Clinical trial NCT04740827
Conditions: Episodic Migraine
Keywords: Episodic migraine
Sponsor: Allergan
Start date: 2021-03-05; Completion date: 2022-08-04
Enrollment: 315 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety, tolerability, and efficacy of Atogepant 60 mg compared with placebo in participants with episodic migraine and who have previously failed 2 to 4 classes of oral prophylactic treatments.

Detailed description:

Arms: arm 1: Participants received atogepant-matching placebo tablets, orally, once daily (QD) for up to 12 weeks in a double-blind (DB) treatment period. arm 2: Participants received atogepant 60 mg, orally, QD for up to 12 weeks in a DB treatment period.
Interventions: intervention 1: Atogepant 60 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Atogepant tablets. intervention 2: Atogepant matching placebo tablets.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
1
Title Page
Protocol Title:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-
controlled, Parallel-group Study to Evaluate the Efficacy, 
Safety, and Tolerability of Oral Atogepant for the 
Prophylaxis of Migraine in Participants with Episodic 
Migraine Who Have Previously Failed 2 to 4 Classes of Oral
Prophylactic Treatments (ELEVATE)
Protocol Number:
3101-304-002
Amendment Number:
Amendment 2
Product:
Atogepant (AGN-241689)
Brief Protocol Title:
Atogepant for prophylaxis of migraine in participants who 
failed previous oral prophylactic treatments
Study Phase: 
3
Sponsor Name:
Allergan Limited
Legal Registered Address:
Allergan Limited
Ground Floor, Marlow International, Parkway
Marlow, Buckinghamshire SL7 1YL
United Kingdom
US Agent:
Allergan Sales, LLC
5 Giralda Farms
Madison, NJ 07940
USA
Regulatory Agency Identifying Number(s): EudraCT Number: 2019-003448-58; IND: 114780
Allergan Medical Safety 
Physician
Contact Information:
Refer to the Study Contacts Page
Allergan Sponsor Signatory:
Vice President, Neuroscience Development
Original Protocol Date:
17 December 2019
Amendment 1 Date
03 April 2020
Amendment 2 Date
01 December 2020
Refer to the final page of this protocol for approval signature.
 
 
 
 
NCT04740827


CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
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SAE Reporting Fax Number/Email:
Business Unit
Email
Phone
Fax
Allergan
IR-Clinical-SAE@allergan.com
Not applicable
+1-714-796-9504 
Backup: 
+1-714-246-5295
The following information can be found on FDA Form 1572 and/or study contacts page: Name 
and contact information of Allergan study personnel and Emergency Telephone Numbers; name, 
address, and statement of qualifications of each investigator; name of each subinvestigator 
working under the supervision of the investigator; name and address of the research facilities to 
be used; name and address of each reviewing IRB; US 21 CFR 312.23 section 6(iii)b.
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:
Implement and conduct this study diligently and in strict compliance with the protocol, GCP, and 
all applicable laws and regulations.
Maintain all information supplied by Allergan in confidence and, when this information is 
submitted to an IRB, IEC or another group, it will be submitted with a designation that the 
material is confidential.
Ensure that all persons assisting with the trial are adequately informed about the protocol, the 
study intervention(s), and their trial-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Signature
Date
The signature of the sponsor signatory is collected on the protocol approval page.
 
 
 
 
 


CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
01 December 2020
Amendment 1
03 April 2020
Original Protocol
17 December 2019
Amendment 2 (01 December 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The changes are to remove one atogepant treatment arm and change the study design to a 2-arm 
study, reduce the sample size, add measures to protect participants or study personnel in 
pandemic situations (eg, COVID-19, such as, replacing office visits by remote visits if needed, 
etc) and to enable participants to roll over into long-term extension study 3101-312-002. In
addition, the amendment is to simplify inclusion and exclusion criteria, clarify study objectives 
and endpoints, study assessments, statistical analyses, and resolve discrepancies in the protocol.
Section No. and Name
Description of Change
Brief Rationale
Throughout
Removed the atogepant 30 mg QD 
treatment arm from the study and 
reduced the total number of 
participants from 627 to 
300 participants (initial protocol 
had 209 participants in each of 
3 treatment arms, the amended 
protocol has 150 participants in 
each of 2 treatment arms). 
The results from the Phase 3 Study 3101-
301-002 demonstrated that the efficacy of 
atogepant 10 mg QD, 30 mg QD, and 
60 mg QD was significantly higher than 
placebo for the prevention of migraine in 
participants with episodic migraine. The 
atogepant 60 mg QD dose had the highest 
efficacy while not having a clinically 
meaningful difference in safety. Therefore, 
the sponsor decided to eliminate the 
atogepant 30 mg QD treatment arm in this 
study and re-estimate the sample size, 
which reduced the number of participants 
required to demonstrate a significant 
difference in atogepant 60 mg QD 
compared to placebo based on observed 
responses in Study 3101-301-002.
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
1.1 Synopsis
Updated in line with changes 
made throughout the protocol.
To update the synopsis with amended items 
in the main body of the protocol.
1.3 Schedule of Activities
Updated to clarify that Visit 1 and 
Visit 2 must be conducted in the 
office. All other visits should be 
conducted in the office unless it is 
necessary to conduct remote visits 
for safety reasons. 
Add measures to protect participants or 
study personnel in pandemic situations (eg, 
COVID-19).
Define the number of scheduled 
study visits
Add measures for participants rolling over 
into Study 3101-312-002 (long-term 
extension study).  
Text was updated to say “Obtain 
VCT consent and perform
verification (United States and 
Canada only)”
Canada will not utilize the VCT 
verification
2.2 Background
Updated section with the results
from the recently completed 
Phase 3 studies (Study 3101-301-
002 and Study 3101-302-002).
To provide the latest clinical study results 
and information to the investigators.
3. Objectives and 
Endpoints
Secondary: The first 3 secondary 
objectives and endpoints have 
been revised for clarification
To clarify and specify the actual secondary 
objectives and endpoints.
Secondary: (for the United States 
only) Added text to clarify the 
previous secondary objective and 
endpoints of evaluating the effect 
of atogepant versus placebo on 
functioning and activity 
impairment by specifying the 
AIM-D domains of Performance 
of Daily Activities and Physical 
Impairment.
To further clarify the previous secondary 
objective and endpoint related to 
functioning and activity impairment by 
specifying the Performance of Daily 
Activities and Physical Impairment 
domains of the AIM-D score..
Exploratory: Deletion of CFB in 
monthly headache-free days at 
Weeks 1-4, 5-8, and 9-12.
To remove redundancy because monthly 
headache-free days will be complementary 
to monthly headache day.
Exploratory: Deletion of CFB in 
monthly headache day pain 
intensity at Weeks 1-4, 5-8, and 
9-12.
To remove redundancy because headache 
pain intensity can be interpreted using 
monthly moderate/severe days.
Exploratory: Deleted Week 16
from HIT-6 and MSQ v2.1
assessments as an endpoint for 
evaluation of efficacy.
Treatment with atogepant or placebo ends
at Week 12 (Visit 7) and it is predicted that 
many participants will enroll in the safety 
extension Study 3101-312-002. So an 
assessment at Week 16 will not assess the 
participant’s ability to function while on 
treatment and the number of participants 
who will actually have a Week 16 (Visit 8) 
will be low.
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
Exploratory: Added an additional 
Exploratory objective and 
endpoint related to Performance of 
Daily Activities.
To further clarify the endpoint in CFB in 
monthly Performance of Daily Activities of 
the AIM-D.
Exploratory: Added an 
Exploratory objective and 
endpoint related to Physical 
Impairment.
To further clarify the endpoint related to 
CFB in monthly Physical Impairment of 
the AIM-D.
Exploratory: Added an 
Exploratory objective and 
endpoint related to the total score 
of the AIM-D.
To further clarify the endpoint related to 
the AIM-D total score.
4.1 Overall Design
Elaboration on how the 
randomization will be stratified by 
number of migraine days during 
the screening/baseline period (4 to 
< 8 and ≥ 8) and the number of 
classes of failed prior prophylactic 
treatments (2 and > 2).
Clarification of stratification strategy.
Adjusted block size for block 
randomization to accommodate 
the deletion of the atogepant 
30 mg QD treatment arm. 
To adjust for the elimination of the 
atogepant 30 mg QD treatment arm.
Reference to Subpopulation A 
removed
To simplify the enrollment requirements
Added that approximately 50% of 
randomized participants will have 
failed >2 classes of prior migraine 
prophylactic medications
To elaborate on the predicted number of 
randomized participants in this study that 
will meet the stratification category of >2 
classes of failed prophylactic treatment.
Define the number of scheduled 
study visits for participants who 
will roll over into Study 3101-312-
002 (long-term extension study) 
and those who do not.
Add measures for participants rolling over 
into Study 3101-312-002 (long-term 
extension study).  
4.2 Justification for Dose
Updated this section with results 
from Study 3101-301-002 that 
verifies that the atogepant 60 mg 
QD dose has a higher efficacy than 
the atogepant 30 mg QD dose 
without adding any safety risk.
Verifies the results from Study CGP-MD-
01 and justifies the deletion of the 
atogepant 30 mg QD treatment arm from 
this study.
5.1 Inclusion Criteria
Inclusion Criterion 2.06.b –
Updated to state “Failed at least
one AND failed or be not suitable 
for a secondtreatment from a 
different medication class as 
listedthe list below:
i. Propranolol OR metoprolol;
ii. Topiramate; 
iii. Flunarizine;
To simplify the enrollment requirements
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
iv. Amitriptyline”
Inclusion Criterion 2.07 removed
To simplify the enrollment requirements
Inclusion Criterion 3.01, updated 
to state: 
“Male participants willing to 
minimize the risk of inducing 
pregnancy for the duration of the 
clinical study and the follow up 
period as detailed below” 
“Female participants willing to 
minimize the risk of inducing 
pregnancy for the duration of the 
clinical study and the follow up 
period as detailed below”
To resolve inconsistency in the description 
of contraception requirements.
5.2 Exclusion Criteria
Revised Exclusion Criterion 3.03 
to clarify the use of barbiturate-
containing and opioid-containing 
analgesics on a monthly basis in 
the 3 months prior to Visit 1
To clarify the conditions of barbiturate- and 
opioid-containing analgesics that would 
exclude participants from this study.
In Exclusion Criterion 3.04, the 
word “oral” was removed and “or 
approved” added in the text “any 
other oral investigational or 
approved CGRP-RA.”
To clarify that the use of any 
investigational or approved CGRP-RA is 
excluded.
In Exclusion Criterion 3.04, 
reference to ubrogepant and 
rimegepant was removed
To clarify that prior use of ubrogepant or 
rimegepant is not exclusionary.
5.3 Criteria for 
Determining that Prior 
Treatment for the 
Prophylaxis of Migraine 
Have Been Failed
Deleted text: “Not suitable for the 
purpose of this study is defined as 
participant is not considered to be 
suitable for the treatment for 
medical reasons such as 
contraindications or precautions 
included in local labels, national 
guidelines or other locally binding 
documents, or other medically 
relevant reasons as confirmed by 
the treating physician. 
Unsuitability of prior migraine 
preventive medication categories 
is to be collected in the eCRF 
based on:
Contraindications or 
precautions included in local 
labels
National guidelines or other 
locally binding documents
Other medically relevant 
reasons”
To harmonize with updated inclusion 
criteria
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
5.5 Screen Failures
Updated to state: “Rescreening of 
screen failures is permitted in 
certain situations (including failure 
to adequately screen due to the 
COVID-19 pandemic),   “
To further clarify possibilities for 
rescreening in pandemic situations (eg, 
COVID-19)
5.5.1 Procedure for 
Duplicate Participant 
Identification – Verified 
Clinical
Reference to Canada removed.
VCT will not be used in Canada.
6.1.4 Intervention 
Allocation Ratio
Elaboration on how the 
randomization will be stratified by 
number of migraine days during 
the screening/baseline period (4 to 
< 8 and ≥ 8) and the number of 
classes of failed prior prophylactic 
treatments (2 and > 2).
Clarification of stratification strategy.
Reference to Subpopulation A
removed.
To harmonize with updated inclusion 
criteria.
Updated  with “Approximately 
50% of randomized participants 
will have failed > 2 classes of 
prior prophylactic treatments.”.
To elaborate on the predicted number of 
randomized participants in this study that 
will meet the stratification category of 
> 2 classes of failed prophylactic treatment.
6.1.5 Other Study Supplies
Deleted text in All supplies neded 
for PK and future biomedical 
research sample collections.
Clarification
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding
Deleted text: “A double-dummy 
design will be used to maintain 
study blind”.
Revised because there is only one matching 
placebo for the atogepant 60 mg tablet.
6.5.3 Prohibited 
Interventions During the 
Study
Added bulleted text: “Ubrogepant
(Ubrelvy®) and rimegepant 
(Nurtec ODT®) is prohibited from 
Visit 1 throughout the study 
period.”
Clarification of prohibited concomitant 
medications
8.3.6 Pregnancy
The text in the first bullet was 
updated: “Details of all 
pregnancies in female participants 
and female partners of male 
participants will be collected 
fromafter the signingstart of the 
ICFstudy intervention and until 
3the Follow-Up Visit (Visit 8) or 
30 days after the last dose of study 
intervention if the Follow-Up Visit 
is not done.”
To extend the period of pregnancy data 
collection in order to ensure consistency 
across the atogepant development program
8.9.1. Activity Impairment 
in Migraine-Diary (AIM-D)
Description of Activity 
Impairment in Migraine-Diary
(AIM-D) updated 
To further clarify the domain structure of 
Activity Impairment in Migraine-Diary
(AIM-D)
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
9.1 Statistical Hypothesis
Added the revised hypothesis that 
atogepant dose has a greater effect 
than placebo.
To add the alternative statistical hypothesis
for the study.
9.2 Sample Size 
Determination
Revised sample size determination 
based on the elimination of the 
atogepant 30 mg QD treatment 
arm, the estimated efficacy 
response for the primary endpoint 
based on the results from Study 
3101-301-002, and the primary 
efficacy endpoint in the United 
States and in the European Union.
To adjust the sample size to accommodate 
the elimination of the atogepant 30 mg QD 
treatment arm and estimated responses in 
the primary efficacy endpoint based on the 
responses from participants in the 
completed study (3101-301-002).
9.4.1.1.2 Secondary efficacy 
endpoints
Added text to clarify the previous 
Secondary objective related to 
Performance of Daily Activities 
and its respective endpoint. Added 
an additional Secondary objective 
and endpoint in this category 
related to Physical Impairment.
To further clarify the previous Secondary 
objective and endpoint related to the 
Performance of Daily Activities of the 
AIM-D and to add an additional Secondary 
objective and endpoint related to the effect 
of Atogepant on Physical Impairment of 
the AIM-D.
9.4.1.1.3 Exploratory 
efficacy endpoints
Deleted exploratory endpoint of 
CFB in monthly headache-free 
days at Weeks 1-4, 5-8, and 9-12 
and average across the 12-week 
treatment period.
To remove redundancy because monthly 
headache-free days will be complementary 
to monthly headache days.
Deleted exploratory endpoint of 
CFB in monthly headache day 
pain intensity at Weeks 1-4, 5-8, 
and 9-12 and average across the 
12-week treatment period.
To remove redundancy because headache 
pain intensity can be interpreted using 
monthly moderate/severe days.
Added an exploratory endpoint 
related to Performance of Daily 
Activities.
To further clarify the endpoint in CFB in 
monthly Performance of Daily Activities of 
the AIM-D.
Added an exploratory endpoint 
related to Physical Impairment.
To further clarify the endpoint related to 
CFB in monthly Physical Impairment of 
the AIM-D.
Added an exploratory endpoint 
related to the total score of the 
AIM-D.
To further clarify the endpoint related to 
the AIM-D total score.
9.4.1.2 Primary Analysis
Added text to further clarify the 
analysis of the primary efficacy 
variable and what parameters will 
be included in the statistical 
model.
To further clarify which stratification 
parameters will be included in the 
statistical model for the analysis and that 
only data collected during the double-blind 
period will be included in the analysis.
9.4.1.2.1Sensitivity 
Analyses in Missing Data 
Handling
Added 2 new subsections for 
sensitivity analyses of the primary 
efficacy data
To further clarify the sensitivity analysis in 
these 2 situations.
9.4.1.2.2 Sensitivity 
Analysis for Possible 
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
Violation of Normality 
Assumption 
9.4.1.3Secondary Analyses
Added text to further define the 
AIM-D assessment of functioning 
and activity impairment by using 
the Performance of Daily 
Activities and Physical 
Impairment domain scores and to 
clarify what parameters will be 
included in the statistical model
for analysis.
To further clarify the analyses used for the 
secondary objectives.
9.4.1.4 Exploratory 
Efficacy Analyses
Added text related to the analyses 
of the exploratory objectives.
To further clarify the analyses used for the 
exploratory objectives.
9.4.4 Subgroup Analyses
Added text related to the subgroup 
analyses.
To further clarify the analyses used for the 
subgroup analyses.
9.6 Off-Treatment 
Hypothetical Estimand
Added text related to an Off-
treatment Hypothetical Estimand
To clarify the analyses used for the Off-
treatment Hypothetical Estimand and the 
subsections.
10.7 Appendix 7: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Revised text specifying that 
nonvasectomized male participants 
should use contraception during 
the intervention period and at least 
3 days after the last dose of study 
intervention. Previously, the text 
just specified the course of the 
study.
Revised text to specify that a male 
condom can be used with or 
without spermicide.
Clarification
Clarification
10.8.1 Visit 1 
(Screening/Baseline) Day -
35 to Day 28
Revised VCT consent and 
verification to be only in the 
United States instead of the United 
States and Canada
Clarification
10.8.2 Visit 2 
(Randomization) Day 1
10.8.3 Visits 3 to 6 (Weeks 2 
to 8)
Revised text to remind participant 
to not only bring e Diary, but also 
to return the study intervention 
kits
Clarification
10.8.4 Visit 7/Early 
Termination (Week 12)
Added text specifying to complete 
the Healthcare Resource 
Utilization Questionnaire
Clarification
10.9 Appendix 9: Examples 
of Prohibited Medications 
In table for Drugs with 
demonstrated efficacy for the 
prevention of migraine: 
Added “Locally approved 
products (eg, oxeterone, 
pizotifen)”
Clarification of prohibited concomitant 
medications
 
 
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
Added text: “Ubrogepant
(Ubrelvy®) and rimegepant 
(Nurtec ODT®) is prohibited from 
Visit 1 throughout the study 
period.”
Clarification of prohibited concomitant 
medications
10.11 Study Visits 
Conducted Remotely
Added Appendix 11 related to 
visits conducted remotely.
To further clarify the Schedule of Activities 
for remote visits and when they are 
permitted.
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore, have not been 
summarized
 
 
 
 
 


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Table of Contents
Title Page .........................................................................................................................................1
Protocol Amendment Summary of Changes Table .........................................................................4
Table of Contents...........................................................................................................................12
List of Tables .................................................................................................................................15
List of Figures................................................................................................................................16
1.
Protocol Summary ................................................................................................................17
1.1.
Synopsis....................................................................................................................17
1.2.
Schema......................................................................................................................23
1.3.
Schedule of Activities (SoA) ....................................................................................24
2.
Introduction...........................................................................................................................28
2.1.
Study Rationale.........................................................................................................28
2.2.
Background...............................................................................................................28
2.3.
Benefit/Risk Assessment ..........................................................................................31
3.
Objectives and Endpoints .....................................................................................................32
4.
Study Design.........................................................................................................................36
4.1.
Overall Design ..........................................................................................................36
4.2.
Justification for Dose................................................................................................36
4.3.
End of Study Definition............................................................................................37
5.
Study Population...................................................................................................................38
5.1.
Inclusion Criteria ......................................................................................................38
5.2.
Exclusion Criteria .....................................................................................................41
5.3.
Criteria for Determining that Prior Treatment for the 
Prophylaxis of Migraine Have Been Failed..............................................................43
5.4.
Lifestyle Considerations ...........................................................................................44
5.4.1.
Meals and Dietary Restrictions..................................................................44
5.4.2.
Caffeine, Alcohol, and Tobacco ................................................................44
5.4.3.
Activity ......................................................................................................44
5.5.
Screen Failures..........................................................................................................44
5.5.1.
Procedure for Duplicate Participant Identification –
Verified Clinical.........................................................................................45
6.
Study Intervention.................................................................................................................46
6.1.
Study Intervention(s) Administered..........................................................................46
6.1.1.
Study Interventions and Formulations.......................................................46
6.1.2.
Control Intervention...................................................................................46
6.1.3.
Study Intervention Regimen and Dosing...................................................46
6.1.4.
Intervention Allocation Ratio ....................................................................47
6.1.5.
Other Study Supplies .................................................................................47
6.2.
Preparation/Handling/Storage/Accountability..........................................................47
6.3.
Measures to Minimize Bias: Randomization and Blinding......................................48
6.4.
Study Intervention Compliance ................................................................................49
 
 
 
 


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6.5.
Concomitant Therapy................................................................................................49
6.5.1.
Permitted Interventions..............................................................................49
6.5.2.
Rescue Interventions..................................................................................49
6.5.3.
Prohibited Interventions During the Study ................................................50
6.6.
Dose Modification ....................................................................................................51
6.7.
Intervention after the End of the Study.....................................................................51
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.................................................................................................52
7.1.
Discontinuation of Study Intervention......................................................................52
7.1.1.
Criteria for Study Termination...................................................................53
7.2.
Participant Discontinuation/Withdrawal from the Study..........................................54
7.3.
Lost to Follow-up......................................................................................................54
8.
Study Assessments and Procedures ......................................................................................55
8.1.
Efficacy and Descriptive Assessments .....................................................................55
8.1.1.
Migraine Day .............................................................................................56
8.1.2.
Headache Day............................................................................................57
8.1.3.
Acute Medication Use Day........................................................................57
8.1.4.
Allodynia Symptom Checklist (ASC-12)..................................................57
8.2.
Safety Assessments...................................................................................................57
8.2.1.
Physical Examinations...............................................................................57
8.2.2.
Vital Signs..................................................................................................57
8.2.3.
Electrocardiograms ....................................................................................58
8.2.4.
Clinical Safety Laboratory Assessments ...................................................58
8.2.5.
Suicidal Risk Monitoring...........................................................................58
8.3.
Adverse Events and Serious Adverse Events ...........................................................59
8.3.1.
Time Period and Frequency for Collecting AE and 
SAE Information........................................................................................59
8.3.2.
Method of Detecting AEs and SAEs .........................................................60
8.3.3.
Follow-up of AEs and SAEs......................................................................60
8.3.4.
Regulatory Reporting Requirements for SAEs..........................................60
8.3.5.
Adverse Reactions, Serious Adverse Reactions, and 
Suspected Unexpected Serious Adverse Reactions –
Expedited reporting within the EU ............................................................61
8.3.6.
Pregnancy...................................................................................................61
8.3.7.
Disease-related Events and/or Disease-related 
Outcomes Not Qualifying as AEs or SAEs ...............................................62
8.3.8.
Protocol-specific AEs ................................................................................62
8.3.9.
AEs of Special Interest...............................................................................62
8.3.10.
Medication Errors ......................................................................................62
8.4.
Treatment of Overdose .............................................................................................63
8.5.
Pharmacokinetics......................................................................................................63
8.5.1.
Blood PK Sampling Procedure..................................................................63
8.5.2.
PK Sample Bioanalysis..............................................................................64
8.6.
Pharmacodynamics ...................................................................................................64
8.7.
Genetics.....................................................................................................................64
 
 
 
 


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8.8.
Biomarkers and Other Assessments..........................................................................64
8.9.
Health Outcome Measures and Health Resource Utilization ...................................64
8.9.1.
Activity Impairment in Migraine-Diary (AIM-D).....................................64
8.9.2.
Activity Level and Activity Limitation......................................................65
8.9.3.
Patient Satisfaction with Study Medication (PSSM).................................65
8.9.4.
Headache Impact Test (HIT-6) ..................................................................65
8.9.5.
Migraine Disability Assessment (MIDAS)................................................65
8.9.6.
Patient Global Impression of Change (PGIC) ...........................................66
8.9.7.
Work Productivity and Activity Impairment 
Questionnaire: Migraine V2.0 (WPAI:MIGRAINE) ................................66
8.9.8.
European Quality of Life – 5 Dimensional (EQ-5D-
5L)..............................................................................................................66
8.9.9.
Patient Global Impression – Severity (PGI-S)...........................................66
8.9.10.
Migraine Specific Quality of Life Questionnaire, 
Version 2.1 (MSQ v2.1).............................................................................67
8.9.11.
Patient-Reported Outcomes Measurement 
Information System Pain Interference –Short Form 
6a (PROMIS-PI) ........................................................................................67
8.9.12.
Patient Health Questionnaire (PHQ-9) ......................................................67
8.9.13.
Healthcare Resource Utilization ................................................................67
9.
Statistical Considerations......................................................................................................69
9.1.
Statistical Hypotheses ...............................................................................................69
9.2.
Sample Size Determination.......................................................................................69
9.3.
Populations for Analyses ..........................................................................................73
9.4.
Statistical Analyses ...................................................................................................73
9.4.1.
Efficacy Analyses ......................................................................................73
9.4.2.
Safety Analyses..........................................................................................79
9.4.3.
PK Analyses...............................................................................................81
9.4.4.
Subgroup Analyses ....................................................................................81
9.5.
Interim Analyses .......................................................................................................81
9.6.
Off-treatment Hypothetical Estimand.......................................................................81
9.6.1.
Treatment Condition of Interest.................................................................81
9.6.2.
Population ..................................................................................................82
9.6.3.
Variable......................................................................................................82
9.6.4.
Accounting of Intercurrent Events.............................................................82
9.6.5.
Population-level Summary.........................................................................82
9.6.6.
Off-treatment Hypothetical Estimand Approach for 
the Secondary Endpoints............................................................................82
10.
Supporting Documentation and Operational Considerations ...............................................84
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...........................................................................................................84
10.1.1.
Regulatory and Ethical Considerations......................................................84
10.1.2.
Financial Disclosure...................................................................................84
10.1.3.
Informed Consent Process .........................................................................84
10.1.4.
Data Protection...........................................................................................86
 
 
 
 


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10.1.5.
Committees Structure.................................................................................86
10.1.6.
Posting Clinical Study Data.......................................................................86
10.1.7.
Data Quality Assurance .............................................................................87
10.1.8.
Summary of Methods of Data Collection..................................................87
10.1.9.
Source Documents .....................................................................................88
10.1.10. Study and Site Closure...............................................................................89
10.1.11. Publication Policy......................................................................................89
10.1.12. Compliance with Protocol..........................................................................90
10.1.13. Participant Privacy.....................................................................................90
10.1.14. Coordinating Investigator ..........................................................................90
10.2.
Appendix 2: Clinical Laboratory Tests.....................................................................90
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...................................................91
10.3.1.
ALT or AST Elevations.............................................................................93
10.3.2.
Potential Hy’s Law Cases..........................................................................94
10.4.
Appendix 4: Abbreviations.....................................................................................100
10.5.
Appendix 5: Standard Discontinuation Criteria......................................................103
10.6.
Appendix 6: Study Tabular Summary ....................................................................104
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information............................................................................................105
10.8.
Appendix 8: Study Schedule Supplement...............................................................108
10.8.1.
Visit 1 (Screening/Baseline) Day -35 to Day -28 ....................................109
10.8.2.
Visit 2 (Randomization) Day 1................................................................110
10.8.3.
Visits 3 to 6 (Weeks 2 to 8) .....................................................................111
10.8.4.
Visit 7/Early Termination (Week 12) ......................................................112
10.8.5.
Visit 8 (End of Study) Week 16...............................................................113
10.8.6.
Unscheduled visits ...................................................................................113
10.9.
Appendix 9: Examples of Prohibited Medications.................................................113
10.10. Appendix 10: Documentation of prior prophylactic treatment 
failures 115
10.10.1. Source documents....................................................................................115
10.10.2. Treatment Failure Worksheet ..................................................................116
10.11. Appendix 11: Study Visits Conducted Remotely...................................................117
10.12. Appendix 12: Protocol Amendment History ..........................................................120
11.
References...........................................................................................................................121
List of Tables
Table 1-1
Schedule of Activities........................................................................................... 24
Table 6-1
Study Interventions............................................................................................... 47
Table 9-1
Statistical Power for Primary and Secondary Endpoints for the United States .... 70
Table 9-2
Statistical Power for Primary and Secondary Endpoints for the EU .................... 71
 
 
 
 


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Table 9-3
Observed Treatment Effect for Primary Endpoint in Atogepant Program and 
Liberty................................................................................................................... 72
Table 10-1
Protocol-required Laboratory Assessments.......................................................... 90
Table 10-2
Highly Effective and Acceptable Contraceptive Methods.................................. 107
Table 10-3
Schedule of Activities for Remote Study Visits ................................................. 118
List of Figures
Figure 1-1
Study Diagram ...................................................................................................... 23
 
 
 
 


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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Atogepant for the 
Prophylaxis of Migraine in Participants with Episodic Migraine Who Have Previously Failed 
2 to 4 Classes of Oral Prophylactic Treatments (ELEVATE)
Protocol Number: 3101-304-002
Brief Title: Atogepant for prophylaxis of migraine in participants who failed previous oral 
prophylactic treatments
Study Phase: 3
Study Rationale: To prospectively assess the safety, tolerability, and efficacy of atogepant 
60 mg QD compared with placebo in the prophylaxis of episodic migraine in participants who
previously failed 2 to 4 classes of oral prophylactic treatments. 
Objectives and Endpoints:
Objectives
Endpoints
Primary
To prospectively test for superiority of atogepant 60 mg
QD versus placebo for the prevention of migraine in 
participants with episodic migraine who have 
previously failed 2 to 4 classes of oral medications for 
the prophylaxis of migraine
Change from baseline (CFB) in mean monthly 
migraine days across the 12-week treatment period.
Secondary
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the proportion of participants with at least 
50% reduction from baseline in monthly migraine days
Achievement of at least a 50% reduction in mean 
monthly migraine days across the 12-week treatment 
period.
To evaluate the effect of atogepant 60 mg QD versus 
placebo for the prophylaxis of headache
CFB in mean monthly headache days across the 
12-week treatment period.
To evaluate the effect of atogepant 60 mg QD versus 
placebo on acute medication use
CFB in mean monthly acute medication use days 
across the 12-week treatment period.
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the impact of migraine on daily activities as
assessed by Migraine Specific Quality of Life 
Questionnaire (MSQ) v2.1 Role Function-Restrictive 
domain score 
CFB in MSQ v2.1 Role Function-Restrictive domain 
score at Week 12
 
 
 
 
 


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Objectives
Endpoints
For the United States only:
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Performance of Daily Activities
For the United States only:
CFB in mean monthly Performance of Daily Activities 
domain score of the Activity Impairment in Migraine 
(AIM-D) across the 12-week treatment period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Physical Impairment
CFB in mean monthly Physical Impairment domain 
score of the AIM-D across the 12-week treatment 
period
For the European Union only:
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the impact of headaches on daily 
functioning as assessed by Headache Impact Test 
(HIT-6)
For the European Union only:
CFB in the HIT-6 total score at Week 12
Overall Study Design:

This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study in participants with episodic migraine who have previously failed 2 to 4 classes of oral
medications for the prophylaxis of migraine
Key Inclusion Criteria
Selected key inclusion criteria are presented below:
Age
Male or female participants ages 18 (or age of legal majority) to 80 years, inclusive, at Visit 1
Type of Participant and Migraine Characteristics
At least a 1-year history of migraine with or without aura consistent with a diagnosis according 
to the ICHD-3, 2018.
Age of the participant at the time of migraine onset < 50 years
History of 4 to 14 migraine days per month on average in the 3 months prior to Visit 1 in the 
investigator’s judgment
4 to 14 migraine days in the 28-day baseline period per eDiary
(Note: A randomization cap of 20% will be instituted to ensure that the planned randomized 
participants include no more than 20% of participants with 4 to <8 migraine days at baseline.)
Completed at least 20 out of 28 days in the eDiary during the baseline period and is able to 
read, understand, and complete the study questionnaires and eDiary per investigator’s 
judgment.
 
