2).
To evaluate the missing rate for this endpoint at Week 12, the number of participants who missed 
at least one ePRO assessment due to COVID-19 will be summarized at each visit in the mITT 
Population (efficacy analyses population).


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Table 18–1
Summary of Collection Devices for Primary and Key secondary endpoints 
Hypothesis 
Testing
Node
Endpoint
Collection 
device
Primary
P1
Change from baseline in mean monthly migraine days across the 12-week 
treatment period
eDiary
Secondary 1
S1
Change from baseline in mean monthly headache days across the 12-week 
treatment period
eDiary
Secondary 2
S2
Change from baseline in mean monthly acute medication use days across the 
12-week treatment period
eDiary
Secondary 3
S3
≥ 50% reduction in 3-month average of monthly migraine days 
eDiary
Secondary 4 
S4
Change from baseline in MSQ v2.1 Role Function Restrictive domain score at 
Week 12
eTablet
Secondary 5
S5
Change from baseline in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week treatment period.
eDiary
Secondary 6 
S6
Change from baseline in mean monthly Physical Impairment domain score of 
the AIM -D across the 12-week treatment period.
eDiary
Power and Sample Size Evaluation
The study achieved the last participants first visit on January 31, 2020.  A total of 910 patients 
were randomized, and the number of randomized participants exceeded the planned sample size 
872. It is expected the missing rate during the pandemic might be slightly higher than the 
missing rate before the pandemic. No big impact for the power and sample size calculation is 
anticipated. 
18.2 Safety and other evaluations
This section specifies analyses related to COVID-19 pandemic from the following aspects: 

Disposition

Study visit (missing entire visit due to COVID-19 or missing assessments due to COVID-19)

Protocol deviation 

Study drug disruption due to COVID-19

TEAEs related with COVID-19
Safety Population will be used for the planned analyses described above. The number of 
participants impacted by COVID-19 during the study will be summarized by treatment group 
and overall. In addition, the number of participants impacted by COVID-19 and their 
corresponding disposition status in the double-blind treatment period and the follow-up period
will be summarized respectively. 
The number of participants who missed at least one entire visit due to COVID-19 will be 
summarized by treatment group and overall. Furthermore, the number of participants who missed 


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at least one assessment due to COVID-19 will be summarized by assessment category 
(laboratory, C-SSRS, urine pregnancy test, vital signs, ECG, and ePRO) and overall. Similar 
summaries will be provided by visit.
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 corona virus infection or 
coronavirus test positive will be provided.
Supporting listings for the described analyses above will be provided.  


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19 Changes to Analyses Specified in Protocol
None.


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20 References
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, 
and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol
2015;14:1081–1090.
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009; 28:586-604.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: A 
framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat 2013; 23:1352–1371.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and 
efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the 
prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet 
Neurol. 2014 Sep;13(9):885-92.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, 
Kroll R, Kohrman B, Bargar R, Hirman J, Smith J; ALD403 study investigators. Safety and 
efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of 
frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 
trial. Lancet Neurol. 2014 Nov;13(11):1100-7. 
Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, 
Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist 
telcagepant for migraine prevention. Neurology. 2014 Sep 9;83(11):958-66. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53:983-97.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data using 
multiple imputation in conjunction with robust regression. Biometrics. 2012 Dec;68(4):1250-9.
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York, NY: Wiley.


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APPENDIX I.
REPORTING SELECTED LABORATORY PARAMETERS IN
CONVENTIONAL UNIT


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Electronic Signatures
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Date
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14:23:57
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Document Originator Approval
26-Jun-2020
13:59:45
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Manager Approval
26-Jun-2020
21:58:07
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Manager Approval
26-Jun-2020
19:06:31
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Document Originator Approval