Clinical trial NCT04829747
Conditions: Chronic Migraine
Keywords: Chronic Migraine Migraine Atogepant AGN-241689
Sponsor: Allergan
Start date: 2021-08-02; Completion date: 2022-01-20
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Migraine is characterized by attacks of throbbing, moderate or severe headache, associated with nausea, vomiting, and/or sensitivity to light and sound. The main objective of the study is to evaluate how safe and effective the atogepant is in preventing chronic migraine in adult Chinese participants who completed study 3101-303-002. Adverse events will be monitored.

Atogepant is an investigational drug being developed to prevent chronic migraine. All participants will receive the same treatment. Approximately 120 adult participants who completed study 3101-303-002 will be enrolled at approximately 25 centers in China.

All participants will receive atogepant oral tablet once daily for 12 weeks.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Detailed description:

Arms: arm 1: Participants will receive fixed dose of Atogepant once daily for 12 weeks.
Interventions: intervention 1: Atogepant
Intervention descriptions: intervention 1: Oral Tablet

Protocol documents:
Prot_000.pdf: 


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The following information can be found on the Study Contacts Page: Name and contact 
information of sponsor study personnel and Emergency Telephone Numbers.


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


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Table of Contents
Title Page ........................................................................................................................................ 1
Table of Contents ............................................................................................................................ 4
List of Tables................................................................................................................................... 8
List of Figures................................................................................................................................. 8
Protocol Summary .......................................................................................................................... 9
1
Background and Clinical Rationale ........................................................................................ 15
1.1 Background....................................................................................................................... 15
1.2 Overview of Atogepant..................................................................................................... 15
1.3 Study Rationale................................................................................................................. 16
1.4 Rationale for Doses and Dose Regimens Selected ........................................................... 16
2
Study Objective and Clinical Hypothesis ............................................................................... 16
2.1 Study Objective................................................................................................................. 16
2.2 Clinical Hypothesis........................................................................................................... 17
3
Study Design........................................................................................................................... 17
3.1 Structure............................................................................................................................ 17
3.2 Data Safety Monitoring Board.......................................................................................... 18
3.3 Adjudication Committee................................................................................................... 18
4
Study Population and Entry Criteria....................................................................................... 18
4.1 Number of Participants ..................................................................................................... 18
4.2 Study Population Characteristics...................................................................................... 18
4.3 Inclusion Criteria .............................................................................................................. 19
4.4 Exclusion Criteria ............................................................................................................. 19
4.5 Permissible and Prohibited Medications/Treatments........................................................ 20
4.5.1
Permissible Medications/Treatments .................................................................... 20
4.5.2
Prohibited Medications/Treatments ...................................................................... 21
4.5.3
Definition of Women of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods......................................................................................... 22
4.5.4
Special Diet or Activities ...................................................................................... 23
4.6 Screen Failures.................................................................................................................. 23
5
Study Intervention................................................................................................................... 23
5.1 Study Intervention and Formulations................................................................................ 23


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5.2 Control Intervention.......................................................................................................... 23
5.3 Methods for Masking/Blinding......................................................................................... 23
5.4 Treatment Allocation Ratio............................................................................................... 24
5.5 Method for Assignment to Treatment Groups/Randomization......................................... 24
5.6 Treatment Regimen and Dosing ....................................................................................... 24
5.7 Storage of Study Intervention........................................................................................... 25
6
Response Measures and Summary of Data Collection Methods............................................ 25
6.1 Safety Measures................................................................................................................ 25
6.1.1
Adverse Events ..................................................................................................... 25
6.1.2
Adverse Events of Special Interest ....................................................................... 25
6.1.3
Clinical Laboratory Determinations ..................................................................... 26
6.1.4
Vital Signs............................................................................................................. 27
6.1.5
Physical Examination............................................................................................ 27
6.1.6
Electrocardiograms ............................................................................................... 27
6.1.7
Columbia-Suicide Severity Rating Scale (C-SSRS)............................................. 27
6.2 Efficacy Measures............................................................................................................. 28
6.2.1
Migraine Day ........................................................................................................ 28
6.2.2
Headache Day....................................................................................................... 29
6.2.3
Acute Medication Use Day and Triptan Use Day................................................. 30
6.3 Health Outcome Measures................................................................................................ 30
6.3.1
Activity Impairment in Migraine – Diary (AIM-D) ............................................. 30
6.3.2
Activity Level and Activity Limitation................................................................. 30
6.3.3
Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1)......... 31
6.4 Other Study Supplies ........................................................................................................ 31
6.5 Summary of Methods of Data Collection......................................................................... 31
7
Statistical Procedures.............................................................................................................. 32
7.1 Analysis Populations......................................................................................................... 32
7.2 Collection and Derivation of Efficacy Assessments......................................................... 32
7.2.1
Efficacy Variables ................................................................................................. 32
7.2.2
Health Outcome Variables .................................................................................... 33
7.3 Hypothesis and Methods of Analysis................................................................................ 33
7.3.1
Safety Analyses..................................................................................................... 33
7.3.2
Efficacy Analyses.................................................................................................. 34
7.4 Subgroup Analyses............................................................................................................ 34
7.5 Sample Size Calculation ................................................................................................... 34


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7.6 Interim Analyses ............................................................................................................... 34
8
Study Visit Schedule and Procedures...................................................................................... 34
8.1 Participant Entry Procedures............................................................................................. 34
8.1.1
Overview of Entry Procedures.............................................................................. 34
8.1.2
Informed Consent and Participant Privacy ........................................................... 35
8.2 Washout Intervals/Run-in ................................................................................................. 35
8.3 Procedures for Final Study Entry...................................................................................... 35
8.4 Visits and Associated Procedures...................................................................................... 36
8.4.1
Open-label Treatment Period (12 Weeks)............................................................. 36
8.4.1.1 Visit 1 (Day 1)........................................................................................... 36
8.4.1.2 Visits 2 and 3 (Week 4 and Week 8) ......................................................... 37
8.4.1.3 Visit 4/Early Termination (Week 12) ........................................................ 38
8.4.2
Safety Follow-up Period (4 Weeks)...................................................................... 39
8.4.2.1 Visit 5/End of Study (Week 16)................................................................ 39
8.5 Instructions for the Participants ........................................................................................ 39
8.6 Unscheduled Visits............................................................................................................ 39
8.7 Compliance with Protocol................................................................................................. 40
8.8 Early Discontinuation of Participants............................................................................... 40
8.9 Withdrawal Criteria........................................................................................................... 41
8.10
Study Termination................................................................................................. 42
9
Adverse Events ....................................................................................................................... 42
9.1 Definitions......................................................................................................................... 42
9.1.1
Adverse Event....................................................................................................... 42
9.1.2
Serious Adverse Event .......................................................................................... 43
9.1.3
Intensity................................................................................................................. 45
9.1.4
Assessment of Causality ....................................................................................... 46
9.1.5
Follow-up of Adverse Events and Serious Adverse Events.................................. 46
9.2 Procedures for Reporting Adverse Events ........................................................................ 47
9.3 Procedures for Reporting a Serious Adverse Event.......................................................... 47
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events........................ 47
9.4 Exposure to Study Intervention During Pregnancy .......................................................... 48
9.5 ALT or AST Elevations..................................................................................................... 48
9.5.1
Potential Hy’s Law Cases..................................................................................... 49
10 Administrative Items............................................................................................................... 50


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10.1
Protection of Human Participants......................................................................... 50
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations.............................................................................. 50
10.1.2 Compliance With IRB or IEC Regulations........................................................... 51
10.1.3 Compliance With Good Clinical Practice............................................................. 51
10.1.4 Compliance With Electronic Records; Electronic Signatures Regulations (US 
21CFR Part 11) ..................................................................................................... 51
10.2
Financial Disclosure.............................................................................................. 51
10.3
Changes to the Protocol ........................................................................................ 52
10.4
Data Protection...................................................................................................... 52
10.5
Participant Privacy................................................................................................ 52
10.6
Documentation...................................................................................................... 52
10.6.1 Source Documents ................................................................................................ 52
10.6.2 Case Report Form Completion ............................................................................. 54
10.6.3 Study Summary..................................................................................................... 54
10.6.4 Retention of Documentation................................................................................. 54
10.7
Labeling, Packaging, and Return or Disposal of Study Intervention ................... 55
10.7.1 Labeling/Packaging............................................................................................... 55
10.7.2 Clinical Supply Inventory..................................................................................... 55
10.7.3 Return or Disposal of Study Intervention and/or Supplies................................... 55
10.8
Monitoring by the Sponsor ................................................................................... 55
10.9
Handling of Biological Specimens ....................................................................... 55
10.10
Publications........................................................................................................... 56
10.11
Coordinating Investigator ..................................................................................... 56
11 References............................................................................................................................... 56
12 Attachments ............................................................................................................................ 58
12.1
Examination Procedures, Tests, Equipment, and Techniques............................... 58
12.1.1 International Classification of Headache Disorders, 3rd Edition ......................... 58
12.2
Examples of Prohibited Medications.................................................................... 76
12.3
Study Visits Conducted Remotely ........................................................................ 78
12.4
Glossary of Abbreviations..................................................................................... 80
12.5
Protocol Amendment 1 Summary......................................................................... 82


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List of Tables
Table 1.
Schedule of Visits and Procedures.................................................................. 13
Table 5-1.
Study Intervention........................................................................................... 24
Table 6–1.
Clinical Laboratory Parameters ...................................................................... 26
Table 12–1.
Remote Visits Schedule of Assessments (ie, Schedule of Visits and 
Procedures) ..................................................................................................... 79
List of Figures
Figure 1.
Study Diagram ................................................................................................ 12


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Protocol Summary
Study Compound: Atogepant
Phase: 3
Study Objective:
Safety and tolerability: To evaluate the safety and tolerability of treatment with atogepant 60 mg once daily over a 
12-week duration for the prevention of migraine in Chinese participants who completed Study 3101-303-002 
(chronic migraine [CM]). 
Efficacy: To evaluate the efficacy of treatment with atogepant 60 mg once daily when administered over 12 weeks 
for the prevention of migraine in Chinese participants with CM.
Clinical Hypotheses:
Atogepant 60 mg once daily is safe and well tolerated when administered over 12 weeks for the prevention of 
migraine in Chinese participants with CM who completed lead-in study 3101-303-002.
Study Design
Structure: Multicenter, open-label, 12-week, safety extension study conducted in China.
Duration: The study will consist of a 12-week treatment period, followed by a 4-week safety follow-up period, for a 
total duration of 16 weeks.
Study Intervention: Atogepant 60 mg once daily 
Control Intervention: Not applicable
Dosage/Dose Regimen: Atogepant 60 mg orally once daily will be administered for 12 weeks.
Randomization: Not applicable
Visit Schedule: After Visit 1, study visits will occur every 4 weeks during the 12-week treatment period. A safety 
follow-up visit will occur 4 weeks after the last dose of atogepant. For details, please see Table 1, the Schedule of 
Visits and Procedures.
Study Population Characteristics
Number of Participants/Sites:  All participants who complete Study 3101-303-002, and meet all eligibility 
requirements, may participate in this study.
Condition/Disease: Migraine with aura or migraine without aura (ICHD-3 Section 1.1 or Section 1.2; see 
Section 12.1.1)
Key Inclusion Criteria:

Eligible participants who completed the double-blind treatment period (Visit 7), and the safety follow-up period 
(Visit 8), if applicable, depending on the timing of study initiation, of Study 3101-303-002 without significant 
protocol deviations (eg, noncompliance to protocol-required procedures) and who did not experience an AE 
that, in the investigator’s opinion, may indicate an unacceptable safety risk


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Key Exclusion Criteria:

Participants requiring any medication, diet, or nonpharmacological treatment on the list of prohibited 
concomitant medications or treatments (see Section 4.5.2 and Attachment 12.2), that cannot be discontinued or 
switched to an allowable alternative. Concomitant medications with demonstrated efficacy for the prevention of 
migraine is exclusionary, except that participants from lead-in study 3101-303-002 taking 1 medication with 
demonstrated efficacy for the prevention of migraine may participate in the current study provided that the dose 
was stable prior to the lead-in study and the participant is willing to continue taking that medication.

Participants with an ECG indicating clinically significant abnormalities at Visit 1

Participants with hypertension (sitting systolic BP > 160 mm Hg or sitting diastolic BP > 100 mm Hg) at Visit 1

Participants with a significant risk of self-harm (C-SSRS), or of harm to others (investigator opinion); 
participants who report suicidal ideation with intent, with or without a plan, (ie, Type 4 or 5 on the C-SSRS) 
since the last visit, must be excluded

Participants with clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease
Response Measures
Safety—AEs, physical examinations, clinical laboratory determinations, vital sign measurements, ECG parameters, 
and the C-SSRS
Efficacy – The efficacy of atogepant for the prevention of migraine will be assessed based on information recorded 
by the participant. An eDiary will be used daily at home to collect data on headache duration, headache 
characteristics, non-headache migraine symptoms, and acute medication use, which will be collectively applied to 
define migraine days, and headache days per the criteria listed in Sections 6.2.1, 6.2.2 and 6.2.3.
General Statistical Methods and Types of Analyses: 
All safety analyses will be performed using the safety population, which consists of all participants who took at least 
1 dose of study intervention (atogepant) in this extension study. All efficacy analyses will be performed using the 
mITT population, consisting of all participants who received at least 1 dose of study intervention (atogepant) and 
had at least 1 evaluable post-baseline 4-week period of eDiary data, in this extension study. 
The safety parameters will include AEs, clinical laboratory evaluations, vital sign measurements, ECG parameters, 
and the C-SSRS. For each of the clinical laboratory, vital sign, and ECG parameters, the baseline value as defined 
for the lead-in study (3101-303-002) will be used as the baseline in this extension study. Continuous variables will 
be summarized by the number of participants and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants.
Efficacy endpoints include change from baseline in monthly migraine days, change from baseline in monthly 
headache days, at least a 50% reduction from baseline in monthly migraine days, and other endpoints. The baseline 
value as defined for the lead-in study (3101-303-002) will be used as the baseline in this extension study. For 
analysis purposes, 4 weeks (28 days) will be considered as 1 month. Descriptive statistics will be provided by visit 
for all efficacy endpoints based on the mITT population using the observed cases approach.


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Sample Size Calculation: 
Chinese participants who complete Study 3101-303-002, and meet all eligibility requirements, may participate in 
this extension study. Approximately 120 Chinese participants are expected to participate in this extension study.


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Figure 1.
Study Diagram
 
 
  
 
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.
Schedule of Visits and Procedures
Study Period
Open-label Treatment Period (12 weeks)
Safety 
Follow-up Period
(4 weeks)
Visit #
Visit 1a
Visit 2
Visit 3
Visit 4/ET
Visit 5/EOS
Week (Day)
Day 1
Week 4 (Day 28)
Week 8 (Day 56)
Week 12 (Day 84)
Week 16 (Day 112)
Visit Windows
N/A
± 3 days
± 3 days
± 3 days
± 3 days
Obtain informed consent and participant privacy
X
Access IWRS
X
X
X
X
X
Assess inclusion/exclusion criteria
X
Collect medical historyb
X
Perform physical examination
X
X
X
Collect vital sign measurementsc
X
X
X
X
X
Perform ECG
X
X
X
Perform urine pregnancy testd
X
X
X
X
X
Collect start date (first day) of last menstrual cycle for women 
having menstrual cycles
X
X
X
X
X
Clinical laboratory determinationse
X
X
X
X
X
eDiary instructions and trainingf
X
Participant eDiary data collectionf,g 
X
eDiary data (headache duration, frequency, characteristics and 
symptoms, acute medication use, AIM-D, Activity Level and 
Activity Limitation) and compliance reviewh
X
X
X
MSQ v2.1 (eTablet)i,j
X
X
X
X
X
C-SSRS (eTablet)k
X
X
X
X
X
Collect eDiary
X
Dispense atogepant
X
X
X
Review atogepant compliance and accountability
X
X
X
Adverse events
X
Concomitant medications/concurrent procedures
X


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a
After providing informed consent for this study, Visit 1 will be conducted on the same day as Visit 7/Visit 8 of the lead-in study (Study 3101-303-002 [Phase 3 CM]); 
procedures conducted as part of Visit 7 of the lead-in study should not be repeated.  Visit 1 must be conducted in office. All other visits, should be conducted in office unless it 
is necessary to conduct a remote visits for the safety of participants (eg, COVID-19 or other pandemic): for details please refer to the Remote Visit Schedule of Assessments in 
Attachment 12.3).
b
Medical history will be collected for participants who have a gap between the last visit of the lead-in study and Visit 1 of this extension study and only new medical history 
during the gap need to be collected.
c
Vital sign measurements: weight, sitting and standing pulse rate, respiratory rate, sitting and standing blood pressure, and body temperature.
d
For WOCBP only, a urine pregnancy test will be performed at all visits. 
e
Clinical laboratory determinations include chemistry, hematology, coagulation parameters (INR), and urinalysis to be collected for all visits. Samples for serology and the 
urine drug screen will be collected only at Visit 1.
f
Participants should begin using the eDiary at Visit 1 and for the duration of the treatment period. 
g
Daily eDiary data collection includes: headache frequency, duration, characteristics, symptoms, acute medication use, AIM-D, Activity Level, and Activity Limitation. 
h
Participants must bring their eDiary to all visits (except Visit 5). 
i
Participant will complete on eTablet.
j
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol. 
k
At all visits, the “Since Last Visit” C-SSRS will be completed for all participants. Clinicians will complete on eTablet.


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1
Background and Clinical Rationale
1.1 Background
According to the Guidelines for Prevention and Treatment of Migraine in China (Yu 2016), the 
prevalence of migraine in China is 9.3%, with a distribution across males and females similar to 
that of the United States. Migraine affects 18% of women and 6% of men in the United States
with peak prevalence occurring between the ages of 25 and 55 years. Approximately one-third of 
patients with migraines have 3 or more migraine attacks per month, and over half report severe 
impairment or the need for bed rest (Lipton 2007). In the United States alone, work loss due to 
migraine is estimated to cost ~ $13 billion annually (Hu 1999). Prevalence is similar in Europe, 
with migraine headache affecting on average 17.6% of women and 8% of men (Stovner 2010). 
Globally, migraine is the 3rd leading cause of years lived with disability with an estimated global 
prevalence of 14.1% (GBD 2016). 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. CM is 
a specific ICHD-3 diagnosis applied to a subset of patients with ≥15 headache days per month 
(Katsarava 2012; Olesen 2004; ICHD-3 2018). This study will evaluate the safety and 
tolerability of atogepant in participants with CM.
1.2 Overview of Atogepant
Atogepant is a potent, selective, oral CGRP receptor antagonist being developed for migraine 
prevention. Additional information on non-clinical pharmacology, toxicology, and PK properties 
of atogepant can be found in the investigator’s brochure. 


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A Phase 2/3 clinical study, CGP-MD-01, compared atogepant 10 mg once daily, atogepant 
30 mg once daily, atogepant 30 mg twice a day, atogepant 60 mg once daily, and atogepant 
60 mg twice a day to placebo. Overall, all the atogepant doses tested were well tolerated. For the 
primary efficacy endpoint of change from baseline in mean monthly migraine days across the 12-
week treatment period, all atogepant doses demonstrated a statistically significant reduction 
compared with placebo in patients with episodic migraine.
The ongoing global study 3101-303-002 to evaluate atogepant for the prevention of CM will 
further explore the dose range that demonstrated statistically significant improvement in the 
reduction of migraine compared to placebo in Study CGP-MD-01. Study 3101-303-002 will 
serve as the lead-in study for the current extension study.
1.3 Study Rationale
The purpose of this study is to evaluate the safety and tolerability of atogepant 60 mg once daily, 
as well as efficacy, when taken for 12 weeks for the prevention of CM.
1.4 Rationale for Doses and Dose Regimens Selected
The Phase 3 pivotal study to evaluate atogepant will test a maximum dose of 60 mg once daily. 
For this reason, the same dose of 60 mg once daily has been selected to evaluate the safety and 
tolerability of atogepant for the prevention of CM in this safety extension study.
2
Study Objective and Clinical Hypothesis 
2.1 Study Objective
Safety and Tolerability: To evaluate the safety and tolerability of treatment with atogepant 60 mg 
once daily over a 12-week duration for the prevention of migraine in Chinese participants who 
completed Study 3101-303-002 (CM).
Efficacy: To evaluate the efficacy of treatment with atogepant 60 mg once daily when 
administered over 12 weeks for the prevention of migraine in Chinese participants with CM.


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2.2 Clinical Hypothesis
Atogepant 60 mg once daily is safe and well tolerated when administered over 12 weeks for the 
prevention of migraine in Chinese participants with CM who completed lead-in study 3101-303-
002.
3
Study Design
3.1 Structure
This is a multicenter, open-label, 12-week, safety extension study conducted in China. 
Participants will be treated with atogepant 60 mg once daily. 
The study will consist of a 12-week treatment period and a 4-week safety follow-up period. 
After signing the informed consent, Chinese participants will directly rollover from Study 3101-
303-002 (Phase 3 CM); hereafter referred to as the lead-in study. As such, participants will have 
Visit 7 from the lead-in study function as Visit 1 for this extension study. After Visit 1, study 
visits will occur every 4 weeks during the 12-week treatment period. A safety follow-up visit 
will occur 4 weeks after the last dose of atogepant. 
Note, there may be participants who complete Visit 7 in the lead-in study before this extension 
study (3101-311-002) has been initiated. Those participants should complete Visit 7/ET and 
Visit 8/EOS Visit (including discontinuation of study intervention) per the lead-in study 
Schedule of Visits and Procedures.
Depending on the timing of the initiation of this extension study (3101-311-002) in relation to 
each participant’s planned Visit 8 schedule in the lead-in study, Visit 1 for this extension study 
can be conducted on the same day as Visit 8/EOS Visit for the lead-in study, or soon thereafter.

If this extension study is initiated prior to the participant’s planned Visit 8 in the lead-in 
study, then Visit 8/EOS Visit in the lead-in study should be conducted on the same day as 
Visit 1 for this extension study (3101-311-002).

If this extension study is not initiated prior to the participant’s planned Visit 8 in the lead-
in study (ie, there is a gap between Visit 8 of the lead-in study and Visit 1 of this 
extension study), then Visit 8/EOS Visit should be conducted as planned per the lead-in 
study Schedule of Visits and Procedures. When this extension study is initiated, the 
participant should return to the clinic as soon as possible, and Visit 1 should be conducted 
per Table 1 Schedule of Visits and Procedures.


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Participants will return to the clinic for safety assessments at 4, 8, and 12 weeks relative to Visit 
1 (Day 1). A safety follow-up visit will occur 4 weeks after the last dose of atogepant 60 mg once 
daily. For details, please see Table 1 Schedule of Visits and Procedures.
The primary objective of the study is to assess the safety and tolerability of treatment with 
atogepant 60 mg once daily over a 12-week duration for the prevention of migraine in Chinese 
participants who completed Study 3101-303-002. The planned safety assessments include 
collection of AEs, clinical laboratory determinations, ECGs, vital sign measurements, physical 
examinations, and the C-SSRS. 
3.2 Data Safety Monitoring Board
Not applicable
3.3 Adjudication Committee
An Adjudication Charter will be established and will describe the process for the surveillance, 
monitoring, and adjudication by an external Clinical Adjudication Committee of events of post-
treatment elevations of ALT and/or AST ≥ 3 × ULN. The purpose of this charter will be to 
provide a standardized process for the adjudication of the events in order to determine whether 
the elevation was related to atogepant.
4
Study Population and Entry Criteria
4.1 Number of Participants
All participants who complete Study 3101-303-002, and meet all eligibility requirements, may 
participate in this study. Approximately 120 participants will be enrolled at approximately 25
centers in China. 
4.2 Study Population Characteristics
Participants eligible to participate in this study completed Visit 7, and Visit 8 if applicable, of 
Study 3101-303-002 without significant protocol deviations (eg, noncompliance to protocol-
required procedures), meet the inclusion criteria, and do not meet the exclusion criteria for this 
study.


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4.3 Inclusion Criteria
1. Written informed consent and participant privacy information (eg, written authorization 
for use and release of health and research study information) obtained from the participant 
prior to initiation of any study-specific procedures.
2. Eligible participants who completed the double-blind treatment period (Visit 7) and the 
follow-up period (Visit 8), if applicable, depending on the timing of study initiation, of 
Study 3101-303-002 without significant protocol deviations (eg, noncompliance to 
protocol-required procedures) and who did not experience an AE that, in the investigator’s 
opinion, may indicate an unacceptable safety risk.
3. Participants must be using a medically acceptable and effective method of birth control
during the course of the entire study, as defined in Section 4.5.3.
4.4 Exclusion Criteria
1. Requirement for any medication, diet (ie, grapefruit juice), or nonpharmacological 
treatment that is on the list of prohibited concomitant medications or treatments (see 
Section 4.5.2 and Attachment 12.2) that cannot be discontinued or switched to an 
allowable alternative medication or treatment. Participants from lead-in study 3101-303-
002 taking 1 medication with demonstrated efficacy for the prevention of migraine may 
participate in the current study provided that the dose was stable for at least 12 weeks 
prior to Visit 1 of the lead-in study and the participant is willing and able to maintain 
taking this medication at a stable dose and dosage regimen throughout the study.
2. Female participant is pregnant, planning to become pregnant during the course of the 
study, or currently lactating. Women of childbearing potential must have a negative urine 
pregnancy test at Visit 1.
3. An ECG with clinically significant abnormalities at Visit 1 as determined by the 
investigator.
4. Hypertension as defined by sitting systolic BP > 160 mm Hg or sitting diastolic 
BP > 100 mm Hg at Visit 1. Vital sign measurements that exceed these limits may be 
repeated only once.
5. Significant risk of self-harm based on clinical interview and responses on the C-SSRS, or 
of harm to others in the opinion of the investigator; participants must be excluded if they 
report suicidal ideation with intent, with or without a plan, (ie, Type 4 or 5 on the 
C-SSRS) since the last visit. 