 
 
 
 


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Participants must meet both criteria below (ie, a and b). Participants must have 
a.
Failed oral migraine prophylaxis medications from 2 to 4 of the medication classes
as listed below:
i.
Propranolol, metoprolol, atenolol, bisoprolol, timolol, or nadolol;
ii.
Topiramate;
iii.
Flunarizine;
iv.
Valproate or divalproex;
v.
Amitriptyline or nortriptyline;
vi.
Venlafaxine or desvenlafaxine;
vii.
Lisinopril;
viii.
Candesartan;
ix.
Locally approved products (eg, oxeterone or pizotifen)
b. Failed at least one treatment from the list below:
i.
Propranolol OR metoprolol;
ii.
Topiramate; 
iii.
Flunarizine;
iv.
Amitriptyline;
(Note: Participant failure of a prophylactic medication can be on the basis of tolerability or 
efficacy and is based on investigator judgement. Refer to Section 5.3 for more detailed 
information. Each prior prophylactic medication failure needs to be documented in the 
Treatment Failure Worksheet, see Section 10.10 [Appendix 10]).
Contraceptives
Male participants willing to minimize the risk of inducing pregnancy, as detailed below:
A male participant must agree to use contraception as detailed in Section 10.7, Appendix 7 of 
this protocol during the intervention period and for at least 3 days after the last dose of study 
intervention and refrain from donating sperm during this period.
Female participants willing to minimize the risk of inducing pregnancy as detailed below.
A female participant is eligible to participate if she is not pregnant (ie, has a negative urine
pregnancy result at the Screening Visit (Visit 1) and Randomization Visit (Visit 2), is not 
planning to become pregnant during the course of the study, is not breastfeeding, and fulfils at 
least one of the following conditions:
a.
Not a woman of childbearing potential (WOCBP) as defined in Section 10.7
(Appendix 7)
OR
 
 
 
 
 


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b. A WOCBP who agrees to follow the contraceptive guidance of using a medically 
acceptable and effective contraceptive method as defined in Section 10.7
(Appendix 7) during the intervention period and for 3 days after the last dose of 
study intervention. 
Key Exclusion Criteria
Selected key exclusion criteria are presented below:
Medical Conditions
Any clinically significant hematologic, endocrine, pulmonary, hepatic, gastrointestinal, or 
neurologic disease

If there is a history of such a disease, but the condition has been stable for more than 
1 year prior to Visit 1, and is judged by the investigator as not likely to interfere with 
the participant’s participation in the study, the participant may be included
Participant has any other concurrent pain condition that, in the opinion of the investigator, may 
significantly impact the current headache disorder (eg, fibromyalgia, facial pain)
In the opinion of the investigator, confounding psychiatric conditions, dementia, epilepsy, or 
significant neurological disorders other than migraine
Clinically significant cardiovascular or cerebrovascular disease per the investigator’s opinion 
including, but not limited to:

Clinically significant ischemic heart disease (eg, unstable angina pectoris)

Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial fibrillation, 
second- or third-degree heart block) or risk factors for Torsade de Pointes (eg, heart 
failure, hypokalemia, bradycardia)

Myocardial infarction, transient ischemic attack, or stroke within 6 months prior to 
Visit 1 

Heart failure defined as New York Heart Association functional classification system, 
Class III or IV
At Visit 1, a user of recreational or illicit drugs (including cannabis regardless of legality) or 
has had a history within the past year of drug or alcohol abuse or dependence
Migraine Characteristics
Has ≥ 15 headache days per month on average across the 3 months prior to Visit 1 in the 
investigator’s judgment
Has ≥ 15 headache days in the 28-day baseline period per eDiary 
Difficulty distinguishing migraine headaches from tension-type or other headaches 
Has a history of migraine accompanied by diplopia or decreased level of consciousness or 
retinal migraine as defined by ICHD-3, 2018
 
 
 
 
 


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Has a current diagnosis of chronic migraine, new persistent daily headache, medication 
overuse headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial 
neuropathy as defined by ICHD-3, 2018
Prior/Concomitant Therapy
Usage during 30 days prior to Visit 1 (unless otherwise indicated) and throughout the study 
period of and requirement for any medication, diet (ie, grapefruit juice), or non-
pharmacological treatment that is on the list of prohibited concomitant medications or 
treatments that cannot be discontinued or switched to an allowable alternative medication or 
treatment. This includes concomitant medications with demonstrated efficacy for the 
prevention of migraine (eg, amitriptyline, topiramate, propranolol) regardless of indication. 
(See Section 6.5.3)
Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, Xeomin®, 
Myobloc®, JeuveauTM) into areas of the head, face, or neck within 6 months prior to Visit 1 
and throughout the study period.
Usage of barbiturate-containing or opioid-containing analgesics > 2 days/month, triptans or 
ergots ≥10 days/month, or simple analgesics (eg, aspirin, NSAIDs, acetaminophen) ≥15 
days/month in the 3 months prior to Visit 1 per investigator’s judgment, or during the baseline 
period. 
(Note: barbiturate-containing analgesics are excluded 30 days prior to screening, during the 
screening/baseline period, and for the duration of the study. Opioid-containing analgesics are 
excluded during the screening/baseline period and throughout the study, however, episodic use 
of opioids for purposes not related to migraine or headache, eg, surgery, is not exclusionary.)
Previous exposure to

Atogepant (AGN-241689 or MK-8031)

Injectable monoclonal antibodies blocking the calcitonin gene-related peptide (CGRP)
pathway within the last 6 months prior to Visit 1

Any other investigational calcitonin gene-related peptide receptor antagonist 
(CGRP-RA)
Diagnostic Assessments
Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or sitting diastolic 
blood pressure > 100 mm Hg at Visits 1 or Visit 2. Vital sign measurements that exceed these 
limits may be repeated only once 
An ECG with clinically significant abnormalities at screening (Visit 1) as determined by the 
investigator
QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 based on the ECG 
report of the central reviewer
 
 
 
 
 


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Clinically significant laboratory values OR any of the following laboratory values at Visit 1:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1 × the upper 
limit of normal (ULN) OR

Total bilirubin > 1 × ULN (except for participants with a diagnosis of Gilbert’s disease) 
OR

Serum albumin < 2.8 g/dL [4.06 µmol/L]
Positive result on the urine drug screen at Visit 1 unless explained by concomitant medication 
use (eg, opioids prescribed for indications other than migraine headache, use of 
benzodiazepines for insomnia, etc). 
History of acute hepatitis within 6 months of screening (Visit 1); or chronic hepatitis 
(including nonalcoholic steatohepatitis); or a positive result on anti-hepatitis A
immunoglobulin M (IgM) antibody, hepatitis B surface antigen, anti–hepatitis C antibody or 
anti-hepatitis E IgM antibody testing at screening (Visit 1)
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) will be established to review unblinded 
safety data and summary reports, identify any safety issues and trends, and make 
recommendations to the sponsor, including modification or early termination of a trial, if 
emerging data show unexpected and clinically significant AEs of treatment. 
Number of Participants:
Approximately 300 participants will be randomized to one of 2 treatment arms (placebo and
atogepant 60 mg QD) in a 1:1 ratio as follows:

Placebo (n = 150)

Atogepant 60 mg QD (n = 150)
Randomization will be stratified based on region (North America, Europe and Asia/Pacific), 
number of migraine days during the screening/baseline period (4 to < 8 and ≥8) and number of 
classes of failed prior prophylactic treatments (2 and > 2). 
Block randomization will be applied with a block size of 4 (2 treatment arms × 2). 
A randomization cap of 20% will be instituted to ensure that the planned randomized participants 
include no more than 20% of participants with 4 to < 8 migraine days at baseline. 
Approximately 50% of randomized participants will have failed > 2 classes of prior prophylactic 
treatments.
Number of Sites:
This study will be conducted at approximately 125 sites globally (North America, Europe and 
Asia/Pacific) including both US (investigational new drug [IND]) sites and non-US (non-IND) 
sites. Data from IND and non-IND study sites will be pooled together for analysis.
 
 
 
 
 


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Intervention Groups and Study Duration:

Patient participation will begin with a 4-week screening/baseline period. Participants who 
complete the 4-week screening/baseline period and meet all entry criteria will be randomized 
to the double-blind treatment period of the study at Visit 2 (Randomization Visit). The 
double-blind treatment period will last 12 weeks, with a subsequent safety follow-up period 
of 4 additional weeks. Total duration of study participation for one participant is 
approximately 20 weeks.

There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline Visit), Visit 2 
(Randomization Visit), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 
8), Visit 7/ET (Week 12), and Visit 8 (Week 16/EOS/Safety Follow-up). The Visit 
8/EOS/safety follow up period must be completed for all participants who take at least one 
dose of study intervention, except for participants rolling over into Study 3101-312-002 
(long-term safety extension study). For these rollover participants the Follow-up Visit will be 
performed in the long-term safety extension study. (Please refer to the Schedule of Activities 
(SoA), Section 1.3).
Data Safety Monitoring Board and Hepatic Events Adjudication Committee: Yes.
1.2.
Schema
Figure 1-1
Study Diagram
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 








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ASC-12 = 12-item Allodynia Symptom Checklist; AIM-D = Activity Impairment in Migraine–Diary; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; eDiary = electronic diary; EQ-5D-5L = European Quality of Life – 5 Dimensional; ET = early termination; eTablet = electronic tablet; 
HIT-6 = Headache Impact Test; INR = international normalized ratio; IWRS = interactive web response system; MIDAS = Migraine Disability Assessment; MSQ 
v2.1 = Migraine Specific Quality of Life Questionnaire, Version 2.1; PGIC = Patient Global Impression of Change; PGI-S = Patient Global Impression – Severity; 
PHQ-9 = Patient Health Questionnaire; PK = pharmacokinetic; PRO = patient-reported outcome; PSSM= Patient Satisfaction with Study Medication, PROMIS-PI 
= Patient-Reported Outcomes Measurement Information System Pain Interference – Short Form 6a; VCT = verified clinical trial; WPAI:MIGRAINE = Work 
Productivity and Activity Impairment Questionnaire: Migraine V2.0.
a
Visit 1 and Visit 2 must be conducted in the office. All other visits, should be conducted in the office unless it is necessary to conduct remote visits for the safety of participants or 
study personnel (eg, COVID-19 or other pandemic situation): for details please refer to the Schedule of Activities for Remote Visits in Section 10.11 (Appendix 11).
b
Effort should be made by site to not schedule Visit 7 earlier than 12 weeks after Day 1 (Day 84) to ensure that participants complete the full 12 weeks of treatment and have 
eDiary data through Day 84.
c
All participants who take at least 1 dose of study intervention must complete the safety follow-up period, except participants rolling over into Study 3101-312-002 (long-term 
safety extension study). For these rollover participants the Follow-up Visit will be performed at the end of the long-term safety extension study
d Vital sign measurements: height, weight, sitting and standing pulse rate, respiratory rate, sitting and standing systolic and diastolic blood pressure, and body temperature. Height 
will be measured only at Visit 1.
e For females of childbearing potential only, urine pregnancy tests will be performed.
f
Clinical laboratory determinations include chemistry, hematology, coagulation parameters (INR), and urinalysis to be collected for all study visits. Samples for serology and the 
urine drug screen will be collected only at screening (Visit 1).
g
PK sample should be collected prior to the first dose at Visit 2, 1 sample should be collected prior to the daily dose taken during one of the Visits 3 to 6, and the remaining 
samples should be collected 1 to 10 hours post the daily dose.
h
Participant should begin using the eDiary as soon as it is dispensed. If it is subsequently determined that the participant has failed entry criteria, the eDiary should be returned to 
site.
i
Participants should bring eDiary to visits and review with coordinators.
j
Data to be captured in the eDiary on a daily basis
k At Visit 1, the Screening/Baseline assessment of the C-SSRS will be completed. At all other study visits, the Since the Last Visit C-SSRS will be completed.
l
Clinicians will complete the C-SSRS on eTablet.
m
PRO measures should be administered prior to any tests and/or evaluations unless indicated otherwise in the protocol (eg, during randomization visit, some tests will be conducted 
prior to PROs for eligibility).
n
EQ-5D-5L will be collected via an eDiary for a period of 1 week in the screening period (administered between the 22nd and 28th days of the Screening/baseline period for a total 
of 7 days), randomization (Study Day 1) until Visit 3 (14 consecutive days from randomization), Visit 4 (± 3 days ie, Study Days 25 to 31 from randomization for a total of 7 
days), Visit 5 (± 3 days ie, Study Days 39 to 45 from randomization for a total of 7 days), Visit 6 (± 3 days ie, Study Days 53 to 59 from randomization for a total of 7 days), and 
Visit 7 (-7 days ie, Study Days 77 to 83 from randomization for a total of 7 days). At Visit 8, the EQ-5D-5L will be administered in an eTablet.
o
The first dose of study intervention should be taken at the study site
p
Collected at Visit 2 only for participants who fail screening
q
Collected at Visit 7/ET only for participants who complete the double-blind treatment period
r
Collected at Visit 8/EOS only for participants who terminate early from the double-blind treatment period 
s
For participants who terminate early from the double-blind treatment period only.
 
 
 


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2.
Introduction
Atogepant is a potent, selective oral calcitonin gene-related peptide receptor antagonist 
(CGRP-RA) being developed for the prophylaxis of migraine.
2.1.
Study Rationale
This study is being performed to prospectively assess the safety, tolerability, and efficacy of 
atogepant 60 mg QD compared with placebo in the prophylaxis of episodic migraine in 
participants who previously failed 2 to 4 classes of oral prophylactic treatments. This 
randomized, double-blind, placebo-controlled Phase 3 study is primarily designed to generate 
data for health technology assessment, and is also a trial to confirm the efficacy of these doses in 
this patient population. The rationale for the overall study design is in Section 4.1.
2.2.
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25 to 55 years. Approximately one-third of these migraineurs have 
3 or more migraine headaches per month, and over half report severe impairment or the need for 
bed rest (Lipton 2007). In the United States alone, work loss due to migraine is estimated to cost 
~ $13 billion annually (Hu 1999). Prevalence is similar in Europe, with migraine headache 
affecting on average 17.6% of women and 8% of men (Stovner and Andree 2010). As of 2016, 
migraine is the second leading cause of disability worldwide (Global Burden of Disease [GBD] 
2017).
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, 
exam, and the exclusion of other headache disorders. Physicians apply clinical criteria to guide 
diagnoses and subsequent treatment. Episodic migraine (EM) can be divided into low frequency 
(LFEM) and high frequency episodic migraine (HFEM) depending on the headache days 
suffered per month (GBD 2017). 
Episodic migraine (EM) is a syndrome diagnosis applied to patients with migraine (with or 
without aura) who have 1 to 14 headache days per month. Chronic migraine is a specific ICHD-3 
diagnosis applied to a subset of patients with ≥15 headache days per month (Katsarava 2012; 
Olesen 2006; ICHD-3 2018). 
This study will include participants with episodic migraine who had failed 2 to 4 classes of prior
oral prophylactic medications. The rationale for targeting this population is 2-fold. Firstly, 
patients on currently available oral prophylactic medications may experience poor tolerability; 
secondly, many of these treatments have shown insufficient efficacy (did not sufficiently reduce 
either severity or frequency) of migraine for many patients (Blumenfeld 2013; Hepp 2017).


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Discontinuation rates for existing oral prophylactic medications are high for both episodic and 
chronic migraine (Blumenfeld 2013). The patterns of prophylactic medication use in persons 
with episodic and chronic migraine were investigated in the cross-sectional, the International 
Burden of Migraine Study (IBMS-II) with 1165 respondents. Persons with episodic and chronic 
migraine reported their use of prophylactic migraine medications including antidepressants, anti-
epileptic drugs, beta-blockers, calcium channel blockers, and other prophylactic medications 
specified by respondents. It was concluded by the authors that the most common reasons for 
discontinuations were lack of efﬁcacy and side effects: 

In persons with episodic migraine, approximately 37% to 48% reported discontinuation of a 
prophylactic medication due to lack of efficacy, whereas 35% to 49% reported 
discontinuation due to side effects.

In persons with chronic migraine, 39% to 48% reported discontinuation due to lack of 
efficacy, and 34% to 53% reported discontinuation due to side effects.
The consequences of the limitations in current oral prophylactic migraine treatments amount to 
both poor adherence (Berger 2012; Hepp 2017) and reluctance to initiate prophylactic treatment 
(Silberstein 2015). In fact, recent studies have indicated that approximately half of migraine 
patients discontinued their initial oral migraine prophylactic treatment within 60 days, which 
might be explained by poor tolerability or lack of efficacy (Blumenfeld 2013; Hepp 2017). 
Moreover, in a US-based retrospective database study it was concluded that approximately 
70% of patients who begin migraine prophylaxis with antidepressants, antiepileptics, or 
beta-blockers are no longer taking these medications at 6 months (Berger 2012). Of those 
patients who continue to take a prophylactic medication, many still have substantial disease 
burden (Silberstein 2015).
Therefore, the proposed population for Study 3101-304-002 reflects clinical practice. There is 
severe unmet need in patients that have failed multiple migraine prophylactic oral medications, 
and these patients are currently often relying on ineffective treatments and many suffer from 
intolerability to currently available medications. 
Atogepant is a potent, selective oral CGRP-RA being developed for migraine prevention. CGRP
is a neuropeptide implicated in the pathophysiology of migraine. CGRP levels in the cranial
venous outflow (ie, external jugular vein) are increased during a migraine attack and
exogenously administered CGRP has been shown to trigger migraine-like headache in 
migraineurs. The majority (80% to 90%) of trigeminal Aδ fibers that innervate the dura contain
CGRP, suggesting that these fibers may be involved in sterile neurogenic inflammation and
migraine pain transmission. Furthermore, the CGRP receptor is present on human meningeal and
cerebral blood vessels. These observations suggest that activation of the trigeminovascular 
system, with release of CGRP, may play a key role in migraine pathogenesis and that inhibition
of CGRP may yield a novel therapeutic approach to treating migraine.
The ability of CGRP inhibition to induce pain relief in the acute treatment of migraine was
initially observed with an intravenous formulation of olcegepant (Olesen 2004), and replicated
by Merck & Co., Inc with an oral formulation of MK-0974 (telcagepant), a highly selective 
CGRP- RA. In Phase 3 studies, telcagepant was superior to placebo in the primary endpoints 
of 2-hour pain freedom, 2-hour pain relief, and the absence of associated symptoms


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(photophobia, phonophobia, and nausea), as well as the key secondary endpoint of 24-hour
sustained pain freedom (Connor 2009). However, serum ALT increases were observed with 
telcagepant. For this reason, the development of these oral CGRP antagonists was stopped.
Atogepant was chemically designed to minimize the potential for reactive metabolites, thereby 
reducing the risk of liver toxicity that has been observed with telcagepant, and MK-3027. An 
extensive Phase 1 program, including a 28-day multiple dose study of doses up to 170 mg QD, 
has been conducted to assess hepatic effects of atogepant. 
A Phase 2/3 clinical study (Study CGP-MD-01) was conducted, which compared atogepant 
10 mg QD, atogepant 30 mg QD, atogepant 30 mg BID, atogepant 60 mg QD and atogepant 
60 mg BID to placebo in prevention of episodic migraine. Overall, all the atogepant doses tested 
were well tolerated and the AE profile of all atogepant doses did not significantly differ from 
placebo. For the primary efficacy endpoint of change from baseline in mean monthly migraine 
days across the 12-week treatment period, all atogepant doses demonstrated a statistically 
significant reduction compared to placebo in participants with episodic migraine.
A recently completed Phase 3 clinical study (Study 3101-301-002) evaluated the efficacy, safety, 
and tolerability of atogepant 10 mg QD, atogepant 30 mg QD and atogepant 60 mg QD 
compared to placebo in the prevention of migraine in participants with episodic migraine after 
12 weeks of treatment. All atogepant doses demonstrated clinically meaningful and statistically 
significant improvement over placebo for the primary endpoint of change from baseline in mean 
monthly migraine days across the 12-week treatment period with LSMD for atogepant vs 
placebo being -1.21, -1.38, -1.72 days for atogepant 10 mg QD, 30 mg QD, 60 mg QD, 
respectively. The LS mean change from baseline for monthly migraine days was -2.48, -3.69, 
-3.86, and -4.20 days for placebo, atogepant 10 mg QD, 30 mg QD, and 60 mg QD, respectively. 
Furthermore, atogepant 30 mg QD and 60 mg QD demonstrated statistically significant 
improvement over placebo for all secondary endpoints of the study. Results suggested a 
clinically relevant dose response relationship and atogepant 60 mg QD demonstrated the highest 
therapeutic effect. All atogepant doses were well tolerated and no significant difference was 
detected in the AE profile of the three atogepant doses. 
In addition to the 12-week Study 3101-301-002 described above, a 52-week Phase 3 study that 
evaluated the long-term safety, tolerability, and efficacy of atogepant 60 mg QD compared to 
standard of care has completed (Study 3101-302-002) in the prevention of episodic migraine. 
Similar to the 12-week studies, atogepant 60 mg QD dose was safe and well tolerated. A 
clinically relevant reduction in mean monthly migraine days, mean monthly headache days, 
mean monthly acute medication use days, and mean monthly triptan use days was achieved 
within the first month and was sustained over the 1-year treatment period. The LS mean change 
from baseline in the monthly migraine days was -3.84 days at Weeks 1-4 and -5.19 days at 
Weeks 49-52.
To date, no safety signal in hepatic lab parameters has been observed in either preclinical or 
clinical studies conducted with atogepant.
A detailed description of the chemistry, pharmacology, efficacy, and safety of atogepant is 
provided in the investigator’s brochure.


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2.3.
Benefit/Risk Assessment
The CGP-MD-01 Phase 2/3 study demonstrated that atogepant is efficacious for the prophylaxis
of migraine. All doses of atogepant demonstrated significant clinical benefit in reducing the 
number of mean monthly migraine days and other endpoints. Atogepant was safe and well 
tolerated in the study. With its mode of action as a CGRP-RA, atogepant is differentiated from 
the currently available oral prophylactic treatments (ie, beta-blockers, anticonvulsants, etc) by its 
favorable side effect and safety profile. With its oral route of administration, it also offers a clear 
benefit if compared to recently approved injectable CGRP-RA monoclonal antibodies. 
This study will compare the efficacy, safety, and tolerability of atogepant 60 mg QD to placebo 
in the prevention of migraine in participants who previously failed 2 to 4 classes of prophylactic 
oral treatments. This patient population especially requires new therapeutic alternatives. 
An independent DSMB will review unblinded safety data throughout the trial and make
recommendations to the sponsor, including modification or early termination of the trial, if
emerging data show unexpected and clinically significant adverse effects of treatment. Although
this is a 12-week placebo-controlled trial, treatment for acute migraine is allowed during the
study.
Overall, the benefit-risk assessment supports the clinical investigation of atogepant for the 
prophylaxis of migraine. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of atogepant may be found in the investigator’s brochure.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To prospectively test for superiority of atogepant 60 mg
QD versus placebo for the prevention of migraine in 
participants with episodic migraine who have 
previously failed 2 to 4 classes of oral medications for 
the prophylaxis of migraine
CFB in mean monthly migraine days across the 
12-week treatment period.
Secondary
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the proportion of participants with at least 
50% reduction from baseline in monthly migraine days
Achievement of at least a 50% reduction .
To evaluate the effect of atogepant 60 mg QD versus 
placebo for the prophylaxis of headache
CFB in mean monthly headache days across the 
12-week treatment period.
To evaluate the effect of atogepant 60 mg QD versus 
placebo on acute medication use
CFB in mean monthly acute medication use days 
across the 12-week treatment period.
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the impact of migraine on daily activities as
assessed by MSQ v2.1 Role Function-Restrictive 
domain score 
CFB in MSQ v2.1 Role Function-Restrictive domain 
score at Week 12
For the United States only:
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Performance of Daily Activities
For the United States only:
CFB in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week 
treatment period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Physical Impairment
CFB in mean monthly Physical Impairment domain 
score of the AIM-D across the 12-week treatment 
period
For the European Union only:
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the impact of headaches on daily 
functioning as assessed by HIT-6
For the European Union only:
CFB in the HIT-6 total score at Week 12
Exploratory
To evaluate the response to atogepant 60 mg QD versus 
placebo as measured by proportion of participants with 
≥ 25%, ≥30%, ≥50%, ≥ 75%, 100% improvement 
(decrease) in monthly migraine days
Achievement of ≥ 25%, ≥30%, ≥ 50%, ≥ 75%, 100% 
improvement (decrease) in monthly migraine days at 
Weeks 1 to 4, 5 to 8, and 9 to 12
Achievement of ≥ 25%, ≥30%, ≥ 75%, 100% 
improvement (decrease) in monthly migraine days 
across the 12-week treatment period
To evaluate the effect of atogepant 60 mg QD versus 
placebo for the prevention of migraine
CFB in monthly migraine days at Weeks 1 to 4, 5 to 8, 
and 9 to 12
 
 
 


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Objectives
Endpoints
To evaluate the temporal effect of atogepant 60 mg QD 
versus placebo for the prevention of headache
CFB in monthly headache days at Weeks 1 to 4, 5 to 8, 
and 9 to 12
CFB in monthly cumulative headache hours at 
Weeks 1 to 4, 5 to 8, 9 to 12, and average across the 
12-week treatment period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on acute migraine-specific medication use
CFB in monthly acute medication use days at Weeks 1
to 4, 5 to 8, and 9 to 12
To evaluate the effect of atogepant 60 mg QD versus 
placebo on acute triptan use
CFB in monthly triptan use days at Weeks 1 to 4, 5 to 
8, 9 to 12, and average across the 12-week treatment 
period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on number of monthly moderate/severe and 
severe headache days
CFB in monthly moderate/severe headache days at 
Weeks 1 to 4, 5 to 8, 9 to 12, and average across the 
12-week treatment period
CFB in monthly severe headache days at Weeks 1 to 4, 
5 to 8, 9 to 12, and average across the 12-week 
treatment period
To evaluate effects of atogepant 60 mg QD versus 
placebo on the impact of headaches on daily 
functioning as assessed by HIT-6 
CFB in the HIT-6 total score at Weeks 4, and 8
(European Union only)
CFB in the HIT-6 total score at Weeks 4, 8, and 12 
(United States only)
To evaluate the response to atogepant 60 mg QD versus 
placebo as measured by proportion of participants with 
at least a 5-point improvement (decrease) from baseline 
in HIT-6 total score
Achievement of at least a 5-point 
improvement (decrease) from baseline in HIT-6 total 
score at Weeks 4, 8, and 12
To evaluate the response to atogepant 60 mg QD versus 
placebo as measured by proportion of participants much 
better or very much better on PGIC
Achievement of a rating of much better or very much 
better at Week 12 assessed by the PGIC
To evaluate patient satisfaction with study medication 
atogepant 60 mg QD versus placebo
Achievement of a rating of satisfied or extremely 
satisfied at Weeks 4, 8, and 12 assessed by the PSSM
To evaluate the effect of atogepant 60 mg QD versus 
placebo on work productivity specific to migraine as 
measured by WPAI:MIGRAINE
CFB from baseline in percent work time missed, 
percent impairment while working, percent overall 
impairment, and percent activity impairment due to 
migraine at Weeks 4, 8, and 12 as assessed by the 
WPAI:MIGRAINE
To evaluate the effect of atogepant 60 mg QD versus 
placebo on generic health-related quality of life, as 
measured by EQ-5D-5L 
CFB in EQ-5D-5L descriptive system index score at 
Weeks 1 to 2, at specified windows around Weeks 4, 
6, 8, 12, and Week 16
CFB in the EQ-5D-5L VAS score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 12, and 
Week 16
To evaluate the effect of atogepant 60 mg QD versus 
placebo on headache-related disability as measured by 
MIDAS total and domain scores
CFB in the MIDAS total score at Week 12
CFB in MIDAS absenteeism score (Questions 1, 3, 
and 5) at Week 12
 
 
 


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Objectives
Endpoints
CFB in MIDAS presenteeism score (Questions 2 and 
4) at Week 12
To evaluate the effect of atogepant 60 mg QD versus 
placebo on participant’s global impression of severity 
in relation to migraine symptoms
CFB in PGI-S score at Weeks 4, 8, and 12
To evaluate the effect of atogepant 60 mg QD versus 
placebo on how daily social and work-related activities 
are prevented by migraine as assessed by MSQ v2.1 
Role Function-Preventive domain score at Weeks 4, 8,
and 12
CFB in the MSQ v2.1 Role Function-Preventive 
domain score at Weeks 4, 8, and 12 
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the impact of migraine on daily social and 
work-related activities as assessed by MSQ v2.1 Role 
Function-Restrictive domain score at Weeks 4 and 8
CFB in the MSQ v2.1 Role Function-Restrictive 
domain score at Weeks 4 and 8 
To evaluate the effect of atogepant 60 mg QD versus 
placebo on emotions associated with migraine as 
measured by MSQ v2.1 Emotional Function domain 
score at Weeks 4, 8, and 12
CFB in the MSQ v2.1 Emotional Function domain 
score at Weeks 4, 8, and 12
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Performance of Daily Activities 
CFB in monthly Performance of Daily Activities 
domain score of the AIM-D at Weeks 1 to 4, 5 to 8, 
and 9 to 12
CFB in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week 
treatment period (European Union only)
To evaluate the effect of atogepant 60 mg QD versus 
placebo on Physical Impairment
CFB in monthly Physical Impairment domain score of 
the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
CFB in mean monthly Physical Impairment domain 
score of the AIM-D across the 12-week treatment 
period (European Union only)
To evaluate the effect of atogepant 60 mg QD versus 
placebo on total score of the AIM-D
CFB in monthly AIM-D total score at Weeks 1 to 4, 5 
to 8, 9 to 12, and average across the 12-week treatment 
period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on activity level and limitation as measured by 
Activity Level and Activity Limitation items
CFB in monthly activity level at Weeks 1 to 4, 5 to 8, 
9 to 12, and average across the 12-week treatment 
period
CFB in monthly activity limitation at Weeks 1 to 4, 
5 to 8, 9 to 12, and average across the 12-week 
treatment period
To evaluate the effect of atogepant 60 mg QD versus 
placebo on the interference of pain on relevant aspects 
of daily life as measured by PROMIS-PI
CFB in PROMIS-PI total score at Weeks 4, 8, and 12
To evaluate the effect of atogepant 60 mg QD versus 
placebo on symptoms of depression as measured by 
PHQ-9
CFB in PHQ-9 score at Week 12
 
 
 


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Objectives
Endpoints
Safety 
To evaluate the safety and tolerability of atogepant 60 
mg QD for the prevention of migraine in participants
with episodic migraine who have previously failed 2 to 
4 classes of oral medications for the prophylaxis of 
migraine
AEs, clinical laboratory tests, ECG results, vital signs, 
C-SSRS
 
 
 


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4.
Study Design
4.1.
Overall Design
This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
conducted at approximately 125 sites globally (North America, Europe and Asia/Pacific). 
Approximately 300 participants will be randomized to one of 2 treatment arms (placebo, and 
atogepant 60 mg QD) in a 1:1 ratio as follows:

Placebo (n = 150)

Atogepant 60 mg QD (n = 150)
Randomization will be stratified based on region (North America, Europe and Asia/Pacific),
number of migraine days during the screening/baseline period (4 to < 8 and ≥8) and number of 
classes of failed prior prophylactic treatments (2 and > 2). 
Block randomization will be applied with a block size of 4 (2 treatment arms × 2). 
A randomization cap of 20% will be instituted to ensure that the planned randomized participants 
include no more than 20% of participants with 4 to < 8 migraine days at baseline.
Approximately 50% of randomized participants will have failed > 2 classes of prior prophylactic 
treatments.
Participation will begin with a 4-week screening/baseline period. Participants who complete the 
4-week screening/baseline period and meet all entry criteria will be randomized to the double-
blind treatment period of the study at Visit 2 (Randomization Visit). The double-blind treatment 
period will last 12 weeks, with a subsequent safety follow-up period of 4 additional weeks. Total 
duration of study participation for one participant is approximately 20 weeks.
There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline Visit), Visit 2 
(Randomization Visit), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), 
Visit 7/ET (Week 12), and Visit 8 (Week 16/EOS/Safety Follow-up). The Visit 8/EOS/safety 
follow-up period must be completed for all participants who take at least one dose of study 
intervention, except for participants rolling over into Study 3101-312-002 (long-term safety 
extension study). For these rollover participants Visit 8 is not required, because the final 
Follow-up Visit will be performed at the end of the long-term safety extension study. For 
participants who screen fail for the long-term safety extension study, the Follow-up Visit of 
Study 3101-304-002 must be completed. (Please refer to the SoA, Section 1.3).
This study is conducted at US (IND) sites and non-US (non-IND) sites. Data from IND and 
non-IND study sites will be pooled together for analysis.
4.2.
Justification for Dose
This study will test one dose of atogepant, 60 mg QD, selected based on the results from the 
Phase 2/3 study CGP-MD-01 and the pivotal study 3101-301-002 in participants with episodic 
migraine. All atogepant doses investigated in Study CGP-MD-01 and Study 3101-301-002 
demonstrated good safety and tolerability. 


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In Study CGP-MD-01, all atogepant doses including 60 mg QD demonstrated a statistically 
significant reduction from baseline in mean monthly migraine days across the 12-week treatment 
period compared to placebo; however, there was no clear dose response relationship. 
In Study 3101-301-002, a clinically relevant dose response relationship was detected. The 
highest investigated dose, atogepant 60 mg QD demonstrated the highest treatment difference 
compared to placebo while there was no clinically significant difference in the AE profile 
between the atogepant doses. Based on these findings, atogepant 60 mg QD has been selected to 
be investigated in the current study.
4.3.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
For Russia, end of study is defined as the last Close Out Visit.
A participant is considered to have completed the study if he/she has not been terminated early 
and has completed all phases of the study including the last scheduled procedure shown in the 
SoA (Section 1.3).


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5.
Study Population
Approximately 300 participants with episodic migraine with or without aura who previously
failed 2 to 4 classes of oral prophylactic treatments will be randomized into the study at 
approximately 125 sites globally (North America, Europe and Asia/Pacific). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
For further information on participant entry procedures, please see Section 8 (Study Assessments 
and Procedures).
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Male or female participants ages 18 (or age of legal majority) to 80 years, inclusive, 
at Visit 1
2.
Type of Participant and Migraine Characteristics
2.01
At least a 1-year history of migraine with or without aura consistent with a diagnosis
according to the ICHD-3, 2018.
2.02
Age of the participant at the time of migraine onset < 50 years
2.03
History of 4 to 14 migraine days (see Section 8.1.1 for definition) per month on 
average in the 3 months prior to Visit 1 in the investigator’s judgment
2.04
4 to 14 migraine days in the 28-day baseline period per eDiary
(Note: A randomization cap of 20% will be instituted to ensure that the planned 
randomized participants include no more than 20% of participants with 
4 to <8 migraine days at baseline.)
2.05
Completed at least 20 out of 28 days in the eDiary during the baseline period and is 
able to read, understand, and complete the study questionnaires and eDiary per 
investigator’s judgment.
 
 
 


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2.06
Participants must meet both criteria below (ie, a and b). Participants must have 
a.
Failed oral migraine prophylaxis medications from 2 to 4 of the 
medication classes as listed below:
i.
Propranolol, metoprolol, atenolol, bisoprolol, timolol, or nadolol;
ii.
Topiramate;
iii. Flunarizine;
iv. Valproate or divalproex;
v.
Amitriptyline or nortriptyline;
vi. Venlafaxine or desvenlafaxine;
vii. Lisinopril;
viii. Candesartan;
ix. Locally approved products (eg, oxeterone or pizotifen)
b. Failed at least one treatment from the list below:
i.
Propranolol OR metoprolol;
ii.
Topiramate; 
iii. Flunarizine;
iv. Amitriptyline
(Note: Participant failure of a prophylactic medication can be on the basis of 
tolerability or efficacy and is based on investigator judgement. Refer to Section 5.3
for more detailed information. Each prior prophylactic medication failure needs to 
be documented in the Treatment Failure Worksheet, see Section 10.10
[Appendix 10]).
 
 
 


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3.
Contraceptives
3.01
Male participants willing to minimize the risk of inducing pregnancy as detailed 
below:
A male participant must agree to use contraception as detailed in Section 10.7, 
Appendix 7 of this protocol during the intervention period and for at least 3 days 
after the last dose of study intervention and refrain from donating sperm during this 
period.
Female participants willing to minimize the risk of inducing pregnancy as detailed 
below:
A female participant is eligible to participate if she is not pregnant (ie, has a 
negative urine pregnancy result at the Screening Visit (Visit 1) and Randomization 
Visit (Visit 2), is not planning to become pregnant during the course of the study, is 
not breastfeeding, and fulfils at least one of the following conditions:
a.
Not a WOCBP as defined in Section 10.7 (Appendix 7)
OR
b. A WOCBP who agrees to follow the contraceptive guidance of using a 
medically acceptable and effective contraceptive method as defined in 
Section 10.7 (Appendix 7) during the intervention period and for 3 days 
after the last dose of study intervention.
4.
Informed Consent
4.01
Written informed consent and participant privacy information (eg, Written 
Authorization for Use and Release of Health and Research Study Information [US 
sites] and written Data Protection consent [EU sites]) obtained from the participant 
prior to any study-related procedures. 
 
