Clinical trial NCT02848326
Conditions: Migraine, With or Without Aura
Sponsor: Allergan
Start date: 2016-09-06; Completion date: 2018-04-23
Enrollment: 834 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and tolerability of the following doses of atogepant (AGN-241689): 10 mg once daily (QD), 30 mg QD, 30 mg twice daily (BID), 60 mg QD, and 60 mg BID for the prevention of episodic migraine and will characterize the dose/response relationship.

Detailed description:

Arms: arm 1: Placebo-matching atogepant capsule orally twice daily in the morning and in the evening for 12 weeks. arm 2: Atogepant 10 mg capsule orally once daily (QD) in the morning and one placebo-matching atogepant capsule orally once daily in the evening for 12 weeks. arm 3: Atogepant 30 mg capsule orally once daily in the morning and one placebo-matching atogepant capsule orally once daily in the evening for 12 weeks. arm 4: Atogepant 30 mg capsule orally twice daily (BID); 1 capsule in the morning and 1 capsule in the evening for 12 weeks. arm 5: Atogepant 60 mg capsule orally once daily in the morning and one placebo-matching atogepant capsule orally in the evening for 12 weeks. arm 6: Atogepant 60 mg capsule orally twice daily; 1 capsule in the morning and 1 capsule in the evening for 12 weeks.
Interventions: intervention 1: Atogepant intervention 2: Placebo-matching Atogepant
Intervention descriptions: intervention 1: Atogepant capsule. intervention 2: Placebo-matching atogepant capsule.

Protocol documents:
Prot_000.pdf: 
NCT02848326 
 
Study ID: CGP‐MD‐01 
 
Title:  A PHASE 2/3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND TOLERABILITY OF MULTIPLE DOSING REGIMENS OF ORAL AGN-
241689 IN EPISODIC MIGRAINE PREVENTION 
 
 
Protocol Amendment 2 Date: 11 Sept 2017 


Allergan Confidential
Protocol CGP-MD-01, Amendment 2
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Title Page
ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information 
which is the property of Allergan
A PHASE 2/3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND TOLERABILITY OF MULTIPLE DOSING REGIMENS OF ORAL 
AGN-241689 IN EPISODIC MIGRAINE PREVENTION
Protocol Number:  
CGP-MD-01, Amendment 2
Phase:
2/3
Name of Investigational Product:
AGN-241689
Sponsor:
US Agent:
Allergan Pharmaceuticals International Limited
Clonshaugh Industrial Estate, Coolock, Dublin 
17, Ireland
Allergan (Sales, LLC)
2525 DuPont Drive
Irvine, California USA
92612
Emergency Telephone Number(s):
Serious Adverse Event Reporting 
Fax Number(s):
Allergan Medical Monitor
Contact Information:
Refer to the Study Contacts Page
Allergan Signatory:
Original Protocol Date:
Protocol Amendment 1 Date:
Protocol Amendment 2 Date:
09 May 2016
11 Nov 2016
11 Sep 2017


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The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and Emergency Telephone 
Numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; US 21 CFR 312.23 
section 6(iii)b.


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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations.

Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(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 investigational product(s), and their trial-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Signature
Date


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Table of Contents
Title Page .................................................................................................................................. 1
Table of Contents ...................................................................................................................... 4
Protocol Summary .................................................................................................................... 8
1.
Background and Clinical Rationale................................................................................. 16
1.1
Background ............................................................................................................ 16
1.2
Overview of AGN-241689..................................................................................... 16
1.3
Rationale For Doses and Dose Regimens Selected................................................ 18
2.
Study Objectives and Clinical Hypotheses...................................................................... 18
2.1
Study Objectives .................................................................................................... 18
2.2
Clinical Hypotheses ............................................................................................... 18
3.
Study Design.................................................................................................................... 19
3.1
Structure................................................................................................................. 19
3.2
Efficacy Assessments............................................................................................. 19
3.5
Data Safety Monitoring Board............................................................................... 20
3.6
Adjudication Committee........................................................................................ 21
4.
Study Population and Entry Criteria................................................................................ 21
4.1
Number of Patients................................................................................................. 21
4.2
Inclusion Criteria.................................................................................................... 21
4.3
Exclusion Criteria................................................................................................... 22
4.4
Permissible and Prohibited Medications/Treatments............................................. 25
4.4.1
Permissible Medications/Treatments.......................................................... 25
4.4.2
Prohibited Medications/Treatments............................................................ 26
4.4.3
Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .............................................................................. 27
4.4.4
Special Diet or Activities............................................................................ 27
5.
Study Treatments ............................................................................................................. 28
5.1
Study Treatments and Formulations ...................................................................... 28
5.2
Control Treatment(s).............................................................................................. 28
5.3
Methods for Masking/Blinding.............................................................................. 28