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6. Any clinically significant hematologic, endocrine, cardiovascular, pulmonary, renal, 
hepatic, GI, or neurologic disease.
7. Participant has a condition or is in a situation which in the investigator's opinion may put 
the participant at significant risk, may confound the study results, or may interfere 
significantly with participation in the study.
8. Any medical or other reasons (eg, unlikely to adhere to the study procedures, keep 
appointments, or is planning to relocate during the study) that, in the investigator’s 
opinion, might indicate that the participant is unsuitable for participation in the study.
4.5
Permissible and Prohibited Medications/Treatments
4.5.1
Permissible Medications/Treatments
Medications that are not specifically prohibited in Section 4.5.2 are allowed, with the following 
clarifications and restrictions.
The following medications for the acute treatment of migraine are allowed during the study:

Any triptan

Any ergot derivative

Any opioid

Any other form of analgesic (including acetaminophen)

Any NSAID agent

Any antiemetic agent
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
SSRI or SNRI will be permitted, provided that treatment is stable for at least 60 days prior to 
screening (Visit 1) and continues without change in dose throughout the study.
Therapy considered necessary for the participant's welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/treatment is in question, please contact 
the sponsor.


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4.5.2
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to Visit 1 (unless otherwise indicated) 
and throughout the study (see Attachment 12.2):

Strong CYP3A4 inhibitors, including but not limited to: systemic (oral/IV) itraconazole, 
ketoconazole, erythromycin, clarithromycin, telithromycin, nefazodone, and HIV 
protease inhibitors

Strong and moderate CYP3A4 inducers, including but not limited to: barbiturates (eg, 
phenobarbital and primidone), systemic (oral/IV) glucocorticoids, nevirapine, efavirenz, 
pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and St. John’s wort

Strong OATP1B1 and OATP1B3 inhibitors (eg, gemfibrozil, cyclosporine)

Drugs with narrow therapeutic margins with theoretical potential for CYP drug 
interactions (eg, warfarin)

Medications with demonstrated efficacy for the prevention of migraine (eg, amitriptyline, 
topiramate, propranolol), excepting 1 medication with demonstrated efficacy for the 
prevention of migraine taken at a stable dose during lead-in study 3101-303-002, which 
may be continued if the participant is willing and able to do so (see Exclusion Criterion 1, 
Section 4.4). 

CBD oil

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, Botox®, Xeomin®, 
Myobloc®, Jeuveua™) into areas of the head, face, or neck within 6 months prior to Visit 
1 and throughout the study period

Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™,
Emgality™, Ajovy®, Vyepti™) within 6 months prior to Visit 1 and through the study 
period.

Herbal and traditional medicine is prohibited from the time the ICF is signed and for the 
duration of study participation.
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, the sponsor should be notified before 
the prohibited medication/treatment is administered.


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4.5.3
Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For purposes of this study, women will be considered of childbearing potential unless they are 
naturally postmenopausal (ie, no menses for 2 years) or permanently sterilized (ie, bilateral tubal 
ligation, bilateral tubal occlusion, bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy). For women of child-bearing potential who may participate in the study, the 
following methods of contraception, if properly used, are generally considered highly effective:

Combined (estrogen and progestogen containing) hormonal contraception such as oral, 
intravaginal, or transdermal (ie, pill, vaginal ring, patch)

Progestogen-only hormonal contraception (with inhibition of ovulation) that is oral, 
injectable, or implantable

IUD or IUS

Vasectomized partner (provided that the partner is the sole sexual partner of study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success)

Sexual abstinence (defined as refraining from heterosexual intercourse for the duration of 
the study)
Acceptable birth control methods which may not be considered as highly effective:

Progestogen-only oral hormonal contraception (where inhibition of ovulation is not the 
primary mode of action)

Male or female condom with or without spermicide (female and male condoms should 
not be used together)

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 


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abstinence. Male participants must also refrain from donating sperm during the course of the 
study.
The investigator and each participant will determine the appropriate method of contraception for 
the participant during participation in the study.
If a woman becomes pregnant during the study, the investigator will notify the sponsor
immediately after the pregnancy is confirmed and the participant will be discontinued from the 
study after appropriate safety follow-up. The investigator will (1) notify the participant’s 
physician that the participant was being treated with atogepant and (2) follow the progress of the 
pregnancy. The investigator must document the outcome of the pregnancy and provide a copy of 
the documentation to the sponsor.
4.5.4
Special Diet or Activities
Participants should refrain from consuming grapefruit or grapefruit juice from the time the ICF is 
signed until completion of the study. Participants should also refrain from making significant 
changes to their diet or caffeine intake during the study.
Alcohol intake should be limited to no more than 1 drink per day throughout the study. A drink 
is defined as a 355 mL can/bottle of beer, a 118 mL glass of wine, or 30 mL of liquor.
4.6 Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently treated. 
5
Study Intervention
5.1 Study Intervention and Formulations
Tablets containing atogepant 60 mg (Formulation Number: 11281X)
5.2 Control Intervention 
Not applicable.
5.3 Methods for Masking/Blinding
This is an open-label study. 


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5.4 Treatment Allocation Ratio
All participants will be treated with atogepant 60 mg once daily.
5.5 Method for Assignment to Treatment Groups/Randomization
Prior to initiation of atogepant in this open-label extension study, each participant who provides 
informed consent will maintain their lead-in study participant number. This number will serve as 
the participant identification number on all study documents. 
At Visit 1, eligible participants will receive atogepant 60 mg once daily.
Before the study is initiated, log in information and directions for the IWRS will be provided to 
each site.
Atogepant will be labeled with kit numbers. The IWRS system will provide the site with the 
specific medication kit number(s) for each participant at Visit 1. Sites will dispense atogepant
according to the IWRS instructions. Sites will also log onto the IWRS at subsequent visits to
obtain a kit number for dispensing atogepant. Sites will receive the IWRS confirmation 
notifications for each transaction. All notifications are to be maintained with the study source 
documents.
Atogepant bottles will be dispensed at the study visits summarized in the Schedule of Visits and 
Procedures (Table 1). Returned atogepant bottles should not be re-dispensed to the participants.
5.6 Treatment Regimen and Dosing
Participants who meet all of the study entry criteria at Visit 1 will be treated with atogepant 60 
mg once daily.
Participants will be provided with atogepant to be taken on an outpatient basis. 
Participants will be instructed to take their atogepant at approximately the same time each day. 
Atogepant will be administered orally for 12 weeks, and participants will be followed for 4 
weeks following completion or discontinuation of the atogepant.
Table 5-1.
Study Intervention
Drug/Dose
Study Intervention Frequency
Route of Administration
Atogepant 60 mg
Once daily
Oral


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5.7 Storage of Study Intervention
Atogepant tablets must be stored at room temperature in a securely locked cabinet. Further 
details regarding the storage of atogepant are in the Study Reference Manual.
6
Response Measures and Summary of Data Collection Methods
6.1 Safety Measures
6.1.1
Adverse Events
Adverse events will be collected from the time of consent through the last visit. For all AEs, the 
investigator must provide an assessment of the severity, causal relationship to the study 
intervention, start and stop date, and seriousness of the event (eg, SAE), document all actions 
taken with regard to the study or control intervention, and detail any other treatment measures 
taken for the AE. For events noted as SAEs, the sponsor must be notified immediately to meet 
their reporting obligations to appropriate regulatory authorities.
6.1.2
Adverse Events of Special Interest
Selected non-serious and serious adverse events are of special interest and will require 
immediate reporting, recording, and follow-up. The following events will be closely monitored:

Treatment-emergent suicidal ideations with intent, with or without a plan, (ie, Type 4 or 5 on 
the C-SSRS) or any suicidal behaviors 

Treatment-emergent elevated ALT or AST laboratory value that is ≥ 3 x ULN

Potential Hy’s law cases: elevated ALT or AST laboratory value that is ≥ 3 x ULN and an 
elevated total bilirubin laboratory value that is ≥ 2 x ULN and, at the same time, an alkaline 
phosphatase laboratory value that is < 2 x ULN.
Reporting requirements for ALT or AST elevations and potential Hy’s law cases are outlined in
Sections 9.5 and 9.5.1. Responses to the C-SSRS that meet the above criterion will be captured 
in the eTablet and monitored by the sponsor. These AEs or events determined to be SAEs must 
be reported appropriately via the designated eCRFs and safety forms.


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6.1.3
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at the visits outlined in 
Table 1. Hematology, chemistry, INR, and urinalysis will be conducted at these visits. Serology 
and the urine drug screen will only be conducted at Visit 1. The investigator will assess the 
clinical significance of any values outside the reference ranges provided by the central 
laboratory. Participants with abnormalities judged to be clinically significant, laboratory values 
that meet withdrawal criteria (Section 8.9), or positive results on the urine drug screen at Visit 1 
will be excluded/withdrawn from the study. Women of childbearing potential will be required to 
have a urine pregnancy test at all visits. A positive pregnancy test at Visit 1 will exclude the 
participant from the study.
Investigators may also perform unscheduled clinical laboratory determinations at any time for 
the purpose of participant safety. 
Participants are not required to fast overnight before coming in for their appointments.
The clinical laboratory parameters to be measured are shown in Table 6–1.
Table 6–1.
Clinical Laboratory Parameters
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, lactate dehydrogenase, creatine kinase, total protein, 
albumin, calcium, phosphorus, uric acid, total cholesterol. The estimated 
glomerular filtration rate will be calculated by the central laboratory
Hematology
Hemoglobin, hematocrit, red blood cell count, red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration), white blood cell count, including differential 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils), platelet count
Urinalysis
Urine dipstick for specific gravity, pH, protein, glucose, ketones, bilirubin, and 
blood; microscopic examination including red blood cells/high-power field, white 
blood cells/high-power field, and casts/low-power field
Coagulation
INR
Serology
At Visit 1 only: anti-hepatitis A IgM antibody, hepatitis B surface antigen, 
anti-hepatitis C antibody, anti-hepatitis E IgM antibody
Urine Drug Screen
Screening for drugs of abuse (eg, marijuana, cocaine, phencyclidine, 
amphetamines, benzodiazepines, barbiturates, opiates) will be conducted using a 
urine drug screen at Visit 1. Those with a positive result on the Visit 1 urine drug 
screen for recreational (including marijuana regardless of legality) or illicit drugs 
or non-disclosed concomitant medications are not allowed to be repeated. For all 
other positive results, the urine drug screen may be repeated with permission 
from the sponsor; a negative result or an explanation of a positive result due to 
concomitant medication use (eg, opioids prescribed for migraine pain) will be 
required for study participation.
INR = International Normalized Ratio


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A central laboratory will be used to evaluate all urine and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory.
6.1.4
Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, and weight will be performed at every visit. Sitting and standing 
BP and pulse rate will be determined as follows: BP and pulse measurements will be performed 
after the participant sits quietly for 5 minutes, followed by a second set of measurements taken 
after the participant stands for at least 3 minutes (but no longer than 10 minutes).
6.1.5
Physical Examination
A complete physical examination will be performed at the visits outlined in Table 1. A 
professionally trained physician or healthcare professional licensed to perform physical 
examinations will examine the participant for any detectable abnormalities of the following body 
systems: general appearance; neck (including thyroid); head, eyes, ears, nose, and throat; lungs; 
heart/cardiovascular; abdomen; neurologic; extremities; back; musculoskeletal; lymphatic; skin; 
and other. The neurologic examination should be conducted to detect the presence of any 
significant sensory/motor abnormalities.
6.1.6
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in Table 1. All ECGs should be 
performed after the participant has been supine for at least 5 minutes. All ECGs performed will 
be saved as a source document. ECGs will be transmitted electronically to the central ECG 
laboratory for analysis according to the instructions provided by the laboratory to be centrally 
read by a cardiologist. The overall interpretation of the clinical significance of the ECG will be 
determined by the investigator and recorded in the participant’s eCRF.
6.1.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and 
behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific 
active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to 
act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active 
suicidal ideation with specific plan and intent). The C-SSRS also captures information about the 
intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons 
for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no 
suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), 


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and 4 (actual attempt). More than 1 classification can be selected provided they represent 
separate episodes. For actual attempts only, the actual or potential lethality is classified for the 
initial, most lethal, and most recent attempts. The C-SSRS will be completed at all study visits. 
At all visits the C-SSRS will be completed for ideation and behavior since last visit for all 
participants. The C-SSRS will be completed on the eTablet by the investigator or designee with 
current and valid training in administering the assessment. A participant should not be released 
from the study center until the results of C-SSRS are reviewed and it is confirmed that the 
participant is not considered to be at risk. Participants who reply with “yes” to questions 4 or 5 in 
the suicidal ideation section or “yes” to any question in the suicidal behavior section of the 
C-SSRS at Visits 2 through 3 must be withdrawn from the study and should receive appropriate 
follow-up as in routine clinical practice, including the ET (Visit 4) and the safety follow-up 
(Visit 5) assessments.
6.2 Efficacy Measures
Efficacy assessments will be based on information recorded by the participant. An eDiary will be 
used daily at home to collect data on headache duration, headache characteristics, non-headache 
migraine symptoms, and acute medication use, which will be collectively applied to define 
migraine days and headache days per the criteria listed in Sections 6.2.1, 6.2.2 and 6.2.3.
The AIM-D, Activity Level, and Activity Limitation will also be collected daily via an eDiary. 
An additional health outcome measure, the MSQ v2.1, will be administered in an eTablet at 
specified clinic visits (Section 6.3).
6.2.1
Migraine Day
A migraine day is defined as any calendar day on which a headache occurs which meets criteria 
A, B, and C OR meets criteria D and E, as listed below, as per participant eDiary. Calendar days 
begin at midnight and last until 11:59 PM (23:59). 
A. Headache has at least two of the following 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)


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B. At least one of the following:
i.
Nausea and/or vomiting 
ii.
Photophobia and phonophobia 
iii.
Typical aura (ie, visual, sensory, or speech/language) accompanying or within 
60 minutes before headache begins
C. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, 
migraine-specific medication (ie, triptan or ergot derivative) was used after the start of 
the headache, in which case no minimum duration will be specified
OR
D. Any headache which fulfills one criterion from (1) and at least one criterion from (2) OR
fulfills at least two criteria from (1) and no criteria from (2).
1) Headache characteristics:
i. Unilateral location
ii. Pulsating quality
iii. Moderate or severe pain intensity
iv. Aggravated by or causing avoidance of routine physical activity 
(eg, walking or climbing stairs)
2) Symptoms:
i. Nausea and/or vomiting
ii. Photophobia and phonophobia
iii. Typical aura (ie, visual, sensory, or speech/language) accompanying or 
within 60 minutes before headache begins
E. Duration of headache lasting 2 hours or longer on a calendar day unless an acute, 
migraine-specific medication (ie, triptan or ergot derivative) was used after the start of 
the headache, in which case no minimum duration will be specified.
6.2.2
Headache Day
A headache day is defined as any calendar day on which headache pain lasting 2 hours or longer 
occurs unless an acute headache medication (eg, ibuprofen, triptan) was used after the start of the 
headache, in which case no minimum duration will be specified. Calendar days begin at midnight 
and last until 11:59 PM (23:59).


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6.2.3
Acute Medication Use Day and Triptan Use Day
An acute medication use day is defined as any day on which a participant reports, per eDiary, the 
intake of allowed medication(s) to treat an acute migraine. The allowed medications include the 
following categories of drugs: triptans, ergots, opioids, analgesics (including acetaminophen), 
NSAIDs (including aspirin), and antiemetics.
A triptan use day is defined as any day on which a participant reports intake of a triptan to treat a 
migraine per eDiary.
6.3 Health Outcome Measures
6.3.1
Activity Impairment in Migraine – Diary (AIM-D)
The AIM-D is an 11-item daily diary measure that assesses the impact of migraine and is 
comprised of two domains that evaluate performance of daily activities (7 items) and physical 
impairment (4 items). Participants are asked to rate the level of difficulty experienced in the past 
24 hours with performance of daily activities (ie, difficulty with household chores, errands, 
leisure activities at home, leisure or social activities outside the home, strenuous physical 
activities, concentrating, and thinking clearly) and physical impairment (ie, difficulty walking, 
moving body, bending forward, moving head) using 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).
6.3.2
Activity Level and Activity Limitation
Two items based on a 24-hour recall will be administered daily using Headache and 
Non-headache versions as additional health outcome measures and for evaluation of the AIM-D. 
The first item will be used to assess activity level within the past 24 hours with a 5-level 
response scale ranging from “No activity – Spent all day lying down” to “Exercised – Brisk 
walk, running, jogging, biking or other activity for 30 or more minutes.” The second item will be 


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used to evaluate activity limitation with a 5-level response scale ranging from “Not at all limited 
– I could do everything” to “Extremely limited”.
6.3.3
Migraine Specific Quality of Life Questionnaire, Version 2.1 
(MSQ v2.1)
The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality of life 
impairments attributed to migraine in the past 4 weeks. It is divided into three domains: Role 
Function Restrictive assesses how migraines limit one’s daily social and work-related activities; 
Role Function Preventive assesses how migraines prevent these activities; and the Emotional 
Function domain assesses the emotions associated with migraines. Participants respond to items 
using a 6-point scale ranging from “none of the time” to “all of the time.” Raw dimension scores 
are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores 
indicate better quality of life.
6.4 Other Study Supplies
The following will be provided by the sponsor or sponsor’s designee:

All supplies needed for blood and urine sampling (central laboratory analysis)

All supplies needed for on-site urine pregnancy test

Shipping materials for shipment of laboratory samples to central laboratory

All supplies needed for ECG assessment including ECG machine 

eTablet(s)

eDiaries
6.5 Summary of Methods of Data Collection
An IWRS will be used to manage atogepant inventory. All office visit data for this study will be 
collected by either the eTablet (eg, C-SSRS) 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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All participants will use an eDiary daily to record the daily total duration of headache, headache 
characteristics, associated symptoms, the worst pain severity, acute medication use, AIM-D,
Activity Level, and Activity Limitation during the open-label treatment period until Visit 4. 
Training for the eDiary will be provided for qualified participants during Visit 1.
7
Statistical Procedures
7.1 Analysis Populations
All safety analyses will be performed using the safety population, consisting of all participants 
who received at least 1 dose of study intervention (atogepant) in this extension study. 
All efficacy analyses will be performed using the mITT population, consisting of participants 
who received at least 1 dose of study intervention (atogepant) in this extension study and had at 
least 1 evaluable post-baseline 4-week period of eDiary data in this extension study.
7.2 Collection and Derivation of Efficacy Assessments
7.2.1
Efficacy Variables
Since the primary objective of this study is to assess the safety and tolerability of 12 weeks of 
atogepant treatment, efficacy variables are not classified as primary, secondary, or additional. 
Efficacy endpoints for evaluation in the atogepant arm are listed below.

Change from baseline in monthly migraine days at each monthly period (ie, each consecutive 
4-week period)

Change from baseline in monthly headache days at each monthly period

Change from baseline in monthly acute medication use days at each monthly period

≥ 25%, ≥ 50%, ≥ 75%, and 100% improvement (decrease) in monthly migraine days at each 
monthly period

Change from baseline in monthly cumulative headache hours at each monthly period

Change from baseline in monthly triptan use days at each monthly period

Change from baseline in monthly moderate/severe headache days at each monthly period

Change from baseline in monthly severe headache days at each monthly period


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7.2.2
Health Outcome Variables
Health outcome endpoints are listed below. The related health outcome analyses will be 
documented in the health economics and outcomes research statistical analysis plan.

Change from baseline in the MSQ v2.1 Role Function Restrictive domain score at Weeks 4, 
8, 12, and 16

Change from baseline in the MSQ v2.1 Role Function Preventive domain score at Weeks 4, 
8, 12, and 16

Change from baseline in the MSQ v2.1 Emotional Function domain score at Weeks 4, 8, 12, 
and 16

Change from baseline in monthly Performance of Daily Activities domain score of the AIM-
D at Weeks 1-4, 5-8, and 9-12, and average across the 12-week treatment period.

Change from baseline in monthly Physical Impairment domain score of the AIM-D at Weeks 
1-4, 5-8, and 9-12, and average across the 12-week treatment period.

Change from baseline in monthly AIM-D total score at Weeks 1-4, 5-8, 9-12, and average 
across the 12-week treatment period.

Change from baseline in monthly Activity Level at Weeks 1 to 4, 5 to 8, and 9 to 12, and 
average across the 12-week treatment period

Change from baseline in monthly Activity Limitation at Weeks 1 to 4, 5 to 8, and 9 to 12, and 
average across the 12-week treatment period
7.3 Hypothesis and Methods of Analysis
7.3.1
Safety Analyses
The safety analyses will be performed using the safety population. The safety parameters will 
include AEs, clinical laboratory evaluations, vital sign measurements, ECG parameters, and the 
C-SSRS. For each of the clinical laboratory, vital sign, and ECG parameters, the baseline value 
as defined for the lead-in study (3101-303-002) will be used as the baseline in this extension 
study (3101-311-002).
Continuous variables will be summarized by the number of participants, and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of participants.


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7.3.2
Efficacy Analyses
The efficacy analyses will be based on the mITT population. For analysis purposes, 4 weeks (28 
days) will be considered as 1 month. The baseline value as defined for the lead-in study will be 
used as the baseline in this extension study. For monthly endpoints, baseline is defined as 
assessments during the last 28 days of baseline period in the lead-in study. For efficacy endpoints 
that are assessed at clinical visits, baseline is defined as the last non-missing efficacy assessment 
before the first dose of study intervention in the lead-in study.
Monthly efficacy endpoints are defined in a prorated fashion. For example, monthly migraine 
days are defined as the total number of recorded migraine days in the eDiary divided by the total 
number of days with eDiary records during each monthly period and multiplied by 28. 
Descriptive statistics will be provided by visit for all efficacy endpoints based on the mITT 
population using the observed cases approach. No inferential statistical analyses will be 
performed for the efficacy parameters.
7.4 Subgroup Analyses
Not applicable.
7.5 Sample Size Calculation
Chinese participants who complete Study 3101-303-002, and meet all eligibility requirements, 
may participate in this extension study. Approximately 120 Chinese participants are expected to 
participate in this extension study. 
7.6 Interim Analyses
No interim analyses are planned.
8
Study Visit Schedule and Procedures
Please see Table 1 for a schematic of the Schedule of Visits and Procedures and Figure 1 for a 
study visit flowchart.
8.1 Participant Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective participants as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study.


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8.1.2
Informed Consent and Participant Privacy
The study will be discussed with the participant, and a participant wishing to participate must 
give informed consent prior to any study-related procedures or change in treatment. The 
participant must also give authorization, and other written documentation in accordance with the 
relevant country and China privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment.
All participants will maintain the lead-in study (3101-303-002) participant identification number; 
this will serve as the participant identification number that will be used on all participant 
documentation throughout the study.
8.2 Washout Intervals/Run-in
This study will not include a washout period.
8.3 Procedures for Final Study Entry
At Visit 1, participants must meet all of the inclusion criteria and must not meet any of the 
exclusion criteria. 
Participants will directly rollover from the lead-in study (3101-303-002 [Phase 3 CM]). As such, 
participants will have Visit 7 from the lead-in study function as Visit 1 for this study after the 
participant signs the informed consent. 
Note, there may be participants who complete Visit 7 in the lead-in study before this extension 
study (3101-311-002) has been initiated. Those participants should complete Visit 7/ET and 
Visit 8/EOS Visit (including discontinuation of study intervention) per the lead-in study 
Schedule of Visits and Procedures.
Depending on the timing of the initiation of this extension study in relation to each participant’s 
planned Visit 8 schedule in the lead-in study, Visit 1 for Study 3101-311-002 can be conducted 
on the same day as Visit 8/EOS Visit for the lead-in study, or soon thereafter.
If this extension study is initiated prior to the participant’s planned Visit 8 in the lead-in study, 
then Visit 8/EOS Visit for the lead-in study should be conducted on the same day as Visit 1 for 
this extension study (3101-311-002).


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If this extension study is not initiated prior to the participant’s planned Visit 8 in the lead-in 
study (ie, there is a gap between Visit 8 and Visit 1), then Visit 8/EOS Visit should be conducted 
as planned per the lead-in study Schedule of Visits and Procedures. When this extension study is 
initiated, the participant should return to the clinic as soon as possible and Visit 1 should be 
conducted per Table 1 Schedule of Visits and Procedures.
8.4 Visits and Associated Procedures
There will be 5 scheduled clinic visits: Visit 1 (Day 1), Visit 2 (Week 4), Visit 3 (Week 8), Visit 
4/ET (Week 12), and Visit 5 (safety follow-up/EOS). For details, please see Table 1, Schedule of 
Visit and Procedures.
8.4.1
Open-label Treatment Period (12 Weeks)
8.4.1.1 Visit 1 (Day 1)

Obtain informed consent and participant privacy.

Register participant in IWRS.

Collect medical history for participants who have a gap between the last visit of the lead-
in study and Visit 1 of this extension study.

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Review and update concomitant medications and concurrent procedures.

Perform urine pregnancy test for women of childbearing potential.

Perform and transmit ECG.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting 
and standing pulse rate, respiration rate, temperature, and weight). 

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Assess inclusion/exclusion criteria.
If the participant continues to meet study entry criteria, including acceptable results from Visit 1 
ECG, pregnancy test, and vital sign measurements (see Section 6.1) the following procedures 
will be carried out at Visit 1.


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
Prior to any other test or evaluations, administer the MSQ v2.1.

Perform physical examination.

Collect blood and urine for clinical laboratory determinations including: chemistry, 
hematology, serology, INR, and urinalysis.

Collect urine for drug screen.

Review and assess AEs.

Provide eDiary instructions and training

Access IWRS and obtain the kit number for atogepant bottle and dispense atogepant 
bottle.
8.4.1.2 Visits 2 and 3 (Week 4 and Week 8)

Review clinical laboratory results from Visit 1 to confirm continued eligibility 
(Visit 2 only) (see Section 8.9).

Prior to any other test or evaluations, administer the MSQ v2.1.

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight).

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG (Visit 3 only).

Collect previous visit atogepant bottle, review participant compliance, and perform 
accountability.

Review and assess AEs.

Review and update concomitant medications/concurrent procedures.


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
Review eDiary data and compliance

Access IWRS to dispense atogepant bottle and enter accountability.
8.4.1.3 Visit 4/Early Termination (Week 12)
Effort should be made by the site to not schedule Visit 4 earlier than 12 weeks after Day 1, to 
ensure participants complete the full 12 weeks of atogepant.

Prior to any other test or evaluations, administer the MSQ v2.1.

Perform physical examination.

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight).

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Perform and transmit ECG.

Review and assess AEs.