 
 


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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Any clinically significant hematologic, endocrine, pulmonary, hepatic, gastrointestinal, 
or neurologic disease

If there is a history of such a disease, but the condition has been stable for more 
than 1 year prior to Visit 1, and is judged by the investigator as not likely to 
interfere with the participant’s participation in the study, the participant may be
included
1.02
Participant has any other concurrent pain condition that, in the opinion of the 
investigator, may significantly impact the current headache disorder (eg, fibromyalgia, 
facial pain)
1.03
In the opinion of the investigator, confounding psychiatric conditions, dementia, 
epilepsy, or significant neurological disorders other than migraine
1.04
History of malignancy in the 5 years prior to Visit 1, except for adequately treated basal 
cell or squamous cell skin cancer, or in situ cervical cancer
1.05
History of any prior gastrointestinal procedures or gastrointestinal conditions 
(eg, diarrhea syndromes, inflammatory bowel disease) that may affect the absorption or 
metabolism of study intervention; participants with prior gastric bariatric interventions 
(eg, Lap Band) which have been reversed are not excluded.
1.06
Clinically significant cardiovascular or cerebrovascular disease per the investigator’s 
opinion including, but not limited to:

Clinically significant ischemic heart disease (eg, unstable angina pectoris)

Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial 
fibrillation, second- or third-degree heart block) or risk factors for Torsade de 
Pointes (eg, heart failure, hypokalemia, bradycardia)

Myocardial infarction, transient ischemic attack, or stroke within 6 months prior 
to Visit 1 

Heart failure defined as New York Heart Association functional classification 
system, Class III or IV
1.07
Significant risk of self-harm based on clinical interview and responses on the C-SSRS, or 
of harm to others in the opinion of the investigator; participants must be excluded if they 
report suicidal ideation with intent, with or without a plan, (ie, Type 4 or 5 on the 
C-SSRS) in the past 6 months or report suicidal behavior in the 6 months prior to Visit 1 
or Visit 2 assessments
1.08
At Visit 1, a user of recreational or illicit drugs (including cannabis regardless of legality) 
or has had a history within the past year of drug or alcohol abuse or dependence
 
 
 


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2.
Migraine Characteristics
2.01
Has ≥ 15 headache days per month on average across the 3 months prior to Visit 1 in the 
investigator’s judgment
2.02
Has ≥ 15 headache days in the 28-day baseline period per eDiary 
2.03
Difficulty distinguishing migraine headaches from tension-type or other headaches 
2.04
Has a history of migraine accompanied by diplopia or decreased level of consciousness 
or retinal migraine as defined by ICHD-3, 2018
2.05
Has a current diagnosis of chronic migraine, new persistent daily headache, medication 
overuse headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful 
cranial neuropathy as defined by ICHD-3, 2018
3.
Prior/Concomitant Therapy
3.01
Usage during 30 days prior to Visit 1 (unless otherwise indicated) and throughout the 
study period of and requirement for any medication, diet (ie, grapefruit juice), or non-
pharmacological treatment that is on the list of prohibited concomitant medications or 
treatments that cannot be discontinued or switched to an allowable alternative medication 
or treatment. This includes concomitant medications with demonstrated efficacy for the 
prevention of migraine (eg, amitriptyline, topiramate, propranolol) regardless of 
indication. (See Section 6.5.3).
3.02
Usage of therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, 
Xeomin®, Myobloc®, JeuveauTM) into areas of the head, face, or neck within 6 months 
prior to Visit 1 and throughout the study period.
3.03
Usage of barbiturate-containing or opioid-containing analgesics > 2 days/month, triptans 
or ergots ≥10 days/month, or simple analgesics (eg, aspirin, NSAIDs, acetaminophen) 
≥15 days/month in the 3 months prior to Visit 1 per investigator’s judgment, or during 
the baseline period. 
(Note: barbiturate-containing analgesics are excluded 30 days prior to screening, during 
the screening/baseline period, and for the duration of the study. Opioid-containing 
analgesics are excluded during the screening/baseline period and throughout the study, 
however, episodic use of opioids for purposes not related to migraine or headache, eg, 
surgery, is not exclusionary.)
3.04
Previous exposure to

Atogepant (AGN-241689 or MK-8031)

Injectable monoclonal antibodies blocking the CGRP pathway within the last
6 months prior to Visit 1

Any other investigational CGRP-RA
3.05
History of hypersensitivity or clinically significant adverse reaction to a CGRP-RA or 
hypersensitivity to any component of the study interventions (atogepant or placebo).
 
 
 


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4.
Prior/Concurrent Clinical Study Experience
4.01
Currently participating or has participated in a study with an investigational compound or 
device within 30 days prior to Visit 1 (this includes studies using marketed compounds or 
devices)
5.
Diagnostic Assessments
5.01
Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or sitting 
diastolic blood pressure > 100 mm Hg at Visits 1 or Visit 2. Vital sign measurements that 
exceed these limits may be repeated only once 
5.02
An ECG with clinically significant abnormalities at screening (Visit 1) as determined by 
the investigator
5.03
QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 based on the 
ECG report of the central reviewer
5.04
Clinically significant laboratory values OR any of the following laboratory values at 
Visit 1:

ALT or AST > 1 × the ULN OR

Total bilirubin > 1 × ULN (except for participants with a diagnosis of Gilbert’s 
disease) OR

Serum albumin < 2.8 g/dL [4.06 µmol/L]
5.05
Positive result on the urine drug screen at Visit 1 unless explained by concomitant 
medication use (eg, opioids prescribed for indications other than migraine headache, use 
of benzodiazepines for insomnia, etc). 
5.06
History of acute hepatitis within 6 months of screening (Visit 1); or chronic hepatitis 
(including nonalcoholic steatohepatitis); or a positive result on anti-hepatitis A IgM 
antibody, hepatitis B surface antigen, anti–hepatitis C antibody or anti-hepatitis E IgM 
antibody testing at screening (Visit 1)
6.
Other
6.01
Employed by or is an immediate family member (parents, spouses, siblings, or children) 
of one of the investigators, study staff, or sponsor
6.02
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 the participant’s participation in the study
6.03
Any medical or other reasons (eg, unlikely to adhere to the study procedures, keep 
appointments, or is planning to relocate during the study) that, in the investigator’s 
opinion, might indicate that the participant is unsuitable for the study
5.3.
Criteria for Determining that Prior Treatment for the Prophylaxis of 
Migraine Have Been Failed 
To be eligible for randomization in this study, participants must have failed 2 to 4 classes of prior 
oral treatments for the prophylaxis of migraine, as described in Section 5.1 Inclusion Criteria. 
 
 
 


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Participant failure of a prophylactic medication can be on the basis of tolerability or efficacy and 
is based on investigator judgement.
For efficacy, investigators must consider:

Failure is defined as no meaningful reduction in frequency of migraine days after an adequate 
trial of at least 2 months at generally accepted therapeutic doses, per investigator judgement 
and participant interview during the past 7 years prior to screening.
For tolerability, investigators should consider:

Failure is defined as discontinuation of a drug treatment due to adverse effects at any 
previous time. 

In assessing failure of a migraine preventive drug on the basis of inadequate tolerability, the 
entire medical history can be considered. For example, a participant who tried and 
discontinued topiramate 10 years ago for cognitive clouding should be considered to have 
failed this treatment. 
5.4.
Lifestyle Considerations
5.4.1.
Meals and Dietary Restrictions
Participants should refrain from consuming grapefruit or grapefruit juice from the time the 
consent form is signed until completion of the study. Participants should also refrain from 
making significant changes to their diet during the study.
5.4.2.
Caffeine, Alcohol, and Tobacco
Participants should also refrain from making significant changes to their caffeine intake during 
the study.
Alcohol intake should be limited to no more than 1 drink per day throughout the study. A drink 
is defined as a 12-ounce (approximately 350 mL) can/bottle of beer, a 4-ounce (approximately 
120 mL) glass of wine, or 1 ounce (approximately 30 mL) of liquor.
Use of recreational drugs, including cannabis, regardless of legality is prohibited throughout the 
study.
5.4.3.
Activity
No restrictions.
5.5.
Screen Failures
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized to treatment. Rescreening of screen failures is permitted in certain 
situations (including failure to adequately screen due to the COVID-19 pandemic), with 
permission from Allergan. A participant who is rescreened will be screened again in the IWRS 
and given a new participant number. However, participants with clinically significant laboratory 
values at Visit 1 (including ALT or AST > 1 × the ULN, total bilirubin > 1 x ULN or serum 


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albumin < 2.8 g/dL), or those with a positive result on the Visit 1 urine drug screen for 
recreational (including marijuana regardless of legality) or illicit drugs or non-disclosed 
concomitant medications are not allowed to be rescreened. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes indicating screen failure as reason for 
ending the study, demography, screen failure details, eligibility criteria, and any SAE.
5.5.1.
Procedure for Duplicate Participant Identification – Verified Clinical
At participating sites in the United States, a central vendor will be used to verify participants’ 
current and past research study status in order to mitigate safety concerns associated with 
duplicate enrollment and protocol deviations associated with multiple trial enrollment. Following 
proper informed consent and after issuing a participant number, each participant will be checked 
in the VCT database, indicated in the Schedule of Activities (Section 1.3). Partial identifiers will 
be utilized. Participants who are identified as verification failures by VCT should not be enrolled 
without documented approval from Allergan.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
The investigational medicinal products used in the current study do not have a marketing 
authorization in any country.
6.1.
Study Intervention(s) Administered
6.1.1.
Study Interventions and Formulations
Tablets containing atogepant 60 mg.
6.1.2.
Control Intervention
Atogepant 60 mg matching placebo.
6.1.3.
Study Intervention Regimen and Dosing
Interventions to be used in this study are listed in Table 6-1. 
Study intervention will be supplied in blister cards and will be labeled with the protocol number, 
storage information, warning language, and instructions to take the tablets as directed. The card 
will also include the medication number. 
Participants who meet all of the study entry criteria at Visit 2 will be randomized and provided 
with study intervention to be taken on an outpatient basis. Sites will subsequently dispense study 
intervention to participants at Visits 3, 4, 5, and 6. Immediately before dispensing the study 
intervention, the investigator (or appropriately trained designee) will write the participant’s 
identification number and the date on the label.
Participants will take their first dose study intervention at the clinic at Visit 2 after laboratory 
sample collection and will be instructed to take their study intervention at approximately the 
same time each day. Study intervention may be taken with or without food. Water is allowed as 
desired. Study intervention will be administered orally for 12 weeks, and participants will be 
followed for 4 weeks following discontinuation of the study intervention.


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Table 6-1
Study Interventions 
Drug/Dose
Study Intervention Product
Study Intervention 
Frequency
Route of 
Administration
Placebo
Placebo
QD (once daily)
Oral
Atogepant 60 mg
Atogepant 60 mg
QD (once daily)
Oral
6.1.4.
Intervention Allocation Ratio
Approximately 300 participants will be randomized to the following 2 treatment arms in a 1:1 
ratio:

Placebo (n = 150)

Atogepant 60 mg QD (n = 150)
Randomization will be stratified based on region (North America, Europe and Asia/Pacific), 
number of migraine days during the screening/baseline period (4 to < 8 and ≥8) and number of 
classes of failed prior prophylactic treatments (2 and > 2).
A randomization cap of 20% will be instituted to ensure that the planned randomized participants 
include no more than 20% of participants with 4 to < 8 migraine days at baseline.
Approximately 50% of randomized participants will have failed > 2 classes of prior prophylactic 
treatments.
6.1.5.
Other Study Supplies
The following will be provided by Allergan or a delegate of Allergan’s:

All supplies needed for blood and urine sampling (central laboratory analysis, urine, and 
urine dipstick reagent strips).

All supplies needed for on-site urine pregnancy test.

All supplies needed for PK sample collections.

Shipping materials for shipment of laboratory samples to central laboratory.

All supplies needed for ECG assessment including ECG machine.

Electronic diaries.

Electronic tablet(s)
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
 
 
 
 
 
 
 
 


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2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Atogepant tablets and matching placebo will be provided in identical blister cards to maintain 
masking of the study. All participants will be instructed to take study intervention once a day 
(1 tablet) at approximately the same time each day. Participants will therefore, receive either 
placebo, or atogepant 60 mg once a day.
Prior to initiation of study intervention, each participant who provides informed consent will be 
assigned a participant number that will serve as the participant identification number on all study 
documents.
At the Randomization Visit (Visit 2), eligible participants will be randomly assigned to 
1 of 2 treatment arms in a 1:1 ratio to receive atogepant 60 mg QD, or placebo. 
An automated IWRS will be used to manage the randomization and intervention assignment 
based on a randomization scheme prepared by Allergan Biostatistics.
Study intervention will be labeled with study intervention kit numbers. The IWRS system will 
provide the site with the specific medication kit number(s) for each randomized participant at the 
time of randomization. Sites will dispense study intervention according to the IWRS instructions. 
Sites will also log onto the IWRS at subsequent visits to obtain a kit number for dispensing study 
intervention. Sites will receive the IWRS confirmation notifications for each transaction. All 
notifications are to be maintained with the study source documents.
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the Allergan Medical Monitor prior to 
unblinding a participant’s study intervention assignment unless this could delay emergency 
treatment of the participant. If a participant’s study intervention assignment is unblinded, 
Allergan Medical Monitor must be notified within 24 hours after breaking the blind. The date 
and reason that the blind was broken must be recorded in the source documentation.


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6.4.
Study Intervention Compliance
For home dosing, study intervention compliance will be closely monitored by participant 
interview and counting the number of tablets dispensed and returned. Before dispensing new 
study intervention at each visit, study center personnel will make every effort to collect all 
unused study intervention and empty blister packs. 
The study center will keep an accurate study intervention disposition record that specifies the 
amount of study intervention administered to each participant and the date of administration.
6.5.
Concomitant Therapy
All prior medication for the prophylaxis of migraine, and any medication or vaccine (including 
over-the-counter, prescription medicines, vitamins, herbal supplements, and/or cannabis or other 
specific categories of interest) that the participant received during 6 months prior to screening, is 
receiving at the time of screening, or receives during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
6.5.1.
Permitted Interventions
Therapy considered necessary for the participant’s welfare and not specifically prohibited, may 
be given at the discretion of the investigator, with the following clarifications and restrictions:

Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.

SSRIs or SNRIs will be permitted provided that treatment is stable for at least 60 days prior 
to screening (Visit 1), continues without change in dose throughout the study and is not 
indicated for the treatment of migraine or headaches, with the exception of venlafaxine or 
desvenlafaxine (see Section 6.5.3).
See also Section 6.5.2.
Therapy considered necessary for the participant's welfare may be given at the discretion of the
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor representative.
6.5.2.
Rescue Interventions
Participants can apply “best supportive care” for the treatment of acute migraine attacks. This 
can include both pharmacological interventions (ie, abortive treatments for acute attacks, see 
below) and non-pharmacological interventions (eg, biofeedback, psychotherapy, acupuncture, 
vagus nerve stimulation, transcutaneous supraorbital nerve stimulation, single-pulse transcranial 
magnetic stimulator or other locally accepted and endorsed non-invasive interventions for acute 
migraine).
The following rescue medications for the acute treatment of migraine are allowed during the 
study:


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
Any triptan

Any ergot derivative

Any other form of analgesic (including acetaminophen, metamizole)

Any NSAID agent

Any antiemetic agent
Use of rescue medication must be recorded in the eDiary. Relevant non-pharmacological
therapies as part of “best supportive care” use for acute migraine attacks should be recorded in 
the eCRF. 
6.5.3.
Prohibited Interventions During the Study
The following medications are prohibited 30 days prior to Visit 1 (unless instructed otherwise in 
the study protocol) and throughout the study period (see also Section 10.9, Appendix 9) for 
examples of prohibited medications): 

Strong and moderate CYP3A4 inhibitors, including but not limited to: systemic 
(oral/intravenous) itraconazole, ketoconazole, fluconazole; erythromycin, clarithromycin, 
telithromycin; diltiazem, verapamil; aprepitant, cyclosporine, nefazodone, cimetidine, 
quinine, and HIV protease inhibitors

Strong and moderate CYP3A4 inducers, including but not limited to: barbiturates 
(eg, butalbital, phenobarbital and primidone), systemic (oral/intravenous) glucocorticoids, 
nevirapine, efavirenz, pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and
St. John’s wort

Strong P-gp inhibitors (eg, clarithromycin, itraconazole, quinidine, verapamil)

Strong OATP1B1/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 prophylaxis of migraine, regardless of 
indication:
o
Propranolol, metoprolol, atenolol, bisoprolol, timolol, or nadolol;
o
Topiramate;
o
Flunarizine;
o
Valproate or divalproex;
o
Amitriptyline or nortriptyline;
o
Venlafaxine or desvenlafaxine;
 
 
 


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o
Lisinopril;
o
Candesartan;
o
Products approved locally for the prophylaxis of migraine (eg, oxeterone or pizotifen)

CBD oil

Cannabis

Injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™, Emgality™, 
Ajovy®) within 6 months prior to Visit 1 and through the study period.

Ubrogepant (Ubrelvy®) and rimegepant (Nurtec ODT®) is prohibited from Visit 1 throughout 
the study period.

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, Xeomin®, 
Myobloc®, JeuveauTM) into areas of the head, face, or neck within 6 months prior to Visit 1 
and throughout the study period.

Cranial traction, nociceptive trigeminal inhibition, occipital nerve block treatments, or dental 
splints for headache, within 4 weeks prior to Visit 1 or at any time during the study 
(including the baseline period).

Use of acupuncture, non-invasive neuromodulation devices (eg, transcutaneous supraorbital 
neurostimulator, single-pulse transcranial magnetic stimulator, vagus nerve stimulator, etc) 
for the prophylaxis of migraine within 4 weeks prior to Visit 1 or at any time during the study 
(including the baseline period).

Any opioid-containing medication is prohibited during the screening/baseline period and any 
time during the study. (Note: episodic use for purposes not related to migraine or headache, 
eg, surgery is allowed. The medical monitor is to be notified.)
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. Therapy considered necessary for the participant’s 
welfare may be given at the discretion of the investigator. The sponsor representative should be 
notified about the administration of prohibited medication/treatment as soon as possible.
6.6.
Dose Modification
This protocol does not allow for any modification from the currently outlined dosing schedule.
6.7.
Intervention after the End of the Study
No study intervention will be administered after the end of the study.
Following the end of study, the participant may be treated as per usual practice and standard of 
care or referred to the participant’s treating physician/general practitioner for further medical 
care at the investigator’s discretion. 
 
 
 


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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and receives study 
medication ceases participation in the study, regardless of circumstances, before the completion 
of the protocol-defined study procedures.
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.
Participants can be prematurely discontinued from the study for one of the following reasons:

Adverse Event

Lack of efficacy

Lost to follow-up

Non-compliance with study drug

Other

Pregnancy

Protocol deviation

Site terminated by sponsor

Study terminated by sponsor

Withdrawal by subject
All randomized participants who prematurely discontinue from the study, regardless of cause, 
should be seen for final study assessments. The final assessments will be defined as completion 
of the evaluations scheduled for Visit 7/ET and Visit 8 EOS (Safety Follow-up Visit), 4 weeks 
post the last dose of study intervention. These participants must continue to complete their 
eDiary through Visit 8 EOS (Safety Follow-up Visit).
7.1.
Discontinuation of Study Intervention
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 receiving study intervention. 
Discontinuation of study intervention also requires discontinuation from the study. Please see 
appropriate sections regarding final assessments to be completed for discontinuation from study.
The following conditions require participants to be withdrawn from study:


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
Women who become pregnant will be withdrawn from the study and should refrain from 
taking further study intervention. The participant should return to the clinic for ET study 
procedures (Visit 7/ET), including the Safety Follow-up Visit (Visit 8) if study intervention 
was taken.

Participants who reply with yes to Questions 4 or 5 in the suicidal ideation section indicating 
having suicidal ideation with intent (with or without plan) or yes to any question in the 
suicidal behavior section of the C-SSRS should receive appropriate follow-up as in routine 
clinical practice. The participant should return to the clinic for ET study procedures 
(Visit 7/ET), including the Safety Follow-up Visit (Visit 8) if study intervention was taken.

Participants who meet any of the below study intervention discontinuation criteria related to 
abnormal liver function tests and are advised not to be rechallenged (see also Section 10.3.1):
o
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%)
o
ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN
o
ALT or AST ≥ 3 × ULN and INR > 1.5
o
ALT or AST ≥ 5 × ULN for more than 2 weeks
o
ALT or AST ≥ 8 × ULN
7.1.1.
Criteria for Study Termination
The sponsor may stop the study (and/or the study site) for any reason with appropriate 
notification.
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If a study is prematurely terminated or suspended due to safety issues, the sponsor shall inform 
all investigators and the regulatory authorities of the termination or suspension and the reason(s) 
for the termination or suspension. The IRB/IEC is also to be informed promptly and provided the 
reason(s) for the termination or suspension by the sponsor or by the investigator, as specified by 


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the applicable regulatory requirements. If a premature termination or suspension occurs, the 
sponsor shall remain responsible for providing resources to fulfill the protocol obligations and 
existing agreements for follow-up of participants enrolled in the study, and each investigator or 
authorized designee shall promptly inform enrolled participants, if applicable.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.
See the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
source data.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.

Discontinuation of specific sites or of the study as a whole are handled as part of Section 
10.1 (Appendix 1).


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.

Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. All assessments will be conducted at the appropriate visits as 
outlined in Section 1.3, the SoA, 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.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. Rescreening of participants may be considered with 
permission from Allergan (Section 5.5). Also, all women of childbearing potential must have 
negative results on the urine pregnancy test at the Screening and Randomization Visits 
(Visits 1 and 2, prior to the first administration of study intervention).

Prior to randomization, it must be confirmed that the participant had 4 to 14 migraine days 
and < 15 headache days during the 28-day baseline period (see Section 8.1.1 for definition) 
and completed the eDiary for at least 20 of the 28 days.

There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), Visit 2 (Randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ET 
(Week 12), and Visit 8 (Follow-up). 

Additional examinations and laboratory assessments may be performed as necessary to 
ensure the safety and well-being of the participants during the study period. Unscheduled 
visit eCRFs should be completed for each unscheduled visit.
8.1.
Efficacy and Descriptive Assessments
Efficacy assessments (including Health Outcome measures) will be based on information 
recorded by the participant. An eDiary will be used daily at home to collect data on headache 
duration, headache characteristics, symptoms, and acute medication use, which will be 
collectively applied to define migraine and headache days per the criteria listed in Sections 8.1.1
and 8.1.2. Efficacy assessments being also Health Outcome measures are presented in 
Section 8.9. 


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8.1.1.
Migraine Day
A migraine day is defined as any calendar day on which a headache which meets criteria A, B, 
and C OR meets criteria D and E, as listed below occurs, 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:
a.
Unilateral location
b. Pulsating quality
c.
Moderate or severe pain intensity
d. Aggravated by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs)
B. At least one of the following:
a.
Nausea and/or vomiting 
b. Photophobia and phonophobia 
c.
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 fulfils one criterion from (1) and at least one criterion from (2) OR 
fulfils 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
 
 
 


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8.1.2.
Headache Day
A headache day is defined as any calendar day on which headache pain lasting 2 hours or longer 
occurs unless an acute headache medication (eg, ibuprofen, triptan) was used after the start of the 
headache, in which case no minimum duration will be specified. Calendar days begin at midnight 
and last until 11:59 PM (23:59).
8.1.3.
Acute Medication 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, analgesics (including acetaminophen), NSAIDs 
(including aspirin), and antiemetics.
A triptan use day is defined as any day on which a participant reports intake of a triptan to treat a 
migraine per participant diary.
8.1.4.
Allodynia Symptom Checklist (ASC-12)
The ASC-12 measures overall allodynia and subtypes. Cutaneous allodynia affects patients with 
migraine and is associated with frequency, severity, disability and associated symptoms of 
migraine. ASC-12 includes 12 questions about the frequency of various allodynic symptoms in 
association with headache attacks. Each item is scored as “0” (ie, very rarely or does not apply to 
me), “1” (less than half the time), or “2” (half the time or more). The ASC-12 will be 
administered (or completed) on the eTablets at the screening visit (visit 1).
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
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.
8.2.2.
Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, body weight, and height (at Visit 1 only), will be performed at 
every visit. Sitting and standing BP and pulse rate will be determined as follows: BP and pulse 
measurements will be performed after the participant sits quietly for 5 minutes, followed by a 
second set of measurements taken after the participant stands for at least 3 minutes (but no longer 
than 10 minutes).


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8.2.3.
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in the SoA (Section 1.3). 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. 
8.2.4.
Clinical Safety Laboratory Assessments
See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency. Hematology, chemistry, coagulation parameters (INR), and 
urinalysis will be conducted at each visit. Serology and the urine drug screen will be conducted 
at Screening (Visit 1). 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.
At screening, the investigator or subinvestigator will assess the clinical significance of any 
values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant’s condition.
Positive results with the urine drug screen at Visit 1, unless explained by previously reported 
concomitant medication use, will be excluded from the study. Urine drug screens positive for 
recreational (including cannabis regardless of legality) or illicit drugs or non-disclosed 
concomitant medications are not allowed to be repeated. All other positive urine drug screens 
may only be repeated with permission from the Sponsor.
A positive pregnancy test at Visit 1 or Visit 2 will exclude the participant from participation in 
the study. Participants who are confirmed to be pregnant during the study will be withdrawn.
All laboratory tests with values considered clinically significant during participation in the study 
or within 30 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the investigator.
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Suicidal Risk Monitoring
Atogepant is considered to be CNS active and participants being treated should be monitored 
appropriately and observed closely for suicidal ideation and behavior. The C-SSRS is a clinician 


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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 [no plan] without intent to act), 4 (active suicidal 
ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with 
specific plan and intent). The C-SSRS also captures information about the intensity of ideation, 
specifically the frequency, duration, controllability, deterrents, and reasons for the most severe 
types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 
(preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual 
attempt). More than 1 classification can be selected provided they represent separate episodes. 
For actual attempts only, the actual or potential lethality is classified for the initial, most lethal, 
and most recent attempts. 
The C-SSRS will be completed at all Study Visits. At screening, the C-SSRS will be completed 
for the participant’s history of suicidal ideation and behavior in lifetime and in the past 6 months. 
At all other administrations, it will be completed for suicidal ideation and suicidal behavior since 
the previous visit. The C-SSRS will be administered on the eTablet by a clinician who has been 
certified to administer the C-SSRS. 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.
Refer to Section 10.3 (Appendix 3) for more information.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3).
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 the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs from the signing of the ICF must be collected until 30 days after the last dose 
of study, regardless of whether or not the participant has been administered study intervention, 
until the Follow-up Visit (Visit 8) (Section 1.3) and as observed or reported spontaneously by 
study participants.
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF and will be considered 
pretreatment AEs.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 10.3 (Appendix 3). The investigator will submit any updated SAE data to the sponsor
within 24 hours of it being available.


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Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3
(Appendix 3).
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs [and AEs of special interest (as defined in Section 8.3.9)]
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3).
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 or 
designee 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.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor or designee with a copy of any postmortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.


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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 local requirements.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.3.5.
Adverse Reactions, Serious Adverse Reactions, and Suspected Unexpected 
Serious Adverse Reactions – Expedited reporting within the EU
For the purposes of expedited reporting within the EU, the Sponsor will follow the applicable 
definitions for ARs, SARs, and SUSARs (for example, as outlined in Article 2 [n,o,p] of 
Directive 2001/20/EC). Also, seriousness criteria for AEs/ARs (as would apply to SARs and
SUSARs) are currently included in the protocol, listed in Section 10.3, Appendix 3.
Adverse Reaction: all untoward and unintended responses to an investigational medicinal 
product related to any dose administered.
Serious Adverse Reaction: an adverse reaction that results in death, is life-threatening, requires 
hospitalisation or prolongation of existing hospitalisation, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect (see Section 10.3, Appendix 3)
for further details pertaining to seriousness criteria).
Suspected Unexpected Serious Adverse Reaction: a serious adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (eg, the investigator’s 
brochure).
8.3.6.
Pregnancy

Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the Follow-Up Visit (Visit 8) 
or 30 days after the last dose of study intervention if the Follow-Up Visit is not done.

If a pregnancy is reported, the investigator should inform the sponsor or designee within 
24 hours of learning of the pregnancy and should follow the procedures outlined in
Section 10.7 (Appendix 7).

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are considered SAEs.


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8.3.7.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs
or SAEs
Signs and symptoms associated with acute migraine attack, eg, aura symptoms, headache pain, 
nausea and vomiting, sensitivity to light or sound, are considered to be manifestations of 
migraine and will be captured in the eDiary as symptoms of the disease but they will not be 
reported as AEs, unless they change in severity or frequency, when they are to be considered as 
AE. If those events meet SAE criteria, they need to be reported as AEs and SAEs as appropriate.
If the investigator considers these manifestations to have a reasonable possibility of relationship 
to the study intervention(s), then they should be reported as AEs or SAEs, respectively.
Please also see Section 10.3 (Appendix 3).
8.3.8.
Protocol-specific AEs
Not applicable.
8.3.9.
AEs of Special Interest
AEs of special interest that warrant ongoing monitoring and rapid communication by the 
investigator to the sponsor are outlined and specific liver safety guidelines to be followed for this 
protocol are outlined in Section 10.3 (Appendix 3). 
8.3.10.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study drug

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration, including wrong site of administration (eg, wrong eye)

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is above the maximum recommended dose according to the 
reference safety information or protocol for the study intervention or comparator as applicable. 
This also takes into account cumulative effects due to overdose.
An overdose is any unintentional administration of atogepant above 60 mg per day as per the 
protocol.
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol.


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8.4.
Treatment of Overdose
For this study, any dose of atogepant greater than 60 mg within a 24-hour time period will be 
considered an overdose.
At present, specific information regarding treatment of overdose of atogepant is not available. In 
case of an overdose, it may be considered that the stomach be emptied and oral gavage with 
activated charcoal be used to help reduce absorption of atogepant.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical safety physician immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until atogepant
can no longer be detected systemically (at least 2 days).
3. Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of study 
intervention if requested by the medical safety physician (determined on a case-by-case 
basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical safety physician based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
8.5.1.
Blood PK Sampling Procedure
A blood sample for PK analysis will be collected on site at Visits 2, 3, 4, 5, 6, and 7/ET from 
participants who consent to participate in the PK substudy. Participants can withdraw consent to 
participate in the PK substudy at any time and should have no further PK samples collected. 
Each participant in the PK substudy will be asked to provide a total of 6 blood samples (1 per 
visit). At Visit 2, the sample should be collected prior to the initial dose of study intervention 
taken at the clinic. During one of the Visits 3 to 6, the sample should be collected prior to the 
daily dose of study intervention (participant should wait to take the dose in the clinic after PK 
sample collection), and the samples collected at the remaining visits should be collected 1 to 10 
hours post the daily dose. At Visit 7 the sample should be collected 1 to 10 hours post the daily
dose.
The date and time of collection of each PK sample will be recorded in the eCRF. In addition, for 
each of the PK samples collected (except the Visit 2 sample) the date and time of taking study 
intervention prior to the PK sample should be recorded. PK samples will be collected, stored 
(frozen), and shipped according to instructions provided in the laboratory manual.
The treatment codes will be provided to the bioanalytical lab using a secure process, ensuring no 
one outside the bioanalytical team is unblinded, to allow only atogepant-treated participant PK 
samples to be analyzed. The bioanalytical method for the determination of individual plasma 
concentrations of atogepant and the performance of the assay during validation and sample 
analysis will be summarized in a separate bioanalytical report, including the results obtained 


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from analysis of the PK samples. The bioanalytical report will be appended to the integrated 
clinical trial report. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical representatives will be unblinded for PK sample bioanalysis during the conduct of 
the study. The unblinding of bioanalytical representatives is to be carried out in a secure manner 
following the sponsor’s standard operating procedures. Extreme care and diligence will be taken 
to ensure no other individuals outside the bioanalytical team will be unblinded.
8.5.2.
PK Sample Bioanalysis
Plasma concentrations of atogepant will be determined using validated liquid chromatography-
tandem mass spectrometry methods.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers and Other Assessments
Biomarkers are not evaluated in this study.
8.9.
Health Outcome Measures and Health Resource Utilization
8.9.1.
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 


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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).
The AIM-D will be collected daily via the eDiary.
8.9.2.
Activity Level and Activity Limitation
Two items based on a 24-hour recall will be administered daily using Headache and 
Non-Headache versions as additional health outcome measures and for evaluation of the AIM-D. 
The first item will be used to assess activity level within the past 24 hours with a 5-level 
response ranging from “No activity –Spent all day lying down” to “Exercised – Brisk walk, 
running, jogging, biking or other activity for 30 or more minutes.” The second item will be used 
to evaluate activity limitation with a 5-level response ranging from “Not at all limited –I could 
do everything” to “Extremely limited.”
Activity Level and Activity Limitation will be collected daily via the eDiary. 
8.9.3.
Patient Satisfaction with Study Medication (PSSM)
Overall satisfaction with the study medication for prevention of migraine will be assessed using a 
single item and a 7-point rating scale ranging from extremely satisfied (0) to extremely 
dissatisfied (6).
The PSSM scale will be administered in the eTablet at the clinic visits as indicated in the SoA
(Section 1.3).
8.9.4.
Headache Impact Test (HIT-6)
The HIT is a 6-question assessment used to measure the impact headaches have on participants’ 
ability to function on the job, at school, at home and in social situations. It assesses the effect that 
headaches have on normal daily life and the participants’ ability to function. Responses are based 
on frequency using a 5-point scale ranging from “never” to “always.” The HIT-6 total score, 
which ranges from 36 to 78, is the sum of the responses – each of which is assigned a score 
ranging from 6 points (never) to 13 points (always).
HIT-6 will be administered in the eTablet at the clinic visits as indicated in the Schedule of 
Activities (Section 1.3).
8.9.5.
Migraine Disability Assessment (MIDAS)
The MIDAS is a 7-item questionnaire designed to quantify headache-related disability over a 
3-month period. The MIDAS score is the sum of missed work or school days, days at work or 
school plus days of household work where productivity was reduced by half or more, missed 
household work days, and missed non-work activity days due to headaches in the last 3 months.
MIDAS will be administered in the eTablet at the clinic visits as indicated in the SoA
(Section 1.3).