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5.4
Treatment Allocation Ratio and Stratification ....................................................... 28
5.5
Method for Assignment to Treatment Groups/Randomization.............................. 28
5.6
Treatment Regimen and Dosing............................................................................. 29
5.7
Storage of Investigational products/Treatments..................................................... 30
6.
Response Measures and Summary of Data Collection Methods..................................... 30
6.1
Efficacy Measures.................................................................................................. 30
6.3
Future Biomedical Research .................................................................................. 34
6.4
Safety Measures ..................................................................................................... 35
6.4.1
Adverse Events........................................................................................... 35
6.4.2
Events of Clinical Interest .......................................................................... 35
6.4.3
Clinical Laboratory Determinations........................................................... 35
6.4.4
Vital Signs .................................................................................................. 36
6.4.5
Physical Examination................................................................................. 37
6.4.6
Electrocardiograms..................................................................................... 37
6.4.7
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................. 37
6.5
Other Study Supplies ............................................................................................. 38
6.6
Summary of Methods of Data Collection .............................................................. 38
7.
Statistical Procedures....................................................................................................... 38
7.1
Analysis Populations.............................................................................................. 38
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments........ 39
7.2.1
Primary Efficacy Variable .......................................................................... 40
7.2.2
Secondary Efficacy Variables..................................................................... 40
7.3
Hypothesis and Methods of Analysis..................................................................... 41
7.3.1
Primary Efficacy Analyses ......................................................................... 41
7.3.2
Secondary Efficacy Analyses ..................................................................... 42
7.6
Subgroup Analyses................................................................................................. 44
7.7
Sample Size Calculation ........................................................................................ 44
7.8
Interim Analyses..................................................................................................... 44


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8.
Study Visit Schedule and Procedures .............................................................................. 45
8.1
Patient Entry Procedures........................................................................................ 45
8.1.1
Overview of Entry Procedures ................................................................... 45
8.1.2
Informed Consent and Patient Privacy....................................................... 45
8.2
Washout Intervals................................................................................................... 45
8.3
Procedures for Final Study Entry........................................................................... 45
8.4
8.5
Instructions for the Patients.................................................................................... 50
8.6
Unscheduled Visits................................................................................................. 51
8.7
Compliance with Protocol...................................................................................... 51
8.8
Early Discontinuation of Patients .......................................................................... 51
8.9
Withdrawal Criteria................................................................................................ 52
8.10 Withdrawal from Future Biomedical Research...................................................... 52
8.11 Study Termination.................................................................................................. 52
9.
Adverse Events ................................................................................................................ 52
9.1
Definitions.............................................................................................................. 53
9.1.1
Adverse Event ............................................................................................ 53
9.1.2
Serious Adverse Event................................................................................ 53
9.1.3
Severity....................................................................................................... 54
9.1.4
Relationship to Study Drug or Study Procedure ........................................ 54
9.2
Procedures for Reporting Adverse Events ............................................................. 54
9.3
Procedures for Reporting a Serious Adverse Event............................................... 54
9.4
Exposure to Investigational Product during Pregnancy......................................... 55
9.5
ALT or AST Elevations.......................................................................................... 56
9.5.1
Potential Hy’s Law Cases........................................................................... 57
9.6
Procedures for Unmasking of Investigational Product .......................................... 58
10. Administrative Items ....................................................................................................... 58
10.1 Protection of Human Patients................................................................................. 58
10.1.1 Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 58
10.1.2 Compliance With IRB or IEC Regulations ................................................ 59


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10.1.3 Compliance With Good Clinical Practice .................................................. 59
10.1.4 Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21CFR Part 11)................................................................................... 59
10.2 Changes to the Protocol ......................................................................................... 59
10.3 Patient Confidentiality ........................................................................................... 59
10.3.1 Patient Privacy............................................................................................ 59
10.4 Documentation....................................................................................................... 60
10.4.1 Source Documents...................................................................................... 60
10.4.2 Case Report Form Completion................................................................... 61
10.4.3 Study Summary.......................................................................................... 61
10.4.4 Retention of Documentation ...................................................................... 61
10.5 Labeling, Packaging, and Return or Disposal of Investigational 
Products/Treatments............................................................................................... 62
10.5.1 Labeling/Packaging.................................................................................... 62
10.5.2 Clinical Supply Inventory .......................................................................... 62
10.5.3 Return or Disposal of Investigational Products/Treatments and/or Supplies
.................................................................................................................... 62
10.6 Monitoring by the Sponsor..................................................................................... 62
10.7 Handling of Biological Specimens ........................................................................ 63
10.8 Publications............................................................................................................ 63
10.9 Coordinating Investigator....................................................................................... 63
11. References........................................................................................................................ 64
12. Attachments..................................................................................................................... 66
12.1 Examination Procedures, Tests, Equipment, and Techniques................................ 66
12.1.1 International Classification of Headache Disorders, 3rd Edition, Beta 
Version ....................................................................................................... 66
12.2 Examples of Prohibited Medications ..................................................................... 81
12.3 Classification of Migraine Preventive Medications............................................... 83
12.4 Glossary of Abbreviations...................................................................................... 84
12.5 Protocol Amendment 1 Summary.......................................................................... 85
12.6 Protocol Amendment 2 Summary.......................................................................... 91