Review and update concomitant medications and concurrent procedures.

Review eDiary data and compliance

Collect eDiary

Collect previous visit atogepant bottle, review participant compliance and perform 
accountability.

Access IWRS to enter study visit and accountability.


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8.4.2
Safety Follow-up Period (4 Weeks)
8.4.2.1 Visit 5/End of Study (Week 16)

Prior to any other test or evaluations, administer the MSQ v2.1.

Perform physical examination.

Assess C-SSRS (the “Since Last Visit” assessment of the C-SSRS will be completed).

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight).

Collect start date (first day) of last menstrual cycle for women having menstrual cycles.

Perform urine pregnancy test for women of childbearing potential.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Review and assess AEs.

Review and update concomitant medications and concurrent procedures.

Access IWRS to enter study visit.
8.5 Instructions for the Participants
Section 4.5.4 provides diet and activity instructions for participants enrolled in the study.
Prohibited medications should be reviewed with the participants. Participants will be instructed 
to return their atogepant bottle(s), both used and unused.
Participants should be instructed to take atogepant 60 mg once daily at approximately the same 
time each day (approximately 24 hours between doses). Study intervention may be taken with or 
without food. Water is allowed as desired.
Participants should use appropriate contraceptive measures for the duration of their participation 
in the study (Section 4.5.3).
8.6 Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to ensure 
the safety and well-being of the participants during the study period. Unscheduled visit eCRFs 
should be completed for each unscheduled visit.


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8.7 Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1, and the timing 
of the visits should occur as close as possible to the day specified. At each visit, the participant
will be asked if the participant changed the dose/regimen of any existing concomitant 
medications or initiated the use of any new concomitant medications since the last visit, to ensure 
compliance with the protocol. 
Atogepant compliance during any period will be closely monitored by counting the number of 
tablets dispensed and returned. Every effort will be made to collect all unused atogepant.
8.8
Early Discontinuation of Participants
A premature discontinuation will occur when a participant who signed the ICF ceases 
participation in the study, regardless of circumstances, before completion of the study. 
Participants can be prematurely discontinued from the study for one of the following reasons:

AE

Lack of efficacy

Lost to follow-up

Non-compliance with study drug

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Withdrawal by subject
Participants may voluntarily withdraw from the study at any time.
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
eCRF. All participants who prematurely discontinue from the study, regardless of cause, should 
be seen for final study assessments. The final assessments will be defined as completion of the 
evaluations scheduled for Visit 4/ET and Visit 5 (safety follow-up/EOS), 4 weeks post the last 
dose of atogepant.


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8.9 Withdrawal Criteria

Participants with the following at Visit 1:
o
Laboratory Results:
o
ALT or AST > 1 x ULN OR
o
total bilirubin > 1 x ULN (except for participants with a diagnosis of Gilbert’s 
disease) OR
o
serum albumin < 2.8 g/dL 
o
Positive result on the urine drug screen unless explained by concomitant 
medication use (eg, opioids prescribed for migraine pain).
o
Positive result on anti-hepatitis A IgM antibody, hepatitis B surface antigen, 
anti–hepatitis C antibody testing, or anti-hepatitis E IgM antibody.
o
ECG Results:
o
QTcF > 450 msec for males and QTcF > 470 msec for females on the final 
central vendor ECG report
o
Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial 
fibrillation, second- or third-degree heart block)

Participants with the following at any study visit:
o
Female participants who become pregnant (Section 9.4)
o
Participants who meet atogepant discontinuation criteria related to abnormal liver 
function tests (Section 9.5), and advised not to be rechallenged, will be withdrawn 
from the study and should refrain from taking atogepant. 
o
Participants who reply with “yes” to questions 4 or 5 in the suicidal ideation section 
or “yes” to any question in the suicidal behavior section of the C-SSRS at Visits 2 and 
3 must be withdrawn from the study. 
o
A participant with a condition and/or a situation that, in the investigator's opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study may be 
withdrawn from treatment.
All withdrawn participants should receive appropriate follow-up as in routine clinical practice, 
including the Visit 4 (ET) and Visit 5 (safety follow-up/EOS) assessments.


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8.10 Study Termination
The study may be stopped at his/her study site at any time by the site investigator. The sponsor
may stop the study (and/or the study site) for any reason with appropriate notification.
9
Adverse Events
AEs occurring during the study will be recorded on an AE eCRF. If AEs occur, the first concern 
will be the safety of the study participants.
9.1 Definitions
9.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant associated with the use 
of atogepant, whether or not considered related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of atogepant. In addition, during Visit 1, AEs 
will be assessed regardless of the administration of a pharmaceutical product.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to atogepant or study procedures, or that caused the 
participant to discontinue atogepant or study (see Section 8.8).
All AEs from the signing of the ICF until the safety follow-up visit (Visit 5), or 30 days after the 
last dose of atogepant if the safety follow-up visit is not done, will be collected at the timepoints 
specified in the Schedule of Visits and Procedures (Table 1), and as observed or reported 
spontaneously by study participants.
Investigators are not obligated to actively seek AE information after conclusion of the study 
participation.


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AEs will be assessed, documented, and recorded in the eCRF throughout the study (ie, after 
informed consent has been obtained). At each visit, the investigator will begin by querying for 
AEs by asking each participant a general, non-directed question such as “How have you been 
feeling since the last visit?” Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about AE occurrences. Care will be taken not to introduce bias 
when detecting AEs and/or SAEs. All reported AEs will be documented on the appropriate 
eCRF.
9.1.2
Serious Adverse Event
An SAE is any AE occurring at any dose that results in any of the following outcomes:
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect


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f.
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive intervention in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
The sponsor considers all cancer AEs as SAEs. 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).
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
participant requires hospitalization is not reportable as an SAE.
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the participant’s entry into the 
study. If it has not been documented at the time of the participant’s entry into the study, then it 
should be documented as a SAE and reported to the sponsor.


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9.1.3
Intensity
The intensity assessment for a clinical AE must be completed using the following definitions as 
guidelines:
Assessment of Intensity
MILD
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
MODERATE
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant.
SEVERE
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
An event is defined as serious when it meets at least 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
Assessment of Causality

The investigator is obligated to assess the relationship between atogepant and each 
occurrence of each AE or SAE.

A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to atogepant administration will 
be considered and investigated.

The investigator will also consult the investigator’s brochure in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the sponsor.

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 non-serious AEs of special interest (as defined 
in Section 6.1.2) will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.


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Prior to database lock, new or updated information will be recorded in the originally completed 
eCRF. If the event is an SAE, it will also need to be reported on the SAE reporting form. Post 
database lock, new or updated SAE information will only be reported on the SAE reporting 
form.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
9.2 Procedures for Reporting Adverse Events
All AEs must be recorded on the appropriate eCRF.
All AEs that are atogepant-related and unexpected (not listed as treatment-related in the current 
investigator's brochure) must be reported to the governing IRB/IEC as required by the IRB/IEC, 
China 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 safety 
follow-up visit (Visit 5), or 30 days after the last dose of atogepant if the safety 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 the sponsor as listed on the Study Contacts Page and recorded on the 
AESI/SAE form. All participants with an SAE must be followed up and the outcomes reported. 
The investigator must supply the sponsor and the IRB/IEC with any additional requested 
information (eg, autopsy reports and discharge summaries).
9.3.1
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention (ie, atogepant) under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the China regulatory authority and 
other regulatory agencies about the safety of a study intervention (ie, atogepant) under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/ IECs, and 
investigators

Investigator safety reports must be prepared for SUSARs according to China regulatory 
requirements and the sponsor’s policy and forwarded to investigators as necessary.


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
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs from the sponsor) will 
review and then file it along with the investigator’s brochure and will notify the IRB/IEC, 
if appropriate according to China requirements.
9.4 Exposure to Study Intervention During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of atogepant and until the safety follow-up visit (Visit 5) or 30 days after 
the last dose of atogepant if the safety follow-up visit is not done. Study center personnel must 
report every pregnancy on the Pregnancy Form (within 24 hours of learning of the pregnancy to 
the Serious Adverse Event Reporting Fax Number[s]: +1-714-796-9504 [back up fax 
number: +1-714-246-5295], email: IR-Clinical-SAE@allergan.com), even if no AE has 
occurred. The pregnancy must be followed to term and the outcome reported by completing a 
follow-up Pregnancy Form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. Elective 
abortions can be SAEs or AEs depending on the reason for the elective abortion (eg, fetal death, 
still birth, congenital anomalies, ectopic pregnancy, which would make the elective abortion an 
SAE). For pregnancy-related SAEs, in addition to the Pregnancy Form, a separate AESI/SAE 
Form must be filed as described in Section 9.3 with the appropriate serious criterion (eg, 
hospitalization) indicated.
9.5 ALT or AST Elevations
A treatment-emergent ALT ≥ 3 × ULN and/or AST ≥3 × ULN is considered an AESI. Any
participant with this laboratory result after atogepant is taken must have repeat testing within 48 
to 72 hours to confirm the abnormality. For this repeat testing, the following laboratory tests 
must be performed: hematology and chemistry panels, INR, serum acetaminophen level, urine 
drugs of abuse screen, and blood alcohol level. An extra blood serology sample must be 
collected and sent to the central laboratory for further diagnostic testing, at a later date, if needed. 
In addition, the investigator will perform a complete history and examination to evaluate the 
participant for possible liver disease.
All AESIs must be reported to the sponsor within 24 hours of the time the investigator becomes 
aware of the event using the abnormal liver function reporting form and the AE eCRF. All new 
elements of history, physical examination, diagnostic testing results, and other relevant medical 
reports are to be reported for each AESI.


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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 the sponsor’s 
medical personnel. In general, the chemistry panel should be repeated 1 to 2 times per week to 
follow the course of ALT/AST elevation.
Atogepant must be discontinued if any of the following criteria are met:

ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (> 5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN

ALT or AST ≥ 3 × ULN and INR > 1.5

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
The participant may be rechallenged with atogepant only after consultation with the sponsor’s
Medical Monitor. Participants should receive appropriate follow-up as per standard of care.
The investigator must contact the sponsor’s Medical Monitor to discuss all cases of 
confirmed ALT/AST elevation ≥ 3 x ULN. All ALT/AST elevations must be followed until 
ALT and AST return to < 1.5 x ULN and there is full clinical resolution.
9.5.1
Potential Hy’s Law Cases
Sites must report every participant who meets the following potential Hy’s law criteria if this 
occurs within the time the participant signs the ICF until 30 days after the last dose of atogepant:

ALT or AST ≥ 3 x ULN AND

Total bilirubin ≥ 2 x ULN AND

Alkaline phosphatase < 2 x ULN


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Study site personnel must report every participant who meets these criteria. Typically, all 
3 analytes will be obtained from the same sample, but they may come from multiple samples 
taken within a 24-hour period. This requirement applies from the time the participant signs the 
ICF for the study until 30 days after the final protocol-defined study visit or the last known dose 
of atogepant (if the final visit does not occur).
A laboratory alert for possible Hy’s law cases will be in place and must notify investigators and 
the sponsor immediately when the above criteria have been met. A possible Hy’s law case must 
be faxed to the sponsor on an abnormal liver function reporting form as soon as possible (within 
24 hours of learning of the possible Hy’s law case) to the SAE/Pregnancy fax number, even if no 
AE has occurred. If the event is serious, please complete the AESI/SAE form. The eCRF for 
possible Hy’s law cases must be completed within 7 calendar days. Every effort to determine the 
cause of the liver enzyme abnormalities must be made, and close monitoring should be initiated 
in conjunction with the medical monitor and medical safety physician and in accordance with the 
FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 
2009. The participant should return to the study site and be evaluated as soon as possible, 
preferably within 48 hours from the time the investigator becomes aware of the abnormal results. 
This evaluation should include laboratory tests, detailed history, and physical assessment.
10 Administrative Items
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines (eg, the ICH Guideline on GCP and China GCP).
10.1 Protection of Human Participants
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations
Written informed consent is to be obtained from each participant prior to any study-related 
activities or procedures in the study, and/or from the participant's legally authorized 
representative.
The following process will be followed:

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed 


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consent that meets the requirements of 21 CFR 50, China regulations, ICH guidelines, 
HIPAA requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study if required by the IRB. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.2 Compliance With IRB or IEC Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) or 
applicable IEC regulations. The investigator must obtain approval from a properly constituted 
IRB/IEC prior to initiating the study and re-approval or review at least annually. The sponsor is 
to be notified immediately if the responsible IRB/IEC has been disqualified or if proceedings 
leading to disqualification have begun. Copies of all IRB/IEC correspondence with the 
investigator should be provided to the sponsor.
10.1.3 Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable China GCP regulations and 
guidelines.
10.1.4 Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signatures.
10.2 Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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10.3 Changes to the Protocol
The investigator must not implement any deviation from or changes to the protocol without 
approval by the sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards to 
study participants, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers).
10.4 Data Protection
Participants will be identified by a unique identifier assigned during the lead-in study. Any 
participant records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with China data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.5 Participant Privacy
Written authorization and other documentation in accordance with the relevant country and 
China 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).
Additional purposes of this study may include publishing of anonymous participant data from the 
study.
10.6 Documentation
10.6.1 Source Documents
Source documents may include a participant's medical records, hospital charts, clinic charts, the 
investigator's participant study files, as well as the results of diagnostic tests such as laboratory 
tests, and ECGs. The investigator's copy of the eCRFs serves as part of the investigator's record 
of a participant's study-related data.


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The following information should be entered into the participant's medical record:

Participant’s name

Participant’s contact information

The date that the participant entered the study, participant number, and participant or 
medication kit number

The study title and/or the protocol number of the study and the name of the sponsor

A statement that informed consent was obtained (including the date). A statement that 
written authorization or China participant privacy required documentation for this study 
has been obtained (including the date)

Dates of all participant visits

Participants medical history

Information regarding participant’s diagnosis of migraine headache

All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications should be recorded.)

Occurrence and status of any AEs

The date the participant exited the study, and a notation as to whether the participant 
completed the study or reason for discontinuation.

The results of laboratory tests performed by the site (eg, results of urine pregnancy tests).

Key study variables
Source documentation practices must follow Section 4.0 of ICH E6, GCP: Consolidated 
Guidance, China GCP, and ALCOA (ie, records must be Attributable, Legible, 
Contemporaneous, Original and Accurate).


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


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10.7 Labeling, Packaging, and Return or Disposal of Study Intervention
10.7.1 Labeling/Packaging
Atogepant tablets will be packaged and labeled with the protocol number, storage information, 
warning language, and instructions to take the tablets as directed. The label will also include the 
kit number. Immediately before dispensing the bottle, the investigator or designee will write the
participant number and date on the label.
10.7.2 Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units
(atogepant) received from the sponsor, dispensed or administered to the participants, the number 
of units returned to the investigator by the participant, and the number of units returned to the 
sponsor during and at the completion of the study. A detailed inventory must be completed for 
atogepant. Atogepant must be dispensed or administered only by an appropriately qualified 
person to participants in the study. Atogepant is to be used in accordance with the protocol for 
participants who are under the direct supervision of an investigator.
10.7.3 Return or Disposal of Study Intervention and/or Supplies
All atogepant and/or supplies will be returned to the sponsor or sponsor’s designee for 
destruction.
10.8 Monitoring by the Sponsor
A representative of the sponsor will monitor the study on a periodic basis. The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.
Authorized representatives of the sponsor or regulatory authority representatives will conduct 
on-site visits to review, audit, and copy study-related documents. These representatives will meet 
with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions.
10.9 Handling of Biological Specimens
Urine pregnancy test kits will be provided by the central laboratory; all urine pregnancy testing 
will be administered on site according to instructions in the central laboratory manual.


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Samples of blood and urine for evaluation of hematology, blood chemistry, urinalysis, urine drug 
screen, INR, and serology will be analyzed at a central clinical laboratory with certification from 
a recognized accreditation agency (eg, College of American Pathology or Clinical Laboratory 
Improvement Amendments certification). 
All samples will be returned to the sponsor or sponsor’s designee for destruction. The sponsor 
shall have full ownership rights to any biological specimens/samples derived from the study. For 
additional details regarding handling of biological specimens, please refer to the Study Reference 
Manual.
10.10 Publications
The sponsor has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between multiple investigators and sites and sponsor personnel. 
Authorship will be established prior to the writing of the manuscript. As this study involves 
multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with the sponsor.
10.11 Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the clinical study 
report.
11 References
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 
195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 
Lancet. 2017;390:1211-1259.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United 
States. Arch Intern Med. 1999;159:813-818.
ICHD-3: Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the Differences Between Episodic 
Migraine and Chronic Migraine. Curr Pain Headache Rep. 2012;16:86–92.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.


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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.
Steiner TJ, Stovner LJ, and Birbeck GL. Migraine: the seventh disabler. J Headache Pain.
2013;14(1):1-2.
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010;11:289–299.
Yu S. Guidelines for Prevention and Treatment of Migraine in China. Chinese journal of pain 
medicine. 2016;22(10):721-727.


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12 Attachments
12.1 Examination Procedures, Tests, Equipment, and Techniques
12.1.1 International Classification of Headache Disorders, 3rd Edition


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


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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 with- out aura. They include various 
combinations of fatigue, diculty in concentrating, neck 
stiness, sensitivity to light and/or sound, nausea, 
blurred vision, yawning  and pallor. Postdromal 
symptoms, most commonly
feeling tired or weary, difficulty with concentration 
and neck stiffness, may follow resolution of
the 
headache, persisting for up to 48 hours; these are 
less well studied.
Migraine attacks can be associated with cranial 
autonomic symptoms and symptoms of cutaneous 
allodynia.
In 
young 
children, 
photophobia 
and 
phonophobia may be inferred from their 
behaviour.
A minority (<10%) of women have attacks of 
migraine in association with the majority of their 
menstrual cycles; most such attacks are without 
aura. Attacks during menstruation tend to be longer 
and accompanied by more severe nausea than 
attacks out- side the menstrual cycle. ICHD-3 
offers criteria for A1.1.1 Pure menstrual migraine 
without aura, A1.1.2 Menstrually related migraine 
without aura and A1.1.3 Non-menstrual migraine 
without aura, but in the Appendix because of 
uncertainty over whether they should be regarded 
as separate entities. Criteria are  also offered for 
A1.2.0.1 Pure menstrual migraine with aura, 
A1.2.0.2 Menstrually related migraine with aura 
and A1.2.0.3 Non-menstrual migraine with aura to 
encourage 
better 
characterization 
of 
these 
uncommon subforms if they are separate entities.
Very frequent migraine attacks are distinguished 
as 1.3 Chronic migraine. When there is associated
medication overuse, both of the diagnoses 1.3
Chronic migraine and 8.2 Medication-overuse
headache should be applied. 1.1 Migraine without
aura is the disease most prone to accelerate with
frequent use of symptomatic medication. Regional
cerebral blood ﬂow imaging shows no changes 
suggestive of cortical spreading depression (CSD) 
during attacks of 1.1 Migraine without aura,
although blood ﬂow changes in the brainstem
may occur, as may cortical changes secondary to
pain activation. This contrasts with the
pathognomonic spreading oligaemiaof1.2
Migrainewithaura.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
path- ways, and the possibility that attacks may
originate in the central nervous system, have 
gainedincreasing attention over the last decades. 
At the same time, the circuitry of migraine pain,
the trigeminovascular system, and several aspects 
of its neurotransmission peripherally and in the
trigeminal nucleus caudalis, central
mesencephalic grey and thalamus, have been
recognized. Highly receptor- speciﬁc acute 


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medications including 5-HT1B/D receptor agonists 
(triptans), 5-HT1F receptor agonists and CGRP
receptor antagonists have demonstrated efficacy
in the acute treatment of migraine attacks. 
Because of their highreceptor-speciﬁcity, their
mechanisms of action pro- vide new insight into 
migraine mechanisms. It is now clear that 1.1
Migraine without aura is a neurobiological 
disorder, while clinical as well as basic
neuroscience stu- dies continue to advance our 
knowledge of migraine mechanisms.
1.2
Migraine with aura
Previously used terms: Classic or classical migraine; 
ophthalmic, hemiparaesthetic, hemiplegic or aphasic 
migraine;
migraine
accompagne´
e;
complicated
migraine.
Description: Recurrent attacks, lasting minutes, of 
unilateral fully reversible visual, sensory or other 
central nervous system symptoms that usually develop 
gradually and are usually followed by headache and 
associated migraine symptoms.
Diagnostic criteria:
A.
At least two attacks fulﬁlling criteria B and C
B.
One or more of the following fully reversible 
aura symptoms:
1.
visual
2.
sensory
3.
speech and/or language
4.
motor
5.
brainstem
6.
retinal
C.
At least three of the following six
characteristics:
1.
at least one aura symptom spreads gradually 
over 5 minutes
2.
two or more aura 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, occur-
ring in over 90% of patients with 1.2 Migraine with 
aura, at least in some attacks. It often presents as a 
fortiﬁcation spectrum:  a zigzag ﬁgure near the  
point  of ﬁxation that may gradually spread right or 
left and assume a laterally convex shape with an 
angulated scintillating edge, leaving absolute or 
variable degrees of relative scotoma in its wake. In 
other cases, scotoma without positive phenomena 
may occur; this is often perceived as being of acute 
onset but, on scrutiny, usually enlarges gradually. 
In children and adolescents, less typical bilateral 
visual symptoms occur that may represent an aura. 
A visual aura rating scale with high speciﬁcity and 
sensitivity has been developed and validated.
Next in frequency are sensory disturbances, in 
the form of pins and needles moving slowly from 
the point of origin and aecting a greater or smaller
part of one side of the body, face and/or tongue.
Numbness may occur in its wake, but numbness 
may also be the only symptom.
Less frequent are speech disturbances, usually 
aphasic but often hard to categorize.
Systematic studies have demonstrated that 
many patients with visual aura occasionally have 
symptoms in the extremities and/or speech 
symptoms. Conversely, patients with symptoms in 
the 
extremities 
and/or
speech 
or language 
symptoms almost always also experience visual 
aura symptoms at  least  during  some  attacks. A 
distinction between migraine with visual aura, 
migraine with hemiparaesthetic aura and migraine 
with speech and/or language aura is probably 
artiﬁcial, and therefore not recognized in this
classiﬁcation: they are all coded as 1.2.1 Migraine 
with typical aura.
When aura symptoms are multiple, they usually 
follow one another in succession, beginning with 
visual, then sensory, then aphasic; but the reverse 
and other orders have been noted. The accepted 


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duration  for most aura symptoms is one hour, but 
motor symptoms are often longer lasting.
Patients with aura symptoms arising from the 
brain- stem are coded as 1.2.2 Migraine with
brainstem aura, but they almost always have 
additional typical aura symptoms. When the aura 
includes motor weakness, the dis- order should be 
coded as 1.2.3 Hemiplegic migraine or one of its 
subforms. 1.2.3 Hemiplegic migraine is classiﬁed as 
a separate subtype because of genetic and 
pathophysiological differences from 1.2.1 Migraine
with typical aura. Patients with 1.2.3 Hemiplegic 
migraine often have brainstem symptoms in
addition.
Patients often ﬁnd it hard to describe their aura
symptoms, in which case they should be instructed
to time and record them prospectively. The clinical  
picture  then becomes clearer. Common mistakes are 
incorrect reports of lateralization, of sudden rather 
than gradual onset and of monocular rather than 
homonymous visual disturbances, as well as of 
duration of aura and mistaking sensory loss for 
weakness. After an initial consultation, use of an
aura diary may clarify the diagnosis.
Migraine aura is sometimes associated with a 
head- ache that does not fulﬁll criteria for 1.1
Migraine without aura, but this is still regarded as a 
migraine headache because of its relation to the aura. 
In other cases, migraine aura may occur without
headache.
Before or simultaneously with the onset of aura 
symptoms, regional cerebral blood ﬂow is decreased   
in the cortex corresponding to the clinically affected 
area and often over a wider area. Blood ﬂow 
reduction usually starts posteriorly and spreads 
anteriorly, and is usually above the ischaemic 
threshold. After one to several hours, gradual 
transition into hyperaemia  occurs in the same 
region. Cortical spreading depression of Lea˜o is the
likely underlying mechanism.
The previously deﬁned syndromes, migraine with 
prolonged aura and migraine with acute-onset aura, 
have been abandoned. It is not rare for aura to  last 
more than one hour but, in most such cases, patients 
have at least two of the other characteristics of
criterion
C. Even when most of a patient’s attacks do not fulﬁl 
criterion C, it is usual that other attacks fulﬁl criteria  
for one of the recognized subtypes or subforms of 1.2 
Migraine with aura, and this should be the diagnosis. 
The few other cases should be coded to 1.5.2 Probable 
migraine with aura, specifying the atypical feature (pro-
longed aura or acute-onset aura) in parenthesis. The 
diagnosis is usually evident after a careful history alone, 
although there are rare secondary mimics including 
carotid dissection, arteriovenous malformation and
seizure.
Prodromal symptoms may begin hours or a day or
two before the other symptoms of a migraine attack 
with aura. They include various combinations of 
fatigue, difﬁculty in concentrating, neck stiness,
sensitivity to light and/or sound, nausea, blurred 
vision, yawning and pallor. The term ‘prodrome’, 
which has replaced ‘pre-
monitory phase’ or 
‘premonitory symptoms’, does not include aura. 
Postdromal symptoms, most commonly feeling tired 
or weary, difficulty with concentration
and neck 
stiffness, may follow resolution of the headache, 
persisting for up to 48 hours; these are less well 
studied.