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8.9.6.
Patient Global Impression of Change (PGIC)
The PGIC is a single item used to measure the participant’s impression of overall change in 
migraine since the first dose of study medication. The measure uses a 7-point rating scale with 
responses ranging from “very much better” to “very much worse.”
PGI-C will be administered in the eTablet at the clinic visits as indicated in the SoA
(Section 1.3).
8.9.7.
Work Productivity and Activity Impairment Questionnaire: Migraine V2.0 
(WPAI:MIGRAINE)
The WPAI:MIGRAINE will be used to assess work productivity specific to migraine. The 
measure uses a one-week recall and contains six questions related to work productivity. The 
WPAI measures both presenteeism and absenteeism. The measure yields four scores expressed 
as impairment percentages ranging from 0 to 100%: Percent work time missed, percent 
impairment while working, percent overall work impairment, and percent activity impairment 
due to migraine.
WPAI-MIGRAINE will be administered in the eTablet at the clinic visits as indicated in the SoA
(Section 1.3).
8.9.8.
European Quality of Life – 5 Dimensional (EQ-5D-5L)
EQ-5D-5L is a generic instrument for use as a measure of health status. The EQ-5D-5L consists 
of 2 components – the EQ-5D descriptive system and the EQ VAS. The descriptive system 
comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression). The respondent is asked to indicate his/her health state by marking the box 
for the most appropriate statement in each of the 5 dimensions. The scoring range of the EQ-5D 
descriptive system is typically from 0 (dead) to 1 (full health). The EQ VAS records the 
respondent’s self-rated health on a vertical, VAS where the endpoints are labelled “Best 
imaginable health state” and “Worst imaginable health state.” The scoring range of the EQ VAS 
is from 0 (worst imaginable health) to 100 (best imaginable health).
EQ-5D-5L will be captured on eDiary during 7 days in the screening/baseline period and during 
specific time periods for Visit 1 to 7, except at Visit 8 (Week 16) where it will be administered 
on an eTablet. For details please refer to Schedule of Activities (Section 1.3) as indicated in the 
Schedule of Activities (Section 1.3).
8.9.9.
Patient Global Impression – Severity (PGI-S)
The PGI-S is a single item used to measure the participant’s impression of severity in relation to 
migraine symptoms overall at the time of administration of the measure. The measure uses a 
5-point rating scale with responses ranging from “none” to “very severe”.
PGI-S will be administered in the eTablet at the clinic visits as indicated in the Schedule of 
Activities (Section 1.3).


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8.9.10.
Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1)
The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality-of-life 
impairments attributed to migraine in the past 4 weeks. It is divided into three domains: Role 
Function Restrictive assesses how migraines limit one’s daily social and work-related activities; 
Role Function Preventive assesses how migraines prevent these activities; and the Emotional 
Function domain assesses the emotions associated with migraines. Participants respond to items 
using a 6-point scale ranging from “none of the time” to “all of the time.” Raw dimension scores 
are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores 
indicate better quality of life.
MSQ V2.1 will be administered in the eTablet at the clinic visits as indicated in the SoA (Section 
1.3).
8.9.11.
Patient-Reported Outcomes Measurement Information System Pain 
Interference –Short Form 6a (PROMIS-PI)
The PROMIS-PI measures self-reported interference of pain on relevant aspects of daily life (ie, 
social, cognitive, emotional, physical, recreational) over the past 7 days. A 5-level response scale 
for all six items ranges from “Not at all” to “Very much.” Scores range from 6 to 30, with higher 
scores indicating greater pain interference. The raw scores are translated into a T-score where the 
T-score rescales the raw score into a standardized score with a mean of 50 and a standard 
deviation of 10.
PROMIS-PI will be administered in the eTablet at the clinic visits as indicated in the SoA
(Section 1.3).
8.9.12.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is a concise, self-administered, validated, screening and diagnostic tool for mental 
health disorder, which has been field-tested in office practice. The screener is quick and user 
friendly, improves the recognition rate of depression, and facilitates diagnosis and treatment. The 
PHQ-9 consists of the 9 diagnostic criteria for depressive disorders in the past 2 weeks from the 
DSM-IV. Participants are asked to indicate the frequency with which they have been bothered by 
9 symptoms of depressive disorders over the previous 2 weeks, on a 4-point scale: 0 (not at all), 
1 (several days), 2 (more than half the days), and 3 (nearly every day). The total score ranges 
from 0 to 27 (from best to worst). A score of 15 to 19 is considered as moderately severe 
depression and 20 to 27 as severe depression.
PHQ-9 will be administered in the eTablet at the clinic visits as indicated in the SoA (Section 
1.3).
8.9.13.
Healthcare Resource Utilization
Healthcare resource utilization questions will be completed in the source documents at the sites 
based on the investigator’s interview with the participant at each study visit. This data will then 
be transcribed into the eCRF thereafter. Healthcare resource utilization questions will include use 
of migraine-specific healthcare resources due to migraine attack (eg, visits to any general 
practitioner, specialist, emergency room, or hospital, and any diagnostic procedures prescribed 
by health care providers). 


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Resource utilization data will be collected paper based at the study visits. 


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The primary null hypothesis is that atogepant treatment dose (atogepant 60 mg QD) is equally 
effective to placebo in decreasing from baseline in mean monthly migraine days across the 12-
week treatment period. The alternative hypothesis is that atogepant dose has a greater effect than
placebo.
For efficacy analyses, data will be analyzed according to participants’ randomization 
assignments, regardless of actual treatment received.
For safety data analyses, the participants will be analyzed according to actual treatment received 
(rather than as randomized).
9.2.
Sample Size Determination
A sample size of 150 randomized participants per treatment group will provide a 97% and 95%
power to detect the treatment difference of -1.7 or -1.6 between atogepant and placebo for the 
primary efficacy endpoint for the United States or the EU, respectively. This sample size was 
selected to provide sufficient power for each of the secondary endpoints in Table 9-1 for the 
United States and Table 9-2 for the EU. 


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Table 9-1
Statistical Power for Primary and Secondary Endpoints for the United States
Hypothesis 
Testing
Endpoint
Treatment 
Difference from 
Placebo
Standard 
Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across the 
12-week treatment period
-1.7
3.5
97%
Secondary 1
Achievement of at least 50% 
reduction in mean monthly 
migraine days across the 12-week 
treatment period
29% Placebo rate
60% atogepant rate
99%
Secondary 2
Change from baseline in mean 
monthly headache days across the 
12-week treatment period
-1.7
3.7
95%
Secondary 3
Change from baseline in mean 
monthly acute medication use days 
across the 12-week treatment 
period
-1.5
3.1
97%
Secondary 4
Change from baseline in MSQ v2.1 
Role Function-Restrictive domain 
score at Week 12
10.8
22.6
96%
Secondary 5
Change from baseline in mean 
monthly Performance of Daily 
Activities domain score of the 
AIM-D across the 12-week 
treatment period
-3.3
7.3
93%
Secondary 6
Change from baseline in mean 
monthly Physical Impairment 
domain score of the AIM-D across 
the 12-week treatment period
-2.4
6.4
81%
 
 
 


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Table 9-2
Statistical Power for Primary and Secondary Endpoints for the EU
Hypothesis 
Testing
Endpoint
Treatment 
Difference from 
Placebo*
Standard 
Deviationa
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across the 
12-week treatment period
-1.6
3.5
95%
Secondary 1
≥ 50% reduction in in mean 
monthly migraine days across the 
12-week treatment period
30% Placebo rate
59% atogepant rate
99%
Secondary 2
Change from baseline in mean 
monthly headache days across the 
12-week treatment period
-1.6
3.7
92%
Secondary 3
Change from baseline in mean 
monthly acute medication use days 
across the 12-week treatment 
period
-1.4
3.2
93%
Secondary 4
Change from baseline in HIT-6 
total score at Week 12
-3.9
7.6
98%
Secondary 5
Change from baseline in MSQ v2.1 
Role Function-Restrictive domain 
score at Week 12
10.9
22.8
96%
a The assumptions applied for the EU were estimated using off-treatment hypothetical estimand approach based on
Advance Study data.
The power calculations are based on the following assumptions:
1) Table 9-3 provides the results from two atogepant studies (CGP-MD-01 and 
3101-301-002 [Advance Study]) and Liberty Study (Reuter 2018) for the primary 
endpoint. The treatment difference for atogepant 60mg QD versus placebo is assumed to 
be observed treatment difference in the atogepant Advance study, which is a relative 
conservative assumption in term of primary endpoint. The standard deviation 
assumptions were based on the variance in Liberty Study and monthly variance observed 
in Advance Study for the primary endpoint. In particular, the assumed treatment 
difference from placebo in change from baseline in mean monthly migraine days across 
the 12-week treatment period is -1.7 days for the United States and is -1.6 days for the 
EU, and the standard deviation is 3.5 days. Detailed treatment difference and standard 
deviation assumptions for secondary endpoints are listed in Table 9-1 for the United 
States and in Table 9-2 for the EU, which are based on the results from the atogepant 
Advance study. 
 
 
 


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Table 9-3
Observed Treatment Effect for Primary Endpoint in Atogepant Program and 
Liberty
Study
Population
Atogepant 60 mg QD 
Treatment Difference from 
Placebo
Standard 
Deviation
Advance
mITT population
-1.72
3.00
Participants with Prior exposure to 
migraine preventive treatment = Yes
-2.16
3.01
Participants with one treatment failures
-1.94
3.04
Participants with two or more treatment 
failures
-2.91
3.34
CGP-MD-01
Participants with Prior exposure to 
migraine preventive treatment = Yes
-1.41
2.97
Liberty
Efficacy Population for Treatment Failure 
study
-1.93 (Average of 12 Weeks)
3.47a
Efficacy Population for Treatment Failure 
study
-1.6 (At month 3)
4.6
a
SD was calculated using variance in liberty and correlation matrix from Advance study
2) A fixed-sequence procedure will be used for multiple comparisons to control the family-
wise Type I error rate at a 0.05 level. The testing sequence is specified in Table 9-1 and
Table 9-2. Once the primary endpoint for atogepant dose is significant at 0.05 (2-sided), 
the secondary endpoints will be tested sequentially. Statistical powers for secondary 
endpoints are conditional on success of prior endpoints (assuming independence among 
the endpoints) in the sequence.
3) The dropout rate is assumed to be 15% for endpoints other than AIM-D related 
endpoints. The dropout rate for AIM-D endpoints is 21%. A higher missing rate for 
AIM-D endpoints was observed in the Advance Study because the related measure was
collected only in Today’s eDiary instead of both Yesterday and Today’s eDiary, If the 
participants may provide less than 14 records of Today’s eDiary within a 28-day period, 
it would lead to missing data.
The assumptions of sample size calculation such as SD and dropout rate will be monitored while 
the study is ongoing and sample size will be adjusted. This blinded analysis of variability in the 
pooled treatment groups will be performed using the primary efficacy analysis model for the 
primary endpoint as described in Section 9.4.1.2 but excluding the terms treatment and treatment 
by visit interaction from model terms.
 
 
 


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9.3.
Populations for Analyses
The analysis populations will consist of participants as defined below:

The ITT population includes all randomized participants. Participants will be summarized 
according to the randomized study intervention.

The mITT population includes all randomized participants who received at least one dose of 
study intervention, had an evaluable baseline period of eDiary data and had at least one 
evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data
during the double-blind treatment period. Participants will be summarized according to the 
randomized study intervention.

The safety population includes all treated participants who received ≥ 1 administration of 
study intervention. Participants will be summarized according to the study intervention they 
actually received.

The PK population includes all participants who have evaluable PK parameters.
The population for EU filing in the estimand framework is defined in Section 9.6.
9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.
9.4.1.
Efficacy Analyses
The efficacy analyses will be based on the mITT population. All statistical tests will be 2-sided 
hypothesis tests performed at the 5% level of significance for main effects and all CIs will be 
2-sided 95% CIs, unless stated otherwise.
9.4.1.1.
Analysis Endpoints
The primary, secondary and exploratory efficacy endpoints are listed below and analyses will be 
defined in the following sections. Analysis of all endpoints listed below will be defined in the 
SAP.
9.4.1.1.1. Primary efficacy endpoint:

The primary efficacy endpoint is the change from baseline in mean monthly migraine days 
across the 12-week treatment period. Baseline is defined as the number of migraine days 
during the last 28 days prior to the randomization date.
9.4.1.1.2. Secondary efficacy endpoints:
Secondary efficacy endpoints for the United States:
 
 
 


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
Achievement of at least a 50% reduction in mean monthly migraine days across the 12-week 
treatment period

Change from baseline in mean monthly headache days across the 12-week treatment period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12

Change from baseline in mean monthly Performance of Daily Activities domain score of the 
AIM-D across the 12-week treatment period

Change from baseline in mean monthly Physical Impairment domain score of the AIM-D 
across the 12-week treatment period
Secondary efficacy endpoints for the EU: 

Achievement of at least a 50% reduction in mean monthly migraine days across the 12-week 
treatment period

Change from baseline in mean monthly headache days across the 12-week treatment period

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period

Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12

Change from baseline in the HIT-6 total score at Week 12
9.4.1.1.3. Exploratory efficacy endpoints:
Exploratory efficacy endpoints for the United States and the EU are provided below. Related 
analysis will be documented in the SAP. 

Achievement of ≥ 25%, ≥30%, ≥ 50%, ≥ 75%, 100% improvement (decrease) in monthly 
migraine days at Weeks 1-4, 5-8, and 9-12

Achievement of ≥ 25%, ≥30%, ≥ 75%, 100% improvement (decrease) in monthly migraine
days across the 12-week treatment period

Change from baseline in monthly migraine days at Weeks 1-4, 5-8, and 9-12

Change from baseline in monthly headache days at Weeks 1-4, 5-8, and 9-12

Change from baseline in monthly cumulative headache hours at Weeks 1-4, 5-8, 9-12, and 
average across the 12-week treatment period
 
 
 


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
Change from baseline in monthly acute medication use days at Weeks 1-4, 5-8, and 9-12

Change from baseline in monthly triptan use days at Weeks 1-4, 5-8, 9-12, and average 
across the 12-week treatment period

Change from baseline in monthly moderate/severe headache days at Weeks 1-4, 5-8, 9-12, 
and average across the 12-week treatment period

Change from baseline in monthly severe headache days at Weeks 1-4, 5-8, 9-12, and average 
across the 12-week treatment period

Change from baseline in the HIT-6 total score at Weeks 4 and 8 (EU only)

Change from baseline in the HIT-6 total score at Weeks 4, 8, and 12 (United States only)

Achievement of at least a 5-point improvement (decrease) from baseline in HIT-6 total score 
at Weeks 4, 8, and 12

Achievement of a rating of “much better” or “very much better” at Week 12 assessed by the 
PGIC

Achievement of a rating of “satisfied” or “extremely satisfied” at Weeks 4, 8, and 12 as 
assessed by the PSSM

Change from baseline in percent work time missed, percent impairment while working, 
percent overall impairment, and percent activity impairment due to migraine at Weeks 4, 8, 
and 12 as assessed by the WPAI:MIGRAINE

Change from baseline in EQ-5D-5L descriptive system index score at Weeks 1 to 2, at 
specified windows around Weeks 4, 6, 8, 12, and Week 16

Change from baseline in the EQ-5D-5L VAS score at Weeks 1 to 2, at specified windows 
around Weeks 4, 6, 8, 12, and Week 16

Change from baseline in the MIDAS total score at Week 12

Change from baseline in MIDAS absenteeism score (Questions 1, 3, and 5) at Week 12

Change from baseline in MIDAS presenteeism score (Questions 2 and 4) at Week 12

Change from baseline in PGI-S score at Weeks 4, 8, and 12

Change from baseline in the MSQ v2.1 Role Function-Preventive domain score at Weeks 4, 
8, and 12 

Change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at Weeks 4 
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
Change from baseline in the MSQ v2.1 Emotional Function domain score at Weeks 4, 8, and 
12

Change from baseline in monthly Performance of Daily Activities domain score of the 
AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12

Change from baseline in monthly Physical Impairment domain score of the AIM-D at Weeks 
1 to 4, 5 to 8, and 9 to 12

Change from baseline in mean monthly Performance of Daily Activities domain score of the 
AIM-D across the 12-week treatment period (EU only)

Change from baseline in mean monthly Physical Impairment domain score of the AIM-D 
across the 12-week treatment period (EU only)

Change from baseline in monthly AIM-D total score at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in monthly activity level at Weeks 1 to 4, 5 to 8, 9 to 12, and average 
across the 12-week treatment period

Change from baseline in monthly activity limitation at Weeks 1 to 4, 5 to 8, 9 to 12, and 
average across the 12-week treatment period

Change from baseline in PROMIS-PI total score at Weeks 4, 8, and 12

Change from baseline in PHQ-9 score at Week 12
9.4.1.1.4. Collection and Derivation of Primary and Secondary Efficacy Assessments
On a daily basis during the 28-day baseline period and throughout the study, participants are to 
record into an eDiary information on the daily total duration of headache, headache specific 
characteristics and symptoms, the worst pain severity, and use of any acute headache pain 
medication. Participants will be able to report headache data, including absence of headache, for 
the day of the eDiary report and for the day immediately prior to the day of the eDiary report, as 
long as information reported is for a time subsequent to the participant’s most recent report. This 
is defined as a one-day “missing-recall” window.
Following randomization on Day 1, there are 4 visits at 2-week intervals, followed by 2 visits at 
4-week intervals; altogether encompassing a 12-week double-blind treatment phase of the study 
and a 4-week safety follow-up phase. In practice, there may or may not be exact 2-week or 
4-week durations between two consecutive visits and the visits might not align with each 28-day 
period recorded in the eDiary (ie, Weeks 1 to 4, 5 to 8 and 9 to 12, corresponding to Days 1 to 
28, 29 to 56, and 57 to 84). Therefore, for data analysis purposes, the number of migraine days 
during the last 28 days prior to the randomization date, will serve as the “baseline”, and change 
from baseline will be calculated for consecutive 28-day periods beginning with the date of the 
first dose of study intervention.


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In order to be randomized, a participant should be in the screening/baseline period for at least 28 
days and must report eDiary data for at least 20 days (including missing recall) during the 28-day 
screening/baseline period. If less than 28 days of baseline data are reported, the number of 
headache days and other such counting variables for “baseline” will be prorated to standardize 
the count to a 28-day equivalent. Subsequent to treatment start, the number of headache days will 
be counted in successive and non-overlapping 4-week (ie, 28-day) windows. Headaches that 
continue into a subsequent 4-week period will be counted (with recorded severity and duration) 
as occurring in each period.
If any eDiary window for a participant has at least 12 but less than 28 days of reported data, the 
prorated approach will be used. If a participant reports less than 12 days of headache data, the 
participant’s observed counts in that particular 28-day eDiary window will be set to missing for 
that window. These prorating rules will be applied to all efficacy analyses of eDiary data unless 
otherwise stated.
9.4.1.2.
Primary Analyses
The primary efficacy analysis is the change from baseline in mean monthly migraine days across 
the 12-week treatment period. 
The primary comparison between treatment groups will be done by a MMRM of the change 
from baseline. The statistical model will include treatment group, visit, region, number of classes 
of failed prior prophylactic treatments, and treatment group by visit interaction as categorical 
fixed effects. It will also include the baseline value and baseline-by-visit interaction as 
covariates. An unstructured covariance matrix will be used to model the covariance of within-
participant repeated measurements. Note that baseline monthly migraine is included in the 
primary model, therefore the stratification of number of migraine days during the 
screening/baseline period (4 to < 8 and ≥ 8) will be excluded in the primary model. On the other 
hand, this stratification will be included in the secondary and exploratory analyses if baseline 
values other than monthly migraine days are included in the corresponding models. The 
Kenward-Roger approximation (Kenward and Roger 1997) will be used to estimate the 
denominator degrees of freedom. The analysis will be performed based on all postbaseline values 
using only the observed cases without imputation of missing values. Pairwise contrasts in the 
MMRM model will be used to make the pairwise comparisons of each atogepant dose to 
placebo. Only data collected during the double-blind period will be included in the analysis. 
Participants are always analyzed based on the treatment group assigned by randomization.
9.4.1.2.1
Sensitivity Analyses in Missing Data Handling
Multiple sensitivity analyses for missing data handling will be conducted and are summarized 
below. Details of the sensitivity analyses will be provided in the statistical analysis plan.
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
A supportive analysis will be performed on the primary endpoint using an ANCOVA model. The 
response variable for the ANCOVA model is the change from baseline in the calculated average 
monthly migraine days during the 12-week treatment period for each participant. The ANCOVA 
model includes terms for treatment, region, number of classes of failed prior prophylactic 
treatments, and baseline score. The treatment difference for atogepant doses versus placebo will 


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be estimated and reported along with the corresponding 95% CI and nominal p-value for 
superiority testing.
Within-group Imputation Based on Observed Data
Sensitivity analysis will be performed based on imputation using participants from the same 
treatment group with observed data under the MAR assumption. Missing data for participants 
who prematurely discontinued are assumed to copy the profile of participants in the same 
treatment group with observed data.
Copy-Reference Approach
Copy-reference approach will be performed on the primary endpoint to assess the robustness of 
the MMRM analysis to possible violation of the MAR assumption. This sensitivity analysis is 
one type of pattern mixture models (PMM), under which data could be missing not at random 
(MNAR), with repeated analyses combined via the reference based multiple imputation 
procedure. Participants who discontinued in the atogepant groups are assumed to have no 
treatment effect after the discontinuation. Participants are assumed to copy the profile of placebo 
arm and missing values are imputed based on the distribution estimated from the placebo group 
under the MAR using copy reference approach.
9.4.1.2.2
Sensitivity Analysis for Possible Violation of Normality Assumption
The normality test is performed on the residuals which are generated by the same MMRM as 
used for the primary efficacy analysis. The residuals are scaled by the inverse Cholesky root of 
its estimated variance-covariance matrix. The Kolmogorov-Smirnov test for normality is applied 
to the de-correlated and scaled residuals and normality test is rejected if p-value from the 
Kolmogorov-Smirnov test is less than 0.01.
If the normality test is rejected, the sensitivity analysis uses multiple imputation in conjunction 
with robust regression to assess the robustness of the primary MMRM analysis to the possible 
violation of normality assumption. This method has been described and referred as ADAP [R] in 
Mehrotra 2012. The detail of the sensitivity analyses will be provided in the SAP.
9.4.1.3.
Secondary Analyses
The secondary endpoints for headache days, acute medication use days, MSQ v2.1 Role 
Function-Restrictive domain score, Performance of Daily Activities domain score of the AIM-D, 
Physical Impairment domain score of the AIM-D, and HIT-6 total score will be analyzed in the 
same manner as that used to analyze the primary endpoint. 
The 50% responder, defined as a participant with at least a 50% reduction from baseline in the 
3-month average of monthly migraine days, will be assessed for each individual. A logistic 
regression model will be used to analyze the proportion of 50% responders across the 12-week 
treatment period. This model assumes a binary distribution for the response and uses a logit link. 
The analysis model will include treatment group, region, and number of classes of failed prior 
prophylactic treatments as categorical fixed effects; baseline value will be included as a 
covariate. The analysis will be performed based on all postbaseline values using only the 
observed cases without imputation of missing values. The treatment difference in terms of odds 


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ratio between each atogepant dose group and placebo will be estimated and tested from this 
model. 
The overall type I error rate for the primary and secondary efficacy endpoints will be controlled 
at the 0.05 level using the fixed sequence procedure following the testing order pre-specified in 
Table 9-1 for the United States and Table 9-2 for the EU. Once one efficacy endpoint is not 
significant, all subsequent endpoints will not be tested.
9.4.1.4.
Exploratory Efficacy Analyses
In general, other efficacy analyses are performed at the nominal significance level, without 
adjusting for multiplicity.
Other efficacy variables will be analyzed as follows:
For selected diary variables with a continuous response range, the baseline score will be included 
as a covariate in an MMRM analysis of the change from baseline. These analyses will be 
performed similarly to the primary MMRM, with focus again on the pairwise contrasts of each 
dose group to placebo.

For variables where the data are essentially binary, comparisons between treatment 
groups will be done with logistic regression for variables with only one post-baseline 
assessment or using generalized linear mixed model for variables with multiple post-
baseline assessments.
Descriptive statistics will be provided by visit for each efficacy variable by treatment group. 
Analysis of some variables will be limited to descriptive summary statistics. Details will be 
specified in the SAP.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, clinical laboratory, vital signs, ECG parameters, 
and C-SSRS. 
For each of the clinical laboratory, vital signs, and ECG parameters, the last nonmissing safety 
assessment before the first dose of study intervention will be used as the baseline for all analyses 
of that safety parameter.
9.4.2.1.
Adverse Events
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date (and time, if known) of the first dose of study intervention. TEAEs 
will be analyzed after treatment start on day 1 through the end of the study. An AE that occurs 
more than 30 days after the last dose of double-blind study treatment or Visit 8 whichever comes 
later will not be counted as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion.
MedDRA nomenclature will be used to code AEs.


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The number and percentage of participants with TEAEs in each study intervention group will be 
tabulated by system organ class and preferred term and by system organ class, preferred term, 
and severity.
The number and percentage of participants with treatment related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
AEs will also be summarized separately for the double-blind treatment and safety follow up 
phases of the study.
Summary tables will be provided for participants with TESAEs and participants with TEAEs 
leading to discontinuation if 5 or more participants reported such events. Listings of all AEs, 
SAEs, and AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Section 10.3 (Appendix 3).
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening) and 
changes from baseline at each assessment will be presented by study intervention for each 
clinical laboratory assessment.
9.4.2.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, weight, respiration rate, 
and temperature) at baseline (screening) and changes from baseline at each assessment will be 
presented by study intervention.
9.4.2.4.
Electrocardiograms 
A 12-lead ECG will be performed at the visits outlined in the SoA, Section 1.3. 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.
9.4.2.5.
Suicidality Assessment
For the C-SSRS, the number of participants with suicidal ideation and suicidal behavior in 
lifetime history, 6 months prior to screening, and after the initial dose of study intervention will 
be summarized by study intervention for the safety population. The Safety Follow-up Visit 
assessment will be presented in the last study intervention the participant received. A supportive 
listing of participants with suicidal ideation or suicidal behavior will be provided for the safety 
population.


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9.4.3.
PK Analyses
A graphical evaluation of the PK and PD data of atogepant will be performed for the 
identification of possible trends. The PK will be evaluated using the existing population PK 
model, updated with data from this study. Individual predictions of atogepant exposure 
(including but not limited to steady state AUC0-Tau and Cmin) will be evaluated graphically for 
potential relationships with efficacy and/or safety endpoints. If graphical evaluation identifies 
possible trends, exploratory PK/PD analyses will be performed for the evaluation and 
quantification of potential relationships via nonlinear mixed effects modeling. Efficacy endpoints 
to be evaluated will include migraine days and responder rates. A stand-alone pharmacometric 
analysis plan will be written, and the analyses results will be reported separately from the 
integrated clinical study report.
9.4.4.
Subgroup Analyses
Subgroup analyses will be performed to evaluate the consistency of treatment effects on the 
primary efficacy endpoint for individual regions (North America, Europe, and Asia/Pacific as 
well as the following subpopulations defined by prior oral prophylactic treatment failure:

Participants who have failed ≥2 prior oral prophylactic treatments with 2 different class of 
treatments

Participants who have failed ≥3 prior oral prophylactic treatments with 2 different class of 
treatments

Participants who have failed ≥ 3 prior oral prophylactic treatments with 3 different class of 
treatments 

Participants who have failed ≥3 prior oral prophylactic treatments, irrespective of class

Participants who have failed ≥ 4 prior oral prophylactic treatments, irrespective of class
If the sample size for one region is small, the subgroup analysis will be performed after pooling 
one or more regions. Details of the subgroup analysis will be provided in the SAP.
9.5.
Interim Analyses
No interim analysis is planned.
9.6.
Off-treatment Hypothetical Estimand
9.6.1.
Treatment Condition of Interest
Participants take assigned treatment by randomization during the double-blind treatment period. 
In addition, permitted intervention, rescue interventions and prohibited interventions are 
described below:

Participants are allowed to take therapies considered necessary for the participant’s welfare 
(Protocol Section 6.5.1) or to apply “best supportive care” including both acute migraine 


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medications and acute non-pharmacological interventions to keep the participants in the 
study (Protocol Section 6.5.2). 

The protocol prohibits participants from starting any new migraine preventive treatments 
during the study (Protocol Section 6.5.3).
9.6.2.
Population
The target population is participants suffering from migraine with aura or migraine without aura
satisfying the inclusion and exclusion criteria as specified in Section 5.
The analysis population is defined to be all randomized participants who received at least 1 dose 
of study intervention, had an evaluable baseline period of eDiary data and had at least
1 evaluable post-baseline 4-week period (Weeks 1-4, 5-8, 9-12) of eDiary data, regardless of 
whether on study intervention or off study intervention.
9.6.3.
Variable
The variable is the same as the primary efficacy endpoint defined in Section 9.4.1.1.1, which is
the change from baseline in the participant’s mean monthly (4-weeks) migraine days across the 
12-week treatment period as derived from the eDiary data.
9.6.4.
Accounting of Intercurrent Events
Intercurrent events and their handling rules are as follows:

Participants who start a new migraine prophylaxis treatment during the double-blind or safety 
follow-up period will have their data during the safety follow-up period after starting the new 
migraine prophylaxis treatment excluded from the data analysis.

Participants who discontinue study intervention due to all reasons other than starting a new 
migraine prophylaxis treatment will have their data collected after discontinuation of study 
intervention and those off-treatment will be included in the analysis.
Detailed methods and procedures will be documented in the SAP prior to study completion.
9.6.5.
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable
means between each atogepant group and placebo.
Participants are always analyzed based on their treatment assignment by randomization. To 
obtain the estimate of treatment effect defined in the off-treatment hypothetical estimand, an 
MMRM similar to the primary analysis specified in Section 9.4.1.2 will be performed on 
observed data including both on-treatment and off-treatment monthly migraine days. 
9.6.6.
Off-treatment Hypothetical Estimand Approach for the Secondary Endpoints
Continuous secondary endpoints will be handled using the same estimand approach defined
above for the primary endpoint.


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The secondary endpoint of 50% responders will be derived using both on-treatment and 
off-treatment observed data as defined in the primary endpoint above. The population-level 
summary for this endpoint is the odds ratio for each atogepant group relative to placebo.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
CIOMS International Ethical Guidelines
o
Applicable ICH/ISO GCP guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval (and approval of the 
appropriate regulatory agency, if required by national law) before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3.
Informed Consent Process

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. 


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
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Written informed consent is to be obtained from each participant prior to enrollment into the 
study and/or from the participant’s legally authorized representatives. The informed consent 
form includes explanation of the following:
1. That the study involves research
2. The objectives of the study
3. The study procedures
4. The expected duration of the participant’s participation in the study
5. The approximate number of participants involved in the study
6. The reasonably foreseeable risks or inconveniences to the participant
7. The alternative procedures or courses of interventions that may be available to the 
participant, and their important potential benefits and risks
8. The compensation and/or intervention available to the participant in the event of 
study-related injury
9. That the participant’s participation in the study is voluntary and that the participant may 
refuse to participate or withdraw from the study at any time, without penalty or loss of 
benefits to which the participant is otherwise entitled
10. That the participant will be informed in a timely manner if information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study
11. The foreseeable circumstances and/or reason under which the participant’s participation in 
the study may be terminated
12. That the monitors, auditors, the IRB, and the regulatory authorities may provide direct 
access to the participant’s original medical records. In such cases, the confidentiality of 
the participant should be protected, and by signing and sealing an informed consent form, 
the participant is authorizing such access.
13. If the results of the study are published, the participant’s identity will remain confidential.
14. The anticipated expenses, if any, to the participant for participating in the study


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15. The anticipated prorated payment, if any, to the participant for participating in the study
16. The name, title, and address of the investigator to contact
17. The person(s) to contact for further information regarding the clinical study and the rights 
of participants, and whom to contact in the event of study-related injury
18. The type of the IRB engaged in the assessment and deliberation about the acceptability of 
the study, items subject to the assessment of each IRB, and other IRB-related items 
relating to the study
19. The participant’s responsibilities
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred to the sponsor will contain the identifier only; participant names or any 
information that would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Committees Structure
10.1.5.1.
Data Safety Monitoring Board
An independent DSMB will be established to review unblinded safety data and summary reports, 
identify any safety issues and trends, and make recommendations to Allergan, including 
modification or ET of the study, if emerging data show unexpected and clinically significant AEs 
of treatment.
Details of the DSMB memberships, standard operational procedures for data monitoring/review, 
frequency of review, and other pertinent details will be provided in a separate DSMB Charter.
10.1.5.2.
Hepatic Event Adjudication Committee
An Adjudication Charter will be established and will describe the process for the blinded 
surveillance, monitoring, and adjudication by the Clinical Adjudication Committee of events of 
post-treatment elevations of ALT and/or AST = 3 × ULN in the atogepant program. The purpose 
of this committee charter will be to provide a standardized process for the adjudication of data 
associated with these events in order to determine whether the elevation was related to atogepant.
10.1.6.
Posting Clinical Study Data
Study information and tabular study results will be posted to the US National Institutes of Health
website www.clinicaltrials.gov. and other publicly accessible sites. Study data and information 


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may be published in non-promotional, peer-reviewed publications either by or on behalf of the 
sponsor. Clinical study reports, safety updates, and annual reports will be provided to the 
regulatory authorities as required.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator as stated in the clinical trial agreement. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 

For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should 
be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
10.1.8.
Summary of Methods of Data Collection
An IWRS will be used to randomize participants and manage study intervention inventory. All 
visit data (ie, non-diary data) for this study will be collected by either the eTablet or, if 
conducted remotely (see Section 10.11, Appendix 11), utilizing a web-based portal (eg, 
questionnaires for PROs) or eCRFs via an electronic data capture system. Source documents will 
be used at the sites and may include a participant’s medical record, hospital charts, clinic charts, 


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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 manual.
Participants will use an eDiary daily to record the daily total duration of headache, headache 
characteristics, associated symptoms, the worst pain severity, and acute medication use both in 
the screening/baseline period and double-blind treatment period until Visit 7/ET. They also will 
record AIM-D, Activity level and Activity limitation, EQ-5D-5L in the eDiary during the 
double-blind treatment period and the safety follow-up period as indicated in the SoA, 
Section 1.3. Training for the eDiary will be provided for qualified participants during the 
Screening/Baseline Visit (Visit 1). 
10.1.9.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data is presented below:
Source documents may include a participant's medical records, hospital charts, clinic charts, the 
investigator's participant study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and ECGs. The investigator's copy of the CRFs serves as part of the 
investigator's record of a participant's study-related data.
The following information should be entered into the participant's medical record:

Participant’s name

Participant’s contact information

The date that the participant entered the study, participant number, and study intervention 
kit numbers

The study title and/or the protocol number of the study and the name of Allergan 

A statement that informed consent was obtained (including the date). A statement that 
written authorization (United States sites only), data protection consent (EU sites only), or 
other country and local participant privacy required documentation for this study has been 
obtained (including the date)

Dates of all participant visits

Participants medical history

Information regarding participant’s diagnosis of migraine headache

All concurrent medications (List all prescription and non-prescription medications being
taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications should be recorded.)