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Protocol Summary
Study Compound(s):  AGN-241689
Phase:  2/3
Study Objective(s): 
To evaluate the safety and tolerability of the following doses and dose regimens of AGN-241689 (10-mg once 
daily [QD], 30-mg QD, 30-mg twice daily [BID], 60-mg QD, and 60-mg BID for the prevention of episodic 
migraine.
To characterize the dose/response relationship across the following doses and dose regimens (10-mg QD, 
30-mg QD, 30-mg BID, 60-mg QD, and 60-mg BID) for the prevention of episodic migraine.
To prospectively test for superiority of the following doses and dose regimens of AGN-241689 (10-mg QD, 
30-mg QD, 30-mg BID, 60-mg QD, and 60-mg BID) versus placebo for the prevention of episodic migraine in 
this pivotal trial.
Clinical Hypotheses:  In individuals with episodic migraine, at least one active treatment arm, 60 mg QD or 60 
mg BID is superior to placebo as measured by the change from baseline in mean monthly migraine/probable 
migraine (MPM) headache days across the 12-week treatment period.
AGN-241689 has an acceptable safety and tolerability profile in patients with episodic migraine.
Study Design
Structure:  Multicenter, randomized, double-blind, placebo-controlled, parallel-group study
Duration:  The study will consist of a 4 week screening and baseline period, a 12-week double-blind treatment 
period, and a safety follow-up period of 4 additional weeks, for a total duration of 20 weeks
Test Product: AGN-241689 10-mg tablets, AGN-241689 30-mg tablets, AGN-241689 60-mg tablets. 
Investigational product will be over-encapsulated to maintain the blind.
Control:  AGN-241689 placebo tablets. Placebo tablets will be over-encapsulated to maintain the blind.
Dosage/Dose Regimen:  10-mg AGN-241689 QD, 30-mg AGN-241689 QD, 60-mg AGN-241689 QD, 30-mg 
AGN-241689 BID, and 60-mg AGN-241689 BID will be administered for 12 weeks duration
Randomization/Stratification:  Patients will be randomized to the following 6 arms  in a 2:1:2:1:2:1 ratio:

Placebo (n = 180)

AGN-241689 10-mg QD (n = 90)

AGN-241689 30-mg QD (n = 180)

AGN-241689 30-mg BID (n = 90)

AGN-241689 60-mg QD (n = 180)

AGN-241689 60-mg BID  (n = 90)
To maintain the blind, investigational product will be over-encapsulated and administered orally for 12 weeks to 
all patients. Patients, therefore, will receive either placebo twice daily, a morning dose of AGN-241689 with an 
evening dose of placebo, or AGN-241689 twice daily.  
No stratification will be performed.
Visit Schedule:  Individual patient participation will begin with a 4-week Screening/Baseline Period.  Patients 
who complete the 4-week Screening/Baseline Period and meet all entry criteria will be randomized at Visit 2 


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(randomization visit).  The Double-Blind treatment period will last 12 weeks, with a Safety Follow-up Period of
4 additional weeks.  
There will be 8 scheduled clinic visits:  Visit 1 (Screening/Baseline), Visit 2 (Randomization), Visit 3 (Week 2), 
Visit 4 (Week 4), Visit 5 (Week 6), Visit 6 (Week 8), Visit 7 (Week 12), and Visit 8 (Safety Follow-up). For 
details, please see Table 1–1, Schedule of Evaluations.
Study Population Characteristics
Number of Patients:  Approximately 810 patients will be randomized into the study
Condition/Disease:  Migraine with aura or Migraine without aura
Key Inclusion Criteria:  

Male or female patients age 18 to 75 years, inclusive, at Visit 1.