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1.2.1 Migraine with typical aura
Description: Migraine with aura, in which aura 
consists 
of 
visual 
and/or 
sensory 
and/or 
speech/language symptoms, but no motor weakness, 
and is characterized by gradual development, 
duration of each symptom no longer than one hour, a 
mix of positive and negative features and complete 
reversibility
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura with both of the following:
1.
fully reversible visual, sensory and/or 
speech/ language symptoms
2.
no motor, brainstem or retinal symptoms.
1.2.1.1 Typical aura with headache
Description: Migraine with typical aura in which 
aura is accompanied or followed within 60 minutes 
by 
head-
ache 
with 
or 
without 
migraine 
characteristics.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine 
with typical aura and criterion B below
B.
Headache, with or without migraine
characteristics, accompanies or follows the
aura within 60 minutes.
1.2.1.2 Typical aura without headache
Description: Migraine with typical aura in which aura 
is neither accompanied nor followed by headache of 
any sort.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine 
with typical aura and criterion B below
B.
No headache accompanies or follows the aura 
within 60 minutes.
Comments: In some patients, a typical aura is 
always followed by migraine headache, but many 
patients have, in addition, attacks with aura followed 
by a less distinct headache or even without 
headache. A number of patients have, exclusively, 
1.2.1.2 Typical aura with- out headache.
In the absence of headache fulﬁlling criteria for 1.1 
Migraine without aura, the precise diagnosis of aura
and its distinction from mimics that may signal 
serious dis- ease (e.g. transient ischaemic attack) 
becomes more difﬁcult and often requires 
investigation. When aura occurs for the ﬁrst time 
after age 40, when symptoms are exclusively 
negative (e.g. hemianopia) or when aura is 
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 


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patients who have attacks with brainstem aura also 
report other attacks with typical aura and should be 
coded for both 1.2.1 Migraine with typical aura
and 1.2.2 Migraine with brainstem aura.
Many of the symptoms listed under criterion B1 
may occur with anxiety and hyperventilation, and 
are therefore subject to misinterpretation.
1.2.3 Hemiplegic1 migraine
Description: Migraine with aura including motor 
weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine 
with aura and criterion B below
B.
Aura consisting of both of the following:
1.
fully reversible motor weakness2
2.
fully reversible visual, sensory and/or 
speech/ language symptoms.
Notes:
1. The term plegic means paralysis in most 
languages, but most attacks are characterized
by motor weakness.
2. Motor symptoms generally last less than 
72 hours but, in some patients, motor weakness 
may persist for weeks.
Comment: It may be difficult to distinguish 
weakness from sensory loss.
1.2.3.1 Familial hemiplegic migraine (FHM)
Description: Migraine with aura including motor 
weak- ness, and at least one ﬁrst- or second-degree 
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 
chromo- some 1; and in FHM3 there are mutations 
in the SCN1A gene (coding for a sodium channel) on 
chromosome 2. There may be other loci not yet
identiﬁed. When genetic testing is done, the genetic
subform(ifdiscovered)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


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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 
weak- ness, and no ﬁrst- or second-degree relative 
has migraine aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 Hemiplegic 
migraine
B.
No ﬁrst- or second-degree relative fulﬁls 
criteria for 1.2.3 Hemiplegic migraine.
Comments: Epidemiological studies have shown that 
sporadic cases occur with approximately the same 
prevalence as familial cases.
The attacks in 1.2.3.2 Sporadic hemiplegic 
migraine have the same clinical characteristics as 
those in 1.2.3.1 Familial hemiplegic migraine. Some
apparently
sporadic cases have known FHM 
mutations and, in some, a ﬁrst- or second-degree 
relative later develops hemiplegic migraine, thus
completing fulﬁlment of the criteria for
1.2.3.1 Familial hemiplegic migraine and requiring a 
change of diagnosis.
Sporadic cases usually require neuroimaging and 
other tests to rule out other causes. A lumbar puncture 
may be necessary to rule out 7.3.5 Syndrome of 
transient headache and neurological deﬁcits with
cerebrospinal ﬂuid lymphocytosis (HaNDL).
1.2.4 Retinal migraine
Description: Repeated attacks of monocular visual 
disturbance, including scintillations, scotomata or 
blindness, associated with migraine headache.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with 
aura and criterion B below
B.
Aura characterized by both of the following:
1.
fully 
reversible, 
monocular, 
positive 
and/or negative visual phenomena (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 eightdays/month,hasthe features ofmigraine
headache.
Diagnostic criteria:
A.
Headache (migraine-like or tension-type-like1) on 
15 days/month for >3 months, and fulﬁlling
criteria B and C
B.
Occurring in a patient who has had at least ﬁve 
attacks fulﬁlling criteria B–D for 1.1 Migraine
with- out aura and/or criteria B and C for 1.2 
Migraine with aura
C.
On 8 days/month for >3 months, fulﬁlling any of 
the following2:
1.
criteria C and D for 1.1 Migraine without
aura
2.
criteria B and C for 1.2 Migraine with aura
3.
believed by the patient to be migraine at 
onset and relieved by a triptan or ergot
derivative
D.
Not better accounted for by another ICHD-3 
diagnosis.3–5
Notes:
1. The reason for singling out 1.3 Chronic migraine
from types of episodic migraine is that it is 
impossible to distinguish the individual episodes of 
headache in patients with such frequent or 
continuous headaches. In fact, the characteristics of 
the headache may change not only from day to day 
but even within  the same day. Such patients are 
extremely dicult to keep medication-free in order 
to observe the natural history of the headache. In 


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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 suggestiveof1.3Chronicmigraine.The
latter disorder evolves over time from 1.1
Migrainewithoutauraand/ or 1.2 Migraine with 
aura; therefore, when these criteria A–C are 
fulﬁlled by headache that, unambiguously, is 
daily and unremitting from <24 hours after its
ﬁrst onset, code as 4.10 New daily persistent
head- ache. When the manner of onset is not
remembered or is otherwise uncertain, code as
1.3 Chronic migraine.
5. The most common cause of symptoms 
suggestive of chronic migraine is medication
overuse, as deﬁned under 8.2 Medication-
overuse headache. Around 50% of patients 
apparently with 1.3 Chronic migraine revert to 
an 
episodic 
migraine 
type 
after 
drug 
withdrawal; such patients are in a sense 
wrongly diagnosed as 1.3 Chronic migraine. 
Equally, many patients apparently overusing 
medication 
do 
not 
improve 
after 
drug 
withdrawal; the diagnosis of 8.2 Medication-
overuse headache may be inappropriate for 
these (assuming that chronicity induced by drug 
overuse is always reversible). For these reasons, 
and because of the general rule to apply all 
relevantdiagnoses, patients meeting criteria for 
1.3 Chronic migraine and for 8.2 Medication-
overuse headache should be coded for both. 
After drug withdrawal, migraine will either 
revert to an episodic type or remain chronic and 
should be re-diagnosed accordingly; in the 
latter case, the diagnosis of 8.2 Medication-
overuse headache may be rescinded.
1.4
Complications of migraine
Comment: Code separately for both the migraine type, 
subtype or subform and for the complication.
1.4.1 Status migrainosus
Description: A debilitating migraine attack lasting 
for more than 72 hours.
Diagnostic criteria:
A.
A headache attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.1 Migraine 
without aura and/or 1.2 Migraine with aura, 
and typical of previous attacks except for its
duration and severity
C.
Both of the following characteristics:
1.
unremitting for >72 hours1
2.
pain
and/or
associated
symptoms
are debilitating2
D.
Not better accounted for by another ICHD-3 
diagnosis.
Notes:
1. Remissions of up to 12 hours due to medication 
or sleep are accepted.
2. Milder cases, not meeting criterion C2, are
coded
1.5.1 Probable migraine without aura.
Comment: Headache with the features of 1.4.1 Status 
migrainosus may often be caused by medication 
overuse. When headache in these circumstances meets 
the criteria for 8.2 Medication-overuse headache, code 
for this dis- order and the relevant type or subtype  of 
migraine  but not for 1.4.1 Status migrainosus. When 
overuse of medication is of shorter duration than three 
months, code for the appropriate migraine type or 
subtype(s) only.
1.4.2 Persistent aura without infarction
Description: Aura symptoms persisting for one 
week or more without evidence of infarction on 
neuroimaging.
Diagnostic criteria:
A.
Aura fulﬁlling criterion B
B.
Occurring in a patient with 1.2 Migraine with
aura and typical of previous auras except that 
one or more aura symptoms persists for 1 week
C.
Neuroimaging shows no evidence of
infarction
D.
Not better accounted for by another ICHD-3 
diagnosis.
Comments: Persistent aura symptoms are rare but 
well documented. They are often bilateral and may 
last for months or years. The one-week minimum in 
criterion B is based on the opinion of experts and 
should be formally studied.
Diagnostic work-up must distinguish 1.4.2
Persistent aura without infarction from 1.4.3 
Migrainous infarction and exclude symptomatic 
aura due to cerebral infarction of other causes. 
Attacks with  prolonged  aura lasting less than one 
week and not fulﬁlling criteria for 1.2.1 Migraine 
with typical aura are coded 1.5.2 Probable migraine 
with aura.


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1.4.3 Migrainous infarction
Description: One or more migraine aura symptoms 
occurring in association with an ischaemic 
brainlesion in the appropriate territory demonstrated 
by neuroimaging, with onset during the course of a 
typical migraine with aura attack.
Diagnostic criteria:
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 sub-
type of migraine coded above, and not fulﬁlling criteria 
for another headache disorder.
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–D
for
1.1 Migraine without aura, or all but one of
criteria A–C for 1.2 Migraine with aura
B.
Not fulﬁlling ICHD-3 criteria for any other head-
ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
Comment: In making a headache diagnosis, attacks that 
fulﬁl criteria for both 2. Tension-type headache and 1.5 
Probable migraine are coded as the former in 
accordance with the general rule that a deﬁnite 
diagnosis always trumps a probable diagnosis. 
However, in patients who already have a migraine 
diagnosis, and where the issue is to count the number of 
attacks they are having (e.g. as an outcome measure in 
a drug trial), attacks fulﬁlling criteria for 1.5 Probable 
migraine should be counted as migraine. The reason for 
this is that mild migraine attacks, or attacks treated 
early, often do not achieve all characteristics necessary 
for a migraine attack diagnosis but nevertheless respond 
to speciﬁc migraine treatments.
1.5.1 Probable migraine without aura Diagnostic
criteria:
A.
Attacks fulﬁlling all but one of criteria A–D
for 1.1 Migraine without aura
B.
Not fulﬁlling ICHD-3 criteria for any other 


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head- ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
1.5.2 Probable migraine with aura
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–C for
1.2
Migraine with aura or any of its subtypes
B.
Not fulﬁlling ICHD-3 criteria for any other 
head- ache disorder
C.
Not better accounted for by another ICHD-3 
diagnosis.
1.6
Episodic syndromes that may be associated with
migraine
Previously 
used 
terms: 
Childhood 
periodic 
syndromes; periodic syndromes of childhood.
Comments: This group of disorders occurs in 
patients who also have 1.1 Migraine without aura 
or 1.2 Migraine with aura, or who have an 
increased likelihood to develop either of these 
disorders. Although historically noted to occur in 
childhood,  they  may  also occur in adults.
Additional conditions that may also occur in 
these patients include episodes of motion sickness 
and
periodic sleep disorders including sleep 
walking, sleep talking, night terrors and bruxism.
1.6.1 Recurrent gastrointestinal disturbance
Previously used terms: Chronic abdominal pain; 
functional abdominal pain; functional dyspepsia; 
irritable bowel syndrome; functional abdominal 
pain syndrome.
Description: 
Recurrent 
episodic 
attacks 
of 
abdominal pain and/or discomfort, nausea and/or 
vomiting, occurring infrequently, chronically or at 
predictable intervals, that may be associated with 
migraine.
Diagnostic criteria:
A.
At least ﬁve attacks with distinct episodes of 
abdominal pain and/or discomfort and/or 
nausea and/or vomiting
B.
Normal gastrointestinal examination and 
evaluation
C.
Not attributed to another disorder.
1.6.1.1 Cyclic vomiting syndrome
Description: Recurrent episodic attacks of intense 
nausea and vomiting, usually stereotypical in the 
individual and with predictable timing of episodes. 
Attacks may be associated with pallor and lethargy. 
There is complete resolution of symptoms between
attacks.
Diagnostic criteria:
A.
At least ﬁve attacks of intense nausea and 
vomiting, fulﬁlling criteria B and C
B.
Stereotypical in the individual patient and 
recur- ring with predictable periodicity
C.
All of the following:
1.
nausea and vomiting occur at least four 
times per hour
2.
attacks last for ≥ 1 hour, up to 10 days
3.
attacks occur ≥ 1 week apart
D.
Complete freedom from symptoms between 
attacks
E.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination 
do not show signs of gastrointestinal disease.
Comments:1.6.1.1 Cyclic vomiting syndrome is 
typically a self-limiting episodic condition 
occurring in child- hood, with periods of complete 
normality between episodes. The cyclic nature is 
the hallmark, and attacks are predictable.
This disorder was ﬁrst included as a childhood 
periodic syndrome in ICHD-II. The clinical features 
of this syndrome resemble those found in 
association with migraine headaches, and multiple 
threads of research over the last years have 
suggested that 1.6.1.1 Cyclic vomiting syndrome is 
a condition related to migraine.
1.6.1.2 Abdominal migraine
Description: An idiopathic disorder seen mainly in 
children as recurrent attacks of moderate to severe 
midline abdominal pain, associated with vasomotor 
symptoms, nausea and vomiting, lasting 2–72 hours 
and with normality between episodes. Headache 
does not occur during these episodes.
Diagnostic criteria:
A.
At least ﬁve attacks of abdominal pain, 
fulﬁlling criteria B–D
B.
Pain has at least two of the following three 
characteristics:
1.
midline location, periumbilical or poorly 
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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
Notes:
1. Attacks tend to recur monthly.
2. Ataxia is more likely in older children within 
the affected age group.
3. The 
differential 
diagnosis 
includes 
gastro-
oesophageal reﬂux, idiopathic torsional dystonia 
and com- plex partial seizure, but particular 
attention must be paid to the posterior fossa and 
craniocervical 
junction 
where 
congenital 
or 
acquired lesions may pro- duce torticollis.
Comments: The child’s head can be returned to 
the neutral position during attacks: some 


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resistance may be encountered but can be 
overcome.
These observations need further validation by 
patient diaries, structured interviews and 
longitudinal data collection.
1.6.3 Benign paroxysmal torticollis may evolve into
1.6.2 Benign paroxysmal vertigo or 1.2 Migraine 
with aura (particularly 1.2.2 Migraine with 
brainstem 
aura) 
or 
cease 
without 
further 
symptoms.
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‘‘migralepsy’’ be considered an obsolete 
concept?  A multicenter retrospective 
clinical/EEG study and review of the literature. 
Epilepsy Behav 2011; 21: 52–59.
1.5 Probable migraine
Granella F, Alessandro RD, Manzoni GC, et al. 
International Headache Society classiﬁcation: 
inter- observer reliability in the diagnosis of 
primary head- aches. Cephalalgia 1994; 14: 16–
20.
Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis 
of migraine: empirical analysis of a large clinical 
sample of atypical migraine (IHS 1.7) patients 
and proposed revision of the IHS criteria. 
Cephalalgia 2001, 21: 584–595.
Rasmussen BK, Jensen R and Olesen J. A
population- based analysis of the diagnostic 
criteria of the International Headache Society.
Cephalalgia 1991; 11: 129–134.
Russell MB and Olesen J. Migrainous disorder and 
its relation to migraine without aura and migraine 
with aura. A genetic epidemiological study. 
Cephalalgia 1996; 16: 431–435.
1.6.1 Recurrent gastrointestinal disturbance
Abu-Arafeh I and Russel G. Prevalence and clinical 
features of abdominal migraine compared with  
those of migraine headache. Arch Dis Child 1995; 
72: 413–417.
Al-Twaijri WA and Shevell MI. Pediatric migraine 
equivalents: occurrence and clinical features in 
prac- tice. Pediatr Neurol 2002; 26: 365–368.
Dignan F, Abu-Arafeh I and Russell G. The 
prognosis of childhood abdominal migraine. Arch 
Dis Child 2001; 84: 415–418.
Drossman  DA  and  Dumitrascu  DL.  Rome   III:   
new standard for functional gastrointestinal 
disorders. J Gastrointestin Liver Dis 2006; 15: 
237–241.
Farquar HA. Abdominal migraine in children. BMJ
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  syn- drome 
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 
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the literature. J Child Neurol 2009; 24: 155–
160.


Allergan Confidential
Protocol 3101-311-002 Amendment 1
76
12.2 Examples of Prohibited Medications

The following medications are prohibited 30 days prior to Visit 1 (unless otherwise 
indicated) and throughout the study:
o
Strong OATP1B1 and OATP1B3 inhibitors (eg, gemfibrozil, cyclosporine)
o
CBD oil
Strong/moderate CYP3A4 inducers
Strong CYP3A4 inhibitors
Anti-depressants/ 
Anti-anxiety
Barbiturates 

Amobarbital 

Aprobarbital 

Butalbital 

Butabarbital 

Mephobarbital 

Pentobarbital 

Phenobarbital 

Secobarbital 
Nefazodone 
Anti-seizure
Carbamazepine 
Oxcarbazepine 
Phenytoin 
Primidone 
Diabetes 
Pioglitazone 
Troglitazone 
Glucocorticoid 
(Systemic)
Betamethasone 
Dexamethasone
Hydrocortisone 
Methylprednisolone 
Prednisolone 
Prednisone 
Triamcinolone 
Antibiotics
Rifabutin 
Rifampicin/Rifampin 
Erythromycin 
Clarithromycin 
Telithromycin
Anti-fungal
Itraconazole 
Ketoconazole 
Anti-HIV
Efavirenz 
Nevirapine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Others
St. John’s wort 
Enzalutamide 
Modafinil 
Armodafinil 


Allergan Confidential
Protocol 3101-311-002 Amendment 1
77
Drugs with narrow therapeutic margins with 
potential for CYP drug interactions
Warfarin 
Digoxin 
Cisapride 
Pimozide 
For participants from lead-in study 
3101-303-002 already taking 1 medication 
with demonstrated efficacy for the 
prevention of migraine are allowed to 
maintain previous preventive medication at 
a stable dose during this study.
Topiramate 
Valproic acid, sodium valproate, divalproex sodium 
Amitriptyline 
Nortriptyline 
Metoprolol 
Atenolol 
Nadolol 
Propranolol 
Timolol 
Flunarizine 
Candesartan 
Lisinopril 
Desvenlafaxine 
Venlafaxine 
The following treatments are prohibited 6 months prior to screening and throughout the 
study period:

Botulinum toxin injections into areas of the head, face, or neck (eg, Dysport®, Botox®, 
Xeomin®, Myobloc®, Jeuveau™)

Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™,
Emgality™, Ajovy®, Vyepti™)


Allergan Confidential
Protocol 3101-311-002 Amendment 1
78
12.3 Study Visits Conducted Remotely
Remote study visits, conducted virtually or by phone, are permitted if the Investigator determines 
there to be a public health risk due to viral infection (eg, COVID-19) to the participant or site 
staff. During remote study visits, the Remote Visit Schedule of Assessments (Table 12–1) will be 
followed. After Visit 1, remote study visits may be performed for up to 8 weeks at the discretion 
of the Investigator, after which, participants who cannot attend in-person for a study visit must 
discontinue from the study. Missed in-person safety assessments (ie, clinical laboratory samples, 
vital signs, and ECGs) should be collected at the next in-person visit. If available, PROs will be 
collected using a web-based portal during remote visits.




Allergan Confidential
Protocol 3101-311-002 Amendment 1
80
12.4 Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
AIM-D
Activity Impairment in Migraine – Diary
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CBD
cannabidiol
CFR
Code of Federal Regulations
CGRP
calcitonin gene-related peptide
CM
chronic migraine
C-SSRS 
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
CYP3A4
cytochrome P450 3A4
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EOS
end of study
ET
early termination
eTablet
electronic tablet
FDA
Food and Drug Administration
GCP
Good Clinical Practices
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd edition
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone releasing system
IV
intravenous
IWRS
interactive web response system
mITT
modified intent to treat
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, Version 2.1


Allergan Confidential
Protocol 3101-311-002 Amendment 1
81
Term/Abbreviation
Definition
NSAID
nonsteroidal anti-inflammatory drug
OATP1B1
organic anion transporting polypeptide 1B1
OATP1B3
organic anion transporting polypeptide 1B3
PK
pharmacokinetic
PRO
patient reported outcome
QD
once daily
QTcF
QT interval corrected for heart rate using Fridericia formula 
(QTcF = QT/(RR)⅓)
RNA
ribonucleic acid
SAE
serious adverse event
SNRI
serotonin norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
WOCBP
women of childbearing potential


Allergan Confidential
Protocol 3101-311-002 Amendment 1
82
12.5
Protocol Amendment 1 Summary
Title: A Phase 3, Multicenter, Open-Label, 12-Week Study to Evaluate the Safety and 
Tolerability of Oral Atogepant for the Prevention of Migraine in Chinese Participants With 
Chronic Migraine
Protocol 3101-311-002
Date of Amendment: July 2020
Amendment Summary
This amendment includes changes made to Protocol 3101-311-002 dated 18 March 2020. The 
protocol was amended to: 

Remove reference to Study 3101-305-002 (regional study of preventive treatment of 
episodic migraine in China and Japan)

Add Attachment 12.3 for study visits to be conducted remotely to eliminate immediate 
potential hazards to participants and study staff due to the COVID-19 pandemic, while 
ensuring participant safety and maintaining data integrity
The table below provides details related to content changes that were made in the protocol, and a 
brief rationale for these changes.  Minor editorial and document formatting revisions have not 
been summarized.
Section
Revision
Rationale
Throughout
Removal of episodic migraine as an indication in this 
study.
Removed in line with 
removal of Study 
3101-305-002.
Throughout
Removal of lead-in Study 3101-305-002 (episodic 
migraine) from protocol.
Due to business decision.
Section 7.4
Removal of statement that subgroup analyses will be 
performed for selected endpoints.
Removal of Study 
3101-305-002 as lead-in 
study.
Attachment 12.3
Addition of “Attachment 12.3 Study Visits Conducted 
Remotely” to describe remote study visits, including a 
Remote Visits Schedule of Assessments.
To eliminate immediate 
potential hazards to 
participants and study staff 
due to the COVID-19 
pandemic while ensuring 
participant safety and 
maintaining data integrity.

SAP_001.pdf: 
C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 of  3 5
Title P a ge
Pr ot oc ol Title: A P H A S E 3, M U L TI C E N T E R, O P E N -L A B E L, 1 2 -W E E K S T U D Y T O
E V A L U A T E T H E S A F E T Y A N D T O L E R A BI LI T Y O F O R A L A T O G E P A N T F O R T H E 
P R E V E N TI O N O F MI G R AI N E I N C HI N E S E P A R TI CI P A N T S WI T H C H R O NI C 
MI G R AI N E
Pr ot oc ol N u m ber:
3 1 0 1- 3 1 1- 0 0 2
C o m p o u n d N u m ber:
A G N - 2 4 1 6 8 9
S p o ns or N a me:
Aller g a n P h ar m ace utic als I nter n ati o n al Li mite d
Le g al Re gistere d A d dress:
M arl o w I nter n ati o n al
T he P ar k w a y, M arl o w S L 7 1 Y L
U nite d Ki n g d o m
C hi n a A ge nt:
Aller g a n I nf or m ati o n C o ns ulti n g ( S h a n g h ai) C o., Lt d.
S uite 5 6 0 5, 5 6 F, 1 2 6 6 West N a nji n g R o a d
Ji n g a n District, S h a n g h ai, 2 0 0 0 4 0 C hi n a
Fi n al S A P A p pr o v al D ate:
1 8 M ar 2 0 2 0
S A P A me n d me nt 1 D ate:
3 1 M a r 2 0 2 2
3 4 9
N C T 0 4 8 2 9 7 4 7


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 of  3 5
T a ble of C o nte nts
List of Ta bles ..............................................................................................................................3
1.
I ntr o d ucti o n..................................................................................................................5
1. 1.
O bject i ves a n d E n d p oi nts .............................................................................................5
1. 2.
St u d y  Desi g n................................................................................................................5
2.
Stati stical H y p ot heses...................................................................................................8
3.
S a m ple Si ze Deter mi nat i on ...........................................................................................9
4.
P o p ul at i ons f or A nal ysis .............................................................................................1 0
5.
Stati stical A nal yses .....................................................................................................1 1
5. 1.
Ge neral C o nsi derati o ns ...............................................................................................1 1
5. 2.
P arti cipa nt Dis p osi tio n ................................................................................................1 1
5. 3.
Efficac y E n d p o i nt A nal ysis a n d Health O utc o m e Meas ures ........................................1 1
5. 3. 1.
Defi nit i on o f E n d p o i nt................................................................................................1 1
5. 3. 2.
Mai n A nal yt ical A p pr oac h..........................................................................................1 2
5. 3. 3.
Ke y E fficac y Meas ures ...............................................................................................1 2
5. 3. 4.
Heal t h O ut c o me Meas ures ..........................................................................................1 3
5. 3. 4. 1.
AI M - D .......................................................................................................................1 3
5. 3. 4. 2.
M S Q ...........................................................................................................................1 4
5. 4.
Ot her Safet y A nal yses ................................................................................................1 4
5. 4. 1.
E xte nt of E x p os ure .....................................................................................................1 4
5. 4. 2.
Treat me nt C o m plia nce ................................................................................................1 4
5. 4. 3.
A d verse E ve nts ...........................................................................................................1 5
5. 4. 4.
A d dit i onal Safet y Assess me nts ...................................................................................1 5
5. 4. 4. 1.
Cli nical La b orat or y  P ar a meters ...................................................................................1 5
5. 4. 4. 2.
Vi t al Sig ns.................................................................................................................. 1 6
5. 4. 4. 3.
Electr ocar di o gra m ......................................................................................................1 6
5. 4. 4. 4.
C ol u m bia -S uici de Se verit y Rat i n g Scale.....................................................................1 6
5. 5.
I nteri m A nal yses.........................................................................................................1 6
6. 
S u p p orti n g D oc u me ntati o n .........................................................................................1 7
6. 1.
A p pe n di x 1 List of A b bre viat i ons ...............................................................................1 7
6. 2.
A p pe n di x 2: C ha n ges t o Pr ot oc ol -Pl a n ne d A nal yses ...................................................1 8
6. 3.
A p pe n di x 3: S u p p orti n g St u d y  I nfor m at i on ................................................................1 9
6. 3. 1.
D e m o gra p hic ..............................................................................................................1 9
6. 3. 2.
Baseli ne a n d Disease C haracterist ics...........................................................................1 9
6. 3. 3.
Pr ot oc ol  De viati ons ....................................................................................................1 9
6. 3. 4.
Me dical Hist or y ..........................................................................................................1 9
6. 3. 5.
Pri or/ C o nc o mi t a nt me dicat i ons ...................................................................................1 9
6. 3. 6.
A d verse E ve nts of S pecial I nterest ..............................................................................2 0
6. 3. 7.
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for Safet y E n d p o i nts ...................................2 0
6. 3. 7. 1.
La b orat or y  val ues i n C o n ve nti o nal U nit ......................................................................2 0
6. 3. 7. 2.
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for Cli nical  La b orat or y 
Para m eters ..................................................................................................................2 2
6. 3. 7. 3.
Cri teria f or He patic La b orat or y A b n or malities ............................................................2 3
3 5 0