Occurrence and status of any AEs


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
The date the participant exited the study, and a notation as to whether the participant 
completed the study or reason for discontinuation.

The results of laboratory tests performed by the site (eg, results of urine pregnancy tests).

Key study variables
Source documentation practices must follow Section 4.0 of ICH E6, GCP: Consolidated 
Guidance, and ALCOA-C (ie, records must be Attributable, Legible, Contemporaneous, Original 
Accurate and Complete).
10.1.10.
Study and Site Closure
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If a study is prematurely terminated or suspended due to safety issues, the sponsor shall inform 
all investigators and the regulatory authorities of the termination or suspension and the reason(s) 
for the termination or suspension. The IRB/IEC is also to be informed promptly and provided the 
reason(s) for the termination or suspension by the sponsor or by the investigator, as specified by 
the applicable regulatory requirements. If a premature termination or suspension occurs, the 
sponsor shall remain responsible for providing resources to fulfill the protocol obligations and 
existing agreements for follow-up of participants enrolled in the study, and each investigator or 
authorized designee shall promptly inform enrolled participants, if applicable.
10.1.11.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.

The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally support
publication of multicenter studies only in their entirety and not as individual site data.


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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.1.12.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB/IEC according to the IRB/IEC’s reporting requirements.
10.1.13.
Participant Privacy
Written authorization (United States sites only), data protection consent (European sites only), 
and other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each participant prior to enrollment into the study, 
and/or from the participant's legally authorized representative in accordance with the applicable 
privacy requirements (eg, HIPAA, European Union Data Protection Directive 95/46/EC [“EU 
Directive”]).
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous participant data from the study.
10.1.14.
Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the clinical study 
report.
10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10-1 below will be performed by the central laboratory. Blood and 
urine samples will be collected, processed, and stored according to the instructions provided by 
the laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5
of the protocol.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
Participants are not required to fast overnight before coming in for their appointments.
Investigators must document their review of each laboratory safety report.
Table 10-1
Protocol-required Laboratory Assessments
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, 
total bilirubin, alkaline phosphatase, AST, ALT, lactate dehydrogenase, creatine 
kinase, total protein, serum albumin, calcium, phosphorus, uric acid, total 
cholesterol. The estimated glomerular filtration rate will be calculated by the central 
laboratory.
 
 
 




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Participants with any AESI(s) will be closely monitored. Selected nonserious and serious 
adverse events are of special interest and will require immediate reporting, recording, and 
follow-up. 
Reporting requirements for ALT or AST elevations and potential Hy’s law cases are outlined 
in Section 10.3.1. and 10.3.2. below. 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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10.3.1.
ALT or AST Elevations
A treatment-emergent ALT ≥ 3 × ULN and/or AST ≥ 3 × ULN is considered an AE of special 
interest.
Any participant with this laboratory result after study intervention was taken must have repeat 
testing within 48 to 72 hours to confirm the abnormality. For this repeat testing, the following 
laboratory tests must be drawn:

hematology panel

chemistry panels

INR

serum acetaminophen level

urine drugs of abuse screen

and blood alcohol level. 
An extra blood serology sample must be collected and sent to the central laboratory for further 
diagnostic testing at a later date if needed. In addition, the investigator will perform a complete 
history and examination to evaluate the participant for possible liver disease.
All AEs of special interest must be reported to 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 AE of 
special interest.
If an ALT or AST ≥ 3 × ULN is confirmed, close medical follow-up is required: For these 
participants, the following laboratory tests must be performed:

anti-hepatitis A IgM

hepatitis B surface antigen

anti-hepatitis B core IgM

hepatitis C antibody

hepatitis C quantitative RNA by polymerase chain reaction

anti-hepatitis E IgM

anti-hepatitis E IgG
 
 
 


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
Cytomegalovirus IgM antibody 

Epstein-Barr Virus IgM antibody. 
The participant must be followed clinically and further medical evaluation (for other causes of 
acute hepatic injury) should be done per the judgment of the investigator and in conjunction 
with medical personnel at the sponsor site. In general, the chemistry panel should be repeated 
1 to 2 times per week to follow the course of ALT/AST elevation.
Study intervention must be discontinued if any of the following criteria are met:

ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of fatigue
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia 
(>5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN

ALT or AST ≥ 3 × ULN and INR > 1.5

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
The participant may be rechallenged with study intervention only after consultation with the 
sponsor’s Medical Monitor. For participants who are not rechallenged with study intervention, 
they should be discontinued from the study and complete an ET Visit (Visit 7/ET assessments) 
and 4-week Follow-up Visit. Participants should receive appropriate follow-up as per SoC.
The investigator must contact the sponsor’s Medical Monitor to discuss all cases of 
confirmed ALT/AST elevation ≥ 3 × ULN. All ALT/AST elevations must be followed 
until ALT and AST return to < 1.5 × ULN and there is full clinical resolution.
10.3.2.
Potential Hy’s Law Cases
Sites must report every participant who meets the following potential Hy’s law criteria if this 
occurs within the time the participant signs the ICF until 30 days after the last dose of study 
intervention:

ALT or AST ≥ 3 x ULN AND

Total bilirubin ≥ 2 x ULN AND

Alkaline phosphatase < 2 x ULN
Study site personnel must report every participant who meets these criteria. Typically, all 3 
analytes will be obtained from the same sample, but they may come from multiple samples 
taken within a 24-hour period. This requirement applies from the time the participant signs the 
ICF for the study until 30 days after the final protocol-defined study visit or the last known 
dose of study intervention (if the final visit does not occur). A laboratory alert for possible 
 
 
 






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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 fulfils any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive intervention in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
 
 
 








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Abbreviation
Definition
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome
CYP3A4
cytochrome P450 3A4
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
EOS
end of study
EQ-5D-5L
European Quality of Life – 5 Dimensional
ET
early termination
eTablet
electronic tablet
EU
European Union
EudraCT
European Clinical Trials Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HFEM
high frequency migraine
HIT-6
Headache Impact Test
HIV
human immunodeficiency virus
HRT
hormonal replacement therapy
ICF
informed consent form
ICH
International Council on Harmonisation
ICHD-3
International Classification of Headache Disorders 3rd edition
IEC
independent ethics committee
IND
investigational new drug
IgG
immunoglobulin G
IgM
immunoglobulin M
INR
international normalized ratio
IRB
institutional review board
ISO
International Organization for Standardization
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
LFEM
low frequency migraine
LS
least squares
LSMD
least squares mean difference
MAR
missing at random
 
 
 


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Abbreviation
Definition
MedDRA
Medical Dictionary for Regulatory Activities Terminology
MIDAS
Migraine Disability Assessment
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MSQ
Migraine Specific Quality of Life Questionnaire
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
OATP
organic-anion-transporting polypeptides
OATP1B1
organic-anion-transporting polypeptides 1B1 subtype
OATP1B3
organic-anion-transporting polypeptides 1B3 subtype
PD
pharmacodynamic
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHQ-9
Patient Health Questionnaire
PK
pharmacokinetic
PRO
patient-reported outcome
PROMIS-PI
Patient-Reported Outcomes Measurement Information System Pain Interference
PSSM
Patient Satisfaction with Study Medication
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)1/3)
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SNRI
serotonin norepinephrine reuptake inhibitor
SoA
schedule of activities
SoC
standard of care
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
VAS
Visual analogue scale
VCT
verified clinical trial
WOCBP
woman of childbearing potential
WPAI:MIGRAINE
Work Productivity and Activity Impairment Questionnaire: Migraine
 
 
 


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10.5.
Appendix 5: Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Failure to meet randomization criteria
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by parent/guardian
An indication that a study participant has been removed from the 
study by the parent or legal guardian
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)
 
 
 


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10.6.
Appendix 6: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).
Parameter 
Group
Parameter
Value
Trial information
Trial Title
A Phase 3, Multicenter, 
Randomized, Double-blind, 
Placebo-controlled, Parallel group 
Study to Evaluate the Efficacy, 
Safety, and Tolerability of Oral 
Atogepant for the Prophylaxis of 
Migraine in Participants with 
Episodic Migraine Who Have 
Previously Failed 2 to 4 Classes of 
Oral Prophylactic Medications
(ELEVATE)
Clinical Study Sponsor
Allergan Pharmaceuticals 
International Limited
Trial Phase Classification
Phase 3 trial
Trial Indication
Prophylaxis of Migraine in 
Participants with Episodic 
Migraine Who Have Previously 
Failed 2 to 4 Classes of Oral 
Prophylactic Medications
Trial Indication Type
Treatment
Trial Type
Efficacy
Safety
Trial Length
Approximately 20 weeks
Planned Country of Investigational Sites
Approximately 125 sites globally 
including both US (IND) sites and 
non-US (non-IND) sites.
Planned Number of Subjects
300
FDA-regulated Device Study
No
FDA-regulated Drug Study
No
Pediatric Study
No
Subject 
information
Diagnosis Group
Participants with Episodic 
Migraine who have previously 
failed 2 to 4 classes of oral
prophylactic medications
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18
Planned Maximum Age of Subjects
80
 
 
 


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Parameter 
Group
Parameter
Value
Sex of Participants
Both
Stable Disease Minimum Duration
At least a 1-year history of 
migraine with or without aura 
consistent with a diagnosis
according to the ICHD-3, 2018
Treatments
Investigational Therapy or Treatment
Atogepant
Intervention Type
Drug
Pharmacological Class of Investigational
Therapy
Selective oral calcitonin gene-
related peptide receptor antagonist
(CGRP-RA)
Dose per Administration
1 (1 tablet)
Dose Units
Atogepant: 60 mg
Dosing Frequency
QD
Route of Administration
Oral
Current Therapy or Treatment
Not applicable
Added on to Existing Treatments
No
Control Type
Placebo
Comparative Treatment Name
Not applicable
Trial design
Study Type
Interventional
Intervention Model
Parallel
Planned Number of Arms
2
Trial Is Randomized
Yes
Randomization Quotient
1:1 ratio 
Trial Blinding Schema
Double-blind
Stratification Factor
Not applicable
Adaptive Design
No
Study Stop Rules
Based on investigator or sponsor 
determination
10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
 
 
 


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Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 24 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following during the intervention period and for at least 3 
days after the last dose of study intervention:

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent

Agree to use a male condom with or without spermicide

In addition, nonvasectomized male participants must refrain from donating sperm
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the course of the study.
Female Participants

Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective or acceptable method of contraception consistently and correctly as 
described in Table 10-2.
 
 
 


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Table 10-2
Highly Effective and Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not an acceptable method of contraception. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
Acceptable Methods
cceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device
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.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
The investigator and each participant will determine the appropriate method of contraception for 
the participant during the participation in the study.
Pregnancy Testing:

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test at screening (Visit 1) and also a negative urine test 
on Day 1 (Visit 2).

Additional pregnancy testing should be performed at each study visit during the study 
intervention period and at the EOS visit (Visit 8), 4 weeks after the last dose of study 
intervention and as required locally.
 
 
 


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Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the sponsor. Generally, the 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or genetic 
abnormalities (whether leading to an elective abortion or not) are always considered to be 
SAEs and will be reported as such. Any poststudy pregnancy-related SAE considered 
reasonably related to the study intervention by the investigator will be reported to the 
sponsor as described in Section 8.3.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and will be withdrawn from the study.
10.8.
Appendix 8: Study Schedule Supplement
There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline), Visit 2 (Randomization), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7/ET (Week 12), 
and Visit 8 (Follow-up). For details, please see Table 1-1 Schedule of Activities.


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10.8.1.
Visit 1 (Screening/Baseline) Day -35 to Day -28

Obtain informed consent and participant privacy

Obtain informed consent for PK substudy (optional)

Obtain VCT consent and perform verification (United States only)

Collect demographic information

Collect medical history

Collect migraine history (3-month retrospective) and confirm diagnosis

Review and record all prior prophylactic headache medications for the lifetime of the 
participant

Complete Treatment Failure Worksheet.

Register participant in IWRS

Review and record prior medications taken in the past 6 months, and all concomitant 
medications and concurrent procedures.

Collect ASC-12

Assess C-SSRS on eTablet (the ‘Screening/Baseline’ assessment of the C-SSRS will be 
completed).

Perform physical examination

Collect vital sign measurements (height, weight, pulse rate, respiratory rate, blood 
pressure, and body temperature). Height will be measured only at Visit 1.

Perform and transmit ECG

Perform urine pregnancy test for women of childbearing potential. Discuss the method of 
contraception with women of childbearing potential and document this method. 

Counsel participants on the importance of maintaining their agreed upon method of 
contraception throughout the study.

Collect blood and urine samples for clinical laboratory determinations (chemistry, 
hematology, INR, urinalysis, and serology).

Collect urine sample for drug screen

Verify if the participant meets inclusion/exclusion criteria at this point
 
 
 


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
Provide eDiary, along with training and instructions. Remind participant to bring eDiary 
to next visit. 

Complete Healthcare Resource Utilization Questionnaire.

Review and assess AEs
10.8.2.
Visit 2 (Randomization) Day 1

Review eDiary data and compliance for eligibility. 

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (sitting and standing systolic and diastolic BP, pulse rate, 
respiration rate, temperature, and weight).

Assess C-SSRS on eTablet (the “Since Last Visit” assessment of the C-SSRS will be 
completed).

Verify if participant meets inclusion/exclusion criteria and is eligible for the study at this 
point.
If the participant continues to meet study entry criteria, including acceptable results from Visit 1 
clinical laboratory tests, pregnancy tests and the urine drug screen (Section 5) the following 
procedures will be carried out at the Randomization Visit (Visit 2):

Prior to any other test or evaluations, administer PRO measures including: HIT-6, PGI-S,
WPAI:MIGRAINE, MIDAS, MSQ v2.1, PROMIS-PI and PHQ-9.

Complete Healthcare Resource Utilization Questionnaire.

Update concomitant medications and concurrent procedures.

Review and assess AEs.

Randomize the participant in IWRS and obtain the kit number for study intervention.

Collect pre-treatment blood and urine samples for chemistry, hematology, INR, and 
urinalysis.

Collect pre-treatment PK sample (for participants who consented).

Dispense study intervention. Participants must take their first dose of study intervention at 
the study site on this day.

Remind participant to bring eDiary and to return study intervention kits (used and unused) 
to all visits.


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10.8.3.
Visits 3 to 6 (Weeks 2 to 8)

Prior to any other test or evaluations, administer PRO measures, including: HIT-6, PGI-S, 
WPAI:MIGRAINE, PSSM, MSQ v2.1, and PROMIS-PI, at the times outlined in Section 
1.3 SoA.

Complete Healthcare Resource Utilization Questionnaire.

Review eDiary data and compliance.

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (weight, pulse rate, respiratory rate, blood pressure, and 
body temperature).

Assess C-SSRS on eTablet (the “Since Last Visit” assessment of the C-SSRS will be 
completed).

Perform and transmit ECG (Visit 5 only).

Update concomitant medications and concurrent procedures.

Review and assess AEs.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Collect PK sample (for participants who consented). During 1 of the Visits 3 to 6, the 
sample should be collected prior to the daily dose of study intervention (participant should 
wait to take the dose in the clinic after PK sample collection), and the samples collected at 
the remaining visits should be collected 1 to 10 hours post the daily dose.

Collect previous visit study intervention, review participant compliance, and perform 
accountability.

Access IWRS to dispense study intervention and enter accountability.

Dispense study intervention.

Remind participant to bring eDiary and to return study intervention kits (used and unused) 
to all visits.


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10.8.4.
Visit 7/Early Termination (Week 12)

Effort should be made by the site to not schedule Visit 7 earlier than 12 weeks after Day 1 
to ensure participants complete the full 12 weeks of treatment and have eDiary data 
through Day 83. Prior to any other test or evaluations, administer PRO measures, 
including: HIT-6, PGIC, PGI-S, WPAI:MIGRAINE, PSSM, MIDAS, MSQ v2.1, 
PROMIS-PI and PHQ-9.

Review eDiary data and compliance.

Complete Healthcare Resource Utilization Questionnaire

Collect eDiary, only from participants who completed the double-blind treatment period 
(Visit 2 to Visit 7/ET; for participants who discontinue study, eDiary collection will occur 
at Visit 8)

Perform physical examination.

Perform urine pregnancy test for women of childbearing potential.

Collect vital sign measurements (weight, pulse rate, respiratory rate, blood pressure, and 
body temperature).

Assess C-SSRS on eTablet (the “Since Last Visit” assessment of the C-SSRS will be 
completed).

Perform and transmit ECG.

Update concomitant medications and procedures.

Review and assess AEs.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Collect post-dose PK sample (for participants who consented). The PK sample should be 
collected 1 to 10 hours post the daily dose.

Collect previous visit study intervention, review participant compliance, and perform 
accountability.

Access IWRS and enter accountability.

Advise participants who early terminated from the double-blind treatment period to 
continue completing their eDiary through the Follow-up Visit. Remind participant to bring 
eDiary to next visit.


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10.8.5.
Visit 8 (End of Study) Week 16

Prior to any other test or evaluations, administer PRO measures, including: EQ-5D-5L, 
HIT-6, and MSQ v2.1.

Collect eDiary from participants who early terminated from the double-blind treatment 
period, review eDiary data and compliance.

Perform physical examination.

Assess C-SSRS on eTablet (the “Since Last Visit” assessment of the C-SSRS will be 
completed).

Collect vital sign measurements (weight, pulse rate, respiratory rate, blood pressure, and 
body temperature).

Perform urine pregnancy test for women of childbearing potential.

Collect blood and urine samples for chemistry, hematology, INR, and urinalysis.

Update concomitant medications and procedures.

Review and assess AEs.

Access IWRS to enter study visit.
10.8.6.
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.
10.9.
Appendix 9: Examples of Prohibited Medications
The following medications are prohibited 30 days prior to screening and throughout the study 
period:

Strong OATP1B1/OATP1B3 inhibitors eg, gemfibrozil (Lopid™)

Strong P-gp inhibitors (eg, clarithromycin (Biaxin™), itraconazole (Sporanox™), quinidine, 
verapamil (Calan™, Calan SR™)

CBD oil


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Strong/moderate CYP3A4 inducers
Strong/moderate CYP3A4 inhibitors
Anti-depressants/
Anti-anxiety
Barbiturates:
Amobarbital (Amytal™)
Aprobarbital (Alurate™)
Butalbital (Fiorinal™, Fioricet™)
Butabarbital (Busodium™ Butisol™)
Mephobarbital (Mebaral™)
Pentobarbital (Nembutal™)
Phenobarbital (Luminal™ Solfoton™)
Secobarbital (Seconal™)
Nefazodone (Serzone™) 
Anti-seizure
Carbamazepine (Atretol™, Carbatrol™, 
Epitol™, Equetro™, Tegretol™)
Oxcarbazepine (Trileptal™)
Phenytoin (Dilantin™, Phenytek™)
Primidone (Myidone™, Mysoline™)
Diabetes 
Pioglitazone (Actos™)
Troglitazone (Rezulin™, Resulin™)
Antiemetic
Aprepitant (Emend™)
Anti-hypertension
Diltiazem (Cardizem™)
Verapamil (Calan™, Calan SR™)
Glucocorticoid 
(Systemic)
Betamethasone (Celestone™)
Dexamethasone (Baycadron™, DexPak™)
Hydrocortisone (Cortef™)
Methylprednisolone (Medrol™)
Prednisolone (Prelone™)
Prednisone (Deltasone™)
Triamcinolone (Kenalog™)
Antibiotics
Rifabutin (Mycobutin™) 
Rifampicin/ Rifampin (Rifadin™, 
Rifater™, Rimactane™) 
Erythromycin (Benzamycin™, 
EryTab™)
Clarithromycin (Biaxin™)
Telithromycin (Ketek™)
Anti-fungal
Fluconazole (Diflucan™, Trican™)
Itraconazole (Sporanox™)
Ketoconazole (Nizoral™)
Anti-HIV
Efavirenz (Stocrin™, Sustiva™) 
Nevirapine (Viramune™)
Indinavir (Crixivan™)
Nelfinavir (Viracept™) 
Ritonavir (Norvir™)
Saquinavir (Fortovase™, Invirase™)
Immune 
Suppressant
Cyclosporine - Oral/IV only (Neoral™,
Sandimmune™)
Others
St. John’s Wort
Enzalutamide (Xtandi™)
Modafinil (Provigil™)
Armodafinil (Nuvigil™)
Buprenorphine (Cizol™, Subutex™, 
Suboxone™)
Quinine
 
 
 


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Drugs with narrow therapeutic 
margins with potential for CYP drug 
interactions
Warfarin (Coumadin™)
Digoxin (Digitek™, Lanoxin™, Digox™)
Cisapride ( Prepulsid™, Propulsid™)
Pimozide (Orap™)
Drugs with demonstrated efficacy for 
the prevention of migraine
Topiramate (Topamax™)
Valproic acid, sodium valproate, divalproex sodium (Depakote™)
Amitriptyline (Elavil™)
Nortriptyline (Pamelor™)
Metoprolol (Lopressor™, Toprol™)
Atenolol (Tenormin™)
Nadolol (Corgard™)
Propranolol (Inderal™)
Timolol (Apo-Timol™)
Flunarizine (Sibelium™)
Candesartan (Atacand™)
Lisinopril (Zestril™, Prinivil™)
Desvenlafaxine (Pristiq™)
Venlafaxine (Effexor™)
Locally approved products (eg, oxeterone, pizotifen)
Non-pharmacologic headache 
interventions
Acupuncture, if used for prophylaxis of migraine
Non-invasive neuromodulation devices (eg, transcutaneous 
supraorbital neurostimulator, single-pulse transcranial magnetic 
stimulator, vagus nerve stimulator), if used for prophylaxis of 
migraine
Cranial traction
Nociceptive trigeminal inhibition
Occipital nerve block treatments
Dental splints for headache
Ubrogepant (Ubrelvy®) and rimegepant (Nurtec ODT®) is prohibited from Visit 1 throughout the 
study.
The following treatments are prohibited 6 months prior to screening and throughout the 
study period:

Therapeutic or cosmetic botulinum toxin injections (eg, Dysport®, BOTOX®, Xeomin®, 
Myobloc®, JeuveauTM) into areas of the head, face, or neck.

Injectable monoclonal antibodies blocking the CGRP pathway (eg, AimovigTM, EmgalityTM, 
Ajovy®).
10.10.
Appendix 10: Documentation of prior prophylactic treatment 
failures
10.10.1.
Source documents
For the source documentation of prior treatment failure, prior medical records with compound 
name, treatment duration, dose and reason for discontinuation, are primarily to be obtained. 
 
 
 


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If obtaining prior medical records is not possible, the investigator is requested to provide an 
affidavit confirming the above information about prior treatment failures according to the 
protocol definition. For these affidavits, if the principal investigator is the treating physician, the 
investigator must provide a dated and signed written note with all required information regarding 
the previously failed medication(s); if the principal investigator is not the treating physician, all 
effort should be made by the investigator to interview the treating physician to confirm the 
required information and provide dated documentation of the interview.
10.10.2.
Treatment Failure Worksheet 
The investigator is required to transcribe data confirming previous oral prophylactic migraine 
treatment failure in the Treatment Failure Worksheet as detailed in the Study Reference Manual. 
If requested by the Medical Monitor, the investigator communicates key screening information 
including the Treatment Failure Worksheet to the Medical Monitor. Decisions regarding 
inclusion of participants at time of enrollment primarily remain at the discretion of the 
investigator. The medical monitor may be consulted if there are questions about whether prior 
treatment failures meet relevant protocol criteria.


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10.11.
Appendix 11: 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 Schedule of Activities for Remote Study Visits (Table 10-3) 
should be followed. 
Remote visits may be conducted between Visit 3 – Visit 8 but participants must attend in office 
assessments at either Visit 3 or Visit 4 to ensure laboratory samples are obtained within the first 
4-weeks of treatments and remote visits should not be performed for greater than 8 weeks.
Missed in-person safety assessments (ie, clinical laboratory samples, vital signs and ECGs) 
should be collected at the next in-person visit. Patient reported outcomes collected using the 
eTablet during in-office visits will be collected using a web-based portal during remote visits.




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AIM-D = Activity Impairment in Migraine–Diary; C-SSRS = Columbia Suicide Severity Rating Scale; eDiary = electronic diary; 
EQ-5D-5L = European Quality of Life – 5 Dimensional; ET = early termination; eTablet = electronic tablet; HIT-6 = Headache 
Impact Test; IWRS = interactive web response system; MIDAS = Migraine Disability Assessment; MSQ v2.1 = Migraine Specific 
Quality of Life Questionnaire, Version 2.1; PGIC = Patient Global Impression of Change; PGI-S = Patient Global Impression –
Severity; PHQ-9 = Patient Health Questionnaire; PRO = patient-reported outcome; PSSM= Patient Satisfaction with Study 
Medication, PROMIS-PI = Patient-Reported Outcomes Measurement Information System Pain Interference – Short Form 6a; 
WPAI:MIGRAINE = Work Productivity and Activity Impairment Questionnaire: Migraine V2.0.
a
Effort should be made by site to not schedule Visit 7 earlier than 12 weeks after Day 1 (Day 84) to ensure that participants complete the full 
12 weeks of treatment and have eDiary data through Day 84.
b
All participants who take at least 1 dose of study intervention must complete the safety follow-up period, except participants rolling over into 
Study 3101-312-002 (long-term safety extension study). For these rollover participants the final Follow-up Visit will be performed at the end 
of the long-term safety extension study.
c For females of childbearing potential only, at home urine pregnancy tests will be performed (provided by sites) and results reported during the 
remote visits
d Study medication to cover 1 remote study visit and urine pregnancy tests may be dispensed at an office visit (if the next visit is anticipated to 
be remote), for curbside pick-up or shipped to participants via an overnight courier.
e The Since the Last Visit C-SSRS will be completed. Clinicians will complete the C-SSRS on eTablet or web backup portal.
f
PRO measures should be administered prior to any tests and/or evaluations.
g
EQ-5D-5L will be collected via an eDiary for a period of 1 week around Visit 4 (± 3 days ie, Study Days 25 to 31 from randomization for a 
total of 7 days), Visit 5 (± 3 days ie, Study Days 39 to 45 from randomization for a total of 7 days), Visit 6 (± 3 days ie, Study Days 53 to 59 
from randomization for a total of 7 days), and Visit 7 (-7 days ie, Study Days 77 to 83 from randomization for a total of 7 days). At Visit 8, the 
EQ-5D-5L will be administered in an eTablet (office visit), or via web portal (remote visit).
h
For participants who terminate early from the double-blind treatment period only.
 
 


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10.12.
Appendix 12: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the Table of Contents.
Amendment 1 (03 April 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The changes are to clarify the study rationale, exclusion criteria, primary and secondary 
statistical analyses, in response to the Grounds for Non-Acceptance (GNA) addressed to 
Allergan during the VHP (Voluntary Harmonisation Procedure) in Europe.
Section No. and Name
Description of Change
Brief Rationale
1.1 Synopsis
Key Exclusion Criteria- added the 
diagnosis of “medication overuse 
headache.” 
Added to clarify that patients with “medication 
overuse headache” will not be enrolled and to 
further clarify this is in accordance with 
inclusion criteria 2.04 and 2.05.
2.1 Study Rationale
Added text to clarify the study 
rationale.
Clarification that the purpose of this Phase 3 
study is primarily to generate data for health 
technology assessment, but is also a pivotal 
trial to confirm the efficacy of the selected 
doses in this patient population.
4.1 Overall Design
Block randomization will be 
applied with a block size of 6 (3 
treatment arms × 2). A block can 
be shared by sites within the same 
region (stratification factor).
To further clarify to the block randomization 
procedure.
5.2 Exclusion Criteria 2.05
Same as above
Same as above.
9.4.1.2 Primary Analysis
9.4.1.3 Secondary Analysis
Added “region” to the analysis 
model.
To further clarify the protocol, region is added 
in the longitudinal model as a factor for both 
the primary and secondary efficacy endpoints 
in sections 9.4.1.2 and 9.4.1.3
 
 
 


CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
121
11.
References
Berger et al, Adherence with Migraine Prophylaxis in Clinical Practice, Pain Practice, Volume 
12, Issue 7, 2012, 541-549.
Blumenfeld et al, Patterns of Use and Reasons for Discontinuation of Prophylactic Medications 
for Episodic Migraine and Chronic Migraine: Results From the Second International Burden of 
Migraine Study (IBMS-II), Headache, 2013.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, Fei K, Assaid C, Lines C, Ho TW. 
Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009 
Sep 22;73(12):970-977.
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.
Hepp Z, Dodick DW, Varon SF, Chia J, Matthew N, Gillard P, Hansen RN, Devine EB. 
Peristence and switching patterns of oral migraine prophylactic medications among patients with 
chronic migraine: A retrospective claims analysis. Cephalagia 2017 Apr; 37(5):470-485.
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 2018: 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, and Lipton RB. Defining the Differences Between Episodic 
Migraine and Chronic Migraine. Curr Pain Headache Rep. 2012;16:86-92.
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997;53:983-997.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, and Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology 2007;68:343-349.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data using 
multiple imputation in conjunction with robust regression. Biometrics. 2012;68(4):1250-1259.
Olesen J, Bousser M-G, Diener H-C, DodickD, First M, Goadsby PJ, Göbel H, Lainez MJA, 
Lance JW, Lipton RB, Nappi G,Sakai F, Schoenen J, Silberstein SD & Steiner TJ. New appendix 
criteria open for a broader concept of chronic migraine. Cephalalgia 2006; 26:742-746.
Reuter U, Goadsby PJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD, Klatt J. Efficacy 
and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous 
preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, 
Phase 3b study. Lancet. 2018;392:2280-2287.
Silberstein Preventative Migraine Treatment, Continuum (Minneap Minn) 2015;21(4):973-989.


CONFIDENTIAL
Protocol 3101-304-002, Amendment 2
Atogepant (AGN-241689)
122
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010:11;289-299.

SAP_001.pdf: 
Atogepant (AGN-241689)
3101-304-002 – Statistical Analysis Plan
Version 2.0 – 21 August 2022
1
Statistical Analysis Plan for Study 3101-304-002
A Phase 3, Multicenter, Randomized, Double blind, 
Placebo-controlled, Parallel group Study to Evaluate 
the Efficacy, Safety, and Tolerability of Oral 
Atogepant for the Prophylaxis of Migraine in 
Participants with Episodic Migraine Who Have 
Previously Failed 2 to 4 Classes of Oral Prophylactic 
Treatments (ELEVATE)
Version:  2.0
 
NCT04740827


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Table of Contents
1.0
Introduction...........................................................................6
2.0
Study Objectives and Design ................................................6
2.1
Objectives, Hypotheses and Estimands................................................... 7
2.2
Study Design Overview........................................................................ 12
2.3
Treatment Assignment and Blinding..................................................... 13
2.4
Sample Size Determination .................................................................. 14
3.0
Endpoints.............................................................................18
3.1
Primary Efficacy Endpoint ................................................................... 18
3.2
Secondary Efficacy Endpoint(s) ........................................................... 18
3.3
Exploratory Efficacy Endpoint(s) ......................................................... 19
3.4
Safety Endpoint(s)................................................................................ 21
4.0
Analysis Populations ...........................................................21
5.0
Participant Disposition........................................................22
6.0
Study Treatment Duration and Compliance .....................23
7.0
Demographics, Baseline Characteristics, Medical
History, and Prior/Concomitant Medications ...................24
7.1
Demographics and Baseline Characteristics.......................................... 24
7.2
Medical History.................................................................................... 25
7.3
Prior and Concomitant Medications...................................................... 25
7.4
Protocol Deviations .............................................................................. 26
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints ....................................26
9.0
Efficacy Analyses.................................................................28
9.1
General Considerations......................................................................... 28
9.2
Handling of Missing Data..................................................................... 28
9.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 29
9.3.1
Primary Efficacy Endpoint(s) ............................................................... 29
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 29
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 32
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 36


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9.4.1
Secondary Efficacy Endpoints.............................................................. 36
9.4.2
Main Analyses of Secondary Efficacy Endpoints.................................. 37
9.5
Exploratory Efficacy Analyses ............................................................. 46
9.6
Efficacy Subgroup Analyses................................................................. 48
10.0
Safety Analyses....................................................................49
10.1
General Considerations......................................................................... 49
10.2
Adverse Events..................................................................................... 49
10.2.1
Treatment-Emergent Adverse Events.................................................... 50
10.2.2
Adverse Event Overview...................................................................... 50
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 51
10.2.4
Deaths, Serious Adverse Events, and Adverse Events Leading to 
Study Treatment Discontinuation.......................................................... 51
10.2.5
Adverse Events of Special Interest........................................................ 51
10.3
Laboratory Data ................................................................................... 52
10.4
Vital Signs............................................................................................ 54
10.5
Other Safety Analyses .......................................................................... 55
10.5.1
Electrocardiogram................................................................................ 55
10.5.2
Columbia-Suicide Severity Rating Scale............................................... 56
11.0
Other Analysis.....................................................................56
11.1
Healthcare Resource Utilization Questionnaire..................................... 56
12.0
Interim Analyses..................................................................56
12.1
Data Monitoring Committee................................................................. 57
13.0
Overall Type-I Error Control.............................................57
14.0
COVID-19 Related Analyses ..............................................59
14.1
Efficacy Evaluation .............................................................................. 59
14.2
Safety and Other Evaluations................................................................ 61
15.0
Version History ...................................................................62
15.1
Changes to Planned Analyses in the Protocol........................................ 65
16.0
References............................................................................65


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List of Tables
Table 1.
Statistical Power for Primary and Secondary Endpoints for the 
United States ........................................................................................ 15
Table 2.
Statistical Power for Primary and Secondary Endpoints for the EU....... 16
Table 3.
Observed Treatment Effect for Primary Endpoint in Atogepant 
Program and Liberty............................................................................. 17
Table 4.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint............................................................................................... 30
Table 5.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoint............................................................................................... 37
Table 6.
Multiple Comparisons Procedure Definitions for the Submission 
in the US .............................................................................................. 58
Table 7.
Multiple Comparisons Procedure Definitions for the European 
Submissions ......................................................................................... 59
Table 8.
Summary of Collection Devices for Primary and Secondary 
Endpoints for Submission in the US ..................................................... 60
Table 9.
Summary of Collection Devices for Primary and Secondary 
Endpoints for European Submissions.................................................... 61
Table 10.
Summary of Changes from SAP Version 1.0 to SAP Version 2.0 ......... 63
Table 11.
SAP Version History Summary ............................................................ 65
Table 12.
Item Values for MSQ Item Responses .................................................. 72
Table 13.
Item Values for HIT-6 Item Responses................................................. 73
Table 14.
PROMIS-PI Raw Score Transformation ............................................... 77
Table 15.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters............................................................................................ 79
Table 16.
Criteria for Hepatic Laboratory Abnormalities...................................... 80
Table 17.
Potentially Clinically Significant Criteria for Vital Signs 
Parameters............................................................................................ 82
Table 18.
Potentially Clinically Significant Criteria for ECG Parameters ............. 83
Table 19.
List of Selected Parameters Reported in Conventional Unit .................. 84
Table 20.
Presenting Laboratory Data Using SI and Conventional Units in 
Narratives............................................................................................. 85


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List of Figures
Figure 1.
Study Schematic................................................................................... 13
List of Appendices
Appendix A.
List of SAP Signatories ........................................................................ 67
Appendix B.
Derivation of Efficacy Variables .......................................................... 68
Appendix C.
Definition of Adverse Events of Special Interest................................... 78
Appendix D.
Potentially Clinically Significant Criteria for Safety ............................. 79
Appendix E.
Laboratory Parameters in Conventional Unit ........................................ 84
Appendix F.
List of Abbreviations............................................................................ 86


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for atogepant 
(AGN-241689) Study 3101-304-002, a phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of 
oral atogepant for the prophylaxis of migraine in participants with episodic migraine who 
have previously failed 2 to 4 classes of oral prophylactic treatments (ELEVATE).
Study 3101-304-003 examines the efficacy and safety of atogepant in participants with 
episodic migraine who have previously failed 2 to 4 classes of oral prophylactic 
treatments.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.  Specifications of tables, figures, and data 
listings and statistical programming plan are contained in separate documents.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 15.1.
2.0
Study Objectives and Design
The objective of this study is to prospectively assess the safety, tolerability, and efficacy 
of atogepant 60mg QD compared with placebo in the prophylaxis of episodic migraine in 
participants who previously failed 2 to 4 classes of oral prophylactic treatments.