At least a 1-year history of migraine with or without aura consistent with a diagnosis according to 
the International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3 beta, 
2013; Section 12.1.1)

Age of the patient at the time of migraine onset < 50 years

History of 4 to 14 migraine/probable migraine headache days per month (see Section 6.1.1 for 
definition) in the 3 months prior to Visit 1in the investigator’s judgment

4 to 14 migraine/probable migraine headache days in the 28-day baseline period per electronic 
diary (eDiary)
Key Exclusion Criteria:

Has a history of migraine accompanied by diplopia or decreased level of consciousness, or retinal 
migraine as defined by ICHD-3 beta version, 2013

Has a current diagnosis of chronic migraine, new persistent daily headache,  trigeminal autonomic 
cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3 beta version, 
2013
 
 
 

Usage of opioids or barbiturates >2 days/month, triptans or ergots ≥10 days/month, or simple 
analgesics (eg, aspirin, non-steroidal anti-inflammatory drugs, acetaminophen) ≥15 days/month in 
the 3 months prior to Visit 1 per investigator’s judgment, or during the baseline period
(barbiturates are excluded during the baseline period and for the duration of the study [see 
Section 12.2 Examples of Prohibited Medications])

Patients with clinically significant hematologic, endocrine, cardiovascular, pulmonary, hepatic, 
gastrointestinal, or neurologic disease.
Response Measures
Efficacy: Frequency of migraine or probable migraine headache days, headache days, and acute medication use
days


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General Statistical Methods and Types of Analyses:  All safety analyses will be performed using the safety 
population, consisting of all patients who received at least one dose of the study treatment.  For safety analyses, 
the patients will be analyzed according to the actual treatment received at the first study treatment visit (rather 
than as randomized).  All efficacy analyses will be performed using the modified intent-to-treat (ITT) 
population, consisting of all randomized patients who received at least 1 dose of study treatment, had an 
evaluable baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 
9-12) of diary data.  For efficacy analyses, the patients will be analyzed according to randomization assignment, 
regardless of actual treatment received.
The primary efficacy endpoint is the change from baseline in mean monthly MPM headache days across the 12-
week treatment period.  Comparisons between each dose group and placebo will be done by a mixed-effects 
model for repeated measures (MMRM) of the change from baseline.  The statistical model will include 
treatment group, visit and treatment group by visit interaction as categorical fixed effects.  It will also include 
the baseline score and baseline-by-visit interaction as covariates.  Pairwise contrasts in the MMRM model will 
be used to make the pairwise comparisons of dose to placebo.  A sensitivity analysis will be performed on the 
primary endpoint to assess the robustness of the MMRM analysis to possible violation of the missing-at-random 
(MAR) assumption.  The sensitivity analysis will be done using a pattern-mixture model (PMM), under which 
data could be missing-not-at-random (MNAR), with repeated analyses combined via the multiple imputation 
(MI) procedure. An additional sensitivity, MI in conjunction with robust regression, will be performed in case 
of non-normality for the primary efficacy endpoint.     
Secondary efficacy endpoints include: (1) Change from baseline in mean monthly headache days across the 12-
week treatment period; (2) Proportion of patients with at least a 50% reduction in mean monthly MPM days 
across the 12-week treatment period; (3) Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period. 
Summary tables for each treatment and for each measurement time will include the number of patients and 
descriptive statistics (mean, standard deviation, median, minimum and maximum) and/or response frequencies.
For continuous variables, pairwise comparisons will be analyzed using MMRM.  For variables where data is 
binary, comparisons between treatment groups will be done by pairwise contrasts using logistic regressions for 
variables with only one postbaseline assessment or using generalized linear mixed model for variables with 
multiple postbaseline assessments.
The overall type I error rate for multiple comparisons across active treatment doses and the primary and 
secondary efficacy parameters will be controlled at the 0.05 level using a graphical approach by Bretz et al
(2011). The weighting strategy of the multiple comparisons is designed to allocate initial alpha equally to the 
QD and BID dose regimens. Within each dosing regimen, individual AGN-241689 doses will be tested in a
hierarchical order from high to low dose, i.e. for primary efficacy endpoint, low dose can be tested only if high 
dose comparison shows statistical significance. In addition, for a given dose comparison versus placebo, the 
strategy has the primary endpoint as gatekeeper to the secondary endpoints so that secondary endpoints can be 
tested only if primary hypothesis of the corresponding dose comparison reaches statistical significance. 
Weighted Bonferroni tests will be used for testing the hypotheses. A complete decision-flow graph and details 
of the graphical multiple comparison procedure will be presented in the statistical analysis plan of this study.
Sample Size Calculation:  
The assumptions and corresponding power assessments for the primary efficacy endpoint are shown in the table 
below. The treatment difference assumption is based on results from other episodic migraine prevention studies:
the placebo-adjusted reduction in monthly migraine days ranged from 1.1 to 2 days (topiramate [Silberstein et
al, 2004 and Brandes et al, 2004], telcagepant [Ho et al, 2014], and CGRP monoclonal antibodies Ph2 studies 