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 of  3 5
6. 3. 7. 4.
P ote nti all y Cli nicall y Si g nifica nt Cri t eria for Vi t al Sig ns ............................................2 4
6. 3. 7. 5.
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for E C G para m eters ....................................2 4
6. 4.
Data ha n dli n g c o n ve nti o n ...........................................................................................2 4
6. 4. 1.
A nal ysis Wi n d o w .......................................................................................................2 4
6. 4. 2.
Der i ve d Efficac y Data ................................................................................................2 6
6. 4. 2. 1.
Deri vat i on of Efficac y E n d p o i nts Base d o n e Diar y Data .............................................2 6
6. 4. 3.
Deri vat i on of Healt h O utc o me E n d p o i nts....................................................................2 7
6. 4. 4.
Re peate d or U nsc he d ule d Assess me nts of Safet y Para m eters ......................................2 9
6. 4. 5.
Missi n g Date of t he Last D ose of St u d y  I nter ve nti o n..................................................2 9
6. 4. 6.
Missi n g Se verit y Assess me nt f or A d verse E ve nts .......................................................2 9
6. 4. 7.
Missi n g Ca usal Relat i ons hi p t o St u d y  tr e at me nt for A d verse 
E ve nts .........................................................................................................................2 9
6. 4. 8.  
Missi n g Date I m p utati o n .............................................................................................3 0
6. 4. 9.
Missi n g Date I nf or mati o n f or Pri or or C o nc o mita nt Me dicat i ons ................................3 1
6. 4. 9. 1.
I nc om p lete Start Date ................................................................................................. 3 1
6. 4. 9. 2.
I nc om p lete St o p Date ................................................................................................. 3 1
6. 4. 1 0.
C haracter Val ues of Cli nical La b orat or y  Para meters...................................................3 2
7.
C o vi d- 1 9 Relate d A nal yses .........................................................................................3 4
8.
Refere nces ..................................................................................................................3 5
List of T a bles
Ta ble 1- 1
Sc he d ule of Visit s a n d Pr oce d ures........................................................................7
Ta ble 6- 1
List of Selecte d Para meters Re p orte d i n C o n ve nt i onal U nit ................................2 1
Ta ble 6- 2
Prese nt i n g La b orat or y Data Usi n g SI a n d C o n ve nti o nal U nits i n Narrati ves.......2 2
Ta ble 6 - 3
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for Cli nical  La b orat or y Para meters ....2 2
Ta ble 6- 4
Cri teria f or He patic La b orat or y A b n or malities ...................................................2 3
Ta ble 6- 5
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for Vi t al Si g ns ...................................2 4
Ta ble 6- 6
P ote nti all y Cli nicall y Sig nifica nt Cri t eria for E C G para m eters ...........................2 4
Ta ble 6- 7
Efficac y a n d Healt h O utc o me A nal ysis Visit Defi nit i ons f or e Diar y Data 
( M o nt hl y)...........................................................................................................2 5
Ta ble 6 - 8
Efficac y A nal ysis Visit Defi nit i ons f or M S Q v 2. 1 ..............................................2 5
Ta ble 6 - 9
Sa fety A nal ysis Visit Defi nit i ons .......................................................................2 5
Ta ble 6 - 1 0
It e m V alu es f or M S Q Ite m  Res p o nses................................................................2 8
Ta ble 6- 1 1
E xa m ples of C o di n g S pecial C haracter Val ues f or Cli nical La b orat or y  Para meters
..........................................................................................................................3 3
3 5 1


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 4 of  3 5
S A P Versi o n H ist or y
S A P Versi o n Hist or y S u m m ar y
S A P 
Versi o n
A p pr o v al D ate
C h a n ge
R ati o n ale
1 
1 8 Mar
2 0 2 0
N ot A p plica ble
Ori gi nal  versio n
2 
3 1 Mar 2 0 2 2
See ta bl e belo w
U p dates t o pr ot oc ol a n d e x pecte d n u m ber 
of  s u bjects i n st u d y
S u m m ar y of C h a n ges fr o m t he Fi n al S A P ( d ate d 1 8 -M a r -2 0 2 0):
Secti o n: Descri pti o n
Re as o n
1.
A d de d Healt h O utc o me e n d p oi nt s fr o m t he 
Pr ot oc ol .
T her e will be n o se parate H O S A P.
2.
Fr o m t he title of t he Fi nal S A P re m o ve d “ or 
E pis o dic”
Per t he u p date d title of t h e Pr ot oc ol 
A me n d me nt 1.
3.
Re m o ve d 3 1 0 1 - 3 0 5-0 0 2 st u d y t hr o u g h o ut t he S A P , 
a n d s u b gr o u p a nal ysis b y lea d -i n st u d y, a n d 
u p date d t he Sa m ple size ( wit h 1 2 0 pa rtici pa nts).
Per t he Pr ot oc ol A me n d me nt 1.
4.
Secti o n 1. 1.: Re m o ve d “ Pri mar y” fr o m ‘ O bjecti ves’
Per t he pr ot oc ol s y n o psis.
5 .
Secti o n 6. 3. 4: Clarifie d t he c ollecti o n of me dical 
hist or y.
6 .
A d de d C O VI D -1 9 relate d data s u m mar y
( T he st u d y C R F is pla n ne d t o be 
u p date d wit h C O VI D - 1 9 later, ~b y 
Ja n uar y)
7.
U p date d s a mple size (t o a p pr o xi matel y 3 ).
D ecrease d d ue t o st o p pi n g 
en r oll me nt of C hi nese patie nts i n t he 
lea d-i n 3 1 0 1- 3 0 3- 0 0 2 st u d y.
8.
Re m o ve t he s u m mar y ta bles a n d prese nt i n listi n gs .
D ue t o s mall n u m ber of s u bjects 
e x pecte d i n t he st u d y
3 5 2


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 5 of  3 5
1.
I ntr o d ucti o n
T his Stati stical A nal ysis Pla n ( S A P) a me n d me nt 1 pr o vi des a tec h nical a n d detaile d ela b orati o n 
of  t he statistical a nal yses of t he safety a n d/ or efficac y data as o utli ne d a n d s pecifie d i n t he 
pr ot oc ol  a me n d me nt 1 of  3 1 0 1- 3 1 1- 0 0 2 date d 0 6 -J ul- 2 0 2 0. T he maj or c ha n ge s t o t he S A P are t o 
eli mi nate or m o dif y s pecifie d efficac y , safet y a n d de m o gra p hic e n d p oi nts, re m o ve lea d-i n 
st u d y 3 1 0 1- 3 0 5- 0 0 2, a n d a d d i n g t he C O VI D-1 9 data s u m maries. S pecificat i ons of ta bles, fi g ures 
a n d data list i n gs are c o ntai ne d i n a se parate d oc u me nt.
1. 1.
O bjecti ves a n d E n d p oi nts
Eac h st u d y o bject i ve is prese nte d wit h c orres p o n di n g e n d p oi nt bel o w:
O bjecti ves
E n d p oi nts

T o e val uate t he safet y a n d t olera bilit y
of  treat me nt wit h at o ge pa nt 6 0 m g 
o nce dail y  ( Q D) o ver a 1 2-wee k 
d urati o n f or t he pre ve nt i on of 
mi grai ne i n C hi nese parti ci pa nts w h o 
c o mplete d St u d y  3 1 0 1- 3 0 3- 0 0 2 
(C hr o nic mi grai ne (C M) ).

T o e val uate t he efficac y  of treat me nt 
wi t h at o ge pa nt 6 0 m g Q D w he n 
a d mi nistere d o ver 1 2 wee ks f or t he 
pre ve nt i on of mi grai ne i n C hi nese 
parti ci pa nts wit h C M.
S afet y Assess me nts
A d verse e ve nts ( A E) , cli nical la b orat or y 
val ues, vital si g ns, electr ocar di o gra m ( E C G), 
C ol u m bia -S uici de Se verit y Rat i n g Scale 
( C- SS R S).
E n d p oi nt s
C ha n ge fr o m baseli ne i n m o nt hl y 
mi grai ne da ys at eac h mo nt hl y  p eri o d 
(i.e. eac h c o nsec uti ve 4-wee k peri o d) .
1. 2.
St u d y Desi g n
T his is a m ult ice nter, o pe n-lab el , 1 2-wee k, safet y e xte nsio n st u d y  c o n d ucte d i n C hi na. 
P arti cipa nts will be treate d wit h at o ge pa nt 6 0 m g o nce dail y , t o be ta ke n o n a n o ut patie nt basis at 
a p pr o xi matel y 2 ce nters.
T he st u d y  will c o nsist of a 1 2-wee k treat me n t peri o d a n d a 4-wee k safet y f oll ow u p peri o d. All 
parti ci pa nts w h o c o m plete St u d y 3 1 0 1- 3 0 3-0 0 2, a n d meet all eli gi bilit y re q uire me nts ma y 
parti ci pate i n t his st u d y. 
After si g ni n g t he i nf or me d c o nse nt, C hi nese partici pa nts will direct l y r oll over fr o m 
St u d y 3 1 0 1 3 0 3- 0 0 2 ( P hase 3 C M); hereafter referre d t o as t he lea d -i n st u d y. As s uc h, 
parti ci pa nts will ha ve Visit 7 fr o m t he lea d -i n st u d y f u ncti on as Visit 1 f or t his e xte nsi o n st u d y
( 3 1 0 1- 3 1 1- 0 0 2). After Visit 1, st u d y visits will occ ur e ver y 4 wee ks d uri n g t he 1 2-wee k 
o pe n -label tr e at me nt perio d. A safet y  fol l ow -u p visi t will occ ur 4 wee ks after t he last d ose of 
at o ge pa nt 6 0 m g i n t he o pe n -la bel treat me nt peri o d.
3 5 3


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 6 of  3 5
N ote, t here ma y  be partici pa nts w h o c o m plete Visit 7 i n t he lea d -i n st u d y befor e t hi s e xte nsio n 
st u d y ( 3 1 0 1- 3 1 1-0 0 2) has bee n i nit iate d. T h ose partici pa nts s h o ul d c om p lete Visit 7/ E T a n d 
Vi sit 8/e n d of st u d y (E O S ) Visit (i ncl u di n g disc o nti n uat i on of st u d y  int er ve nt i on) per t he l ea d-i n 
st u d y Sc he d ule of Visits a n d Pr oce d ures.
De pe n di n g o n t he ti mi n g o f t he i nit iati on of t his e xte nsi o n st u d y ( 3 1 0 1-3 1 1 - 0 0 2), i n relati o n t o 
eac h partici pa nt’s pla n ne d Visit 8 sc he d ule i n t he lea d-i n st u d y, Visit 1 for t hi s e xte nsi on st u d y  
ca n be c o n d ucte d o n t he sa me da y as Visit 8/ E O S Visit f or t he lea d -i n st u d y, or s o o n t hereafter.

If t his e xte nsi on st u d y  is i nitiate d pri or t o t he partici pa nt’s pla n ne d Visit 8 i n t he lea d-i n 
st u d y, t he n Visit 8/ E O S Visit i n t he lea d-i n st u d y s h o uld be c o n d ucte d o n t he sa me da y  as 
Vi sit 1 for t hi s e xte nsi on st u d y  ( 3 1 0 1- 3 1 1-0 0 2).

If t his e xte nsio n  st u d y is n ot i nitiate d prior t o t he parti ci pa nt’s pla n ne d Visit 8 i n t he lea d-i n 
st u d y (ie, t here is a ga p bet wee n Visit 8 of t he lea d-i n st u d y a n d Visit 1 of t his e xte nsi on 
st u d y), t he n Visit 8/ E O S s h o uld be c o n d ucte d as pla n ne d per t he lea d -i n stu d y Sc he d ule of 
Vi sits a n d Pr oce d ures. W he n t his e xte nsi on st u d y  is i nitiate d, t he partici pa nt s h o ul d ret ur n t o 
t he cli nic as s o o n as p ossi ble, a n d Visit 1 f or t his e xte nsio n st u d y s h o uld be c o n d ucte d per 
Ta ble 1 - 1 Sc he d ule of Visits a n d Pr oce d ures.
P arti cipa nts will ret ur n t o t he cli nic f or safet y assess me nts at 4, 8, a n d 1 2 wee ks relat i ve t o 
Vi sit 1. A safet y f oll ow- u p visit will occ ur 4 wee ks after t he last d ose of at o ge pa nt 6 0 m g o nce 
dail y . F or details, please see Ta ble 1- 1 Sc he d ule of Visits a n d Pr oce d ures.
T he pri mar y  o bjecti ve of t he st u d y is t o assess t he safety a n d t olera bi lity of  treat me nt wit h 
at o ge pa nt 6 0 m g o nce dail y o ver a 1 2-wee k d urati o n f or t he pre ve nt i on of mi grai ne i n C hi nese 
parti ci pa nts w h o c o m plete d St u d y 3 1 0 1-3 0 3- 0 0 2 ( C M). T he pla n ne d safet y assess me nts i ncl u de 
c ollect i on of A Es, cli nical la b orat or y  deter mi nati ons, E C Gs, vital si g n meas ure me nts, p h y sical 
e xa mi nat i ons, a n d t he C -S S R S.
3 5 4


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 7 of  3 5
T a ble 1- 1
Sc he d ule of Visits a n d Pr oce d ures
St u d y Peri o d
O pe n -l a bel Tre at me nt Peri o d ( 1 2 wee ks)
S afet y 
F oll o w -u p 
Peri o d
( 4 wee ks)
Visit #
Visit 1 a
Visit 2  
Visit 3  
Visit 4
Visit 5/ E O S
Wee k ( D ay)
D ay 1
Wee k 4 
( D ay 2 8)
Wee k 8 
( D ay 5 6)
Wee k 1 2 
( D ay 8 4)
Wee k 1 6 
( D ay 1 1 2)
Visit Wi n d o ws
N/ A
± 3 da ys
± 3 da ys
± 3 da ys
± 3 da ys
O btai n I nf or me d C o nse nt a n d partici pa nt pri vac y
X
Access I W R S
X  
X  
X  
X  
X
Assess i ncl usi o n/e xcl usi o n criteria
X
C ollect me dical hist or y b
X
Perf or m p h ysical e xa mi nati o n
X
X  
X
C ollect vital si g n meas ure me nts c
X
X
X
X
X
Perf or m E C G
X
X
X
Perf or m uri ne pre g na nc y test d
X
X
X
X
X
Cli nical la b orat or y deter mi nati o ns e
X
X
X
X
X
e Diar y i nstr ucti o ns a n d trai ni n g f
X
Partici pa nt e Diar y data c ollecti o n f, g 
X
e Diar y data ( hea dac he d urati o n, fre q ue nc y, c haracteristics a n d 
s y m pt o ms, ac ute me dicati o n use, AI M-D, acti vit y le vel a n d 
acti vit y li mitati o n) a n d c o m plia nce re vie wh
X  
X  
X
M S Q v 2. 1 (e Ta blet)
i,j
X
X
X
X
X
C -S S R S (e Ta blet) k
X
X
X
X
X
C ollect e Diar y
X
Dis pe nse at o ge pa nt
X
X
X
Re vie w at o ge pa nt c o m plia nce a n d acc o u nta bilit y
X
X
X
A d verse e ve nts
X
C o nc o mita nt me dicati o ns/c o nc urre nt pr oce d ures
X
C M = c hr o nic mi grai ne; C- S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; E C G = electr ocar di o gra m; E O S = e n d of st u d y; 
E T = earl y ter mi nati o n; e Ta blet = electr o nic ta blet; I N R = i nter nati o nal n or malize d rati o; I W R S = i nteracti ve we b res p o nse 
s yste m; W O C B P = w o me n of c hil d beari n g p ote ntial.
a
After pr o vi di n g i nf or me d c o nse nt f or t his st u d y, Visit 1 will be c o n d ucte d o n t he sa me da y as Visit 7 / Visit 8 of t he lea d -i n 
st u d y ( St u d y 3 1 0 1- 3 0 3-0 0 2 [ P hase 3 C M] ); pr oce d ures c o n d ucte d as part of Visit 7 of t he lea d -i n st u d y s h o ul d n ot be 
re peate d. Visit 1 m ust be c o n d ucte d i n office. All ot her visits, s h o ul d be c o n d ucte d i n office u nless it is necessar y t o c o n d uct 
a re m ote visits f or t he safet y of partici pa nts (e g, C O VI D-1 9 or ot her pa n de mic): f or details please refer t o t he Re m ote Visit 
Sc he d ule of Assess me nts i n t he pr ot oc ol).
b
Me dical hist or y will be c ollecte d
f or partici pa nts w h o ha ve a ga p bet wee n t he last visit of t he lea d -i n st u d y a n d Visit 1 of 
t his e xte nsi o n st u d y a n d o nl y ne w me dical hist or y d uri n g t he ga p nee d t o be c ollecte d.
c
Vital si g n meas ure me nts: wei g ht, sitti n g a n d sta n di n g p ulse rate, res pirat o r y rate, sitti n g a n d sta n di n g bl o o d press ure, a n d 
b o d y te m perat ure.
d
F or W O C B P
o nl y, a uri ne pre g na nc y test will be perf or me d at all visits. 
e
Cli nical la b orat or y deter mi nati o ns i ncl u de c he mistr y, he mat ol o g y, c oa g ulati o n para meters (I N R), a n d uri nal ysis t o be 
c ollecte d f or all visits. Sa m ples f or ser ol o g y a n d t he uri ne dr u g scree n will be c ollecte d o nl y at Visit 1.
f
Partici pa nts s h o ul d be gi n usi n g t he e Diar y at Visit 1 a n d f or t he d urati o n of t he treat me nt peri o d .
g
Dail y  e Diar y data c ollecti o n i ncl u des: hea dac he fre q ue nc y, d urati o n, c haracteristics, s y m pt o ms, ac ute me dicati o n use, 
AI M -D, Acti vit y Le vel, a n d Acti vit y Li mitati o n.
h
Partici pa nts m ust bri n g t heir e Diar y t o all visits (e xce pt Visit 5).
i
Partici pa nt will c o m plete o n e Ta blet.
j
P R O meas ures s h o ul d be a d mi nistere d pri or t o a n y tests a n d/ or e val uati o ns u nless i n dicate d ot her wise i n t he pr ot oc ol.
k
At all visits, t he “ Si nce Last Visit” C -S S R S will be c o m plete d f or all partici pa nts. Cli nicia n s will c o m plete o n e Ta blet.
3 5 5


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 8 of  3 5
2.
St atistic al H y p ot heses
Si nce t he pri mar y  o bjecti ve of t his st u d y is t o assess t he safety a n d t olera bilit y of 1 2 wee ks of 
at o ge pa nt treat me nt, t here is n o statistical h y p ot hesis s pecifie d f or t he st u d y.
3 5 6


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 9 of  3 5
3.
S a m ple Size Deter mi n ati o n
C hi nese partici pa nts w h o c o m plete St u d y  3 1 0 1- 3 0 3- 0 0 2, a n d meet all eli gi bilit y re q uire me nts, 
ma y partici pate i n t his e xte nsi o n st u d y . A p pr o xi matel y 3 C hi nese parti ci pa nts are e x pecte d t o 
parti ci pate i n t his e xte nsi o n st u d y . T he sa m ple size is differe nt fr o m  t he sa m ple size pla n ne d i n 
t he pr ot oc ol.
3 5 7


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 0 of  3 5
4.
P o p ul ati o ns f or A n al ysis
T he a nal ysis p o p ulat i ons will c o nsist of partici pa nts as defi ne d bel o w.

T he Safet y p o p ul at i on will  c o nsist of all p artici pa nts w h o recei ve at least o ne d ose of t he 
st u d y int er ve ntio n ( at oge pa nt) i n t his e xte nsi o n st u d y .

T he m I T T p o p ul at i on will c o nsist of all part ici pa nts w h o recei ve d at least 1 d ose of st u d y 
i nter ve nt i on (at o ge pa nt) i n t his e xte nsi on st u d y  a n d ha d at least 1 eval ua ble p ost -baseli ne 
4- wee k peri o d of e Diar y data i n t his e xte nsi o n st u d y .

T he list i n g of seri o us a d verse e ve nts a n d partici pa nts w h o die d will be pr o vi de d f or t he 
Scree ne d p o p ul at i on. T he Scree ne d p o p ulati o n will  c o nsist of all r oll over parti ci pa nts 
fr om lea d-i n 3 1 0 1- 3 0 3- 0 0 2, w h o si g ne d i nf or me d c o nse nt f or t he st u dy.
3 5 8


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 1 of  3 5
5.
St atistic al A n al yses
5. 1.
Ge ner al C o nsi der ati o ns

Efficac y e n d p o i nts will be liste d usi n g t he m I T T p o p ulat i on.

S afet y e n d p o i nts will be liste d usi n g t he Safet y p o p ul at i on.

P arti al dates will be treate d as missi n g i n c o m p utati on or i n varia ble deri vat i on u nless
s pecifie d ot her wise, b ut will be liste d i n t he data listi n gs as t he y a p pear o n t he e C R F.

T he baseli ne val ue as defi ne d f or t he lea d -i n st u d y will be use d as t he baseli ne i n t his 
e xte nsi o n st u d y . F or mo nt hl y e n d p oi nts, baseli ne is defi ne d as assess me nt s d uri n g t he last
2 8 da y s of baseli ne peri o d i n t he lea d-i n st u d y. F or efficac y a n d safet y e n d p o i nts t hat are 
assesse d at cli nical visit s, baseli ne is defi ne d as t he last n o n-missi n g efficac y or safet y 
assess me nt , res pecti vel y, bef ore t he first d ose of st u d y  int er ve nt i on i n t he lea d-i n st u dy .

St u d y  int er ve nt i on is treat me nt a d mi nistere d (at o ge pa nt 6 0 m g Q D ).

I n ge neral, st atistical a nal yse s will be perf or me d usi n g S A S versi on 9. 4 or hi g her

Me d D R A versi o n 2 4. 0 or hi g her will be use d t o c o de a d verse e ve nts , a n d me dical hist or y

W H O Dr u g Gl o bal B 3 ( v. 2 0 2 1 0 3 or hi g her ) will be use d t o c o de me dicat i ons .
5. 2.
P artici p a nt Dis p ositi o n
T he dis p osit i on will be liste d f or partici pa nts.
5. 3.
Effic ac y E n d p oi nt A n al ysis a n d He alt h O utc o me Me as ures
5. 3. 1.
Defi niti o n of E n d p oi nt
Si nce t he pri mar y  o bjecti ve of t his o pe n -lab el  e xte nsi on st u d y is t o assess t he safety a n d 
t olera bilit y of 1 2 wee ks of at o ge pa nt treat me nt, efficac y e n d p o i nts are n ot classifie d as pri mar y, 
sec o n dar y, or a d ditio nal .