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2.1
Objectives, Hypotheses and Estimands
Objectives
Hypotheses
Estimands
Primary Efficacy
To prospectively 
test for superiority 
of atogepant 60 mg 
QD versus placebo 
for the prevention 
of migraine in 
participants with 
episodic migraine 
who have 
previously failed 
2 to 4 classes of 
oral medications 
for the prophylaxis 
of migraine
Null: atogepant 60 mg QD is 
equally effective to placebo in 
decreasing from baseline in 
mean monthly migraine days 
across the 12-week treatment 
period
Alternative:  atogepant 60 mg 
QD is superior to placebo in 
decreasing from baseline in 
mean monthly migraine days 
across the 12-week treatment 
period
Efficacy is to be measured using change from 
baseline in mean monthly migraine days 
across the 12-week treatment period
For the United States:
The difference in the mean change from 
baseline in mean monthly migraine days 
across the 12-week treatment period between 
atogepant group and placebo in the Modified 
Intent-to-Treat (mITT) Population. Data after 
the discontinuation from double-blind 
treatment period will be excluded and assumed 
missing at random (MAR).
For the European Union
The difference in the mean change from 
baseline in mean monthly migraine days 
across the 12-week treatment period between 
atogepant group and placebo in the Off-
treatment Hypothetical Estimand Population 
regardless of premature discontinuation of 
study drug. Data after starting a new migraine 
prophylaxis treatment use during the follow-
up period will be excluded.


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Objectives
Hypotheses
Estimands
Secondary Efficacy
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo on the 
proportion of 
participants with at 
least 50% 
reduction from 
baseline in monthly 
migraine days
Null hypothesis: atogepant
60 mg QD is equally effective to 
placebo in the achievement of at 
least 50% reduction from 
baseline in monthly migraine 
days across the 12-week 
treatment period
Alternative hypothesis:  
atogepant 60 mg QD is superior
to placebo in the achievement of
at least 50% reduction from 
baseline in monthly migraine 
days across the 12-week 
treatment period
Efficacy is to be measured using the 
achievement of at least 50% reduction from 
baseline in monthly migraine days across the 
12-week treatment period
For the United States:
The odds ratio in participants achieving at 
least 50% reduction in 3-month average of 
monthly migraine days between atogepant 
group and placebo in the mITT Population. 
Data after the discontinuation from double-
blind treatment period will be excluded.
For the European Union
The odds ratio in participants achieving at 
least 50% reduction in 3-month average of 
monthly migraine days between atogepant 
group and placebo in the Off-treatment 
Hypothetical Estimand Population regardless 
of premature discontinuation of study drug. 
Data after starting a new migraine prophylaxis 
treatment use during the follow-up period will 
be excluded.


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Objectives
Hypotheses
Estimands
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo for the 
prophylaxis of 
headache
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in decreasing from 
baseline in mean monthly 
headache days across the 
12-week treatment period
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in decreasing from 
baseline in mean monthly 
headache days across the 
12-week treatment period
Efficacy is to be measured using change from 
baseline in mean monthly headache days 
across the 12-week treatment period
For the United States:
The difference in mean change from baseline 
in mean monthly headache days across the 
12-week treatment period between atogepant 
group and placebo in the mITT Population. 
Data after the discontinuation from double-
blind treatment period will be excluded and 
assumed missing at random (MAR).
For the European Union
The difference in the mean change from 
baseline in mean monthly headache days 
across the 12-week treatment period between 
atogepant group and placebo in the Off-
treatment Hypothetical Estimand Population 
regardless of premature discontinuation of 
study drug. Data after starting a new migraine 
prophylaxis treatment use during the follow-
up period will be excluded.


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Objectives
Hypotheses
Estimands
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo on acute 
medication use
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in decreasing from 
baseline in mean monthly acute
medication use days across the 
12-week treatment period
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in decreasing from 
baseline in mean monthly acute
medication use days across the 
12-week treatment period
Efficacy is to be measured using change from 
baseline in mean monthly acute medication 
use days across the 12-week treatment period
For the United States:
The difference in mean change from baseline 
in mean monthly acute medication use days 
across the 12-week treatment period between 
atogepant group and placebo in the mITT 
Population. Data after the discontinuation 
from double-blind treatment period will be
excluded and assumed missing at random 
(MAR).
For the European Union
The difference in the mean change from 
baseline in mean monthly acute medication 
use days across the 12-week treatment period 
between atogepant group and placebo in the 
Off-treatment Hypothetical Estimand 
Population regardless of premature 
discontinuation of study drug. Data after 
starting a new migraine prophylaxis treatment 
use during the follow-up period will be 
excluded.


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Objectives
Hypotheses
Estimands
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo on the 
impact of migraine 
on daily activities 
as assessed by 
MSQ v2.1 Role 
Function-
Restrictive domain 
score 
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in increasing from 
baseline in MSQ v2.1 Role 
Function-Restrictive domain 
score at Week 12
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in increasing from 
baseline in MSQ v2.1 Role 
Function-Restrictive domain 
score at Week 12
Efficacy is to be measured using change from 
baseline in the MSQ v2.1 Role Function-
Restrictive domain score at Week 12
For the United States:
The difference in mean change from baseline 
in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 between atogepant 
group and placebo in the mITT Population. 
Data after the discontinuation from double-
blind treatment period will be excluded and 
assumed missing at random (MAR).
For the European Union
The difference in mean change from baseline 
in MSQ v2.1 Role Function-Restrictive 
domain score at Week 12 between atogepant 
group and placebo in the Off-treatment 
Hypothetical Estimand Population regardless 
of premature discontinuation of study drug. 
Data after starting a new migraine prophylaxis 
treatment use during the follow-up period will 
be excluded.
For the United 
States only:
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo on 
Performance of 
Daily Activities
For the United States only:
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in decreasing from 
baseline in mean monthly 
Performance of Daily Activities 
domain score of the AIM-D 
across the 12-week treatment 
period
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in decreasing from 
baseline in mean monthly 
Performance of Daily Activities 
domain score of the AIM-D 
across the 12-week treatment 
period
Efficacy is to be measured using change from 
baseline in mean monthly Performance of 
Daily Activities domain score of the AIM-D 
across the 12-week treatment period
The difference in mean Change from baseline
in mean monthly Performance of Daily 
Activities domain score of the AIM-D across 
the 12-week treatment period between 
atogepant group and placebo in the mITT 
Population. Data after the discontinuation 
from double-blind treatment period will be 
excluded and assumed missing at random 
(MAR).


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Objectives
Hypotheses
Estimands
To evaluate the 
effect of atogepant 
60 mg QD and 
atogepant 60 mg 
QD versus placebo 
on physical 
impairment
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in decreasing from 
baseline in mean monthly
Physical Impairment domain
score of the AIM-D across the 
12-week treatment period
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in decreasing from 
baseline in mean monthly
Physical Impairment domain
score of the AIM-D across the 
12-week treatment period
Efficacy is to be measured using change from 
baseline in mean monthly Physical 
Impairment domain score of the AIM-D across 
the 12-week treatment period
The difference in mean Change from baseline 
in mean monthly Physical Impairment domain
score of the AIM -D across the 12-week 
treatment period between atogepant group and 
placebo in the mITT Population. Data after 
the discontinuation from double-blind 
treatment period will be excluded and assumed 
missing at random (MAR).
For the European 
Union only:
To evaluate the 
effect of atogepant 
60 mg QD versus 
placebo on the 
impact of 
headaches on daily 
functioning as 
assessed by HIT-6
For the European Union only:
Null hypothesis: atogepant 
60 mg QD is equally effective to 
placebo in decreasing from
baseline in the HIT-6 total score 
at Week 12
Alternative hypothesis: 
atogepant 60 mg QD is superior 
to placebo in decreasing from 
baseline in the HIT-6 total score 
at Week 12
Efficacy is to be measured using change from 
baseline in the HIT-6 total score at Week 12
The difference in mean change from baseline 
in the HIT-6 total score at Week 12 between 
atogepant group and placebo in the Off-
treatment Hypothetical Estimand Population 
regardless of premature discontinuation of 
study drug. Data after starting a new migraine 
prophylaxis treatment use during the follow-
up period will be excluded.
2.2
Study Design Overview
This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study planned to be conducted at approximately 125 sites globally (North America, 
Europe, and Asia/Pacific).
Participation will begin with a 4-week screening/baseline period. Participants who 
complete the 4-week screening/baseline period and meet all entry criteria will be 
randomized to the double-blind treatment period of the study at Visit 2 (Randomization 
Visit). The double-blind treatment period will last 12 weeks, with a subsequent safety 
follow-up period of 4 additional weeks. Total duration of study participation for one 
participant is approximately 20 weeks.


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There will be 8 scheduled clinic visits: Visit 1 (Screening/Baseline Visit), Visit 2 
(Randomization Visit), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 
(Week 8), Visit 7/ET (Week 12), and Visit 8 (Week 16/EOS/Follow-up). The 
Visit 8/EOS/follow-up period must be completed for all participants who take at least one 
dose of study intervention, except for participants rolling over into Study 3101-312-002 
(long-term safety extension study). For these rollover participants Visit 8 is not required, 
because the final Follow-up Visit will be performed at the end of the long-term safety 
extension study. For participants who screen fail for the long-term safety extension study, 
the Follow-up Visit of Study 3101-304-002 must be completed.
Per study design (Protocol Sections 10.8.4 and 10.8.5), eDiary data will be collected for 
participants who early terminated from the double-blind treatment period during the 4 
weeks between V7 (Early termination visit) and V8 (Follow-up Visit).
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
Approximately 300 participants will be randomized to one of 2 treatment arms (placebo, 
and atogepant 60 mg QD) in a 1:1 ratio as follows:


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●
Placebo (n = 150)
●
Atogepant 60 mg QD (n = 150)
Randomization will be stratified based on region (North America, Europe, and 
Asia/Pacific), number of migraine days during the screening/baseline period (4 to < 8 and 
≥ 8) and number of classes of failed prior prophylactic treatments (2 and > 2). Block 
randomization will be applied with a block size of 4 (2 treatment arms × 2). Though the 
study was planned to include sites in Asia/Pacific, no participants were enrolled from this 
region.
A randomization cap of 20% will be instituted to ensure that the planned randomized 
participants include no more than 20% of participants with 4 to <8 migraine days at 
baseline. Approximately 50% of randomized participants will have failed > 2 classes of 
prior prophylactic treatments.
2.4
Sample Size Determination
A sample size of 150 randomized participants per treatment group will provide a 97% and 
95% power to detect the treatment difference of -1.7 or -1.6 between atogepant and 
placebo for the primary efficacy endpoint for the United States or the EU, respectively.  
This sample size was selected to provide sufficient power for each of the secondary 
endpoints in Table 1 for the United States and in Table 2 for the EU.


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Table 1.
Statistical Power for Primary and Secondary Endpoints for the 
United States
Hypothesis 
Testing 
Endpoint
Treatment 
Difference from 
Placebo
Standard Deviation
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across 
the 12-week treatment period
-1.7
3.5
97%
Secondary 1
Achievement of at least 50% 
reduction in mean monthly 
migraine days across the 
12-week treatment period
29% Placebo 
rate, 60% 
atogepant rate
Not applicable
99%
Secondary 2
Change from baseline in mean 
monthly headache days across 
the 12-week treatment period
-1.7
3.7
95%
Secondary 3
Change from baseline in mean 
monthly acute medication use 
days across the 12-week 
treatment period
-1.5
3.1
97%
Secondary 4
Change from baseline in MSQ 
v2.1 Role Function-
Restrictive domain score at 
Week 12
10.8
22.6
96%
Secondary 5
Change from baseline in mean 
monthly Performance of Daily 
Activities domain score of the 
AIM-D across the 12-week 
treatment period
-3.3
7.3
93%
Secondary 6
Change from baseline in mean 
monthly Physical Impairment 
domain score of the AIM-D 
across the 12-week treatment 
period
-2.4
6.4
81%


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Table 2.
Statistical Power for Primary and Secondary Endpoints for the EU
Hypothesis 
Testing 
Endpoint
Treatment 
Difference from 
Placeboa
Standard 
Deviationa
Statistical 
Power
Primary
Change from baseline in mean 
monthly migraine days across 
the 12-week treatment period
-1.6
3.5
95%
Secondary 1
Achievement of at least 50% 
reduction in mean monthly 
migraine days across the 
12-week treatment period
30% Placebo 
rate, 59% 
atogepant rate
Not applicable
99%
Secondary 2
Change from baseline in mean 
monthly headache days across 
the 12-week treatment period
-1.6
3.7
92%
Secondary 3
Change from baseline in mean 
monthly acute medication use 
days across the 12-week 
treatment period
-1.4
3.2
93%
Secondary 4
Change from baseline in 
HIT-6 total score at Week 12
-3.9
7.6
98%
Secondary 5
Change from baseline in MSQ 
v2.1 Role Function-Restrictive 
domain score at Week 12
10.9
22.8
96%
a.
The assumptions applied for the EU were estimated using off-treatment hypothetical estimand approach based 
on Advance Study data.
The power calculations are based on the following assumptions:
1.
Table 3 provides the results from two atogepant studies (CGP-MD-01 and 
3101-301-002 [Advance Study]) and Liberty Study (Reuter 2018) for the primary 
endpoint. The treatment difference for atogepant 60mg QD versus placebo is 
assumed to be observed treatment difference in the atogepant Advance study, 
which is a relative conservative assumption in term of primary endpoint. The 
standard deviation assumptions were based on the variance in Liberty Study and 
monthly variance observed in Advance Study for the primary endpoint. In 
particular, the assumed treatment difference from placebo in change from baseline 


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in mean monthly migraine days across the 12-week treatment period is -1.7 days 
for the United States and is -1.6 days for the EU, and the standard deviation is 
3.5 days. Detailed treatment difference and standard deviation assumptions for 
secondary endpoints are listed in Table 1 for the United States and in Table 2 for 
the EU, which are based on the results from the atogepant Advance study. 
Table 3.
Observed Treatment Effect for Primary Endpoint in Atogepant 
Program and Liberty
Study
Population
Atogepant 60 mg QD 
Treatment Difference 
from Placebo
Standard 
Deviation
Advance
mITT population
-1.72
3.00
Participants with Prior exposure to 
migraine preventive treatment = Yes 
-2.16
3.01
Participants with one treatment 
failures
-1.94
3.04
Participants with two or more 
treatment failures
-2.91
3.34
CGP-MD-01
Participants with Prior exposure to 
migraine preventive treatment = Yes
-1.41
2.97
Liberty
Efficacy Population for Treatment 
Failure study
-1.93 (Average of 12 
Weeks)
3.47a
Efficacy Population for Treatment 
Failure study
-1.6 (At month 3)
4.6
a.
SD was calculated using variance in liberty and correlation matrix from Advance study
2.
A fixed-sequence procedure will be used for multiple comparisons to control the 
family-wise Type I error rate at a 0.05 level. The testing sequence is specified in 
Table 1 and Table 2. Once the primary endpoint for atogepant dose is significant 
at 0.05 (2-sided), the secondary endpoints will be tested sequentially. Statistical 
powers for secondary endpoints are conditional on success of prior endpoints 
(assuming independence among the endpoints) in the sequence.


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3.
The dropout rate is assumed to be 15% for endpoints other than AIM-D related 
endpoints. The dropout rate for AIM-D endpoints is 21%. A higher missing rate 
for AIM-D endpoints was observed in the Advance Study because the related 
measure was collected only in Today's eDiary instead of both Yesterday and 
Today's eDiary.  If the participants provide less than 14 records of Today's eDiary 
within a 28-day period, it would lead to missing data.
The assumptions of sample size calculation such as SD and dropout rate will be monitored 
while the study is ongoing and sample size will be adjusted.  This blinded analysis of 
variability in the pooled treatment groups will be performed using the primary efficacy
analysis model for the primary endpoint as described in Section 9.3.2 but excluding the
terms treatment and treatment by visit interaction from model terms.
3.0
Endpoints
3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in mean monthly migraine 
days across the 12-week treatment period.  Baseline is defined as the number of migraine 
days during the last 28 days prior to the randomization date.
3.2
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints for the United States:
●
Achievement of at least a 50% reduction in mean monthly migraine days across 
the 12-week treatment period
●
Change from baseline in mean monthly headache days across the 12-week 
treatment period
●
Change from baseline in mean monthly acute medication use days across the 
12-week treatment period
●
Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at 
Week 12


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●
Change from baseline in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week treatment period
●
Change from baseline in mean monthly Physical Impairment domain score of 
the AIM-D across the 12-week treatment period
Secondary efficacy endpoints for the EU:
●
Achievement of at least a 50% reduction in mean monthly migraine days across 
the 12-week treatment period
●
Change from baseline in mean monthly headache days across the 12-week 
treatment period
●
Change from baseline in mean monthly acute medication use days across the 
12-week treatment period
●
Change from baseline in the HIT-6 total score at Week 12
●
Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at 
Week 12
3.3
Exploratory Efficacy Endpoint(s)
Exploratory efficacy endpoints for the United States and EU are provided below:
●
Achievement of ≥ 25%, ≥30%, ≥ 50%, ≥ 75%, 100% improvement (decrease) 
in monthly migraine days at Weeks 1-4, 5-8, and 9-12
●
Achievement of ≥ 25%, ≥30%, ≥ 75%, 100% improvement (decrease) in 
monthly migraine days across the 12-week treatment period
●
Change from baseline in monthly migraine days at Weeks 1-4, 5-8, and 9-12 
●
Change from baseline in monthly headache days at Weeks 1-4, 5-8, and 9-12 
●
Change from baseline in monthly cumulative headache hours at Weeks 1-4, 5-
8, 9-12, and average across the 12-week treatment period 
●
Change from baseline in monthly acute medication use days at Weeks 1-4, 5-8, 
and 9-12
●
Change from baseline in monthly triptan use days at Weeks 1-4, 5-8, 9-12, and 
average across the 12-week treatment period 


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●
Change from baseline in monthly moderate/severe headache days at Weeks 1-4, 
5-8, 9-12, and average across the 12-week treatment period 
●
Change from baseline in monthly severe headache days at Weeks 1-4, 5-8, 9-
12, and average across the 12-week treatment period 
●
Change from baseline in the HIT-6 total score at Weeks 4, and 8 (European 
Union only) 
●
Change from baseline in the HIT-6 total score at Weeks 4, 8, and 12 (United 
States only)
●
Achievement of at least a 5-point improvement (decrease) from baseline in total 
HIT-6 score at Weeks 4, 8, and 12
●
Achievement of a rating of "much better" or "very much better" at Week 12 
assessed by the PGIC
●
Achievement of a rating of "satisfied" or "extremely satisfied" at Weeks 4, 8, 
and 12 as assessed by the PSSM
●
Change from baseline in percent work time missed, percent impairment while 
working, percent overall impairment, and percent activity impairment due to 
migraine at Weeks 4, 8, and 12 as assessed by the WPAI: MIGRAINE
●
Change from baseline in EQ-5D-5L descriptive system index score at Weeks 1 
to 2, at specified windows around Weeks 4, 6, 8, 12, and Week 16
●
Change from baseline in the EQ-5D-5L VAS score at Weeks 1 to 2, at specified 
windows around Weeks 4, 6, 8, 12, and Week 16
●
Change from baseline in the MIDAS total score at Week 12
●
Change from baseline in MIDAS absenteeism score (Questions 1, 3, and 5) at 
Week 12
●
Change from baseline in MIDAS presenteeism score (Questions 2 and 4) at 
Week 12
●
Change from baseline in PGI-S score at Weeks 4, 8, and 12
●
Change from baseline in the MSQ v2.1 Role Function-Preventive domain score 
at Weeks 4, 8, and 12
●
Change from baseline in the MSQ v2.1 Role Function-Restrictive domain score 
at Weeks 4, and 8


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●
Change from baseline in the MSQ v2.1 Emotional Function domain score at 
Weeks 4, 8, and 12
●
Change from baseline in monthly Performance of Daily Activities domain 
score of the AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
●
Change from baseline in monthly Physical Impairment domain score of the 
AIM-D at Weeks 1 to 4, 5 to 8, and 9 to 12
●
Change from baseline in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week treatment period (EU only)
●
Change from baseline in mean monthly Physical Impairment domain score of 
the AIM-D across the 12-week treatment period (EU only)
●
Change from baseline in monthly AIM-D total score at Weeks 1 to 4, 5 to 8, 9 
to 12, and average across the 12-week treatment period
●
Change from baseline in monthly activity level at Weeks 1 to 4, 5 to 8, 9 to 12, 
and average across the 12-week treatment period
●
Change from baseline in monthly activity limitation at Weeks 1 to 4, 5 to 8, 9 
to 12, and average across the 12-week treatment period
●
Change from baseline in PROMIS-PI total score at Weeks 4, 8, and 12
●
Change from baseline in PHQ-9 score at Week 12
3.4
Safety Endpoint(s)
The safety parameters include adverse events (AEs), clinical laboratory, vital sign, 
electrocardiographic (ECG), and C-SSRS.  For clinical laboratory, vital sign, and ECG 
parameters, the last non-missing safety assessment before the first dose of treatment will 
be used as the baseline for all analyses of that safety parameter.
All AEs and other safety data will be presented in the listings at the subject level.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Intent-to-Treat (ITT) Population includes all randomized participants.


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The Safety Population includes all participants who received at least 1 dose of study 
intervention. All safety analyses will be performed using the Safety Population and based 
on the treatment actually received, regardless of assigned treatment according to the 
planned randomization. Participants will be summarized according to the study treatment 
received for the majority of treatment period.
The Modified Intent-to-Treat (mITT) Population includes all randomized participants who 
received at least 1 dose of study intervention, had an evaluable baseline period of eDiary 
data and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 
to 12) of eDiary data during the double-blind (DB) treatment period.  All efficacy 
analyses described will be performed using the mITT population unless specified 
otherwise and based on the randomization assignment, regardless of the actual treatment 
received.
The Off-treatment Hypothetical Estimand Population includes all randomized participants 
who received at least 1 dose of study treatment, had an evaluable baseline period of 
eDiary data and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 
8, 9 to 12) of eDiary data during the DB treatment period and follow-up period, regardless 
of whether on study treatment or off study treatment. This population is used for the 
primary estimand in the support of the European submissions.
5.0
Participant Disposition
The number of participants screened will be summarized overall by region; the number of 
participants in the ITT, Safety, mITT, and Off-treatment Hypothetical Estimand 
Populations will be summarized by treatment group and study site, by treatment group 
and region, and by treatment group and country.
A summary of participant accountability will be provided where the number of 
participants in each of the following categories will be summarized for each treatment 
group and pooled across treatment groups:
●
Participants enrolled (randomized) in the study;


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Participants in each region [North America and Europe], number of migraine 
days during the screening/baseline period [< 4, 4 to < 8, and ≥ 8], and number 
of classes of failed prior prophylactic treatments [2 and > 2]);
●
Participants who took at least one dose of study drug;
●
Participants who completed double-blind treatment period;
●
Participants who prematurely discontinued the double-blind treatment period 
(including reasons for premature discontinuation);
"Actual" stratification will be re-derived using data from eDiary and eCRF based on 
algorithms detailed in the SPP Section 3.2.  A summary table and list of participants with 
inconsistent randomization stratum against IWRS will be provided.
For end of study participation, the number and percentage of participants who completed 
the follow-up period (or did not with associated reasons) will be summarized overall and 
by treatment group.  In addition, the number and percentage of participants who signed 
informed consent for long-term safety extension Study 3101-312-002 will be summarized.
6.0
Study Treatment Duration and Compliance
For the Safety Population, duration of treatment will be summarized for each treatment 
group.  Duration of treatment is defined for each participant as last dose date minus first 
dose date + 1.  Duration of treatment will be summarized using the number of participants 
treated, mean, standard deviation, median, minimum, and maximum.  In addition, the 
number and percentage of participants in each treatment duration of ≥ 1 day, ≥ 7 days, 
≥14 days, ≥ 21 days, ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥ 56 days, ≥ 63 days, 
≥70 days, ≥ 77 days, ≥ 84 days will be summarized.  Participant-years, calculated by 
summing the duration of exposure across the respective set of participants and dividing 
this sum by 365.25, will be summarized by treatment group.
Treatment compliance for a specific period is defined as the number of study medications 
actually taken during that period divided by the number of study medications that should 
have been taken during the same period.  Percent treatment compliance as well as the 


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associated compliance categories (< 80%, 80% - 120%, > 120%) will be summarized in
each period between 2 consecutive visits, as well as in the entire treatment period from the 
first dose of the double-blind study interventions actually taken to the last dose of double-
blind study intervention actually taken for the Safety Population.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics and baseline characteristics will be summarized overall and by treatment 
group for the Safety Population, mITT Population and Off-treatment Hypothetical 
Estimand Population.  Disease characteristics, medical history, and prior and concomitant 
medication will be summarized for the Safety Population.  Categorical variables will be 
summarized with the number and percentage of participants; percentage will be calculated 
based on the non-missing observations.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean and standard deviation, 
median, Q1, Q3, minimum, and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, race group (white, 
all other races), age group (< 20, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥ 70), region 
(North America and Europe).
Disease characteristics are contained in migraine history, including diagnosis, duration of 
disorder, the use of migraine prevention medication in the past, number and percentage of 
participants who failed 2, 3, or 4 classes of prior prevention medications, number and 
percentage of participants who failed preventive medication by class, average number of 
migraine or headache days per month at baseline and in the last 3 months, acute 
medications taken to treat migraine headaches, and advice on lifestyle alterations.
Baseline efficacy parameters (monthly migraine days, monthly headache days, monthly 
acute medication use days, Migraine Specific Quality of Life Questionnaire [MSQ] v2.1 


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Role Function-Restrictive domain score, monthly performance of daily activities domain 
score of the Activity Impairment in Migraine - Diary [AIM-D], and monthly physical 
impairment domain score of the AIM-D) will be summarized by treatment group for 
mITT Population.  Baseline efficacy parameters (monthly migraine days, monthly 
headache days, monthly acute medication use days, Headache Impact Test [HIT-6] total 
score, and Migraine Specific Quality of Life Questionnaire [MSQ] v2.1 Role Function-
Restrictive domain score) will be summarized by treatment group for Off-Treatment 
Hypothetical Estimand Population.
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of participants in 
each medical history category (by MedDRA system organ class and preferred term) will 
be summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in descending 
frequency of the atogepant 60 mg QD group within each SOC.  Participants reporting 
more than one condition/diagnosis will be counted only once in each row (SOC or 
preferred term).  In addition, non-drug therapies will be summarized overall and by 
treatment group.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by therapeutic class and generic 
name.  Concomitant medication will be summarized for the double-blind treatment period 
and follow-up period.  A prior medication is defined as any medication taken prior to the 
date of the first dose of study drug.  A concomitant medication is defined as any 
medication that started prior to the date of the first dose of study drug and continue to be 
taken after the first dose of study drug or any medication that started on or after the date 
of the first dose of study drug, but not after the date of the last dose of study drug plus 
30 days or Visit 8 whichever comes later.  The number and percentage of participants 


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taking medications will be summarized by therapeutic class and generic name based on
the World Health Organization Drug Dictionary Enhanced WHODD version March 2021
for both prior and concomitant medications.  The number and percentage of participants 
with failed prior oral preventive migraine medications will be summarized by class and 
generic name.  In addition, a table for concomitant medications used by ≥5% participants 
during the double-blind treatment period will be provided.
7.4
Protocol Deviations
The number and percentage of participants with significant protocol deviations will be 
summarized by study intervention group in the Intent-to-Treat Population.
A listing of participants with significant protocol deviations will be provided.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints
The primary efficacy endpoint (defined in Section 3.1) will be analyzed based on the 
mITT population in support of the submission in the US and the following methods will 
be used to address potential intercurrent events:
●
Regardless of whether allowed rescue medications are taken or not, data are 
included in the analysis.
●
Data after the premature discontinuation from the double-blind study period 
will be excluded and are assumed missing at random.
The primary endpoint will be analyzed in the Off-treatment Hypothetical Estimand 
population in support of the European submissions and the following methods will be 
used to address potential intercurrent events:
●
Regardless of whether allowed rescue medications are taken or not, data are 
included in the analysis.
●
Participants who started a new migraine prophylaxis treatment during the 
double-blind or safety follow-up period will have their data after starting the 


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new migraine prophylaxis treatment during the follow-up period excluded from 
the analysis.
●
Participants who discontinue study treatment due to all reasons other than 
starting a new migraine prophylaxis treatment will have their data collected 
after discontinuation of study treatment, and those off-treatment data will be 
included in the analysis.
The key secondary efficacy endpoint of key secondary endpoint (defined in Section 3.2) 
will be analyzed based on the mITT population or the Off-treatment Hypothetical 
Estimand population and the following methods will be used to address the potential 
intercurrent events:
●
Continuous secondary endpoints based on eDiary data will be handled using the 
same approach defined above for the primary endpoint in the corresponding 
analysis population. 
●
The 50% responder, defined as a participant achieving at least a 50% reduction 
from baseline in the 3-month average of monthly migraine days.
In support of the submission in the US:
○
Regardless of whether allowed rescue medications are taken or not, data 
are included in the analysis.
○
Data after the premature discontinuation from the double-blind study 
period will be excluded. The average of monthly migraine days is 
calculated for each participant based on available monthly migraine days 
during the double-blind period, and then the participant is dichotomized as 
a responder or non-responder.
In support of the European submissions:
○
Regardless of whether allowed rescue medications are taken or not, data 
are included in the analysis.
○
Participants who started a new migraine prophylaxis treatment during the 
double-blind or safety follow-up period will have their data after starting 
the new migraine prophylaxis treatment during the follow-up period 
excluded from the analysis.


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○
Participants who discontinue study treatment due to all reasons other than 
starting a new migraine prophylaxis treatment will have their data collected 
after discontinuation of study treatment, and those off-treatment data will 
be included in the analysis. The average of monthly migraine days is 
calculated for each participant based on available monthly migraine days, 
and then the participant is dichotomized as a responder or non-responder.
9.0
Efficacy Analyses
9.1
General Considerations
The efficacy endpoints for migraine day, headache day and acute medication use day are 
defined in protocol Section 8.1.  All efficacy analyses will be conducted in the mITT 
Population in support of submission in the US and in the Off-treatment Hypothetical 
Estimand population in support of European submissions. 
The primary analysis will be performed after all ongoing participants have completed the 
double-blind treatment period and follow-up period and the database has been locked.  
This will be the only and final analysis for the secondary efficacy endpoints as well as all 
other efficacy endpoints in the double-blind treatment period.
Unless otherwise specified, any participant who is randomized based on a wrong stratum 
will be analyzed according to the actual stratum the participant belong to.
9.2
Handling of Missing Data
Missing data will be handled using the following methods for the primary efficacy 
analysis. Details can be found in Section 9.3.2 and Section 9.3.3.
●
Mixed model for repeated measures (MMRM) based on observed data 
collected during the double-blind treatment period (Primary efficacy approach 
for the US)
●
ANCOVA model based on 3-month average of the monthly migraine days
●
Within-group imputation based on observed data


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●
Copy-reference approach
●
MMRM based on primary measures collected during the double-blind and 
follow-up periods (Primary efficacy approach for the EU)
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the change from baseline in mean monthly migraine 
days across the 12-week treatment period.  Baseline is defined as the number of migraine 
days during the last 28 days prior to the randomization date. 
9.3.2
Main Analysis of Primary Efficacy Endpoint
The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 4.