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[Dodick et al, 2014; Dodick et al, 2014; Bigal et al, 2015; Sun et al, 2016], and their Ph3 studies results reported 
from American Headache Society & American Academy of Neuroscience 2017). Common standard deviation is 
estimated based on blinded interim data assessments of this study. Power is calculated via 10,000 simulations 
based on multiplicity adjustment.
60mg BID 
(n=90)
30mg BID 
(n=90)
60mg QD 
(n=180)
30mg QD 
(n=180)
10mg QD 
(n=90)
Assumed Treatment
difference vs. placebo
(placebo n = 180)
-1.6
-1.5
-1.5
-1.4
-1.2
Effect size
(Common SD = 3.0)
0.53
0.5
0.5
0.47
0.4
Power
97.0%
91.4%
99.3%
98.1%
80.3%
QD = once daily; BID = twice daily; SD = standard deviation.


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1.
Background and Clinical Rationale 
1.1 Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
occurring between the ages of 25-55 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 et al, 2005, Lipton et al, 2007). In the US alone, work loss due to 
migraine is estimated to cost ~ $13 billion annually (Hu et al, 1999). Prevalence is similar in 
Europe, with migraine headache affecting on average 17.6% of women and 8% of men 
(Stovner, 2010). It is currently ranked by the World Health Organization (WHO) as 19th 
among causes of disability (Katsarava et al, 2012).
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) is a syndrome diagnosis 
applied to patients with migraine (with or without aura) who have 1-14 headache days per 
month. Chronic migraine (CM) is a specific ICHD-3 beta version diagnosis applied to a 
subset of patients with ≥15 headache days per month (Katsarava et al, 2011; Olesen et al, 
2006; ICHD-3 beta version, 2013). This study will evaluate the efficacy, safety and 
tolerability of AGN-241689 in patients with episodic migraine.
1.2 Overview of AGN-241689
AGN-241689 is a potent, selective oral calcitonin gene-related peptide (CGRP) receptor 
antagonist being developed for migraine prevention. CGRP is a neuropeptide implicated in
the pathophysiology of migraine. CGRP levels in the cranial venous outflow (i.e, 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 


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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 (IV) formulation of olcegepant (Olesen et al,
2004), and replicated by Merck & Co., Inc with an oral formulation of MK-0974
(telcagepant), a highly selective CGRP receptor antagonist (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 (photophobia,
phonophobia, and nausea), as well as the key secondary endpoint of 24-hour sustained pain
freedom (Connor, 2009). However, serum alanine aminotransferase (ALT) increases were 
observed with telcagepant.  For this reason, the development of these oral CGRP antagonists 
was stopped.
Recently, several phase 2 trials have been published that further establish proof-of-concept of 
CGRP as a therapeutic target in the prevention of episodic and chronic migraine 
(Dodick DW, Goadsby PJ, Silberstein SD, et al, 2014; Bigal et al, 2015; Dodick DW, 
Goadsby PJ, Spierings EL, et al, 2014).  Specifically, TEV-48125, LY-2951742, and ALD-
403 are injectable monoclonal antibodies shown to be efficacious in the prevention of 
migraine that act by targeting CGRP and blocking the CGRP pathway thought to be involved 
in migraine pathophysiology. AGN-241689 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 AGN-241689. To date, no safety signal in hepatic lab parameters has been 
observed in either preclinical or clinical studies conducted with AGN-241689.
The purpose of this study is to prospectively assess the safety, tolerability and efficacy of 10-, 
30- and 60-mg once daily (QD) and 30- and 60-mg twice daily (BID) doses of AGN-241689
compared with placebo in the prevention of episodic migraine, in a randomized, double-
blind, placebo-controlled Phase 2/3 study.  This study is designed to be a pivotal trial, and 
will be used to support registration applications.
Additional information on non-clinical pharmacology, toxicology, and pharmacokinetic 
properties of AGN-241689 can be found in the Investigator’s Brochure.  