T he f oll owi n g e n dp oi nt will be liste d:C ha n ge fr o m baseli ne i n m o nt hl y  mi grai ne da ys at 
eac h mo nt hl y  p erio d (ie, eac h c o nsec ut i ve 4-wee k peri o d)
Ot her efficac y meas ures c ollecte d, i ncl u di n g healt h o utc o m e e n d p o i nts, will be prese nte d i n 
listi n gs.
O n a dail y basis d uri n g t he o pe n -label tr e at me nt perio d, parti ci pa nts are t o rec or d i nt o a n e Diar y
i nf or mat i on o n t he dail y  t ot al d uratio n of  hea dac he, hea dac he s pecific c haracterist ics a n d 
s y m pt o ms, t he w orst pai n se verity,  a n d use of a n y ac ute hea dac he pai n me dicati on. Parti ci pa nt s 
will be a ble t o re p ort hea dac he data, i ncl u di n g a bse nce of hea dac he, f or t he da y  of t he e Diar y 
re p ort an d f or t he da y i m me diatel y pri or t o t he da y of t he e Diar y re p ort, as l o n g as i nf or mat i on 
re p orte d is f or a ti me s u bse q ue nt t o t he partici pa nt’s m ost rece nt re p ort. T his is defi ne d as a o ne-
d a y  “ missi n g-recall” wi n d o w.
F o ll owi n g Visi t 1, t here are 3 visits at 4- wee k i nter vals e nc o m passi n g a 1 2 -wee k o pe n -label
treat me nt peri o d of  t he st u d y a n d a 4-wee k safety f ollo w - u p p eri o d . I n practice, t here ma y or 
ma y n ot be e xact 4- wee k d urati o ns bet wee n t w o c o nsec uti ve visits a n d t he visits mi g ht n ot ali g n 
wi t h eac h 2 8-d a y  p erio d rec or de d i n t he e Diar y  (ie, Wee ks 1 t o 4, 5 t o 8 a n d 9 t o 1 2, 
3 5 9


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 2 of  3 5
c orres p o n di n g t o Da ys 1 t o 2 8, 2 9 t o 5 6, a n d 5 7 t o 8 4). T heref ore, f or m o nt hl y data a nal ysis 
p ur p oses, t he n u m ber of mi grai ne da ys will be calc ulate d f or c o nsec uti ve 2 8 -d a y  p erio ds 
be gi n ni n g wit h Da y 1 , t he first d ose date of t he o pe n-la bel st u d y int er ve nt i on.
F or m ore details refer t o t he Pr ot oc ol A me n d me nt 1 Secti o ns 6. 2 a n d 6. 3.
5. 3. 2.
M ai n A n al ytic al A p pr o ac h
M i grai ne da ys will  be liste d base d o n t he mI T T p o p ulat i on.
5. 3. 3.
Ke y Effic ac y Me as ures
A mi gr ai ne d a y is defi ne d as a n y cale n dar da y o n w hic h a hea dac he occ urs w hic h meets criteria 
A, B, a n d C O R meets criteria D a n d E, as liste d bel o w, as per partici pa nt e Diar y. Cale n dar da ys 
be gi n at mi d ni g ht a n d last u ntil 1 1: 5 9 P M ( 2 3: 5 9).
A.
Hea dac he has at least t w o of t he f o ll owi n g f o ur c haracterist ics:
i.
U nilateral l ocati o n
ii. P ul sati n g q uality
iii. M o derate or se vere pai n i nte nsit y
i v. A g gra vate d b y  or ca usi n g av o i da nce of r o uti ne p h ysical acti vity (e g, wal ki n g or 
cli m bi n g stairs)
B.
At  least o ne of t he f oll owi n g:
i.
Na usea a n d/ or v o mit i n g 
ii. P h ot o p h o bi a a n d p h o n o p h o bia
iii. T y pical  a ur a (ie, vis ual, s e ns or y, or s peec h/la n g ua ge) acc o m pa n yi n g or wit hi n 
6 0 mi n utes bef ore hea dac he be gi ns
C.
D urati o n of  hea dac he lasti n g 2 h o urs or l o n ger o n a cale n dar da y u nless a n ac ute, 
mi grai ne -s pecific me dicatio n (ie, tri pta n or er g ot deri vat i ve) was use d after t he start of t he 
hea dac he, i n w hic h case n o mi ni m u m d urat i on will be s pecifie d .
O R
D.
A n y hea dac he w hic h f ulfills o ne criteri o n fr o m ( 1) a n d at least o ne criteri o n fr o m ( 2) O R 
f ulfills at least t w o criteria fr o m ( 1) a n d n o criteria fr om ( 2).
1)
Hea dac he c haracterist ics:
i.
U nilateral l ocati o n
ii. P ul sati n g q uality
iii. M o derate or se vere pai n i nte nsit y
i v. A g gra vate d b y  or ca usi n g a v oida nce of r o uti ne p h ysical act i vity (e g, wal ki n g or 
cli m bi n g stairs)
2)
S y m pt o m s:
i.
Na usea a n d/ or v o mit i n g
ii. P h ot o p h o bi a a n d p h o n o p h o bia
iii. T y pical  a ur a (ie, vis ual, s e ns or y, or s peec h/la n g ua ge) acc o m pa n yi n g or wit hi n 
6 0 mi n utes bef ore h ea dac he be gi ns
3 6 0
 
 
 


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 3 of  3 5
B.
D urati o n of  hea dac he lasti n g 2 h o urs or l o n ger o n a cale n dar da y u nless a n ac ute, mi grai ne-
s pecific me dicati on (i e, tripta n or er g ot deri vati ve) was use d after t he start of t he hea dac he, i n 
w hic h case n o mi ni m u m d urati o n will be s pecifie d.
A he a d ac he d a y is defi ne d as a n y cale n dar da y o n w hic h hea dac he pai n lasti n g 2 h o urs or l o n ger 
occ urs u nless a n ac ute hea dac he me dicat i on (e g, i b u pr ofe n, tri pta n) was use d after t he start of t he 
hea dac he, i n w hic h case n o mi ni m u m d urat i on will be s pecifie d. N ote t hat a ntie met ics will n ot 
be c o u nte d as a n ac ute hea dac he me dicat i on f or hea dac he da y ide nt ificati o n. Cale n dar da ys be gi n 
at mid ni g ht a n d l ast u ntil 1 1: 5 9 P M ( 2 3: 5 9).
A n ac ute me dic ati o n use d a y is defi ne d as a n y da y o n w hic h a partici pa nt re p orts, per e Diar y, 
t he i nta ke of all o we d me dicat i on(s) t o treat a n ac ute mi grai ne. T he all o we d me dicati o ns i ncl u de 
t he f o ll owi n g cate g ori es of dr u gs: tri pta ns, er g ots, o pi oi ds, a nal gesics (i ncl u di n g aceta mi n o p he n), 
N S AI Ds (i ncl u di n g as piri n), a n d a nt iemet ics.
A tr i pt a n use d a y is defi ne d as a n y da y o n w hic h a partici pa nt re p orts i nta ke of a tri pta n t o treat 
a migrai ne per e Diar y .
Hea dac he da y  pai n i nte nsit y is defi ne d as t he w orst pai n i nte nsity o n a n y hea dac he da y  w here 
hea dac he pai n i nte nsit y will be s u bject i vel y rate d b y t he patie nt o n a scale fr o m mil d t o se vere:

Mil d pai n ( = 1)

M o derate pai n ( = 2)

Se vere pai n ( = 3)
If partici pa nts e x perie nce n o hea dac he i n a da y, t he n t he c orres p o n di n g pai n i nte nsity of  t hat da y 
will be set as missi n g.
5. 3. 4.
He alt h O utc o me Me as ures
T he AI M -D, Act i vity Le vel, a n d Act i vity Li mi tati o n will als o be c ollecte d dail y via a n e Diar y.
T he M S Q v 2. 1 will be a d mi nistere d i n a n e Ta blet at s pecifie d visits.
AI M -D a n d M S Q v 2. 1 will be liste d o n mI T T p o p ulat i on.
5. 3. 4. 1.
AI M - D
T he AI M -D is a n 1 1 -ite m dail y diar y  meas ure t hat assesses t he i m pact of mi grai ne a n d is 
c o mprise d of t w o d o mai ns t hat e val uate perf or ma nce of dail y  a cti vities ( 7 ite ms) a n d p h ysical 
i m pair me nt ( 4 ite ms). Partici pa nts are as ke d t o rate t he le vel of diffic ulty e x perie nce d i n t he past 
2 4 h o urs wit h perf or ma nce of dail y acti vit ies (ie, diffic ult y wi t h ho use h ol d c h ores, erra n ds, 
leis ure acti vities at h o me, leis ure or s ocial acti vities o utside t he h o me, stre n u o us p h ysical 
acti vit ies, c o nce ntrati n g, a n d t hi n ki n g clearl y) a n d p h ysical i m pair me nt (ie, diffic ult y w al ki n g, 
m o vi n g b o d y , be n di n g f or war d, a n d m o vi n g hea d) usi n g a 6-p oi nt rati n g scale ra n gi n g fr o m “ N ot 
diffic ult at all,” “ A little diffic ult,” “ S o me w hat diffic ult,” “ Ver y  diffic ult,” “ E xtre mel y diffic ult,” 
a n d “I c o ul d n ot d o it at all.” T hree i te ms i ncl u de a res p o nse of “I di d n ot …,” f or e xa m ple, “I di d 
n ot ha ve erra n ds pla n ne d.” T he AI M -D was de vel o pe d as a n electr o nic dail y diar y  wit h t he sa me 
set of q uesti ons a d mi nistere d i n hea dac he a n d n o n -hea dac he versi o ns. T he Hea dac he versi o n is 
a d mi nistere d o n da ys w he n a partici pa nt re p orts a hea dac he a n d t he N o n -Hea dac he versi o n is 
a d mi nistere d o n da ys w he n a partici pa nt d oes n ot re p ort ha vi n g a hea dac he. T he AI M -D i nstr ucts 
3 6 1
 
 
 


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 4 of  3 5
parti ci pa nts t o a ns wer eac h q uest i on base d o n t he le vel of diffic ult y e x perie nce d i n t he past 
2 4 h o urs f or b ot h versi o ns, wit h “ d uri n g y o ur hea dac he” i n dicate d f or t he AI M -D Hea dac he . I n 
a d ditio n t o t he t w o d o m ai n sc ores, a t otal sc ore usi n g all 1 1 ite ms ca n als o be calc ulate d. Eac h 
ra w dail y d oma i n sc ore, as well as t he ra w dail y  t ot al sc ore, are tra nsf or me d t o a 0-1 0 0 scale, 
wi t h hi g her sc ores i n dicati n g greater i m pact of mi grai ne (i.e., hi g her disease b ur de n).
T w o i t e ms base d o n a 2 4-h o ur recall will be a d mi nistere d dail y usi n g Hea dac he a n d N o n 
hea dac he versi o ns as a d dit i onal healt h o utc o m e meas ures a n d f or e val uati o n of t he AI M- D. T he 
first it e m will be use d t o assess acti vity le vel wit hi n t he past 2 4 h o urs wit h a 5 le vel res p o nse 
scale ra n gi n g fr om “ N o acti vit y – S pe nt all da y l yi n g d o w n” t o “ E xercise d – Bri s k wal k, r u n nin g, 
j og gi n g, bi ki n g or ot her acti vit y f or 3 0 or more mi n utes.” T he sec o n d ite m will be use d t o 
e val uate acti vit y li mitati on wi t h a 5-level res p o nse scale ra n gi n g fr o m “ N ot at all li mite d – I 
c o uld d o e ver y t hi n g” t o “ E xtre mel y li mite d”.
O verall sat isfacti on wi t h t he st u d y me dicatio n f or pre ve nt i on of mi grai ne will be assesse d usi n g a 
si n gle ite m a n d a 7-p oi nt rati n g scale ra n gi n g fr o m e xtre mel y satisfie d ( 0) t o e xtre mel y 
di ssatisfie d ( 6).
5. 3. 4. 2.
M S Q
T he M S Q v 2. 1 is a 1 4 -ite m q uesti on naire desi g ne d t o meas ure healt h- relate d q uality- of -life 
i m pair me nts attri b ute d t o mi grai ne i n t he past 4 wee ks. It is di vi de d i nt o t hree d o mai ns: R ole 
F u nct i on- Restri ct i ve assesses h o w mi grai nes li mit o ne’s dail y s ocial a n d w or k-relate d acti vities; 
R ol e F u nct i on- Pre ve nt i ve assesses h o w mi grai nes pre ve nt t hese acti vities; a n d t he E m oti o nal 
F u nct i on d o mai n assesses t he e m oti o ns ass oci ate d wit h mi grai nes. Partici pa nts res p o n d t o ite ms 
usi n g a 6 -p oi nt scale ra n gi n g fr o m “ n o ne of t he ti me” t o “all of t he ti me.” Ra w di me nsi o n sc ores 
are c o mp ut e d as a s u m of ite m res p o nses a n d rescale d t o a 0 t o 1 0 0 scale, w here hi g her sc ores 
i n dicate better q uality of  life.
T he detaile d al g orit h ms f or deri vat i on of t he a b o ve healt h o utc o me meas ures are prese nte d i n 
Secti o n 6. 4. 3
5. 4.
Ot her S afet y A n al yses
5. 4. 1.
E xte nt of E x p os ure
Treat me nt dail y  d ose will be liste d o n Safet y P o p ulati on.
5. 4. 2.
Tre at me nt C o m pli a nce
D osi n g c o m p lia nce f or a s pecifie d peri o d is defi ne d as t he t otal n u m ber of o pe n -label st u d y 
i nter ve nt i ons act uall y ta ke n b y a partici pa nt d uri n g t hat peri o d di vi de d b y t he n u m ber of o pe n -
la bel st u d y int er ve nt i ons t hat were e x pecte d t o be ta ke n d uri n g t he sa me peri o d m ult i plie d b y 
1 0 0. T he t otal n u m ber of ta blets act uall y ta ke n d u ri n g a s pecific peri o d will be calc ulate d fr o m 
t he st u d y int er ve nt i on rec or d. T reat me nt c o m p lia nce a n d d urati o n will be liste d f or t he Safet y 
p o p ul at i on.
3 6 2


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 5 of  3 5
5. 4. 3.
A d verse E ve nts
A d verse e ve nts ( A Es) will be c o de d usi n g t he Me dical Dict i onar y  for Re g ul at or y Acti vities 
( Me d D R A) versi on 2 2 . 1 or hi g her.
A n A E will be c o nsi dere d as a treat me nt -e mer ge nt a d verse e ve nt ( T E A E) if t he A E be ga n or 
w orse ne d (i ncrease d i n se verit y or beca me seri o us) o n or after t he date of t he first d ose of 
d o u bl e- bli n d st u d y  tr e at me nt i n t he lea d-i n st u d y. A n A E t hat occ urs m ore t ha n 3 0 da ys after t he 
last d ose of o pe n -label st u d y treat me nt or t he safet y f o ll o w-u p visit ( Visi t 5 ) i n t his e xte nsi on 
st u d y w hic he ver c o m es later will n ot be c o u nte d as a T E A E. Per case re p ort f or m i nstr ucti o ns, a 
ne w A E rec or d will be create d f or a n y  A E t hat w orse ns; t heref ore, T E A Es ca n be i de ntifie d as 
t hose A Es ca pt ure d i n St u d y 3 1 0 1- 3 1 1- 0 0 2 wi t h rec or de d o nset date o n or after t he date of t he 
first d ose of lea d-i n d o u ble -bli n d st u d y treat me nt a n d wit hi n 3 0 da ys after t he last d ose of 
o pe n -label st u d y treat me nt or Visit 5 w hic he ver c o mes later .
A n A E will be c o nsi dere d as a treat me nt -e mer ge nt S A E ( T E S A E) if it is a T E A E t hat als o meets 
S A E cri t eria.
T E A Es t hat starte d after t he date of last d ose of o pe n -la bel st u d y treat me nt will be c o nsi dere d as 
ne wl y e mer ge nt T E A Es ( N E A E).
O nl y T E A Es t hat starte d o n or after t he date of first d ose of o pe n -la bel st u d y treat me nt will be 
s u m marize d.
A Es will be liste d o n t he Safet y P o p ul at i on.
5. 4. 4.
A d d iti o n al S afet y Assess me nts
5. 4. 4. 1.
Cli nic al L a b or at or y P ar a meters
La b orat or y  para meters i n sta n dar d u nits at eac h assess me nt ti me p oi nt will be liste d b y st u d y 
i nter ve nt i on gr o u p f or t he f o ll owi n g la b orat or y  para meters:
C ate g or y
P ar a meter
C he mistr y
S o di u m, p otassi u m, c hl ori de, bicar b o nate, gl uc ose, bl o o d urea nitr o ge n, 
creati ni ne, t otal bilir u bi n, al kali ne p h os p hatase, as partate a mi n otra nsferase, 
ala ni ne a mi n otra nsferase, lactate de h y dr o ge nase, creati ne ki nase, t otal pr otei n, 
al b u mi n, calci u m, p h os p h or us, ur ic aci d, t otal c h olester ol, t he esti mate d 
gl o mer ular filtrati o n rate
He mat ol o g y
He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, re d bl o o d cell i n dices ( mea n 
c or p usc ular v ol u me, mea n c or p usc ular he m o gl o bi n, mea n c or p usc ular 
he m o gl o bi n c o nce ntrati o n), w hite bl o o d cell c o u nt, i ncl u di n g differe ntial 
( ne utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, a n d bas o p hils), platelet c o u nt
Ur i nal ysis
S pecific gra vit y, p H
Cli nical la b orat or y  test values will  be c o nsi dere d p ote ntiall y cli nicall y si g nifica nt ( P C S) if t hey 
meet ei t her t he lo wer -li mit or hi g her-li mit P C S criteria liste d i n Sect i on 6. 3. 7. 2 . P C S l a b orat or y 
val ues will be liste d.
3 6 3


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 6 of  3 5
P arti cip a nts wi t h a n a dj u dicate d case (i.e. A L T ≥ 3 x U L N or A S T ≥ 3 x U L N) will be liste d wit h 
t heir A L T a n d A S T assess me nts, a dj u dicati on dates, relat i ons hi p of  A L T or A S T ele vat i on t o 
st u d y int er ve ntio n, a n d c o nf o u n di n g fact or(s). A d dit i onal listi n gs will be pr o vi de d f or 
parti ci pa nts w h o meet A L T ≥ 3 x U L N or A S T ≥ 3 x U L N a n d/ or p ote ntial H y’s la w a n d ha ve 
o ne of t he f o ll owi n g cate g ori es: at least 1 a b n or mal li ver bio c h e mistr y ris k fact or, at least 1 li ver 
di sease si g n a n d s y m pt o m, at least 1 li ver dia g n ostic test perf or me d, c o ns ultati o n wit h a 
s pecialist f or li ver e val uat i on, li ver la b tests perf or me d, a n d dr u g scree n perf or me d, res pect i vel y.
P ote nti al H y’s La w crit eria wit hi n a 2 4-h o ur wi n d o w is defi ne d b y a p ost baseli ne ele vati o n o f 
ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n o tra nsferase ( A S T) ≥ 3 x U L N, al o n g wit h t otal 
bilir u bi n ( T B L) ≥ 2 x U L N a n d a n o n -ele vate d alkali ne p h os p hatase ( A L P) < 2 x U L N, all base d 
o n bl o o d dra ws c ollecte d wi t hi n a 2 4-h o ur peri o d.
5. 4. 4. 2.
Vit al Si g ns
List i n gs f or vit al si g ns (s yst olic a n d diast olic bl o o d press ures [sitti n g a n d sta n di n g], p ulse rate 
[sitti n g a n d sta n di n g], res pirat or y rate, te mperat ure, wei g ht, ort h ostati c s yst olic bl o o d press ure, 
ort h ostati c diast olic bl o o d press ure, a n d ort h ostatic p ulse rate ) at eac h assess me nt ti me p oi nt will 
be liste d. Ort h ostatic vit al si g n val ues ( ort h ostatic s yst olic a n d diast olic bl o o d press ures, a n d 
ort h ostati c p ulse rate) are defi ne d as t he c orres p o n di n g sta n di n g meas ure me nt mi n us sitti n g 
meas ure me nt of s yst olic a n d di ast olic blo o d press ures a n d p ulse rate res pecti vel y.
Vi t al si g n val ues will be c o nsi dere d P C S if t he y meet b ot h t he o bser ve d val ue criteri o n a n d t he 
c ha n ge fr o m baseli ne val ue criteri o n, if b ot h criteria are a vaila ble, or meet eit her t he o bser ve d 
val ue cri t erio n or t he c ha n ge fr o m  baseli ne val ue criteri o n t hat will be detaile d i n Sect i on 6. 3. 7. 4 . 
P articipa nts w h o ha ve P C S p ost baseli ne vital si g n val ues will be liste d.
5. 4. 4. 3.
Electr oc ar di o gr a m
List i n gs f or E C G para meters (ie, heart rate, P R i nter val, Q R S i nter val, R R i nter val, Q T i nter val, 
a nd Q Tc i nter val) at eac h assess me nt ti me p oi nt will be prese nte d. T he Q Tc will be calc ulate d 
usi n g b ot h t he Fri dericia c orrecti o n a n d t he Bazett c orrecti o n.
E C G para meter val ues are c o nsi dere d P C S if E C G val ues meet eit her t he act ual val ue or c ha n ge 
fr om bas eli ne P C S hi g h criteria liste d i n Ta ble 6- 5 . P artici pa nts wit h P C S p ost baseli ne val ues 
will be liste d.
5. 4. 4. 4.
C ol u m bi a -S uici de Se verit y R ati n g Sc ale
F or C -S S R S, partici pa nts wit h s uici dal i deat i on or s uici dal be ha vi or as rec or de d o n t he C -S S R S 
will be liste d f or t he Safet y p o p ul at i on .
5. 5.
I nteri m A n al yses
N o i nt eri m a nal ysis is pla n ne d.
3 6 4


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 7 of  3 5
6.
S u p p orti n g D oc u me nt ati o n
6. 1.
A p pe n di x 1 List of A b bre vi ati o ns
Te r m/ A b bre vi ati o n
Defi niti o n
A E
a d verse e ve nt
AI M - D
Act i vit y I m pair me nt i n Mi grai ne – Diar y
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
B P
bl o o d press ure
C M
c hr o nic mi grai ne
C N S
ce ntral ner v o us s yste m
C- S S R S
C ol u m bia -S uici de Se verit y Rati n g Scale
D B P
d iast olic bl o o d press ure 
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
e D iar y
electr o nic diar y
E T
earl y ter mi nati o n
e T a blet
electr o nic ta blet
I W R S
i nteracti ve we b res p o nse s yste m
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
mI T T
m o difie d i nte nt -t o-tr eat
M S Q v 2. 1
Mi grai ne S pecific Q ualit y of Life Q uesti o n naire, versi o n 2. 1
N E A E
ne wl y e mer ge nt T E A E ( N E A E)
P T
preferre d ter m
Q D
o nce dail y
Q Tc F
Q T i nter val c orrecte d f or heart rate usi n g t he Fri dericia f or m ula
Q Tc B
Q T i nter val c orrecte d f or heart rate usi n g t he Bazett f or m ula
S A E
seri o us a d verse e ve nt
S B P
syst olic bl o o d press ure
S O C
s yste m or ga n class
T E A E
treat me nt-e mer ge nt a d verse e ve nt
U L N
u p per li mit of n or mal
3 6 5


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 8 of  3 5
6. 2.
A p pe n di x 2 : C h a n ges t o Pr ot oc ol -Pl a n ne d A n al yses
T he f o ll owi n g c ha n ges t o t he Pr ot oc ol a me n d me nt 1 were ma de i n t his S A P:
1.
Secti o n 7. 2. 2 of t he pr ot oc ol a me n d me nt 1 stat e d t hat “T he relate d healt h o utc o me 
a nal yses will be d oc u me nte d i n t he healt h ec o n o mics a n d o utc o mes researc h statistical 
a nal ys is pla n.” I nstea d, t hese health o utc o me a nal yses are a d de d t o t his S A P d oc u me nt .
2.
Re m o v e d f oll owi n g efficac y  v ari a bles:

C ha n ge fr o m baseli ne i n mo nt hl y hea dac he da ys at eac h m o nt hl y peri o d .

C ha n ge fr o m baseli ne i n mo nt hl y ac ute m e dicat i on use da y s at eac h mo nt hl y peri o d .

≥ 2 5 %, ≥ 5 0 %, ≥ 7 5 %, a n d 1 0 0 % i m pr o ve me nt ( decrease) i n m o nt hl y mi grai ne da ys
at eac h mo nt hl y peri o d .

C ha n ge fr o m baseli ne i n m o nt hl y c u m ulat i ve hea dac he h o urs at eac h m o nt hl y peri o d

C ha n ge fr o m baseli ne i n m o nt hl y tri pta n use da ys at eac h mo nt hl y peri o d

C ha n ge fr o m baseli ne i n m o nt hl y m o derate/se vere hea dac he da ys at eac h m o nt hl y 
p eri o d

C ha n ge fr om baseli ne i n m o nt hl y  se vere hea dac he da ys at eac h mo nt hl y  p erio d .

Ot her Heal t h O utc o m e e n d p oi nts (see Secti o n 5. 3. 1)
3.
Efficac y varia bles will be liste d, a n d will n ot be s u m marize d.
4.
Re m o ve d f oll owi n g de m o gra p hic ta ble s u m maries. W here n ote d i n t he b o d y  of t he S A P, 
data will be prese nt e d i n listi n gs:

A nal ysis p o p ulati o ns

S u m mar y  of e nr oll me nt cate g or y

C o nc o mita nt me dicat i on d uri n g t he f oll ow- u p peri o d
5.
Re m o v e d f ol l owi n g safet y s u m maries. W here n ote d i n t he b o d y of t he S A P, data will be 
prese nte d i n list i n gs:

T E A Es b y  S O C, P T a n d se verit y

N E A Es

C o m m o n ( ≥2 %) T E A Es b y  P T

S u m mar y  of baseli ne, p ost-baseli ne, a n d c ha n ge fr o m baseli ne i n la b ora t or y 
para m eters

S u m mar y  of baseli ne, p ost-baseli ne, a n d c ha n ge fr o m baseli ne i n vital si g ns

S u m mar y  of baseli ne, p ost-baseli ne, a n d c ha n ge fr o m baseli ne i n E C G
3 6 6


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 1 9 of  3 5
6. 3.
A p pe n di x 3: S u p p orti n g St u d y I nf or m ati o n
6. 3. 1.
De m o gr a p hic 
D e m o gra p hic para meters will be liste d f or t he Safet y p o p ul at i ons.
6. 3. 2.
B aseli ne a n d Dise ase C h ar acteristics
B aseli ne c haracterist ics ( weig ht; hei g ht; a n d b o d y  mass i n de x, calc ulate d as wei g ht [ k g]/( heig ht 
[ m])2 will be liste d f or t he Safet y.
6. 3. 3.
Pr ot oc ol De vi ati o ns
Pr ot oc ol  de viati ons will be defi ne d i n Pr ot oc ol  De viati on Re q uire me nt S pecificat i on, i ncl u di n g 
i m p orta nce classificati on. P artici pa nts wi t h im p orta nt pr ot oc ol de viat i ons will be liste d f or Safety 
p o p ul at i on.
6. 3. 4.
Me dic al Hist or y
Me dical hist or y  i n t his st u d y will be c o llecte d f or partici pa nts w h o ha ve a ga p bet wee n t he last 
visit of t he lea d -i n st u d y a n d Visit 1 of t his e xte nsi o n st u d y a n d o nl y n e w me dical hist or y
c ollecte d d uri n g t he ga p will be liste d.
A b n or m alities i n part ici pa nts’ me dical a n d s ur gical hist or y will be c o de d usi n g t he Me dical 
Di ct i on ar y for Re g ulat or y  Act i vities, versi on 2 3. 0 or ne wer. P artici pa nts wit h a b n or malit ies i n 
me dical a n d s ur gical hist ories fr o m t he lea d-i n st u d y i n eac h s yste m or ga n class ( S O C) a n d 
preferre d ter m ( P T) will be liste d f or t he Safety p o p ul at i on.
Mi grai ne hist o r y, incl u di n g dia g n osis, d urati o n of dis or der, use of mi grai ne pre ve nt i on 
me dicat i on i n t he past, a vera ge n u m ber of mi grai ne or hea dac he da ys per m o nt h i n t he last 
3 m o nt hs, ac ute m e dicat i ons ta ke n t o treat mi grai ne hea dac hes, a n d a d vice o n lifest yle 
alt ernat i ons fr om t he lea d-i n st u d y will be liste d f or t he Safet y p o p ul at i on.
6. 3. 5. 
Pri or/ C o nc o mit a nt me dic ati o ns
Pri or me dic ati o n is defi ne d as a n y me dicati on ta ke n bef ore t he date of t he first d ose of lea d-i n 
st u d y tr e at me nt.
C o nc o mit a nt me dic ati o n f or t his st u d y is defi ne d as a n y me dicat i on ta ke n o n or after t he date of 
t he first d ose of o pe n -label st u d y treat me nt.
P articipa nts will be liste d b y A nat o mical T hera pe utic C he mical ( A T C) 4 class a n d preferre d ter m 
( P T) f or b ot h pri or me dicat i ons a n d c o nc o mit a nt me dicat i ons i n t he Safet y p o p ul at i on. 
C o nc o mita nt me dicat i ons will be liste d f ort he Safet y P o p ulat i on.
If a partici pa nt t o o k a s pecific me dicati on m ult i ple ti mes or t o o k m ulti ple me dicat i ons wi t hi n a 
s pecific t hera pe utic class, t hat partici pa nt w o ul d be c o u nte d o nl y o nce f or t he c o de d dr u g na me 
or t hera pe utic class. A n y pri or a n d c o nc o mit a nt me dicat i ons will be i ncl u de d i n list i n gs.
T he m e dicatio n data will be c o de d usi n g t he W orl d Healt h Or ga nizat i on ( W H O) Dr u g Gl o bal B 3 
versi o n Marc h 2 0 1 9 or hi g her.
3 6 7


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 0 of  3 5
6. 3. 6.
A d verse E ve nts of S peci al I nterest
Per t he 3 1 0 1 - 3 1 1-0 0 2 P r ot oc ol Secti o n 6.1. 2 , selecte d n o n-seri o us a n d seri o us a d verse e ve nts are 
of  s pecial i nterest a n d will re q uire i m me diate re p orti n g, rec or di n g, a n d f oll ow- u p. T he f o ll owi n g 
e ve nts w ill be cl os el y  mo ni t or e d:

Treat me nt -e mer ge nt s uici dal i deat i ons wit h i nte nt, wit h or wit h o ut a pla n, (ie, T y pe 4 or 5 
o n t he C -S S R S) or a n y  s uici dal be ha vi ors.