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Table 4.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of Intercurrent 
Events
Statistical 
Summary
Primary in 
support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications
as rescue 
medications 
are allowed 
to keep 
participants 
in the study
Change 
from 
baseline in 
mean 
monthly 
migraine 
days 
across the 
12-week 
treatment 
period
The Off-
treatment 
Hypothetical 
Estimand 
Population (see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken or 
not, data are included in 
the analysis.
IE2: Participants who start 
a new migraine 
prophylaxis treatment 
during the double-blind or 
safety follow-up period 
will have their data after 
starting the new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from the 
analysis.
IE3: Participants who 
discontinue study treatment 
due to all reasons other 
than starting a new 
migraine prophylaxis 
treatment will have their 
data collected after 
discontinuation of study 
treatment, and those off-
treatment data will be 
included in the analysis.
The 
difference 
in mean 
change 
from 
baseline in 
mean 
monthly 
migraine 
days 
across the 
12-week 
treatment 
period 
between 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of Intercurrent 
Events
Statistical 
Summary
Primary in 
support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
participants 
in the study
Change 
from 
baseline in 
mean 
monthly 
migraine 
days 
across the 
12-week 
treatment 
period
The Modified 
Intent-to-Treat 
(mITT) 
Population (see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken or 
not, data are included in 
the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random. 
The 
difference 
in mean 
change 
from 
baseline in 
mean 
monthly 
migraine 
days 
across the 
12-week 
treatment 
period 
between 
atogepant 
group and 
placebo
Primary analysis in support of the submission in the US
The primary endpoint will be analyzed using a mixed model for repeated measures 
(MMRM) on the mITT population. The response variable is the change from baseline to 
each postbaseline month in monthly migraine days. The model will include treatment 
group, visit (derived as Weeks 1 - 4, Weeks 5 - 8, and Weeks 9 - 12), region, number of 
classes of failed prior prophylactic treatments (2 and >2), and treatment group by visit 
interaction as categorical fixed effects. It will also include the baseline monthly migraine 
days and baseline-by-visit interaction as covariates. Note that baseline monthly migraine 
is included in the primary model, therefore the stratification of number of migraine days 
during the screening/baseline period (4 to < 8 and ≥ 8) will be excluded in the primary 
model. The analysis will be performed based on evaluable postbaseline data using only 
the observed cases without missing data imputation. For submission in the US, only data 
collected during the double-blind period will be included in the analysis.


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Restricted maximum likelihood method will be used. The within-patient correlation will 
be modeled using the unstructured covariance matrix. If the model does not converge, 
then the Toeplitz covariance structure will be used. If the model with the Toeplitz 
covariance structure does not converge, then the compound symmetry covariance 
structure will be used. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. Contrast will be constructed to obtain the average 
treatment effects across the 12-week treatment period to compare atogepant treatment 
group versus the placebo group. Treatment effect and treatment comparison will be 
estimated by the LS Means and their difference in LS Means, along with their SE and 
95% confidence interval, and the p-value corresponding to the between-treatment group 
difference.
Primary analysis in support of the European submissions
Analysis of the primary endpoint will be conducted on the Off-treatment Hypothetical 
Estimand population based on treatment as randomized. The change from baseline to
each postbaseline month in monthly migraine days will be analyzed using MMRM similar 
to the primary analysis specified for submission in the US.  The analysis will be 
performed based on observed data collected from both double-blind treatment period and 
follow-up period.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
Sensitivity analyses of the primary analysis of the primary efficacy endpoint are given 
below.  Four sensitivity analyses and one supplementary analysis will be provided for the 
estimand in support of the submission in the US. In addition, copy-reference approach for 
sensitivity analysis will be provided for the estimand in support of the European 
submissions.


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Sensitivity Analyses in Missing Data Handling
ANCOVA Model Based on 3-month Average of the Monthly Migraine Days
A supportive analysis will be performed on the primary endpoint using an ANCOVA 
model.  The response variable for the ANCOVA model is the change from baseline in the 
calculated average monthly migraine days during the 12-week treatment period for each 
participant.  The ANCOVA model includes treatment, region, number of classes of failed 
prior prophylactic treatments (2 and >2) as fixed factors, and baseline monthly migraine 
days as a covariate.  The treatment difference for atogepant dose versus placebo will be 
estimated and reported along with the corresponding 95% CI and nominal p-value for 
superiority testing.  There are no missing data for this analysis because participants who 
discontinued the treatment are assumed to maintain the same mean (observed while on 
treatment) for 3 months (12 weeks).
Within-group Imputation Based on Observed Data
A Sensitivity analysis will be performed based on imputation using participants from the 
same treatment group with observed data under the MAR assumption.  Missing data for 
participants who prematurely discontinued are assumed to copy the profile of participants 
in the same treatment group with observed data.  The details of imputation are as follows:
1.
Create partial imputation dataset using MI based on the MCMC approach in each 
treatment group. Imputed dataset will consist of 100 copies of original dataset and 
is assumed to follow monotone missing pattern.
2.
Impute missing data in each existing copy by treatment group using observed data 
in the corresponding treatment group based on monotone regression.  Each of the 
100 imputed datasets will then be analyzed using an ANCOVA model with 
treatment, region, number of classes of failed prior prophylactic treatments (2 and 
> 2) as fixed factors, and baseline monthly migraine days as a covariate.
3.
The ANCOVA analysis results from 100 completed datasets are combined for 
overall estimation and inference using Rubin's rule1 to produce a pooled estimate 


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of LS mean difference, its SE, and corresponding p-value for the test of null 
hypothesis of no treatment effect.
Copy-Reference Approach
Copy-reference approach is one type of pattern-mixture models (PMM), under which data 
could be missing-not-at-random (MNAR), with repeated analyses combined via the 
reference based multiple imputation (MI) procedure.2  This approach is to assess the 
robustness of the MMRM analysis to possible violation of the missing-at-random (MAR) 
assumption in the primary analysis.
Step 1. A few intermittent missing values will be imputed by the Markov Chain Monte 
Carlo (MCMC) at first. The MCMC imputation assumes missing-at-random (MAR) for 
intermittent missing data. The MCMC method will be implemented using SAS Proc MI 
statement "MCMC impute=monotone." This is achieved with the use of option 
IMPUTE = MONOTONE in the MCMC statement.  Then the rest of the missing data will 
follow monotone missing pattern.
Step 2. Implementation of the copy reference method are as follows:
1.
The reference-based approach uses the placebo group as the reference. The 
missing values in the reference group are imputed using the observed data in that 
group under the missing-at-random assumption. The missing pattern is defined by 
the participant's last visit with a non-missing value. The mean vector and the 
covariance matrix of the multivariate normal distribution are estimated for 
reference group. The imputation of missing data is not based on each of the 
reasons of early termination, because there may not be sufficient non-missing 
efficacy data in each of the reason categories to serve as a stable reference.
2.
For atogepant treatment group, missing values are imputed based on the 
distribution estimated from the reference group (placebo group).


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The first PROC MI will be performed 100 times using MCMC method for partial 
imputation of the data with a non-monotone missing pattern. The output dataset will then 
be used as the input dataset for the next PROC MI. Note that the output dataset already 
contains 100 copies of the original dataset. With the next invocation of MI procedure, the 
missing data will be filled in (Step 1 and 2) for the existing copies. This is achieved with 
the use of NIMPUTE=1 and a BY _Imputation_ statement. Finally, each of the 
100 imputed datasets will be analyzed using an analysis of covariance (ANCOVA) model. 
For a given imputed dataset, the average change from baseline in monthly migraine days 
is calculated across the 3 post-baseline months and is used as the response variable in the 
model. The model includes treatment group, region, number of classes of failed prior 
prophylactic treatments (2 and >2) as fixed factors, and baseline monthly migraine days as 
a covariate. The LS mean difference and corresponding SE is estimated from the model 
comparing each atogepant treatment group with the placebo group.
The ANCOVA analysis results from 100 completed datasets are combined for overall 
estimation and inference using Rubin's rule1 to produce a pooled estimate of LS mean 
difference, its SE, and corresponding p-value for the test of null hypothesis of no 
treatment effect.
Supplementary Analyses of the Primary Efficacy Endpoint
The estimand in support of the European submissions will serve as one supplementary 
analysis of the primary efficacy endpoint for the estimand in support of the submission in 
the US, and vice versa.
Sensitivity Analysis for Possible Violation of Normality Assumption
This sensitivity analysis uses MI in conjunction with robust regression to assess the 
robustness of the primary MMRM analysis to the possible violation of normality 
assumption. This method has been described and referred as ADAP [R].3 The details of 
the method are as follows.


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The normality test is performed on the residuals which are generated by the same MMRM 
as used for the primary efficacy analysis. The residuals are scaled by the inverse 
Cholesky root of its estimated variance-covariance matrix. The Kolmogorov-Smirnov test 
for normality is applied to the de-correlated and scaled residuals and normality test is 
rejected if p-value from the Kolmogorov-Smirnov test is less than 0.01.
If the normality test is rejected, sensitivity analysis below will be performed:
1.
Create complete datasets using MI based on the Markov chain Monte Carlo 
(MCMC) approach. Imputed data will consist of 20 complete datasets.
2.
Each of the 20 complete datasets will be analyzed using robust regression (M-
estimation) to protect against either observed outliers in the original incomplete 
dataset, or imputed outliers in the completed datasets. For a given complete 
dataset, the average change from baseline in monthly migraine days is calculated 
across the 3 post-baseline months and is used as the response variable in the robust 
regression model. The model includes treatment group, region, number of classes 
of failed prior prophylactic treatments (2 and >2) as fixed factors, and baseline 
monthly migraine days as a covariate. The mean difference and corresponding SE 
are estimated from the model comparing atogepant treatment group with the 
placebo group.
3.
The robust analysis results from 20 completed datasets are combined for overall 
estimation and inference using Rubin's rule1 to produce a pooled estimate of 
treatment difference, its SE, and corresponding p-value for the test of null 
hypothesis of no treatment effect.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
See Section 3.2.


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9.4.2
Main Analyses of Secondary Efficacy Endpoints
The attributes of the estimands corresponding to the key secondary efficacy endpoints are 
summarized in Table 5.
Table 5.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 1
in support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B:
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Achievement 
of at least a 
50% 
reduction in 
mean 
monthly 
migraine days 
across the 
12-week 
treatment 
period 
(yes/no)
mITT 
Population 
(see Section 
4.0) 
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded. 
The average of monthly 
migraine days is 
calculated for each 
participant based on 
available monthly 
migraine days during 
the double-blind period, 
and then the participant 
is dichotomized as a 
responder or non-
responder.
The odds 
ratio in 
participants 
achieving at 
least a 50% 
reduction in 
3-month 
average of 
monthly 
migraine days 
between 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 2
in support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean 
monthly 
headache 
days across 
the 12-week 
treatment 
period
mITT 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
headache
days across 
the 12-week 
treatment 
period 
between 
atogepant 
group and 
placebo
Secondary 3
in support of 
the 
submission 
in the US
Arm A:
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean 
monthly 
acute 
medication 
use days 
across the 
12-week 
treatment 
period
mITT 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
acute 
medication 
use days
across the 
12-week 
treatment 
period 
between 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 4
in support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
MSQ v2.1 
Role 
Function 
Restrictive 
domain score 
at Week 12
mITT 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random.
The 
difference in 
mean change 
from baseline 
in MSQ v2.1 
Role 
Function 
Restrictive 
domain score 
at Week 12 
between 
atogepant 
group and 
placebo
Secondary 5
in support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean
monthly 
Performance 
of Daily 
Activities 
domain score 
of the AIM-D 
across the 12-
week 
treatment 
period
mITT 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
Performance 
of Daily 
Activities 
domain score 
of the AIM-D 
across the 
12-week 
treatment 
period 
between each 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 6
in support of 
the 
submission 
in the US
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean 
monthly 
Physical 
Impairment 
domain score 
of the AIM -
D across the 
12-week 
treatment 
period
mITT 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Data after the 
discontinuation from 
double-blind treatment 
period are excluded and 
assumed missing at 
random.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
Physical 
Impairment 
domain score 
of the AIM -
D across the 
12-week 
treatment 
period 
between each 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 1
in support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Achievement 
of at least a 
50% 
reduction in 
mean 
monthly 
migraine days 
across the 
12-week 
treatment 
period 
(yes/no)
The Off-
treatment 
Hypothetical 
Estimand 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis.
IE2: Participants who 
start a new migraine 
prophylaxis treatment 
during the double-blind 
or safety follow-up 
period will have their 
data after starting the 
new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from 
the analysis.
IE3: Participants who 
discontinue study 
treatment due to all 
reasons other than 
starting a new migraine 
prophylaxis treatment 
will have their data 
collected after 
discontinuation of study 
treatment, and those 
off-treatment data will 
be included in the 
analysis. The average 
of monthly migraine 
days is calculated for 
each participant based 
on available monthly 
migraine days, and then 
the participant is 
dichotomized as a 
responder or non-
responder.
The odds 
ratio in 
participants 
achieving at 
least a 50% 
reduction in 
3-month 
average of 
monthly 
migraine days 
between 
atogepant 
group and 
placebo 


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 2
in support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean 
monthly 
headache 
days across 
the 12-week 
treatment 
period
The Off-
treatment 
Hypothetical 
Estimand 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Participants who 
start a new migraine 
prophylaxis treatment 
during the double-blind 
or safety follow-up 
period will have their 
data after starting the 
new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from 
the analysis.
IE3: Participants who 
discontinue study 
treatment due to all 
reasons other than 
starting a new migraine 
prophylaxis treatment 
will have their data 
collected after 
discontinuation of study 
treatment, and those 
off-treatment data will 
be included in the 
analysis.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
headache 
days across 
the 12-week 
treatment 
period 
between each 
atogepant 
group and 
placebo 


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 3
in support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
mean 
monthly 
acute 
medication 
use days 
across the 
12-week 
treatment 
period 
The Off-
treatment 
Hypothetical 
Estimand 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Participants who 
start a new migraine 
prophylaxis treatment 
during the double-blind 
or safety follow-up 
period will have their 
data after starting the 
new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from 
the analysis.
IE3: Participants who 
discontinue study 
treatment due to all 
reasons other than 
starting a new migraine 
prophylaxis treatment 
will have their data 
collected after 
discontinuation of study 
treatment, and those 
off-treatment data will 
be included in the 
analysis.
The 
difference in 
mean change 
from baseline 
in mean 
monthly 
acute 
medication 
use days
across the 
12-week
treatment 
period 
between each 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 4 
in support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60 mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
the HIT-6 
total score at 
Week 12
The Off-
treatment 
Hypothetical 
Estimand 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis. 
IE2: Participants who 
start a new migraine 
prophylaxis treatment 
during the double-blind 
or safety follow-up 
period will have their 
data after starting the 
new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from 
the analysis.
IE3: Participants who 
discontinue study 
treatment due to all 
reasons other than 
starting a new migraine 
prophylaxis treatment 
will have their data 
collected after 
discontinuation of study 
treatment, and those 
off-treatment data will 
be included in the 
analysis.
The 
difference in 
mean Change 
from baseline 
in the HIT-6 
total score at 
Week 12 
between each 
atogepant 
group and 
placebo


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 5
in support of 
the 
European 
submissions
Arm A: 
Placebo
Arm B: 
Atogepant 
60mg QD
Acute 
migraine 
medications 
as rescue 
medications 
are allowed 
to keep 
patients in 
the study
Change from 
baseline in 
MSQ v2.1
Role 
Function 
Restrictive 
domain score 
at Week 12
The Off-
treatment 
Hypothetical 
Estimand 
Population 
(see 
Section 4.0)
IE1: Regardless of 
whether allowed rescue 
medications are taken 
or not, data are included 
in the analysis.
IE2: Participants who 
start a new migraine 
prophylaxis treatment 
during the double-blind 
or safety follow-up 
period will have their 
data after starting the 
new migraine 
prophylaxis treatment 
during the follow-up 
period excluded from 
the analysis.
IE3: Participants who 
discontinue study 
treatment due to all 
reasons other than 
starting a new migraine 
prophylaxis treatment 
will have their data 
collected after 
discontinuation of study 
treatment, and those 
off-treatment data will 
be included in the 
analysis.
The 
difference in 
mean Change 
from baseline 
in MSQ v2.1 
Role 
Function 
Restrictive 
domain score 
at Week 12 
between each 
atogepant 
group and 
placebo
The secondary endpoints for headache days, acute medication use days, Performance of 
Daily Activities domain score of the AIM-D, and Physical Impairment domain score of 
the AIM-D will be analyzed in the same manner as that used to analyze the primary 
endpoint. For MSQ v2.1 Role Function Restrictive domain score and HIT-6 total score, 
the analysis will be performed similarly to the primary MMRM, with focus on the 
pairwise contrasts of atogepant dose group to placebo at Week 12.  Some participants may 
have MSQ v2.1 or HIT-6 assessed at Visit 8, which will not be included in MMRM


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models.  Note that the stratification of number of migraine days during the 
screening/baseline period (4 to < 8 and ≥ 8) will be included in the secondary efficacy
analyses if baseline values other than monthly migraine days are included in the 
corresponding models.
The 50% responder, defined as a participant with the achievement of at least a 50% 
reduction from baseline in the 3-month average of monthly migraine days, will be 
assessed for each participant. A logistic regression model will be used to analyze the 50% 
responders across the 12-week treatment period. This model assumes a binary 
distribution for the response and uses a logit link. The analysis model will include 
treatment group, region, the stratification of number of classes of failed prior prophylactic 
treatments (2 and >2), and baseline monthly migraine days. The treatment difference in 
terms of odds ratio between each atogepant dose group and placebo will be estimated and 
tested from this model.
For the analyses in the mITT population, the 50% responder will be derived using data 
collected from the double-blind period.  For the analyses in Off-treatment Hypothetical 
Estimand population, the 50% responder will be derived using data collected from the 
double-blind period and follow-up period; data after participants started a new 
prophylaxis treatment during the follow-up period will be excluded.
9.5
Exploratory Efficacy Analyses
For variables with a continuous response range, analyses will be performed similarly to 
that used for the primary analysis, with focus again on the pairwise contrasts of each dose 
group to placebo. Baseline in the primary MMRM model will be replaced with 
corresponding endpoint baseline.  Note that the stratification of number of migraine days 
during the screening/baseline period (4 to < 8 and ≥ 8) will be included in the additional 
efficacy analyses if baseline values other than monthly migraine days are included in the 
corresponding models.  There is only one post-baseline assessment for MIDAS and 
PHQ-9, and thus ANCOVA model will be used to analyze MIDAS and PHQ-9 related 
endpoints with model terms including treatment group, region, the stratification of 


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number of classes of failed prior prophylactic treatments (2 and >2), number of migraine 
days during the screening/baseline period (4 to < 8 and ≥ 8) and corresponding baseline 
score.  For the endpoints change from baseline in HIT-6, MSQ 2.1 and EQ-5D-5L
descriptive system index score and vas score, Week 16 (follow up visit) will not be 
included in MMRM model fitting.  Only descriptive statistics for Week 16 will be 
provided.
For variables where the data are essentially binary, comparisons between treatment groups 
will be done using a generalized linear mixed model for variables with multiple 
postbaseline assessments. A generalized linear mixed model will assume a binary 
distribution for the response and uses a logit link. The analysis model will include 
treatment group, visit, region, number of classes of failed prior prophylactic treatments 
(2 and >2), and treatment group-by-visit interaction as categorical fixed effects; baseline 
value and baseline-by-visit interaction will be included as covariates.  If baseline values
other than monthly migraine days is included in the model, then number of migraine days 
during the screening/baseline period (4 to < 8 and ≥ 8) will also be included in the 
corresponding analysis. Participants will be included as random effects with unstructured 
covariance matrix in the model to account for the correlation among repeated 
measurements. If the model does not converge, then the Toeplitz covariance structure 
will be used. If the model with the Toeplitz covariance structure does not converge, then 
the compound symmetry covariance structure will be used. The analysis will be 
performed based on all postbaseline values using only the observed cases without 
imputation of missing values. As there is no baseline assessment for the endpoint 
patient's satisfaction with study medication, baseline monthly migraine days will be 
included in the model.
For binary endpoints with only one postbaseline assessment (for example, PGIC 
responder) or responders across 12-week double-blind treatment period, a logistic 
regression model will be used to model the probability of a response or event with model 
terms including treatment group, region, number of classes of failed prior prophylactic 
treatments (2 and >2), and corresponding baseline.  If baseline values other than monthly 


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migraine days is included in the model, then number of migraine days during the 
screening/baseline period (4 to < 8 and ≥ 8) will also be included in the corresponding 
analysis.  As there is no baseline assessment for PGIC, baseline monthly migraine days 
will be used in the logistic regression model as a covariate for PGIC responder analyses.
Plots of fitted (least squares) mean changes and their standard errors for monthly migraine 
days, monthly headache days and monthly acute medication use days from the MMRM 
will be presented by treatment group and 4-week interval.
Plots of achievement of ≥25%, ≥30%, ≥ 50%, ≥ 75%, and 100% improvement (decrease) 
in monthly migraine days will be presented by treatment group and 4-week interval, 
respectively.
In addition, cumulative distribution graph of percent improvement (decrease) in mean 
monthly migraine days across 12-week treatment period will be provided by treatment 
group.
9.6
Efficacy Subgroup Analyses
Subgroup analyses for primary efficacy endpoint will be performed based on the 
following subpopulations:
●
Region: North America and Europe
●
Participants who had baseline migraine days: 4 to < 8 and ≥ 8
●
Participants who have failed 2 classes of prior oral prophylactic treatments 
●
Participants who have failed ≥3 classes of prior oral prophylactic treatments
●
Participants who have failed 3 classes of prior oral prophylactic treatments
The same model as that of the primary MMRM model in primary efficacy analysis in 
Section 9.3.2 will be utilized based on mITT population in support of submission in the 
US and on the Off-treatment Hypothetical Estimand Population in support of European
submissions. For each subgroup analysis, treatment effect and treatment comparison will 


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be estimated by the LS Means and their difference in LS Means, along with their SE and 
95% confidence intervals (CIs).
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Population.  Safety summaries will be 
presented by treatment group.  For the safety analysis, participants are assigned to a 
treatment group based on the treatment actually received, regardless of the treatment 
randomized.
A participant's actual treatment will be determined by the most frequent dose regimen 
received.
The safety parameters will include adverse events (AEs), clinical laboratory, vital sign, 
electrocardiographic (ECG), and C-SSRS. For clinical laboratory, vital sign, and ECG, 
the last non-missing safety assessment before the first dose of treatment will be used as 
the baseline for all analyses of that safety parameter. Continuous variables will be 
summarized by number of participants and mean, SD, median, Q1, Q3, minimum, and 
maximum values. Categorical variables will be summarized by number and percentage of 
participants.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Class (SOCs) and preferred terms (PTs) according to the version of MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each participant for 
calculating percentages, unless stated otherwise.  In addition, if the same adverse event 
occurs multiple times within a participant, the highest severity and level of relationship to 
investigational product will be reported.  Only AEs captured in Study 3101-304-002 will 


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be considered for TEAEs in this study. For participants rolling over into 
Study 3101-312-002 (extension study), AEs captured in the extension study will be 
summarized in the extension Study 3101-312-002 although some AEs might occur within 
30 days after the last dose from Study 3101-304-002.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose 
of study drug.  Events when the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  An AE that occurs more than 30 days after the last 
dose of double-blind study treatment or Visit 8 whichever comes later will not be counted 
as a TEAE. All treatment-emergent AEs will be summarized overall, as well as by 
primary MedDRA SOC and Preferred Term.  The SOCs will be presented in alphabetical 
order, and the PTs will be presented in descending percentage in atogepant 60 mg QD 
group within each SOC. 
The number and percentage of participants experiencing treatment-emergent AEs will be 
summarized.
TEAEs that started after the date of last dose of study treatment will be considered as 
newly emergent. The number and percentage of participants reporting newly emergent 
TEAEs in each treatment group will be summarized by system organ class and preferred 
term for participants who entered the safety follow-up period.
10.2.2
Adverse Event Overview
An overall of AEs will be presented consisting of the number and percentage of 
participants experiencing at least one event for each of the following AE categories.
●
Any treatment-emergent SAEs
●
Any treatment-emergent AEs related to study drug according to the investigator
●
Any serious treatment-emergent AEs
●
Any treatment-emergent AEs leading to discontinuation of study drug


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●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; and by maximum severity and SOC and PT.  
Specific adverse events will be counted once for each participant for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a participant, the highest severity and level of relationship to 
investigational product will be reported.
The incidence of common (≥ 2% of participants [after rounding] in any treatment group) 
TEAEs will be summarized by preferred term, and treatment group. A similar 5% table 
will be provided as well. 
10.2.4
Deaths, Serious Adverse Events, and Adverse Events 
Leading to Study Treatment Discontinuation 
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a 
TEAE that additionally meets any SAE criterion.  TESAEs, TEAEs leading to premature 
discontinuation of study treatment, and TEAEs leading to death will be summarized by 
SOC and PT.  Tabular listings will be provided for all AEs, all deaths, all SAEs, and 
TEAEs leading to premature discontinuation of study treatment.
10.2.5
Adverse Events of Special Interest
An adverse event of special interest (serious or nonserious) is one of scientific and 
medical concern specific to the sponsor's study intervention or program, which warrants 
ongoing monitoring and rapid communication by the investigator to the sponsor.  Such an 
event might warrant further investigation in order to characterize and understand it.
The following AESI(s) have been identified for the study intervention(s):


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●
Treatment-emergent suicidal ideations with intent, with or without a plan, (i.e., 
Type 4 or 5 on the C-SSRS) or any suicidal behaviors.
●
Treatment-emergent elevated ALT or AST laboratory value ≥ 3 × ULN.
●
Potential Hy's law cases: elevated ALT or AST laboratory value that is 
≥3 × ULN and an elevated total bilirubin laboratory value that is ≥ 2 × ULN 
and, at the same time, an alkaline phosphatase laboratory value that is 
< 2 × ULN.
AESIs will be summarized.  Listing of AESIs will be provided.
10.3
Laboratory Data
The clinical laboratory tests defined in the protocol (e.g., hematology, clinical chemistry
and urinalysis) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, Q1, 
Q3, minimum and maximum.  Mean change from baseline to each applicable post-
baseline visit will be summarized with the number of observations, baseline mean, and 
visit mean.  The change from baseline mean, standard error will be presented for the mean 
change from baseline within each treatment group.  In addition, descriptive statistics for 
values and changes from the baseline values in conventional units at each assessment time 
point will be presented for selected clinical laboratory parameters listed in Appendix E. A 
description of reporting the lab values in conventional units in patient narratives (along 
with the standard reporting in SI units) is presented at the end of Appendix E.
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table will be provided to summarize shifts from baseline to the final post-baseline 
value.
Laboratory abnormalities will be evaluated based on potentially clinically significant
(PCS) criteria (Table 15).  For each laboratory PCS criterion, the number and percentage 


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of participants who have a laboratory value meeting the criteria will be summarized.  
Listings will be provided to summarize subject-level laboratory data for participants 
meeting PCS criteria.  A listing of all AEs for participants with PCS Lab values will be 
provided.
In addition, ALT, AST, alkaline phosphatase, and total bilirubin will be categorized in 
Table 16.  The number and percentage of participants meeting each of the criteria for 
postbaseline hepatic laboratory abnormalities listed in Table 16 will be summarized. The 
percentages will be calculated relative to the number of participants with at least 
1 available postbaseline assessment.  The numerator will be the total number of 
participants having at least 1 postbaseline value that meets the specific category during the 
study.  A supportive listing will also be provided.
The number and percentage of participants with an adjudicated case (i.e., ALT ≥ 3 × ULN 
and/or AST ≥ 3 × ULN) will be summarized by treatment group and by relationship of 
ALT or AST elevation to study medication. The percentages will be calculated relative to 
the number of participants with at least 1 adjudicated case. The numerator will be the 
number of participants with at least 1 adjudicated case in the specific category of 
relationship. If a participant has more than 1 adjudicated case, he or she will be counted 
in the most relevant category of relationship.
Participants with an adjudicated case (i.e., ALT ≥ 3 × ULN or AST ≥ 3 × ULN) will be 
listed with their ALT and AST assessments, adjudication dates, relationship of ALT or 
AST elevation to study medication, and confounding factor(s). Additional listings will be 
provided for participants who meet ALT ≥ 3 × ULN or AST ≥ 3 × ULN and/or potential 
Hy's law and have one of the following categories: at least 1 abnormal liver biochemistry 
risk factor, at least 1 liver disease sign and symptom, at least 1 liver diagnostic test 
performed, consultation with a specialist for liver evaluation, liver lab tests performed, 
and drug screen performed, respectively. 


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A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided: ALT ≥ 3 × ULN or AST ≥ 3 × ULN that is 
associated with an increase in bilirubin ≥ 2 × ULN and alkaline phosphatase < 2 × ULN.
A listing of urine pregnancy test results will be provided for female participants of child-
bearing potential with at least one positive result.
10.4
Vital Signs
Vital sign measurements of systolic and diastolic blood pressures (sitting and standing), 
pulse rate (sitting and standing), respiratory rate, temperature, weight, orthostatic systolic 
blood pressure, orthostatic diastolic blood pressure, and orthostatic pulse rate will be 
summarized.  Orthostatic vital sign values (orthostatic systolic and diastolic blood 
pressures, and orthostatic pulse rate) are defined as the corresponding standing 
measurement minus sitting measurement of systolic and diastolic blood pressures and 
pulse rate respectively.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, Q1, 
Q3, minimum and maximum.  Mean change from baseline to each applicable post-
baseline visit will be summarized for each vital sign variable, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error will be presented for the mean change from baseline within each treatment group.
Vital sign variables will be evaluated based on PCS criteria (Table 17).  For each vital 
sign PCS criterion, the number and percentage of participants who have a vital sign value 
meeting the criteria will be summarized.  Listings will be provided to summarize subject-
level vital sign data for participants meeting PCS criteria.  In addition, a tabular display 
showing all AEs that occurred in participants who had PCS postbaseline vital sign values 
will be provided.


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10.5
Other Safety Analyses
10.5.1
Electrocardiogram
Descriptive statistics for ECG parameters (i.e., heart rate, PR interval, QRS interval, RR 
interval, QT interval, and QTc interval) at baseline, postbaseline, and changes from 
baseline values at each postbaseline timepoint will be presented by treatment group.
ECG parameter values are considered PCS if ECG values meet either the actual value or 
change from baseline PCS high criteria listed in Table 18.  The number and percentage of 
participants with PCS postbaseline values will be tabulated by study treatment.  The 
percentages will be calculated relative to the number of participants with an available non-
PCS baseline value and at least 1 postbaseline assessment.  The numerator will be the 
total number of participants with an available non-PCS baseline value and at least 1 PCS 
postbaseline ECG value during the study.  A supportive listing of participants with PCS 
postbaseline values will be provided.  A listing of all AEs for participants with PCS ECG 
values will also be provided.
To evaluate ECG postbaseline values of clinical interest, the number and percentage of 
participants with post-treatment QTcF > 450 msec, > 480 msec, and > 500 msec will be 
tabulated by treatment group.
The number and percentage of participants with an increase > 30 msec but ≤ 60 msec, and 
with an increase > 60 msec in QTcF will be tabulated. Participants will be counted only 
once for the most severe category. A supportive listing of participants with postbaseline 
QTcF increases > 30 msec will be provided, including the PID number, study center, and 
all QTc values (including changes from baseline). A listing of all AEs for participants 
with postbaseline QTcF increases > 30 msec will also be provided.
A shift table from baseline to the end of double-blind treatment period in the investigator's 
overall interpretation of the ECG will be presented by treatment group for the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant. 


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A tabular display of participants with postbaseline clinically significant ECG 
abnormalities according to the investigator's overall interpretation will be provided.
10.5.2
Columbia-Suicide Severity Rating Scale
For C-SSRS, the number and percentage of participants with suicidal ideation or suicidal 
behavior as recorded on the C-SSRS will be summarized by treatment group for the 
Safety Population. The distribution of responses for most severe suicidal ideation and 
most severe suicidal behavior in the participant's lifetime history, in the past 6 months, in 
the double-blind treatment period, and in the follow-up period will also be presented by 
treatment group. Supportive listings will be provided and will include the PID number, 
study center number, treatment group, lifetime history, and postbaseline values. Intensity 
of suicidal ideation and suicidal behavior type will also be included in these listings.  A 
listing of all AEs occurring in participants who have suicidal ideation or suicidal behavior 
will also be provided.
11.0
Other Analysis
11.1
Healthcare Resource Utilization Questionnaire
Healthcare resource utilization questions will include use of migraine-specific healthcare 
resources due to migraine attack.  The number and percentage of participants who visit to 
any general practitioner, specialist, emergency room, or hospital, and any diagnostic 
procedures prescribed by health care providers will be provided by treatment group over 
the past 12 weeks and since last visit, respectively, for the Safety Population.  In addition, 
total number of days spent in the hospital for all admissions during a specific period will 
be provided by treatment group for Safety Population.
12.0
Interim Analyses
No interim analysis is planned for this study.


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12.1
Data Monitoring Committee
An independent DSMB will be established to review unblinded safety data and summary 
reports, identify any safety issues and trends, and make recommendations to AbbVie, 
including modification or ET of the study, if emerging data show unexpected and 
clinically significant AEs of treatment.
Details of the DSMB memberships, standard operational procedures for data 
monitoring/review, frequency of review, and other pertinent details will be provided in a 
separate DSMB Charter.
13.0
Overall Type-I Error Control
A fixed-sequence procedure will be used for multiple comparisons to control the family-
wise Type I error rate at a 0.05 level. Once the primary endpoint for atogepant dose is 
significant at 0.05 (2-sided), the secondary endpoints will be tested. The testing sequence 
is specified for the US and EU in Table 6 and Table 7.


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Table 6.
Multiple Comparisons Procedure Definitions for the Submission in 
the US
Nodes
Alternate Hypothesis
Weight
Initial Local 
Significance 
Level
P1
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly migraine days across 
the 12-week treatment period 
1
α
S1
Atogepant 60 mg is significantly different from placebo in 
the achievement of at least a 50% reduction in mean monthly 
migraine days across the 12-week treatment period
0
α×0=0
S2
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly headache days across 
the 12-week treatment period 
0
α×0 = 0
S3
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly acute medication use 
days across the 12-week treatment period
0
α×0=0
S4
Atogepant 60 mg is significantly different from placebo in 
change from baseline in the MSQ v2.1 Role Function 
Restrictive domain score at Week 12
0
α×0=0
S5
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly Performance of Daily 
Activities domain score of the AIM-D across the 12-week 
treatment period
0
α×0=0
S6
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly Physical Impairment 
domain score of the AIM-D across the 12-week treatment 
period
0
α×0=0


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Table 7.
Multiple Comparisons Procedure Definitions for the European 
Submissions
Nodes
Alternate Hypothesis
Weight
Initial Local 
Significance 
Level
P1
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly migraine days across 
the 12-week treatment period 
1
α
S1
Atogepant 60 mg is significantly different from placebo in 
≥50% reduction in 3-month average of monthly migraine 
days
0
α×0=0
S2
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly headache days across 
the 12-week treatment period 
0
α×0 = 0
S3
Atogepant 60 mg is significantly different from placebo in 
change from baseline in mean monthly acute medication use 
days across the 12-week treatment period
0
α×0=0
S4
Atogepant 60 mg is significantly different from placebo in 
change from baseline in the HIT-6 total score at Week 12
0
α×0=0
S5
Atogepant 60 mg is significantly different from placebo in 
change from baseline in the MSQ v2.1 Role Function 
Restrictive domain score at Week 12
0
α×0=0
14.0
COVID-19 Related Analyses
14.1
Efficacy Evaluation
Efficacy Endpoints
Table 8 and Table 9 describe the collection devices for primary and secondary endpoints
for US and EU respectively. For US, the primary endpoint and 5 secondary endpoints are 
collected via eDiary and for EU, the primary endpoint and 3 secondary endpoints are 
collected via eDiary according to protocol design. Minimal disruption is expected for 
these endpoints because participants are expected to complete eDiary at home and submit 
the responses every day.