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1.3 Rationale For Doses and Dose Regimens Selected 
The ability of a CGRP antagonist to block capsaicin induced increases in dermal blood flow 
has been used as a pharmacodynamic assay to determine doses which inhibit peripheral 
CGRP function and estimate potentially effective clinical doses in migraine (Hewitt et al,
2011; Li et al, 2014). Based on this model, doses of AGN-241689 of 10 mg QD, 30 mg QD, 
and 60 mg QD are potentially effective doses for migraine prevention.  In addition, the PK 
characteristics of AGN-241689 suggest the possibility that a BID dosing regimen may 
provide better 24-hour CGRP inhibition than does a QD regimen. Based on these 
considerations, this study will investigate doses of AGN-241689 10 mg, 30 mg, and 60 mg 
QD and doses of 30 mg and 60 mg BID for 12 weeks.  
Prior testing in the Phase 1 program suggests that the range of doses tested will be well-
tolerated and safe in humans.  Daily dosing of 170 mg per day was studied in healthy 
subjects for 28 days; this was well-tolerated with an unremarkable AE profile and no 
significant elevations of ALT or aspartate aminotransferase (AST) were observed.  Results 
from the 28-day multiple dose study and other Phase 1 studies support the safety and 
tolerability of the dose range tested in this protocol. 
2.
Study Objectives and Clinical Hypotheses
2.1 Study Objectives
To evaluate the safety and tolerability of the following doses and dose regimens of 
AGN-241689 (10-mg QD, 30-mg QD, 30-mg BID, 60-mg QD, and 60-mg BID) for the 
prevention of episodic migraine. 
To characterize the dose/response relationship across the following doses and dose regimens 
(10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, and 60 mg BID) for the prevention of 
episodic migraine.
To prospectively test for superiority of the following doses and dose regimens of 
AGN-241689 (10-mg QD, 30-mg QD, 30-mg BID, 60-mg QD, and 60-mg BID) versus 
placebo for the prevention of episodic migraine in this pivotal trial
2.2 Clinical Hypotheses
In individuals with episodic migraine, at least one active treatment arm, 60 mg QD or 60 mg 
BID is superior to placebo as measured by the change from baseline in mean monthly MPM 
days across the 12-week treatment period.


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AGN-241689 has an acceptable safety profile and is well tolerated in patients with episodic 
migraine.
3.
Study Design
3.1 Structure
This is a multi-center, randomized, double-blind, placebo-controlled, parallel group study 
conducted at approximately 75 sites in the United States.   Approximately 810 patients will 
be randomized to one of six treatment arms (placebo, 10-mg QD, 30-mg QD, 30-mg twice 
daily, 60-mg QD, and 60-mg twice daily) in a 2:1:2:1:2:1 ratio as follows::
o
Placebo (n = 180)
o
AGN-241689 10-mg QD (n = 90)
o
AGN-241689 30-mg QD (n = 180)
o
AGN-241689 30-mg BID (n = 90)
o
AGN-241689 60-mg QD (n = 180)
o
AGN-241689 60-mg BID  (n = 90)
More patients will be allocated to the 30-mg QD and 60-mg QD arms to maximize the power 
to detect a difference from placebo in the primary endpoint.  Although fewer patients are 
allocated to the BID regimen arms and the 10-mg QD arm, these are still adequately powered 
to detect a clinically meaningful difference.  
To maintain the blind, investigational product will be administered orally twice daily for 
12 weeks to all patients. Patients, therefore, will receive either placebo twice daily, a morning 
dose of AGN-241689 with an evening dose of placebo, or AGN-241689 twice daily.  
Patient participation will begin with a 4-week Screening/Baseline Period.  Patients 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. 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 (Safety Follow-up). For details, 
please see Table 1–1, Schedule of Visit and Procedures.
3.2 Efficacy Assessments
Efficacy assessments will be based on information recorded by the patient.  An eDiary will 
be used daily at home to collect data on headache duration, headache characteristics, 


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symptoms, and acute medication use, which will be collectively applied to define migraine, 
probable migraine, and headache days per the criteria listed in Sections 6.1.1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5 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. 


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Details of the DSMB memberships, standard operational procedures for data 
monitoring/review, frequency of review, and other pertinent details will be provided in a 
separate DSMB Charter.
3.6 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 x the upper limit of normal (ULN) in the 
AGN-241689 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 AGN-241689.
4.
Study Population and Entry Criteria
4.1 Number of Patients 
Approximately 810 patients will be randomized at approximately 75 sites in the US. 
4.2 Inclusion Criteria
The following are requirements for entry into the study: 
1. Written informed consent and patient privacy information (eg, Written 
Authorization for Use and Release of Health and Research Study Information) 
obtained from the patient prior to initiation of any study-specific procedures.
2. Male or female patients ages 18 to 75 years, inclusive, at Visit 1.
3. At least a 1-year history of migraine with or without aura consistent with a 
diagnosis according to the International Classification of Headache Disorders, 3rd
edition, beta version (ICHD-3 beta, 2013; Section 12.1.1)
4. Age of the patient at the time of migraine onset < 50 years
5. History of 4 to 14 migraine/probable migraine headache days per month (see 
Section 6.1.1 for definition) on average in the 3 months prior to Visit 1 in the 
Investigator’s judgment 
6. 4 to 14 migraine/probable migraine headache days in the 28-day baseline period 
per electronic diary (eDiary)


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7. Completed at least 20 out of 28 days in the eDiary during baseline period and is 
able to read, understand, and complete the study questionnaires and eDiary per 
Investigator’s judgment.
 