Treat me nt -e mer ge nt ele vate d A L T or A S T la b val ue ≥ 3 × U L N.

P ote nti al H y’s la w cases: ele vate d AL T or A S T l a b val ue t hat is ≥ 3 × U L N a n d a n 
ele vate d t otal bilir u bi n la b val ue t hat is ≥ 2 × U L N a n d, at t he sa me ti me, a n al kali ne 
p h os p hatase la b val ue t hat is < 2 × U L N.
T he dis pla y  of  a b o ve are descri be d i n t he c orres p o n di n g S A P Secti ons 5. 4. 4. 1 a n d 5. 4. 4. 4 .
6. 3. 7.
P ote nti all y Cli nic all y Si g nific a nt Criteri a f or S afet y E n d p oi nts
La b orat or y  val ues i n co n ve nti o n al  unit , t he p ote ntiall y cli nicall y si g nifica nt criteria f or cli nical 
la b orat or y para meters, He pati c la b orat or y ab n or m alities, vit al si g ns a n d E C G para meters are 
pr o vi de d i n t he f o ll owi n g sect i ons.
6. 3. 7. 1.
L a b or at or y v al ues i n C o n ve nti o n al U nit
6. 3. 7. 1. 1.
B ac k gr o u n d
All la b orat or y para meters are re p orte d i n t he I nter nati o nal S yste m ( SI) u nits as sta n dar d practice. 
I n a d diti on, selecte d la b orat or y  para meters (liste d i n Ta ble 6- 1 ) will be re p orte d i n c o n ve nti onal 
u nits t o facilitate i nter pretati o n a n d re p orti n g f or t he C S R a n d f ut ure la beli n g.
6. 3. 7. 1. 2.
List of P ar a meters Re p orte d i n C o nve nti o n al U nit 
T he list of selecte d para meters re q uire d t o be re p orte d i n c o n ve nt i ona l u nit is pr o vide d i n
Ta ble 6- 1 .
3 6 8


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 1 of  3 5
T a ble 6- 1
List of Selecte d P ar a meters Re p orte d i n C o n ve nti o n al U nit
N u m ber
L a b or at ory P ar a meter
C o nve nti o n al U nit
Deci m al Pl aces
1
Ala ni ne A mi n otra nsferase ( S G P T)
U/ L
0
2
Al b u mi n
g / d L
1
3
Al kali ne P h os p hatase
U/ L
0
4
As partate A mi n otra nsferase ( S G O T)
U/ L
0
5
Bilir u bi n, Direct ( C o nj u gate d)
m g/ d L
1
6
Bilir u bi n, I n direct ( U nc o nj u gate d)
m g/ d L
1
7
Bilir u bi n, T otal
m g/ d L
1
8
Bl o o d Urea Nitr o ge n
m g/ d L
0
9
Calci u m
m g/ d L
1
1 0
C h olester ol, H D L
m g/ d L
0
1 1
C h olester ol, L D L
m g/ d L
0
1 2
C h olester ol, L D L direct a n d calc ulate d (c o m bi ne d)
( T his l a b p ar a meter c o ul d be t he s a me as # 1 1) 
m g/ d L
0
1 3
C h olester ol, T otal
m g/ d L
0
1 4
Creati ne Ki nase
U/ L
0
1 5
Creati ni ne
m g/ d L
1
1 6
Gl uc ose
m g/ d L
0
1 7
I ns uli n
uI U/ m L
1
1 9
Ur ic Aci d
m g/ d L
1
2 0
He m o gl o bi n
g / d L
1
6. 3. 7. 1. 3.
A n alysis a n d Re p orti n g F or m at i n C o nve nti o n al U nits
1)
F or i n di vi d ual cli nical st u d y  re p orts f or t he ce ntral ner v o us s yste m (C N S ) pr oj ects, t he 
selecte d la b orat or y para meters (Ta ble 6- 1 ) will be liste d i n c o n ve nti o nal u nits 
2)
P arti cipa nt narrati ves ge nerate d b y t he statist ical pr o gra m mi n g tea m will als o i ncl u de t he 
val ues i n c o n ve nt i onal u nit s for t he sel ecte d la b para meters ( Ta ble 6- 1 ). T hat will be 
acc o m plis he d b y prese nt i n g t he val ues i n c o n ve nti o nal u nits wit hi n t he pare nt heses ne xt t o 
t he val ues i n SI u nits. A n e xa m ple is pr o vi de d i n Ta ble 6- 2 f or lab para meter ‘Bilir u bi n, 
T ot al ’, f or w hic h ‘ u mol / L’ is t he SI u nit a n d ‘ mg/ d L’ is t he c o n ve nti onal u nit.
3 6 9


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 2 of  3 5
T a ble 6- 2
Prese nti n g L a b or at or y D at a Usi n g SI a n d C o n ve nti o n al U nits i n N arr ati ves
L A B O R A T O R Y D A T A
L a b Test
Test N a me
N or m al R a n ge
VI SI T 0 1  
VI SI T 0 5  
VI SI T 0 7 
L o w
Hi g h
2 0 1 2- 0 7- 0 3 
2 0 1 2- 0 8- 0 7 
2 0 1 2 - 0 9-0 4 
…
C H E MI S T R Y 
Bilir u bi n, T otal 
( u m ol/ L ( m g/ d L)) 
0 ( 0) 
1 8. 8 1 
( 1. 1) 
6. 8 4 ( 0. 4)  
5. 1 3 ( 0. 3)  
5. 1 3 ( 0. 3) 
…
6. 3. 7. 2.
P ote nti all y Cli nic all y S i g nific a nt Criteri a f or Cli nic al L a b or at or y P ar a meters
T a ble 6 - 3
P ote nti all y Cli nic all y Si g nific a nt Criteri a f or Cli nic al L a b or at or y P ar a meters
P C S Criteri a
C ate g or y
P ar a meter
SI U nit
P C S L o w
P C S Hi g h
C he mistr y
Al b u mi n
g/ L
< 0. 8 × L L N
> 1. 2 × U L N
Ala ni ne a mi n otra nsferase
U/ L
—
≥ 3. 0 × U L N
Al kali ne p h os p hatase
U/ L
—
≥ 3. 0 × U L N
As partate a mi n otra nsferase
U/ L
—
≥ 3. 0 × U L N
Bicar b o nate
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
Bilir u bi n, t otal
μ m ol/ L
—
≥ 1. 5 × U L N
Bl o o d urea nitr o ge n
m m ol/ L
—
> 1. 5 × U L N
Calci u m
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
C hl ori de
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
C h olester ol, t otal
m m ol/ L
—
> 1. 6 × U L N
Creati ni ne
μ m ol/ L
—
> 1. 5 × U L N
Creati ne ki nase
U/ L
—
> 2. 0 × U L N
Esti mate d gl o mer ular filtrati o n rate
m L/ mi n/ 1. 7 3 m 2
< 6 0
—
Gl uc ose, n o nfasti n g
m m ol/ L
< 0. 8 × L L N
> 2. 0 × U L N
Lactate de h y dr o ge nase ( L D H)
U/ L
—
> 3. 0 × U L N
P h os p h o r us
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
P otassi u m
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
Pr otei n, t otal 
g/ L
< 0. 9 × L L N
> 1. 1 × U L N
S o di u m
m m ol/ L
< 0. 9 × L L N
> 1. 1 × U L N
Ur ic aci d 
μ m ol/ L
—
> 1. 2 × U L N
He mat ol o g y
Bas o p hils, a bs ol ute cell c o u nt
1 0 9/ L
—
> 2. 0 × U L N
E osi n o p hils, a bs ol ute cell c o u nt
1 0 9/ L
—
> 2. 0 × U L N
He mat ocrit
Rati o
< 0. 9 × L L N
> 1. 1 × U L N
He m o gl o bi n
g/ L
< 0. 9 × L L N
> 1. 1 × U L N
L y m p h oc y tes, a bs ol ute cell c o u nt
1 0 9/ L
< 0. 7 × L L N
> 1. 3 × U L N
M o n oc ytes, a bs ol ute cell c o u nt
1 0 9/ L
< 0. 5 × L L N
> 2. 0 × U L N
Ne utr o p hils, a bs ol ute cell c o u nt
1 0 9/ L
< 0. 7 × L L N
> 1. 3 × U L N
Platelet c o u nt
1 0 9/ L
< 0. 5 × L L N
> 1. 5 × U L N
Re d bl o o d cell c o u nt
1 0 1 2/ L
< 0. 9 × L L N
> 1. 1 × U L N
W hite bl o o d cell c o u nt
1 0 9/ L
< 0. 9 × L L N
> 1. 5 × U L N
Ur i nal ysis
p H
p H
< 0. 9 × L L N
> 1. 1 × U L N
Gl uc ose
m m ol/ L
—
At least 1 +
Pr otei n 
g/ L
—
At least 1 +
S pecific gra vit y
—
—
> 1. 1 × U L N
L L N = l o wer li mit of n or mal val ue; U L N = u p per li mit of n or mal val ue; n or mal val ue pr o vi de d b y la b orat or y.
SI = Le S ystè me I nter nati o nal d’ U nités (I nter nati o nal S yste m of U nits).
3 7 0


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 3 of  3 5
6. 3. 7. 3.
Criteri a f or He p atic L a b or at or y A b n or m alities
T a ble 6- 4
Criteri a f or He p atic L a b or at or y A b n or m alities
L a b or at or y P ar a meter
C ate g ories
A L T
≥ 1 × U L N
≥ 1. 5 × U L N
≥ 2 × U L N
≥ 3 × U L N
≥ 5 × U L N
≥ 1 0 × U L N
≥ 2 0 × U L N
A S T
≥ 1 × U L N
≥ 1. 5 × U L N
≥ 2 × U L N
≥ 3 × U L N
≥ 5 × U L N
≥ 1 0 × U L N
≥ 2 0 × U L N
A L T or A S T
≥ 1 × U L N
≥ 1. 5 × U L N
≥ 2 × U L N
≥ 3 × U L N
≥ 5 × U L N
≥ 1 0 × U L N
≥ 2 0 × U L N
Bilir u bi n T otal
≥ 1 × U L N
≥ 1. 5 × U L N
≥ 2 × U L N
≥ 3 × U L N
≥ 5 × U L N
≥ 1 0 × U L N
≥ 2 0 × U L N
Al kali ne P h os p hatase
≥ 1 × U L N
≥ 1. 5 × U L N
≥ 2 × U L N
≥ 3 × U L N
≥ 5 × U L N
≥ 1 0 × U L N
≥ 2 0 × U L N
C o nc urre nt Ele vati o ns 1
A L T or A S T > = 3 × U L N a n d Bilir u bi n T otal ≥ 1. 5 × U L N
A L T or A S T > = 3 × U L N a n d Bilir u bi n T otal ≥ 2 × U L N
P ote ntial H y’s La w 1
A L T or A S T ≥ 3 × U L N a n d Bilir u bi n T otal ≥ 2 × U L N a n d
A L P < 2 × U L N
A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; T B L = t otal bilir u bi n; A L P = al kali ne 
p h os p hatase; U L N = u p per li mit of n or mal ( val ue pr o vi de d b y t he la b orat or y).
1 Ele vati o ns are fr o m t he sa me da y
3 7 1


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 4 of  3 5
6. 3. 7. 4.
P ote nti all y Cli nic all y S i g nific a nt Criteri a f or Vit al Si g ns
T a ble 6- 5
P ote nti all y Cli nic all y Si g nific a nt Criteri a f or Vit al Si g ns
P ar a meter
Fl a g
Criteri a
O bser ve d V al ue
C h a n ge fr o m B aseli ne
S yst olic bl o o d press ure, m m H g
Hi g h
≥ 1 8 0
I n crease of ≥ 2 0
L o w
≤ 9 0
Decrease of ≥ 2 0
D iast olic bl o o d press ure, m m H g
Hi g h
≥ 1 0 5
I n crease of ≥ 1 5
L o w
≤ 5 0
Decrease of ≥ 1 5
P ulse rate, b p m
Hi g h
≥ 1 2 0
I n crease of ≥ 1 5
L o w
≤ 5 0
Decrease of ≥ 1 5
Wei g ht, k g
Hi g h
—
I n crease of ≥ 7 %
L o w
—
Decrease of ≥7 %
Ort h ostatic S B P c ha n ge, m m H g
L o w
≤ -2 0
—
Ort h ostatic D B P c ha n ge, m m H g
L o w
≤ -1 5
—
Ort h ostatic P ulse rate c ha n ge, b p m
Hi g h
≥ 2 5
—
S B P = S yst olic bl o o d press ure, D B P = Diast olic bl o o d press ure, b p m = beats per mi n ute.
6. 3. 7. 5.
P ote nti all y Cli nic all y S i g nific a nt Criteri a f or E C G p ar a meters
T a ble 6- 6
P ote nti all y Cli nic all y Si g nific a nt Criteri a f or E C G p ar a meters
P ar a meter
U nit
Criteri o n
Q R S i nter val
msec
≥ 1 5 0
P R i nter val
msec
≥ 2 5 0
Q Tc ( Q Tc B or Q Tc F) i nter val
msec
> 5 0 0
Q Tc ( Q Tc B or Q Tc F) i nter val
msec
I n crease fr o m baseli ne > 6 0
Q Tc = Q T i nter val c orrecte d f or heart rate. 
Q Tc B = Q T i nter val c orrecte d f or heart rate usi n g t he Bazett f or m ula.
Q Tc F = Q T i nter val c orrecte d f or heart rate usi n g t he Fri dericia f or m ula.
6. 4.
D at a h a n dli n g c o n ve nti o n
D a y  1 is defi ne d as da y  for t he date of t he first d ose of o pe n-label st u d y i nter ve nt i on. T here is n o 
D a y  0 or Wee k 0. Treat me nt d a y is relat i ve t o t he date of t he first d ose of o pe n-la bel st u d y 
i nter ve nt i on.
6. 4. 1.
A n al ysis Wi n d o w
T he a nal ysis visit wi n d o ws f or m o nt hl y  efficac y a n d healt h o utc o me (e xce pt f or M S Q) e n d p oi nts 
base d o n dai l y e Di ar y data are defi ne d as f oll o ws:
3 7 2


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 5 of  3 5
T a ble 6- 7
Effic ac y a n d He alt h O utc o me A n al ysis Visit Defi niti o ns f or e Di ar y D at a ( M o nt hl y)
A n al ysis P h ase
A n al ysis Visit ( Deri ve d)
e Di ar y Wi n d o w
Lea d -i n St u d y
Baseli ne
Baseli ne fr o m lea d -i n st u d y
O pe n -la bel Treat me nt Peri o d
Wee ks 1 – 4
Treat me nt Da y [ 1, 2 8]
Wee ks 5 – 8
Treat me nt Da y [ 2 9, 5 6]
Wee ks 9 – 1 2
Treat me nt Da y [ 5 7, 8 4]
T he a nal ysis visit wi n d o ws f or M S Q v 2. 1
are defi ne d as f o ll ows :
T a ble 6- 8
Effic ac y A n al ysis Visit Defi niti o ns f or M S Q v 2. 1
A n al ysis Visit ( Deri ve d)
Sc he d ule d Visit D a y a
Wi n d o w
Baseli ne
Visit 1 ( E nr oll me nt )
Baseli ne fr o m lea d -i n st u d y
Wee k 4
Da y  2 8 ( Visit 2)
Treat me nt Da y [ 1, 4 2]
Wee k 8
Da y  5 6 ( Visit 3)
Treat me nt Da y [ 4 3, 7 0]
Wee k 1 2
Da y  8 4 ( Visit 4/ E T)
Treat me nt Da y > = 7 1 a n d wit hi n t he o pe n -la bel
treat me nt peri o d
Wee k 1 6 
(F oll o w -u p)
Da y  1 1 2 (Visit 5)
Treat me nt Da y [ e n d of t he o pe n -la bel treat me nt 
peri o d + 1, t he last st u d y visit]
E T = earl y ter mi nati o n.
a Relati ve t o t he date of t he first d ose of o pe n -la bel st u d y treat me nt.
T he a nal ysis visit wi n d o ws f or safety e n d p o i nts are defi ne d as f oll ows :
T a ble 6- 9
S afet y A n al ysis Visit Defi niti o ns
A n al ysis Visit ( Deri ve d)
Sc he d ule d Visit D a y a
Wi n d o w
Baseli ne
Baseli ne fr o m lea d -i n st u d y
Wee k 4
Da y  2 8 ( Visit 2)
Treat me nt Da y [ 1, 4 2]
Wee k 8
Da y  5 6 ( Visit 3)
Treat me nt Da y [ 4 3, 7 0]
Wee k 1 2
Da y  8 4 ( Visit 4)
Treat me nt Da y > = 7 1 a n d wit hi n t he o pe n -la bel
treat me nt peri o d
E n d of t he 
O pe n -la bel treat me nt Peri o d
Last a vaila ble assess me nt d uri n g t he o pe n -la bel 
treat me nt peri o d
Wee k 1 6
(F oll o w -u p)
Da y  1 1 2 (Visit 5)
Treat me nt Da y [ e n d of t he o pe n -la bel treat me nt 
peri o d + 1, t he last st u d y visit]
E n d of st u d y
Last a vaila ble assess me nt after treat me nt start date, 
i.e. occ urs at fi nal visit (e x pecte d Da y 1 1 2) o r E T
a Relati ve t o t he date of t he first d ose of o pe n -la bel st u d y i nterve nti o n .
E n d of Treat me nt is defi ne d as t he last a vaila ble assess me nt d uri n g o pe n -la bel treat me nt peri o d, i.e. o n or bef ore t he treat me nt 
e n d date. E n d of Treat me nt res ults will be prese nte d i n s u m mar y ta bles f or cli nical la b orat or y val ues, electr ocar di o gra m a n d 
vi tal si g ns.
E n d of St u d y is defi ne d as t he last a vaila ble assess me nt d uri n g t he st u d y, i ncl u di n g o pe n -la bel a n d safet y f oll o w-u p peri o d. 
E n d of St u d y res ults will be prese nte d i n s u m mar y ta bles f or safet y para meters, i ncl u di n g b ut n ot li mite d t o cli nical lab orat or y 
val ues, a n d vital si g ns ( n ot f or electr ocar di o gra ms, as t hese data were n ot c ollecte d d uri n g f oll o w-u p peri o d) .
E T = earl y ter mi nati o n. E O S =e n d of st u d y.
3 7 3


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 6 of  3 5
6. 4. 2.  
Deri ve d Effic ac y D at a
6. 4. 2. 1.
Deri v ati o n of Effic ac y E n d p oi nts B ase d o n e Di ar y D at a
F or a nal ysis p u r p oses, f o ur wee ks ( 2 8 da ys) will be c o nsidere d as o ne m o nt h. O n a dail y  basis 
d uri n g t he 4 -wee k baseli ne peri o d a n d t hr o u g h o ut t he o pe n -la bel treat me nt peri o d, partici pa nts 
are t o rec or d e Diar y i nf or mati on o n t he d urati o n of hea dac he, hea dac he s pecific c haracterist ics 
a n d s y m pt o ms, t he pai n se verit y,  a n d use of a n y ac ute hea dac he pai n me dicati on. Dail y hea dac he 
di ar y data c o nsists of data fr o m “t o da y’s dair y” c o m plete d o n t hat da y a n d “ yester da y’s diar y” 
c o mplete d o n t he f o ll owi n g da y . P artici pa nts are t o re p ort hea dac he data i n “t o da y’s diar y” i n t he 
e ve ni n g at a n y time fr om 1 9: 0 0 t o 2 3: 5 9 a n d t o c o m plete “ yester da y’s diar y” o n t he f o ll owi n g 
d a y  t o a d d t he re mai ni n g hea dac he data of pre vi o us e ve ni n g u ntil mi d ni g ht. I n case partici pa nts 
miss “t o da y’s diar y”, t he y  ca n re p ort t he w h ole-d a y  hea dac he data i n “ yester da y’s diar y” o n t he 
f oll owi n g da y. I n case partici pa nts miss “ yester da y’s diar y”, hea dac he data fr o m “t o da y’s diar y” 
alo ne will  be use d as dail y  hea dac he diar y data. If b ot h “t o da y’s diar y” a n d “ yester da y’s dair y” 
are missi n g o n o ne da y, t he dail y hea dac he diar y data will be treate d as missi n g.
Dail y hea dac he diar y  data will be mer ge d fr o m “t o da y’s diar y” a n d “ yester da y’s diar y” as 
f oll owi n g a n d will be use d t o deri ve mi grai ne da y a n d hea dac he da y.

Dail y hea dac he t ot al d uratio n: s u m mat i on of  hea dac he d urati o ns fr o m “t o da y’s diar y” 
a n d “ yester da y’s diar y”

Dail y h ea dac he pai n se verit y: t he w orst pai n se verit y fr om “t o da y’s diar y” a n d 
“ yester da y’s diar y”

Dail y hea dac he c haracterist ics a n d s y m pt o ms: prese nt if prese nt i n o ne of “t o da y’s diar y” 
a n d “ yester da y’s diar y” 

Dail y ac ute h ea dac he me dicat i on usa ge : c o m bi nati o n of ac ute hea dac he me dicati ons 
usa ge fr o m “t o da y’s diar y” a n d “ yester da y’ s diar y ”
If t here are d u plicate rec or ds of dail y diar y data f or t he sa me partici pa nt o n t he sa me da y wit h t he 
sa me t ype, t he set of rec or ds wit h t he last f or m access dateti me will be use d i n t he a nal ysis.
T he m o nt hl y mi grai ne da ys is defi ne d t he t otal n u m ber of rec or de d mi grai ne da ys i n t he e Diar y 
di vi de d b y t he t otal n u m ber of da ys wit h e Diar y rec or ds d uri n g eac h m o nt hl y  p erio d a n d 
m ult i plie d b y 2 8. T he baseli ne val ue as defi ne d f or t he lea d -i n st u d y will be use d as t he baseli ne 
i n t his e xte nsi on st u d y . F or eac h p ost baseli ne 4 -wee k treat me nt peri o d, a mi ni m u m o f 1 4 da ys’ 
e D iary data d uri n g t hat peri o d is re q uire d f or t he mi grai ne da ys t o be e val ua ble. If a parti ci pa nt 
d oes n ot ha ve at least 1 4 da ys of diar y data f or a m o nt hl y tr e at me nt perio d, t he mi grai n e da ys f or 
t hat peri o d will be c o nsi dere d as missi n g. Mi grai ne d a y s will be deri ve d f or eac h parti ci pa nt at  
baseli ne a n d f or eac h p ost baseli ne m o nt hl y treat me nt peri o d ( Wee ks 1 -4, 5 - 8, 9- 1 2). T he sa me 
met h o d t o deri ve m o nt hl y mi grai ne da ys will be use d t o deri ve m o nt hl y hea dac he da ys, m o nt hl y 
ac ute me dicat i on use da ys, m o nt hl y tri pta n use da ys, m o nt hl y c u m ulat i ve hea dac he h o urs, 
m o nt hl y  hea dac he da y pai n i nte nsit y, mo nt hl y  mo derate/se vere hea dac he da ys, a n d m o nt hl y  
se vere hea dac he da ys.
If a s u bject re p orts ‘ Yes’ t o t he i nta ke of all o we d me dicati on(s) t o treat a n ac ute mi grai ne b ut 
d oes n ot list a n y  of t h e m in t he di ar y, t he n t he ac ute me dicat i on use da ys will n ot be c o u nte d i n 
t his sit u atio n.
3 7 4


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 7 of  3 5
S u bse q ue nt t o D a y  1, t he n u m ber of hea dac he da ys will be c o u nte d i n s uccessi ve a n d n o n-
o verl a p pi n g 4 -wee k (ie, 2 8 -da y) wi n d o ws. Hea dac hes t hat c o nti n ue i nt o a s u bse q ue nt 4 -wee k 
p eri o d will be c o u nte d ( wit h rec or de d se verit y a n d d uratio n) as occ urri n g i n eac h peri o d.
If a n y p ost baseli ne e Diar y wi n d o w f or a partici pa nt has at least 14 b ut less t ha n 2 8 da ys of 
re p orte d data, t he pr orate d a p pr oac h will be use d. If a partici pa nt re p orts less t ha n 14 da ys of 
hea dac he data, t he partici pa nt’s o bser ve d c o u nts i n t hat partic ular 2 8 -d a y  e Diar y wi n d o w will be 
set t o missi n g f or t hat wi n d o w. T hese pr orati n g r ules will be a p plie d t o all efficac y a nal yses o f 
e Diar y data u nless ot her wise state d.
M o nt hl y efficac y  e n d p oi nts are defi ne d i n a pr orate d fas hi on. F or e xa m ple, m o nt hl y mi grai ne 
da ys are defi ne d as t he t otal  n u m ber of rec or de d mi grai ne da ys i n t he e Diar y di vi de d b y t he t otal 
n u m ber of da ys wit h e Diar y rec or ds d uri n g eac h m o nt hl y peri o d a n d m ult i plie d b y 2 8.
6. 4. 3.
Deri v ati o n of He alt h O utc o me E n d p oi nts
AI M -D Rel ate d E n d p oi nts Deri v ati o n
As descri be d i n Pr ot oc ol  A me n d me nt 1 Sectio n 6. 3 , t he AI M-D was de vel o pe d as a dail y  e Di ar y 
wi t h a recall peri o d 2 4 h o urs. B y desi g n, it is c ollecte d i n t he t o da y diar y o nl y. T he sc ori n g of t he 
f oll owi n g e n d p o i nts is c om p lete d i n 2 ste ps.