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The secondary endpoints, MSQ v2.1 Role Function Restrictive domain score at Week 12 
and HIT-6 total score at Week 12, will be collected using eTablet as one electronic patient 
reported outcome (ePRO) at site. Participants are required to complete the ePRO 
measures remotely at Visit 7 (Week 12) according to remote-visit procedure.
To evaluate the missing rate for this endpoint at Week 12, the number of participants who 
missed at least one ePRO assessment due to COVID-19 will be summarized at each visit 
in the efficacy analysis population of Off-Treatment Hypothetical Estimand (mITT
population for US and Off-treatment Hypothetical Estimand population for EU 
respectively).
Table 8.
Summary of Collection Devices for Primary and Secondary 
Endpoints for Submission in the US
Hypothesis 
Testing
Node
Endpoint
Collection 
Device
Primary
P1
Change from baseline in mean monthly migraine days across the 12-week 
treatment period
eDiary
Secondary 1
S1
Change from baseline in mean monthly headache days across the 12-week 
treatment period
eDiary
Secondary 2
S2
Change from baseline in mean monthly acute medication use days across 
the 12-week treatment period
eDiary
Secondary 3
S3
Achievement of at least a 50% reduction in mean monthly migraine days 
across the 12-week treatment period
eDiary
Secondary 4 
S4
Change from baseline in MSQ v2.1 Role Function Restrictive domain score 
at Week 12
eTablet
Secondary 5
S5
Change from baseline in mean monthly Performance of Daily Activities 
domain score of the AIM-D across the 12-week treatment period.
eDiary
Secondary 6 
S6
Change from baseline in mean monthly Physical Impairment domain score 
of the AIM -D across the 12-week treatment period.
eDiary


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Table 9.
Summary of Collection Devices for Primary and Secondary 
Endpoints for European Submissions
Hypothesis 
Testing
Node
Endpoint
Collection 
Device
Primary
P1
Change from baseline in mean monthly migraine days across the 
12-week treatment period
eDiary
Secondary 1
S1
Change from baseline in mean monthly headache days across the 
12-week treatment period
eDiary
Secondary 2
S2
Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period
eDiary
Secondary 3
S3
Achievement of at least a 50% reduction in mean monthly 
migraine days across the 12-week treatment period
eDiary
Secondary 4
S4
Change from baseline in HIT-6 total score at Week 12
eTablet
Secondary 5
S5
Change from baseline in MSQ v2.1 Role Function Restrictive 
domain score at Week 12
eTablet
14.2
Safety and Other Evaluations
This section specifies analyses related to COVID-19 pandemic from the following 
aspects:
●
Disposition
●
Study visits and study procedures
●
Protocol deviation
●
Treatment interruption due to COVID-19
●
TEAEs related with COVID-19 and supplemental signs and symptoms
●
COVID-19 status (COVID-19 testing results or contact with a COVID-19 
positive person)
●
COVID-19 vaccine
Safety Population will be used for the planned analyses described above. The number of 
participants impacted by COVID-19 during the study will be summarized by treatment 
group and overall. In addition, the number of participants impacted by COVID-19 and 


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their corresponding disposition status in the double-blind treatment period and the follow-
up period will be summarized respectively.
The number of participants who missed at least one entire visit, had impacted in-person 
clinic visits, and had remote visits using audio or video due to COVID-19 will be 
summarized by treatment group and overall. Furthermore, the number of participants who 
missed at least one assessment due to COVID-19 will be summarized by assessment 
category (laboratory, C-SSRS, urine pregnancy test, vital signs, ECG, and ePRO) and 
overall. Similar summaries will be provided by visit.
The number of participants with significant protocol deviation due to COVID-19 will be 
provided. The number of participants with study drug interruption due to COVID-19 will 
be provided as well. The number of participants with TEAEs related to COVID-19
infection and supplemental signs and symptoms will be provided.
The number and percentage of participants who received a COVID-19 vaccine will be 
tabulated by Anatomical Therapeutic Chemical (ATC) 4 class and preferred term (PT).  
The number and percentage of participants with TEAEs and serious TEAEs related to 
COVID-19 vaccine will be summarized by treatment and overall.
Supporting listings for the described analyses above will be provided.
15.0
Version History
This Statistical Analysis Plan (SAP) for Study 3101-304-002 is based on the protocol 
amendment 2 dated 01 December 2020.  Summary of changes from SAP version 1.0 to 
SAP version 2.0 is provided in Table 10.


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Table 10.
Summary of Changes from SAP Version 1.0 to SAP Version 2.0
Date
Section
Description
08 JUL 2022
1.0
Add a description for tables specification in separate document
08 JUL 2022
1.0
Add a statement for changes to planned analysis in the protocol
15 JUL 2022
2.0
Modify the title of Section 2.0
05 JUL 2022
2.0
Add the objective of the study in Section 2.0
15 JUL 2022
2.3
Delete block sharing description 
20 JUL 2022
2.3
Delete 'Asia/Pacific' from the whole document
12 JUL 2022
3.3
Update efficacy endpoints analyses of HIT-6 and MSQ 2.1 at Week 
16
05 AUG 2022
4.0
Modify 'EU filing' to 'European submissions' in the whole document
30 JUL 2022
5.0
Update description of disposition summary
30 JUL 2022
5.0
Add a sub-group '< 4' to the factor 'number of migraine days during 
the screening/baseline period.'
30 JUL 2022
5.0
Delete disposition summary for mITT Population and Off-treatment 
Hypothetical Estimand Population
09 JUL 2022
5.0
Add comparing inconsistency between eDiary data and IWRS 
09 JUL 2022
6.0
Update title for Section 6.0
05 AUG 2022
6.0
Provide the definition of participant-years
02 AUG 2022
7.1
Add Baseline efficacy parameters descriptions
29 JUL 2022
7.2
Modify Medical History summary table description
30 JUL 2022
7.2
Add a section for non-drug therapy 
09 JUL 2022
7.3
Modify concomitant medications summary table description
30 JUL 2022
7.3
Add ≥ 5% common concomitant medication summary table
01 AUG 2022
7.4
Move Protocol Deviations section from Appendix to Section 7.4
30 JUL 2022
8.0
Delete 'of primary endpoint'
07 JUL 2022
9.1
Add the definitions of migraine day, headache day and acute 
medication use day.
30 JUL 2022
9.3.2
Add 'mITT Population'
07 JUL 2022
9.3.3
Add a sentence to summarize sensitivity and supplementary analyses
30 JUL 2022
9.3.3
Clarify no missing data in ANCOVA model
01 AUG 2022
9.4
Modify the title of Section 9.4
30 JUL 2022
9.4.2
Clarify only providing descriptive statistics for MSQ 2.1 and HIT-6 
data at Visit 8


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Date
Section
Description
30 JUL 2022
9.4.2
Modify 'individual' to 'Participant'
10 JUL 2022
9.5
Add PHQ-9, HIT-6 and MSQ 2.1 in the summary description
30 JUL 2022
9.5
Add factor 'region' in the GLMM model
10 JUL 2022
9.5
Add a description for models not converged.
07 JUN 2022
9.6
Revise this section for additional subgroup and model specifications
10 JUL 2022
10.2
Add a section to describe AEs obtained in 3101-312-002 study
29 JUL 2022
10.2.1
Modify AE summary table description
10 JUL 2022
10.2.1
Indicate the population as 'participants who entered the safety 
follow-up period'
29 JUL 2022
10.2.2
Delete 'Any severe treatment emergent AE' and 'Any treatment 
emergent AE leading to death'
31 JUL 2022
10.2.3
Delete 'by participant number and SOC and PT'
28 JUL 2022
10.2.3
Add '[after rounding]'
31 JUL 2022
10.2.4
Revise this section for TESAEs and Deaths
31 JUL 2022
10.3
Delete the sentences for local lab and lab due to SAE. 
01 AUG 2022
10.3
Add descriptions for AEs with PCS listings of Lab, vital sign and 
CSSRS data.
15 JUN 2022
10.3
Revise '>' to '≥' for Hy's Law definition
02 AUG 2022
10.4
Provide the definitions of Orthostatic vital signs parameters
08 JUL 2022
13.0
Remove '(P1)' and '(S1)'
08 AUG 2022
14.2
Add a summary for Covid-19 analyses
04 AUG 2022
15.0
Revise protocol version and SAP version history
05 AUG 2022
15.1
Add a section for 'Changes to Planned Analyses in the Protocol'
04 AUG 2022
Appendix A
Add Appendix A for List of SAP Signatories
04 AUG 2022
Appendix C
Update the definition of AESI
31 JUL 2022
Appendix D
Delete SI Units for 'Glucose' and 'Protein.' Update PCS of 'Glucose'
31 JUL 2022
Appendix E
Remove 'Triglycerides' from lab parameters
20 JUL 2022
Appendix F
Update the List of Abbreviations


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Table 11.
SAP Version History Summary
Version
Date
Summary
1.0
11 MAY 2021
Initial Version
2.0
21 AUG 2022
Final Version
15.1
Changes to Planned Analyses in the Protocol
Collection and Derivation of Primary and Secondary Efficacy Assessments in protocol 
Section 9.4.1.1.4 was updated. Original "12 days" criteria for using prorated approach 
were modified to "14 days."
The subgroup analyses for the primary efficacy endpoint (protocol Section 9.4.4) were 
updated in SAP Section 9.6.
16.0
References
1.
Rubin DB. (1987). Multiple Imputation for Nonresponse in Surveys. New York, 
NY: Wiley.
2.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with 
protocol deviation: A framework for relevant, accessible assumptions, and 
inference via multiple imputation. J Biopharm Stat. 2013;23(6):1352-71.
3.
Mehrotra DV, Li X, Liu J, et al. Analysis of longitudinal clinical trials with 
missing data using multiple imputation in conjunction with robust regression. 
Biometrics. 2012;68(4):1250-9.
4.
Berger A, Bloudek L, Varon S, et al. Adherence with Migraine Prophylaxis in 
Clinical Practice. Pain Pract. 2012;12(7)541-9.
5.
Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efficacy of 
TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet 
Neurol. 2015;14(11):1081-90.


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6.
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially 
rejective multiple test procedures. Stat Med. 2009;28(4):586-604.
7.
Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an 
antibody to calcitonin gene-related peptide, for the prevention of frequent episodic 
migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 
trial.  Lancet Neurol.  2014;13(11):1100-07.
8.
Dodick DW, Goadsby PJ, Spierings EL, et al. Safety and efficacy of LY2951742, 
a monoclonal antibody to calcitonin gene-related peptide, for the prevention of 
migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet 
Neurol. 2014;13(9):885-92.
9.
Goadsby P, Dodick D, Trugman J, et al. Efficacy, Safety, and Tolerability of 
Orally Administered Atogepant for the Prevention of Episodic Migraine: Results 
from a Phase 2b/3 Study. Presented at the 17th Biennial Migraine Trust.  
International Symposium (MTIS 2018). Sept 6-Sept 9, 2018a; London, UK.
10.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53(3):983-97.
11.
Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP 
receptor antagonist telcagepant for migraine prevention. Neurology. 
2014;83(11):958-66. 


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Appendix A.
List of SAP Signatories
Name
Title
Role/Functional Area
Senior Manager, Statistics
Author
Director, Statistics
Clinical Statistics
Senior Director, Statistics
Therapeutic Area statistics Lead
Manager, Statistical Programming
Statistical Programming
Medical Director
Medical/Scientific Monitor


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Appendix B.
Derivation of Efficacy Variables
A.1 Derivation of Efficacy Endpoints Based on eDiary Data
For analysis purposes, four weeks (28 days) will be considered as one month. On a daily 
basis during the 4-week baseline period and throughout the double-blind treatment period, 
participants are to record eDiary information on the duration of headache, headache 
specific characteristics and symptoms, the pain severity, and use of any acute headache 
pain medication (see protocol Sections 8.1.1, 8.1.2, 8.1.3). Daily headache diary data 
consists of data from "today's diary" completed on that day and "yesterday's diary"
completed on the following day. Participants are to report headache data in "today's 
diary" in the evening at any time from 19:00 to 23:59 and to complete "yesterday's diary"
on the following day to add the remaining headache data of previous evening until 
midnight. In case participants miss "today's diary," they can report the whole-day 
headache data in "yesterday's diary" on the following day. In case participants miss 
"yesterday's diary," headache data from "today's diary" alone will be used as daily 
headache diary data. If both "today's diary" and "yesterday's dairy" are missing on one 
day, the daily headache diary data will be treated as missing.
Daily headache diary data will be merged from "today's diary" and "yesterday's diary" as 
following and will be used to derive migraine day and headache day.
●
Daily headache total duration: summation of headache durations from "today's 
diary" and "yesterday's diary"
●
Daily headache pain severity: the worst pain severity from "today's diary" and 
"yesterday's diary"
●
Daily headache characteristics and symptoms: present if present in one of 
"today's diary" and "yesterday's diary"
●
Daily acute headache medication usage: combination of acute headache 
medications usage from "today's diary" and "yesterday's diary."
●
For the derivation of headache day, the participant is considered to have taken a 
non-antiemetic acute headache medication if the participant has taken such a 
medication in either "today's diary" or "yesterday's diary."


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Moderate/severe headache day is defined as a headache day during which the maximum 
pain severity is either moderate or severe. Severe headache day is defined as a headache 
day during which the maximum pain severity is severe.
If a participant confirmed no headache for the Question 1 in eDiary, then the participant 
will not answer subsequent questions related to headache symptoms, duration, and acute 
headache mediation use by design. Thus, the acute medication use for that diary ('today'
or 'yesterday') will be treated as 'No' when deriving acute medication use day.
The monthly migraine days is defined the total number of recorded migraine days in the 
eDiary divided by the total number of days with eDiary records during each monthly 
period and multiplied by 28. For baseline, a minimum of 20 days' eDiary data during the 
4-week baseline period is required for the migraine days to be evaluable. For each 
postbaseline 4-week treatment period, a minimum of 14 days' eDiary data during that 
period is required for the migraine days to be evaluable. If a participant does not have at 
least 14 days of diary data for a monthly treatment period, the migraine days for that 
period will be considered as missing. Migraine days will be derived for each participant 
at baseline and for each postbaseline monthly treatment period (Weeks 1-4, 5-8, 9-12). 
The same method to derive monthly migraine days will be used to derive monthly 
headache days, monthly acute medication use days, monthly triptan use days, monthly 
cumulative headache hours, monthly moderate/severe headache days, and monthly severe 
headache days.
If a participant confirmed that acute medications were taken and entered medications in 
the eDiary, then the acute medication use day will be set to 'Yes.' If a subject reports 'Yes'
to the intake of allowed medication(s) to treat an acute migraine but does not list any of 
them in the diary, then the acute medication use days will not be counted in this situation 
and vice versa.


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A.2 Derivation of Health Outcome Endpoints
AIM-D Related Endpoints Derivation
The AIM-D was developed as a daily eDiary with a recall period 24 hours. By design, it 
is collected in the today diary only.  The scoring of the following endpoints is completed 
in 2 steps.
●
Monthly Performance of Daily Activities domain score of the AIM-D
●
Monthly Physical Impairment domain score of the AIM -D
●
Monthly AIM -D total score
Step 1: Calculate AIM-D daily domain score and total score
Daily performance of daily activities score will be calculated based on the summation of 
items 1-5 and 10 and 11, ranging from 0-35. A daily performance of daily activities 
domain score will be calculated if 4 or more item scores have non-missing responses. 
When the response category "I did not have <errands, leisure or social, strenuous 
activities> planned" (items 2, 4, and 5), is selected, the response will be considered 
missing. The corresponding performance of daily activities domain score will be 
calculated by summing the non-missing item scores and dividing by the number of non-
missing items and then multiplying by 7, provided that 4 or more item scores are 
available; otherwise, it will be set to missing. The raw daily score will be transformed to 
a 0-100 scale by multiplying by 100 and dividing by the highest raw score (35).
Daily physical impairment scores will be calculated based on the summation of items 6-9, 
ranging from 0-20. A daily physical Impairment score will be calculated if 2 or more item 
scores have non-missing responses. The corresponding physical Impairment score will be 
calculated by summing the non-missing item scores and dividing by the number of non-
missing items and then multiplying by 4, provided that 2 or more item scores are 
available; otherwise, it will be set to missing. The raw daily score will be transformed to 
a 0-100 scale by multiplying by 100 and dividing by the highest raw score (20).


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A daily total score will be calculated based on the summation of items 1-11, ranging from 
0-55. A Total Score will be calculated if 6 or more items scores have non-missing 
responses.  When the response category "I did not have <errands, leisure or social, 
strenuous activities> planned" (items 2, 4, and 5), is selected, the response will be 
considered missing. The corresponding Total Score will be calculated by summing the 
non-missing item scores and dividing by the number of non-missing items and then 
multiplying by 11, provided that 6 or more item scores are available; otherwise, it will be 
set to missing. The raw score will be transformed to a 0-100 scale by multiplying by 100 
and dividing by the highest raw score (55).
Step 2: Calculate Monthly Scores and Baseline Score
Monthly scores will be calculated using the average daily scores only if there are at least 
14 non-missing daily scores in the corresponding monthly (28-day) period. The 
corresponding monthly scores will be calculated by summing the non-missing daily 
domain scores and dividing by the number of non-missing daily domain, provided that 14 
or more daily scores are available; otherwise, it will be set to missing.
Activity Level and Activity Limitation
Monthly activity level score will be calculated by summing the non-missing daily scores 
and dividing by the number of these scores, provided that 14 or more daily scores are 
available in the corresponding monthly (28-day) period; otherwise, it will be set to 
missing.  Same rule will be applied to the calculation of monthly activity limitation score.
MSQ Related Endpoints Derivation
MSQ v2.1 consists of 14 items with a 4-week recall period. The scoring of the MSQ is 
completed in following 3 steps.


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Step 1: Final item value assignment.
Precoded item values and final item values for each MSQ item response are shown in
Table 12.
Table 12.
Item Values for MSQ Item Responses
Response Categories
Precoded Item Value
Final Item Value
None of the time
1
6
A little bit of the time
2
5
Some of the time
3
4
A good bit of the time
4
3
Most of the time
5
2
All of the time
6
1
Step 2:  Computation of raw domain (dimension) scores
Once a final item value has been assigned to each item, a raw score can be computed for 
each MSQ domain. Role Function Restrictive domain includes Items 1 - 7, Role Function 
Preventive domain includes Items 8 - 11, and Emotional Function domain includes 
Items 12 - 14. The raw score for each domain is the algebraic sum of the final item values 
for all items in that domain.
Missing data handling: if a respondent answered at least half of the items in a domain (or 
half plus one in the case of scales with an odd number of items), a missing item value can 
be estimated using the average of the other completed items within the same dimension.
In detail, for MSQ v2.1 Role Function Restrictive domain, the 7 individual item responses 
using final item value will be summed, resulting in the raw domain score ranging from 7 
to 42 with higher scores indicating better quality of life. If there are missing item 
responses, the raw domain score will be calculated by summing the non-missing item 
responses using final item value and dividing by the number of non-missing items and 


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then multiplying by 7 provided that 4 or more items in the domain are completed; 
otherwise it will be set to missing. For MSQ v2.1 Role Function Preventive and 
Emotional domains, the raw domain scores will be calculated similarly using final item 
value respectively. If there are missing item responses, the corresponding raw domain 
score will be calculated by summing the non-missing item responses using final item 
value and dividing by the number of non-missing items and then multiplying by the 
number of questions in that domain provided that 2 or more domain items are completed; 
otherwise it will be set to missing. 
Step 3: Linear transformation to a 0 to 100 scale.
The transformation formula for each MSQ 2.1 domain is listed below
●
Role Function -Restrictive:
●
Role Function-Preventive:
●
Emotional Function:
HIT-6 Total Score Derivation
For HIT-6 total score, pre-coded item values and final item values for each item response 
are shown in Table 13. Total score is calculated by summing 6 sub-item responses, 
resulting in the total score ranging from 36 to 78 with higher scores indicating greater 
impact. If any sub item is missing, then total score will be missing.
Table 13.
Item Values for HIT-6 Item Responses
Response Categories
Precoded Item Value
Final Item Value
Never
0
6
Rarely
1
8
Sometimes
2
10
Very Often
3
11
Always
4
13


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The HIT-6 instrument has a recall period of 4 weeks for 3 of the 6 items.
MIDAS Related Endpoints Derivation
MIDAS total score is derived as the sum of first 5 of questions (i.e., the sum of days 
missing work or school, Productivity at work or school reduced, Not do household work, 
Productivity in household work reduced, Miss family social or leisure activities).  If any 
sub item is missing, the MIDAS total score will be missing.
The MIDAS absenteeism score is derived as the sum of Questions 1, 3 and 5. If any sub 
item is missing, then the MIDAS absenteeism score will be missing.  The MIDAS 
presenteeism score is derived as the sum of Questions 2 and 4. If any sub item is missing, 
then the MIDAS presenteeism score will be missing.
WPAI: MIGRAINE Related Endpoints Derivation 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows:
Questions:
●
Q1 = currently employed (working for pay).
●
Q2 = missed work hours because of problems associated with your migraine
●
Q3 = missed work hours due to other reason.
●
Q4 = hours actually worked.
●
Q5 = migraine affected productivity while working.
●
Q6 = migraine affected regular daily activity.
Scores:
Multiply scores by 100 to express in percentages.
●
Percent work time missed due to migraine (absenteeism): Q2/(Q2 + Q4)


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●
Percent impairment while working due to migraine (presenteeism): Q5/10
●
Percent overall work impairment due to migraine (overall work productivity 
loss): Q2/(Q2 + Q4) + (1- (Q2/(Q2 + Q4))) × (Q5/10)
●
Percent activity impairment due to migraine (regular activity impairment): 
Q6/10
If the response to Q1 ("Currently employed?") is No or missing, absenteeism, 
presenteeism, and overall work productivity loss will all be set to missing.
EQ-5D-5L Score Derivation
The EQ-5D-5L is made up of two components: health state description and evaluation.
The description component consists of five dimensions: mobility, self-case, usual 
activities, pain/discomfort, and anxiety/depression. The mobility dimension queries the 
participant's walking ability. The self-care dimension queries the participant's ability to 
wash or dress by himself. The usual activities dimension assesses the participant's 
performance in "work, study, housework, family or leisure activities." The 
pain/discomfort dimension measures how much pain or discomfort a participant has. The 
anxiety/depression dimension assesses how anxious or depressed a participant is. The 
respondents rate their level of severity for each dimension using a 5-level scale (EQ-5D-
5L) by ticking (or placing a cross) in the box against the most appropriate statement in 
each of the 5 dimensions. The second component of the EQ-5D-5L is a visual analogue 
scale (EQ-VAS) by which participants can rate their overall health from 0 (worst 
imaginable health state) to 100 (best imaginable health state).
With the EQ-5D-5L, rating levels can be coded as numbers 1, 2, 3, 4 or 5 which 
correspond to "have no problems," "have slight problems," "have moderate problems," 
"have severe problems," and "unable to do/have extreme problems," respectively. As a 
result, a participant's health state can be defined by a 5-digit number by combining the 
numeric levels from the 5 dimensions, ranging from 11111 ("have no problems" in all 
5 dimensions) to 55555 ("unable to do/have extreme problems" in all 5 dimensions). The 


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index value for the EQ-5D-5L will be derived using an international standardized 
protocol.
EQ-5D-5L will be captured on eDiary during 7 days in the screening/baseline period and 
during specific time periods for Visit 1 to 7, except at Visit 8 (Week 16) where it will be 
administered on an eTablet. The index score and VAS score for a specific period will be 
calculated as the average of available scores in that period respectively if at least 50% of 
daily scores are available; otherwise, the scores will be set as missing. For example, for a 
period of 14 days, at least 7 assessments are required; and for a period of 7 days, at least 
4 assessments are required.
PROMIS-PI T-Score Derivation
The PROMIS-PI measures self-reported interference of pain on relevant aspects of daily 
life (i.e., social, cognitive, emotional, physical, recreational) over the past 7 days. A 
5-level response scale for all 6 items ranges from 1 to 5, corresponding to item response 
of "Not at all" to "Very much." The raw score of PROMIS-PI is the sum of all 6 items, 
ranging from 6 to 30. If one or more items are missing, the raw score will be set to 
missing. A raw score can be standardized into a T-score with a mean of 50 and standard 
deviation of 10 using Table 14. Higher raw or T-scores indicate greater pain interference.


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Table 14.
PROMIS-PI Raw Score Transformation
Raw 
Score
T-Score
Raw 
Score
T-Score
Raw 
Score
T-Score
Raw 
Score
T-Score
6
41.1
13
56.6
20
63.0
27
69.8
7
48.6
14
57.6
21
63.8
28
71.0
8
50.7
15
58.6
22
64.8
29
72.6
9
52.2
16
59.5
23
65.7
30
76.3
10
53.4
17
60.4
24
66.7
11
54.5
18
61.2
25
67.6
12
55.6
19
62.1
26
68.7
Patient Health Questionnaire (PHQ-9)
The PHQ-9 consists of the 9 diagnostic criteria for depressive disorders in the past 
2 weeks from the DSM-IV. Participants are asked to indicate the frequency with which 
they have been bothered by 9 symptoms of depressive disorders over the previous 
2 weeks, on a 4-point scale: 0 (not at all), 1 (several days), 2 (more than half the days), 
and 3 (nearly every day). The total score ranges from 0 to 27 (from best to worst). A 
score of 15 to 19 is considered as moderately severe depression and 20 to 27 as severe 
depression. A Total Score will be calculated using (sum of non-missing items) × 9 
/(number of non-missing items) if 5 or more items scores have non-missing responses.


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Appendix C.
Definition of Adverse Events of Special Interest
The definition of Adverse Events of Special Interest (AESI) is described in Section 10.2.5


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Appendix D.
Potentially Clinically Significant Criteria for Safety
The potentially clinically significant criteria for clinical laboratory parameters, vital signs 
and ECG parameters are provided in the following tables.
Clinical laboratory parameters are provided in the following tables.
Table 15.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters
PCS Criteria
Category
Parameter
SI Unit
PCS Low
PCS High
Chemistry
Albumin
g/L
< 0.8 × LLN
> 1.2 × ULN
Alanine aminotransferase
U/L
—
≥ 3.0 × ULN
Alkaline phosphatase
U/L
—
≥ 3.0 × ULN
Aspartate aminotransferase
U/L
—
≥ 3.0 × ULN
Bicarbonate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Bilirubin, total
μmol/L
—
≥ 1.5 × ULN
Blood urea nitrogen
mmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.6 × ULN
Creatinine
μmol/L
—
> 1.5 × ULN
Creatine kinase
U/L
—
> 2.0 × ULN
Estimated glomerular filtration 
rate
mL/min/1.73m
2
< 60 
mL/min/1.73m2
—
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 2.0 × ULN
Lactate dehydrogenase (LDH)
U/L
—
> 3.0 × ULN
Phosphorus
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Uric acid 
μmol/L
—
> 1.2 × ULN


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PCS Criteria
Category
Parameter
SI Unit
PCS Low
PCS High
Hematology
Basophils, absolute cell count
109/L
—
> 2.0 × ULN
Eosinophils, absolute cell count
109/L
—
> 2.0 × ULN
Hematocrit
Ratio
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Lymphocytes, absolute cell 
count
109/L
< 0.7 × LLN
> 1.3 × ULN
Monocytes, absolute cell count
109/L
< 0.5 × LLN
> 2.0 × ULN
Neutrophils, absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.9 × LLN
> 1.5 × ULN
Urinalysis
pH
pH
< 0.9 × LLN
> 1.1 × ULN
Glucose
—
—
Positive 1
Protein 
—
—
Positive 2
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value; ULN = upper limit of normal value; normal value provided by laboratory.
SI = Le Système International d'Unités (International System of Units).
1.
Any results other than trace or normal will be considered as positive.
2.
Any results other than trace or negative will be considered as positive.
Table 16.
Criteria for Hepatic Laboratory Abnormalities
Laboratory Parameter
Categories
ALT
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN


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Laboratory Parameter
Categories
AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT or AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Bilirubin Total
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Alkaline Phosphatase
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN


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Laboratory Parameter
Categories
Concurrent Elevations1
ALT or AST ≥3 × ULN and Bilirubin Total ≥ 1.5 × ULN
ALT or AST ≥3 × ULN and Bilirubin Total ≥ 2 × ULN
Potential Hy's Law1
ALT or AST ≥ 3 × ULN and Bilirubin Total ≥ 2 × ULN 
and ALP < 2 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ALP = alkaline phosphatase; 
ULN = upper limit of normal (value provided by the laboratory).
1.
Elevations are from the same day
Vital sign values will be considered PCS if they meet both the observed value criterion 
and the change from baseline value criterion, if both criteria are available, or meet either 
the observed value criterion or the change from baseline value criterion that is detailed in 
the following table.
Table 17.
Potentially Clinically Significant Criteria for Vital Signs 
Parameters
Parameter
Flag
Criteria
Observed Value
Change from Baseline
Systolic blood pressure, mmHg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic blood pressure, mmHg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
Orthostatic SBP change, mmHg
Low
≤ -20
—
Orthostatic DBP change, mmHg
Low
≤ -15
—
Orthostatic Pulse rate change, bpm
High
≥ 25
—
SBP = Systolic blood pressure, DBP = Diastolic blood pressure, bpm = beats per minute.


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ECG parameter values are considered PCS if ECG values meet either the actual value or 
change from baseline PCS high criteria listed in the following table.
Table 18.
Potentially Clinically Significant Criteria for ECG Parameters
Parameter
Unit
Criterion
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTc (QTcB or QTcF) interval 
msec
> 500
QTc (QTcB or QTcF) interval
msec
Increase from baseline > 60


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Appendix E.
Laboratory Parameters in Conventional Unit
All clinical laboratory parameters will be reported in the International System (SI) units as 
standard practice.  In addition, descriptive statistics for values and changes from baseline 
in conventional units at all assessed visits will be reported for selected laboratory 
parameters as listed in the following table.
Table 19.
List of Selected Parameters Reported in Conventional Unit
Number
Laboratory Parameter
Conventional Unit
Decimal Places
1
Alanine Aminotransferase (SGPT)
U/L
0
2
Albumin
g/dL
1
3
Alkaline Phosphatase
U/L
0
4
Aspartate Aminotransferase (SGOT)
U/L
0
5
Bilirubin, Direct (Conjugated)
mg/dL
1
6
Bilirubin, Indirect (Unconjugated)
mg/dL
1
7
Bilirubin, Total
mg/dL
1
8
Blood Urea Nitrogen
mg/dL
0
9
Calcium
mg/dL
1
10
Cholesterol, HDL
mg/dL
0
11
Cholesterol, LDL
mg/dL
0
12
Cholesterol, LDL direct and calculated 
(combined)
(This lab parameter could be the same as #11) 
mg/dL
0
13
Cholesterol, Total
mg/dL
0
14
Creatine Kinase
U/L
0
15
Creatinine
mg/dL
1
16
Glucose
mg/dL
0
17
Uric Acid
mg/dL
1
18
Hemoglobin
g/dL
1
Patient narratives will also include the values in conventional units for the selected lab
parameters in below table. That will be accomplished by presenting the values in 
conventional units within the parentheses next to the values in SI units. 


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Table 20.
Presenting Laboratory Data Using SI and Conventional Units in 
Narratives
LABORATORY DATA
Lab Test
Test Name
Normal Range
VISIT01
VISIT05
VISIT07
Low
High
2012-07-03
2012-08-07
2012-09-04
CHEMISTRY 
Bilirubin, Total 
(µmol/L (mg/dL)) 
0 (0)
18.81 
(1.1)
6.84 (0.4)
5.13 (0.3)
5.13 (0.3)


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Appendix F.
List of Abbreviations
Abbreviation/Term
Definition
AE
adverse event
AESI
adverse events of special interest
AIM-D
Activity Impairment in Migraine –Diary
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
bpm
beats per minute
CI
confidence interval
C-SSRS
Columbia–Suicide Severity Rating Scale
DBP
Diastolic blood pressure
DSMB
Data Safety Monitoring Board
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
ePRO
electronic Patient Reported Outcome
eDiary
electronic diary
eTablet
electronic tablet
EM
episodic migraine
EOS
end of study
EQ-5D-5L
European Quality of Life –5 Dimensional
ET
early termination
FWER
familywise error rate
GLMM
generalized linear mixed model
HIT-6
Headache Impact Test
ITT
intent-to-treat
IWRS
interactive web response system
LLN
lower limit of normal value
LS
least squares 
MAR
missing-at-random
MCMC
Markov chain Monte Carlo


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Abbreviation/Term
Definition
MI
multiple imputation
MIDAS
Migraine Disability Assessment
MedDRA
Medication Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MNAR
missing-not-at-random
MSQ v2.1
Migraine Specific Quality of Life Questionnaire, Version 2.1
PCS
potentially clinically significant
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression –Severity
PHQ-9
Patient Health Questionnaire
PID
participant identification
PMM
pattern-mixture model
PRO
patient reported outcomes
PROMIS-PI
Patient-Reported Outcomes Measurement Information Systems Pain Interference –
Short Form 6a
PSSM
Patient Satisfaction with Study Medication
PT
preferred term
Q1
first quartile (25th percentile of the data)
Q3
third quartile (75th percentile of the data)
QD
once daily
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SBP
Systolic blood pressure
SD
standard deviation
SE
standard error
SI
Le Système International d'Unités (International System of Units)
SOC
standard of care
TBL
total bilirubin
TEAE
treatment-emergent adverse event


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Abbreviation/Term
Definition
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal value
VAS
visual analogue scale
WHO
World Health Organization
WPAI: MIGRAINE
Work Productivity and Activity Impairment Questionnaire: Migraine Version V2.0