4.3 Exclusion Criteria
The following are criteria for exclusion from participating in the study:
1. Difficulty distinguishing migraine headaches from tension-type or other 
headaches
2. Has a history of migraine with accompanied by diplopia or decreased level of 
consciousness or retinal migraine as defined by ICHD-3 beta version, 2013
3. Has a current diagnosis of chronic migraine, new persistent daily headache, 
trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial 
neuropathy as defined by ICHD-3 beta version, 2013
 
 
 
 
 
8. Usage of opioids or barbiturates > 2 days/month, triptans or ergots 
≥10 days/month, or simple analgesics (eg, aspirin, non-steroidal anti-
inflammatory drugs [NSAIDs], acetaminophen) ≥15 days/month in the 3 months 


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prior to Visit 1 per investigator’s judgment, or during the baseline period
(barbiturates are excluded during the baseline period and for the duration of the 
study [see Section 12.2 Examples of Prohibited Medications])
9. Woman is pregnant, planning to become pregnant during the course of the study, 
or currently lactating. Women of childbearing potential must have a negative 
urine pregnancy test at Visit 1 and Visit 2
 
 
 
 
 
 
 
 
 
 
 


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15. 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 patient’s participation in the study, the patient 
may be included
16. 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, or 
anti–hepatitis C antibody testing
 
 
 
 
 
 
 
 
20. 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
 
 
 


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4.4 Permissible and Prohibited Medications/Treatments
4.4.1
Permissible Medications/Treatments
Medications which are not specifically prohibited in Section 4.4.2 are allowed, with the 
following clarifications and restrictions:
The following medications for the acute treatment of migraine are allowed during the study:

any triptan

any ergot derivative

any opioid

any other form of analgesic (including acetaminophen)

any NSAID agent

any antiemetic agent


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Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
Selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine reuptake 
inhibitors (SNRI) will be permitted provided that treatment is stable for at least 60 days prior 
to screening (Visit 1) and continues without change in dose throughout the study.
Therapy considered necessary for the patient's welfare may be given at the discretion of the 
investigator.  If the permissibility of a specific medication/treatment is in question, please 
contact Allergan.
4.4.2
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to Visit 1(unless otherwise indicated)
and throughout the study period: 

Strong and moderate cytochrome P450 3A4 (CYP3A4) inhibitors, including but not 
limited to:  systemic (oral/intravenous [IV]) itraconazole, ketoconazole, fluconazole; 
erythromycin, clarithromycin, telithromycin; diltiazem, verapamil; aprepitant, 
cyclosporine, nefazodone, cimetidine, quinine, and HIV protease inhibitors

Strong and moderate CYP3A4 inducers, including but not limited to:  barbiturates (eg, 
phenobarbital and primidone), systemic (oral/IV) glucocorticoids, nevirapine, efavirenz, 
pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and St. John’s wort

Strong organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors (eg, 
gemfibrozil) 

Drugs with narrow therapeutic margins with theoretical potential for CYP drug 
interactions (eg,warfarin)

Medications with demonstrated efficacy for the prevention of migraine (eg, amitriptyline, 
topiramate, propranolol). Refer to Section 12.3.

Botulinum toxin injections (eg, Botox®) into areas of the head, face, or neck within 6 
months prior to Visit 1 and throughout the study period

Acupuncture, TENS (transcutaneous electrical nerve stimulation), cranial traction, 
nociceptive trigeminal inhibition or occipital nerve block treatments, or dental splints for 
headache, within 4 weeks prior to entry into the baseline phase at week -4 or at any time 
during the study (including the week -4 to day 1 baseline phase)