M o nt hl y Perf or ma nce of Dail y  Acti vit ies d o mai n sc ore of t he AI M-D

M o nt hl y P h ysical I m pair me nt d o mai n sc ore of t he AI M - D

M o nt hl y AI M -D t otal  sc ore
Ste p 1: Calc ulate AI M -D dail y d o ma i n sc ore a n d t otal sc ore
Dail y P erfor ma nce of D ail y Act i vities sc ore will be calc ulate d base d o n t he s u mmat i on of ite ms 
1 -5 a n d 1 0 a n d 1 1, ra n gi n g fr o m 0 -3 5. A dail y P erf or ma nce of D ail y Acti vit ies d o mai n sc ore will 
be calc ulate d if 4 or m ore ite m sc ores ha ve n o n -missi n g res p o nses. W he n t he res p o nse cate g or y  
“I did n ot ha ve <erra n ds, leis ure or s ocial, stre n u o us acti vit ies > pla n ne d” (it e ms 2, 4, a n d 5), is 
selecte d, t he res p o nse will be c o nsi dere d missi n g. T he c orres p o n di n g P erfor m a nce of D ail y 
A ct i vities d oma i n sc ore will be calc ulate d b y s u m mi n g t he n o n-missi n g ite m sc ores a n d di vi di n g 
b y t he n u m ber of n o n -missi n g i t e ms a n d t he n mul tipl yi n g b y 7, pr o vi de d t hat 4 or m ore ite m 
sc ores are a vaila ble; ot her wise it will be set t o missi n g. T he ra w dail y sc ore will be tra nsf or me d 
t o a 0-1 0 0 scale b y m ult i pl yi n g b y 1 0 0 a n d di vi di n g b y t he hi g hest ra w sc ore ( 3 5).
Dail y P h ys ical Im pair me nt sc ores will be calc ulate d base d o n t he s u m mat i on of ite ms 6 -9, 
ra n gi n g fr o m 0-2 0. A dail y P h ys ical I m pair me nt sc ore will be calc ulate d if 2 or m ore ite m sc ores 
ha ve n o n -missi n g res p o nses. T he c orres p o n di n g P h ysical I m pair me nt sc ore wi ll be calc ulate d b y  
s u m mi n g t he n o n-missi n g ite m sc ores a n d di vi di n g b y  t he n u m ber of n o n-missi n g ite ms a n d t he n 
m ult i pl yi n g b y 4, pr o vi de d t hat 2 or m ore ite m sc ores are a vaila ble; ot her wise it will be set t o 
missi n g. T he ra w dail y sc ore will be tra nsf or m e d t o a 0 -1 0 0 scale b y m ult i pl yi n g b y 1 0 0 a n d 
di vi di n g b y t he hi g hest ra w sc ore ( 2 0).
A dail y  t ot al sc ore will be calc ulate d base d o n t he s u m mati on of ite ms 1 -1 1, ra n gi n g fr o m 0- 5 5. 
A T otal  Sc ore will be calc ulate d if 6 or mor e i t e ms sc ores ha ve n o n-missi n g res p o nses. W he n t he 
res p o nse cate g or y “I did n ot ha ve <erra n ds, leis ure or s ocial, stre n u o us acti vit ies > pla n ne d” 
(it e ms 2, 4, a n d 5), is selecte d, t he res p o nse will be c o nsi dere d missi n g. T he c orres p o n di n g T otal 
Sc ore will be calc ulate d b y  s u m mi n g t he no n -missi n g ite m sc ores a n d di vi di n g b y t he n u m ber of 
3 7 5


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 8 of  3 5
n o n- missi n g ite ms a n d t he n m ult i pl yi n g b y 1 1, pr o vi de d t hat 6 or mor e i t e m sc ores are a vaila ble; 
ot her wi se it will be set t o missi n g. T he ra w sc ore will be tra nsf or me d t o a 0-1 0 0 scale b y 
m ult i pl yi n g b y 1 0 0 a n d di vi di n g b y  t he hi g hest ra w sc ore ( 5 5).
Ste p 2: Calc ulate M o nt hl y Sc ores a n d Baseli ne Sc ore
M o nt hl y sc ores will be calc ulate d usi n g t he a vera ge dail y  sc ores o nl y if t here are at least 1 4 n o n-
missi n g dail y sc ores i n t he c orres p o n di n g m o nt hl y ( 2 8 - day)  p erio d. T he c orres p o n di n g m o nt hl y  
sc ores will be calc ulate d b y s u m mi n g t he n o n-missi n g dail y d o ma i n sc ores a n d di vi di n g b y t he 
n u m ber of n o n -missi n g dail y sc ores, pr o vide d t hat 1 4 or m ore dail y  sc ores are a vaila ble; 
ot her wi se it will be set t o missi n g.
M o nt hl y act i vity le vel sc ore will be calc ulate d b y s u m mi n g t he n o n-missi n g dail y sc ores a n d 
di vi di n g b y t he n u m ber of t hese sc ores, pr o vi de d t hat 1 4 or m ore dail y sc ores are a vaila ble i n t he 
c orres p o n di n g m o nt hl y ( 2 8 -d a y ) p erio d; ot her wise it will be set t o missi n g. Sa me r ule will be 
a p plie d t o t he calc ulat i on of m o nt hl y act i vity li mitatio n sc ore.
M S Q Rel ate d E n d p oi nts Deri v ati o n
M S Q v 2. 1 c o nsists of 1 4 ite ms wit h a 4 -wee k recall peri o d. T he sc ori n g o f t he M S Q is 
c o mplete d i n f oll o wi n g 3 ste ps.
Ste p 1: Fi na l ite m v alue assi g n me nt.
Prec o de d i t e m val ues a n d fi nal ite m val ues f or eac h M S Q ite m res p o nse are s h o w n i n
Ta ble 6- 1 0 .
T a ble 6 - 1 0
Ite m V al ues f or M S Q Ite m Res p o nses
Res p o nse C ate g ories
Prec o de d Ite m V al ue
Fi n al Ite m V al ue
N o ne of t he ti me
1
6
A little bit of t h e ti me
2
5
S o me of t he ti me
3
4
A g o o d bit of t he ti me
4
3
M ost of t he ti me
5
2
All of t he ti me
6
1
Ste p 2: C o m p utati o n of ra w d o mai n( di me nsi o n) sc ores
O nce a fi nal ite m val ue has bee n assi g ne d t o eac h ite m, a ra w sc ore ca n be c o m p ute d f or eac h 
M S Q d o m ai n. R o le F u ncti o n -R estri ct i ve d o mai n i ncl u des Ite ms 1 - 7, R ol e F u nct i on- Pre ve nti ve 
d o m ai n i ncl u des Ite ms 8 - 1 1, a n d E m oti o nal F u ncti o n d o mai n i ncl u des Ite ms 1 2 - 1 4. T he ra w 
sc ore f or eac h d o mai n is t he al ge braic s u m o f t he fi nal ite m val ues f or all ite ms i n t hat d o mai n.
Missi n g data ha n dli n g: if a res p o n de nt a ns were d at least half of t he ite ms i n a d o mai n ( or half 
pl us o ne i n t he case o f scales with a n o d d n u m ber of ite ms), a missi n g ite m val ue ca n be 
esti mate d usi n g t he a vera ge of t he ot her c o m plete d i te ms wit hi n t he sa me di me nsi on.
I n detail, f or M S Q v 2. 1 R ole F u ncti o n-R estri ct i ve d o mai n, t he 7 i n di vi d ual ite m res p o nses usi n g 
fi nal ite m val ue will be s u m me d, res ulti n g i n t he ra w d o mai n sc ore ra n gi n g fr o m 7 t o 4 2 wit h 
hi g her sc ores i n dicat i n g better q ualit y of life. If t here are missi n g ite m res p o nses, t he ra w d o mai n 
sc ore will be calc ulate d b y s u m mi n g t he n o n-missi n g ite m res p o nses usi n g fi nal ite m val ue a n d 
3 7 6


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 2 9 of  3 5
di vi di n g b y t he n u m ber of n o n -missi n g ite ms a n d t he n m ult i pl yi n g b y 7 pr o vi de d t hat 4 or m ore
ite ms i n t he d o mai n are c o m p lete d; ot her wise it will be set t o missi n g. F or M S Q v 2. 1 R ole 
F u nct i on- Pre ve nt i ve a n d E m oti o nal F u nct i on d o mai ns, t he ra w d o mai n sc ores will be calc ulate d 
si milarl y usi n g fi nal ite m val ue res pecti vel y. If t here are missi n g ite m res p o nses, t he 
c orres p o n di n g ra w d o mai n sc ore will be calc ulate d b y s u m mi n g t he n o n-missi n g ite m res p o nses 
usi n g fi nal ite m val ue a n d di vi di n g b y t he n u m ber of n o n -missi n g ite ms a n d t he n m ult i pl yi n g b y 
t he n u m ber of q uesti o ns i n t hat d o mai n pr o vi de d t hat 2 or m ore d o mai n ite ms are c o m plete d; 
ot her wi se it will be set t o missi n g.
Ste p 3: Li near tra nsf or mat i on t o a 0 t o 1 0 0 scale.
T he tra nsf or mat i on f or mul a f or eac h M S Q v 2. 1 d o mai n are liste d bel o w

R ol e F u nct i on- Restri ct i ve: 
(          )∗   
R ol e F u nct i on- Pre ve nt i ve: 
(          )∗   
E m oti o nal F u nct i on:           
(          )∗   6. 4. 4.
Re pe ate d or U nsc he d ule d Assess me nts of S afet y P ar a meters
Baseli ne is defi ne d as t he last assess me nt ma de bef ore t he first d ose of d o u ble -bli n d st u d y 
treat me nt i n t he lea d-i n st u d y. If e n d-of -st u d y assess me nts are re peate d or if u nsc he d ule d visits 
occ ur, t he last n o n missi n g p ost baseli ne assess me nt will be use d as t he e n d -of -st u d y assess me nt 
f or ge nerati n g s u m mar y statistics. H o we ver, all p ost baseli ne assess me nts will be use d f or P C S 
val ue deter mi nati o ns, a n d all assess me nts will be prese nte d i n t he data list i n gs.
6. 4. 5.
Missi n g D ate of t he L ast D ose of St u d y I nter ve nti o n
W he n t he date of t he last d ose of t he o pe n -la bel st u d y i nter ve nt i on is missi n g, all eff orts s h o uld 
be ma de t o o btai n t he date fr o m t he In vest i gat or. If it is still missi n g after all eff orts ha ve bee n 
ma de , t h e last a vaila ble st u d y i nter ve nt i on date will be use d i n t he calc ulati o n of treat me nt 
d urati o n . 
6. 4. 6.
Missi n g Se verit y Assess me nt f or A d v erse E ve nts
If se verity is missi n g f or a n A E t hat starte d bef ore t he date of t he first d ose of o pe n -label st u d y 
treat me nt , a n i nte nsity of  mil d will be assi g ne d. If se verity is missi n g f or a n A E t hat starte d o n or 
after t he date of t he first d ose of o pe n -la b el st u d y tr e at me nt , a n i nte nsity of  se vere will be 
assi g ne d. T he i m p ute d val ues f or se verit y assess me nt will be use d f or t he i nci de nce s u m mar y; 
t he val ues will be s h o w n as missi n g i n t he data listi n gs.
6. 4. 7.
Missi n g C a us al Rel ati o ns hi p t o St u d y tre at me nt f or A d verse E ve nts
If t he ca usal relati o ns hi p t o t he o pe n -label st u d y treat me nt is missi n g f or a n A E t hat starte d o n or 
after t he date of t he first d ose of o pe n -lab el st u d y tr e at me nt , a ca usality of yes will be assi g ne d. 
T he i m p ute d val ues f or ca usal relat i ons hi p t o o pe n -label treat me nt will be use d f or t he i nci de nce 
s u m mar y; t he val ues will be s h o w n as missi n g i n t he data list i n gs.
3 7 7


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 0 of  3 5
6. 4. 8.
Missi n g D ate I m p ut ati o n
T he f o ll owi n g i m p utati o n r ul es o nl y a p pl y t o cases i n w hic h t he start date f or A Es is i nc o m plete 
(ie, part l y missi n g).
Missi n g m o nt h a n d d a y
If t he year of t he i nc om p lete start date is t he sa me as t he year of t he first d ose of o pe n -label st u d y 
treat me nt, t he mo nt h a n d da y  of t he first d ose of o pe n -la bel st u d y treat me nt will be assi g ne d 
t o t he missi n g fiel ds
If t he year of t he i nc o m plete start date is bef ore t he year of t he first d ose of o pe n -label st u d y 
treat me nt, Dece m ber 3 1 will be assi g ne d t o t he missi n g fiel ds
If t he year of t he i nc om p lete start date is after t he year of t he first d ose of o pe n -lab el st u d y 
treat me nt, Ja n uar y 1 will be assi g ne d t o t he missi n g fiel ds
Missi n g m o nt h o nl y
If o nl y t h e mo n t h is missi n g, t he da y will be treate d as missi n g a n d b ot h t he m o nt h a n d t he da y 
will be re place d acc or di n g t o t he a b o ve pr oce d ure
Missi n g d a y o nl y
If t he m o nt h a nd y e ar of t he i nc o m plete start date are t he sa me as t he m o nt h a n d year of t he first 
d ose of o pe n -label st u d y treat me nt, t he da y of t he first d ose of o pe n -la bel st u d y tr e at me nt 
will be assi g ne d t o t he missi n g da y
If either t he y ear of t he i nc o m p lete start dat e is bef ore t he year of t he date of t he first d ose of 
o pe n -label st u d y treat me nt or if b ot h years are t he sa me b ut t he m o nt h of t he i nc o m p lete start 
date i s bef ore t he m o nt h of t he date of t he first d ose of o pe n -label st u d y treat me nt, t he last 
d a y  of t he m o nt h will be assi g ne d t o t he missi n g da y
If either t he y ear of t he i nc o m p lete start date is after t he year of t he date of t he first d ose of o pe n -
la bel st u d y treat me nt or if b ot h years are t he sa me b ut t he mo nt h of t he i nc o m p lete start date 
is after t he mo nt h of t he date of t he first d ose of o pe n -la bel st u d y treat me nt, t he first da y of 
t he mo nt h will  be assi g ne d t o t he missi n g da y
If t he st o p date is c om p lete a n d t he i m p ute d start date as a b o ve is after t he st o p date, t he start 
date will be i m p ute d b y t he st o p date.
If t he start date is c om p letel y missi n g a n d t he st o p date is c om p lete, t he f oll owi n g al g ori t h m will 
be use d t o i m p ute t he start date:

If t he st o p date is after t he date of t he first d ose of o pe n -label st u d y treat me nt, t he date of t he 
first d ose of  o pe n -label st u d y treat me nt will be assi g ne d t o t he missi n g start date
If t he st o p date is bef ore t he date of t he first d ose of o pe n -la bel st u d y treat me nt, t he st o p date will 
be assi g ne d t o t he missi n g start date
3 7 8


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 1 of  3 5
6. 4. 9.
Missi n g D ate I nf or m ati o n f or Pri or or C o n c o mit a nt Me dic ati o ns
F or pri or or c o nc o mita nt me dicati o ns, i ncl u di n g resc ue me dicati o ns, i nc o m p lete (ie, partl y  
missi n g) start dates a n d/ or st o p dates will be i m p ute d. W he n t he start date a n d t he st o p date are 
b ot h i nc o m p lete f or a partici pa nt , t he start date will be i m p ute d first.
6. 4. 9. 1.
I nc o m plete St art D ate
T he f o ll owi n g r ul es will be a p plie d t o i m p ute t he missi n g n u meric fiel ds f or a n i nc o m p lete prior 
or c o nc o mita nt me dicat i on start date. If t he st o p date is c o m plete ( or i m p ute d) a n d t he i m p ute d 
start date is after t he st o p date, t he start date will be i m p ute d usi n g t he st o p date.
Missi n g m o nt h a n d d a y
If t he year of t he i nc om p lete start date is t he sa me as t he year of t he first d ose of o pe n -label st u d y 
treat me nt, t he mo nt h a n d da y  of t he first d ose of o pe n -label st u d y treat me nt will be assi g ne d 
t o t he missi n g fiel ds
If t he year of t he i nc om p lete start date is bef ore t he year of t he first d ose of o pe n -label st u d y 
treat me nt, Dece m ber 3 1 will be assi g ne d t o t he missi n g fiel ds
If t he year of t he i nc om p lete start date is after t he year of t he first d ose of o pe n -lab el st u d y 
treat me nt, J a n u ary 1 will be assi g ne d t o t he missi n g fiel ds
Missi n g m o nt h o nl y
If o nl y t h e mo n t h is missi n g, t he da y will be treate d as missi n g a n d b ot h t he m ont h a n d t he da y  
will be re place d acc or di n g t o t he a b o ve pr oce d ure
Missi n g d a y o nl y
If t he m o nt h a n d ye ar of t he i nc o m plete start date are t he sa me as t he m o nt h a n d year of t he first 
d ose of o pe n -label st u d y treat me nt, t he da y of t he first d ose of o pe n -la bel st u d y tr e at me nt 
will be assi g ne d t o t he missi n g da y
If either t he y ear of t he i nc o m p lete start date is bef ore t he year of t he date of t he first d ose of 
o pe n -label st u d y treat me nt or if b ot h years are t he sa me b ut t he m o nt h of t he i nc o m p lete start 
date i s bef ore t he m o nt h of t he date of t he first d ose of o pe n -label st u d y treat me nt, t he last 
d a y  of t h e mo nt h will be assi g ne d t o t he missi n g da y .
If either t he y ear of t he i nc o m p lete start date is after t he year of t he date of t he first d ose of o pe n -
la bel st u dy treat me nt or if b ot h years are t he sa me b ut t he mo nt h of t he i nc o m p lete start date 
is after t he m o nt h of t he date of t he first d ose of o pe n -la bel st u d y treat me nt, t he first da y of 
t he mo nt h will  be assi g ne d t o t he missi n g da y
6. 4. 9. 2.
I nc o m plete St o p D ate
T he f o ll owi n g r ul es will be a p plie d t o i m p ute t he missi n g n u meric fiel ds f or a n i nc o m p lete prior 
or c o nc o mita nt me dicat i on st o p date. If t he date of t he last d ose of st u d y  treat me nt is missi n g, 
r e place it wit h t h e last visit date i n t he i m p utatio ns descri be d bel o w. If  t he i m p ute d st o p date is 
bef ore t he start date (i m p ute d or n o ni m p ute d start date), t he i m p ute d st o p date will be e q ual t o 
t he start date.
3 7 9


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 2 of  3 5
Missi n g m o nt h a n d d a y
If t he year of t he i nc om p lete st o p date is t he sa me as t he year of t he last d ose of st u d y tr e at me nt, 
t he m o nt h a n d da y of t h e last d ose of st u d y tr e at me nt will be assi g ne d t o t he missi n g fiel ds
If t he year of t he i nc om p lete st o p date is bef ore t he year of t he last d ose of st u d y tr e at me nt, 
Dece m ber 3 1 will be assi g ne d t o t he missi n g fiel ds
If t he year of t he i nc om p lete st o p date is after t he year of t he last d ose of st u d y treat me nt, 
Ja n uar y 1 will be assi g ne d t o t he missi n g fiel ds
Missi n g m o nt h o nl y
If o nl y t h e mo n t h is missi n g, t he da y will be treate d as missi n g a n d b ot h t he m o nt h a n d t he da y 
will be re place d acc or di n g t o t he a b o ve pr oce d ure
Missi n g d a y o nl y
If t he m o nt h a n d ye ar of t he i nc o m plete st o p date are t he sa me as t he m o nt h a n d year of t he last 
d ose of st u d y  treat me nt, t he da y of t h e last d ose of st u d y tr e at me nt will be assi g ne d t o t he 
missi n g da y
If either t he y ear of t he i nc o m p lete st o p date is bef ore t he year of t he date of t he last d ose of 
st u d y tr e at me nt or if b ot h years are t he sa me b ut t he m o nt h of t he i nc o m p lete st o p date is 
bef ore t he m o nt h of t he date of t he last d ose of st u d y  treat me nt, t he last da y of t h e mo nt h will 
be assi g ne d t o t he missi n g da y
If either t he y ear of t he i nc o m p lete st o p date is after t he year of t he date of t he last d ose of st u d y 
treat me nt or if b ot h years are t he sa me b ut t he m o nt h of t he i nc o m p lete st o p date is after t he 
m o nt h of t he date of t he last d ose of st u d y  treat me nt, t he first da y of t h e mo nt h will be 
assi g ne d t o t he missi n g da y
6. 4. 1 0.
C h ar acter V al ues of Cli nic al L a b or at or y P ar a meters
If t he re p orte d val ue of a cli nical la b orat or y para meter ca n n ot be use d i n a statistical s u m mar y 
ta ble beca use, f or e xa m ple, a c haracter stri n g is re p orte d f or a para meter of t he n u meric t y pe, a 
c o de d value m ust be a p pr o priatel y  deter mi ne d f or use i n t he statistical a nal yses. T he act ual 
val ues, h o we ver, as re p orte d i n t he data base will be prese nte d i n t he data listi n gs.
Ta ble 6 - 1 1 s h o ws e xa m ples of h o w s o me p ossi ble la b orat or y res ults s h o ul d be c o de d f or t he 
a nal ysis.
3 8 0


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 3 of  3 5
T a ble 6- 1 1
E x a m ples of C o di n g S peci al C h ar acter V al ues f or Cli nic al L a b or at or y P ar a meters
L a b or at ory Test,
SI U nit
P ossi ble L a b or at ory Res ults
C o de d V al ue f or A n alysis
C H E MI S T R Y
A L T, U/ L
< 5
5
A S T, U/ L
< 5
5
Bilir u bi n, t otal, μ m ol/ L
< 2
2
U RI N A L Y SI S
Gl uc ose, m m ol/ L
= O R > 5 5, ≥ 5 5, > 0
P ositi ve
≤ 0, ne gati ve
Ne gati ve
p H
> 8. 0, ≥ 8. 0
8. 0
≥ 8. 5
8. 5
Pr otei n
= O R > 3. 0, ≥ 3. 0, > 0
P ositi ve
≤ 0
Ne gati ve
A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; SI = Le Systè me I nter n ati o n al d’ U nités (I nter nati o nal 
S y ste m of U nits).
3 8 1


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 4 of  3 5
7.  
C o vi d- 1 9 Rel ate d A n al yses
T his sect i on s pecifie d a nal yses relate d t o C O VI D -1 9 pa n de mic fr o m t he f o ll owi n g as pects:

Di s p ositio n

St u d y  visits a n d st u d y pr oce d ures

Pr ot oc ol  de viati on

Treat me nt i nterr u pti o n d ue t o C O VI D - 1 9

T E A Es relate d wit h C O VI D -1 9 a n d s u p ple me ntal si g ns a n d s y m pt o ms

C O VI D -1 9 stat us ( C O VI D -1 9 testi n g res ults or c o ntact wit h a C O VI D - 1 9 p osit i ve 
pers o n)
S af et y P o p ul at i on will be use d f or t he pla n ne d a nal yses descri be d a b o ve. T he n u m ber of
parti ci pa nts wit h st u d y visits i m pacte d b y C O VI D-1 9 will be s u m marize d b y t he classificat i on of 
st u d y visits. F urt her more, t he n u m ber of partici pa nts w h o misse d at least o ne e nt ire visit d ue t o 
C O VI D -1 9 will be s u m mar ize d.
T he n u m ber of partici pa nts wit h si g nifica nt pr ot oc ol de viati o n d ue t o C O VI D -1 9 will be
pr o vi de d. T he n u m ber of partici pa nts wit h st u d y  dr u g disr u pti o n d ue t o C O VI D-1 9 will be 
pr o vi de d as well. T he n u m ber of partici pa nts wit h T E A Es relate d t o C O VI D - 1 9 will be ta b ulate d 
b y preferre d ter ms, a n d relate d s u p ple me ntal si g ns a n d s y m pt o ms will be liste d. C O VI D- 1 9 
stat us, i.e., testi n g res ults or c o ntact wit h a C O VI D-1 9 p osit i ve pers o n, will be s u m marize d.
S u p p orti n g list i n gs f or t he descri be d a nal yses a b o ve will be pr o vi de d.
3 8 2


C O N FI D E N TI A L
Statistical A nal ysis Pla n 3 1 0 1 - 3 1 1-0 0 2 A me n d me nt 1
[ At o ge pa nt]
Pa ge 3 5 of  3 5
8.
Refere nces
Bi gal M E, D o di c k D W , Ra p o p ort A M, Sil berstei n S D, Ma Y, Ya n g R, et al. Safety,  t olera bilit y,  
a n d efficac y of T E V-4 8 1 2 5 f or pre ve nt i ve treat me nt of hi g h-fre q ue nc y e pis o dic mi grai ne: a 
m ult ice ntre, ra n d o mise d, d o u ble-bli n d, place b o- c o ntr olle d, p hase 2 b st u d y. La ncet Ne ur ol 
2 0 1 5; 1 4: 1 0 8 1 - 1 0 9 0.
I C H D-3: Hea dac he Classificat i on C o m mittee of t he I nter nati o nal Hea dac he S ociet y (I H S). T he 
I nter nati o nal Classificati on of Hea dac he Dis or ders, 3r d e dit i on. Ce p halal gia. 2 0 1 8; 3 8( 1): 1 - 2 1 1.
Katsara va Z, B use D C, Ma nac k A N, Li pt o n R B. Defi ni n g t he Differe nces Bet wee n E pis o dic
Mi grai ne a n d C hr o ni c Mi grai ne. C urr Pai n Hea dac he Re p. 2 0 1 2; 1 6: 8 6 – 9 2
3 8 3