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The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan should be notified 
before the prohibited medication/treatment is administered.
4.4.3
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For purposes of this study, females will be considered of childbearing potential unless they 
are naturally postmenopausal (ie, no menses for 2 years) or permanently sterilized (ie, 
bilateral tubal ligation, bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).  
For women of childbearing potential who may participate in the study, the following methods 
of contraception, if properly used, are generally considered reliable: hormonal contraceptives
(ie, oral, patch, vaginal ring, injection, implant), male condom with intravaginal spermicide, 
diaphragm or cervical cap with spermicide, intrauterine device, vasectomized partner, or 
sexual abstinence.
For males who may participate in the study, the following methods of contraception, if 
properly used, are generally considered reliable: post-bilateral vasectomy, barrier 
contraception or sexual abstinence. Male participants must also refrain from donating
sperm during the course of the study.
The investigator and each patient will determine the appropriate method of contraception for 
the patient during the participation in the study.
If a female becomes pregnant during the study, the investigator will notify Allergan
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow-up.  The investigator will (1) notify the patient’s physician 
that the patient was being treated with an investigational drug AGN-241689 and (2) follow 
the progress of the pregnancy.  The investigator must document the outcome of the 
pregnancy and provide a copy of the documentation to Allergan.
4.4.4
Special Diet or Activities 
Patients should refrain from consuming grapefruit or grapefruit juice from the time the 
consent form is signed until completion of the study.  Patients should also refrain from 
making significant changes to their diet or caffeine intake during the study.
Alcohol intake should be limited to no more than 3 drinks per day throughout the study.  A 
drink is defined as a 12-ounce can/bottle of beer, a 4-ounce glass of wine, or 1 ounce of 
liquor.


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5.
Study Treatments 
5.1 Study Treatments and Formulations
Over-encapsulated tablets containing 10-mg 
, 30-mg 
 and 60-mg 
 of AGN-241689
5.2 Control Treatment(s) 
Placebo 
over-encapsulated tablets 
5.3 Methods for Masking/Blinding
All study treatments will be provided in identical blister cards to maintain masking of the 
study.
Over-encapsulation will also be implemented to maintain study masking, and all patients will 
be instructed to take investigational product twice daily (one capsule in the morning and one 
capsule in the evening) at approximately the same times each day.  Patients, therefore, will 
receive either placebo twice daily, a morning dose of AGN-241689 with an evening dose of 
placebo, or AGN-241689 twice daily.  
5.4 Treatment Allocation Ratio and Stratification 
Patients will be randomized to the following 6 arms  in a 2:1:2:1:2:1 ratio:

Placebo (n =180)

AGN-241689 10-mg QD (n = 90)

AGN-241689 30-mg QD (n = 180)

AGN-241689 30-mg BID (n = 90)

AGN-241689 60-mg QD (n = 180)

AGN-241689 60-mg BID  (n = 90)
No stratification will be performed.
5.5 Method for Assignment to Treatment Groups/Randomization
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a patient number that will serve as the patient identification number on all study 
documents.


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Central implementation of by-site randomization will be used for this study to assign patients 
into treatment groups.  
At the time of randomization (i.e., Visit 2), eligible patients will be randomized by blocks in 
a 2:1:2:1:2:1 ratio into the following arms: placebo, 10-mg AGN-241689 QD, 30-mg AGN-
241689 QD, 30-mg AGN-241689 twice daily, 60-mg AGN-241689 QD, and 60-mg AGN-
241689 twice daily.
An automated interactive web response system  (IWRS) will be used to manage the 
randomization and treatment assignment based on a randomization scheme prepared by 
Allergan Biostatistics.
Investigational product will be labeled with medication kit numbers.  The IWRS system will 
provide the site with the specific medication kit number(s) for each randomized patient at the 
time of randomization.  Sites will dispense investigational product  according to the IWRS 
instructions.  Sites will also log onto the IWRS at subsequent visits to obtain a kit number for 
dispensing investigational product. Sites will receive the IWRS confirmation notifications for 
each transaction.  All notifications are to be maintained with the study source documents.
5.6 Treatment Regimen and Dosing
Treatments to be used in this trial are listed in (Table 5–1).  Patients who meet all of the study 
entry criteria at Visit 2 will be randomized and provided with investigational product to be 
taken on an outpatient basis.  Sites will subsequently dispense investigational product to 
patients at Visits 3, 4, 5, and 6.  Patients will take their first dose of investigational product at 
the clinic at Visit 2 (Section 8.5) and will be instructed to take their investigational product
twice daily (approximately 12 hours interval between doses)  at approximately the same 
times each day.  Investigational product will be administered orally for 12 weeks, and 
patients will be followed for 4 weeks following discontinuation of the investigational 
product.


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Table 5–1
Study Treatments 
Drug/Dose
Investigational 
Product
Frequency
Investigational Product
Administration (AM/PM)
Route of Administration
Placebo
Twice Daily
Placebo/
Placebo
Oral (capsule)
AGN-241689 10 mg 
QD
Twice Daily
AGN-241689 10 mg/
Placebo
Oral (capsule)
AGN-241689 30 mg 
QD
Twice Daily
AGN-241689 30 mg/
Placebo
Oral (capsule)
AGN-241689 30 mg 
BID
Twice Daily
AGN-241689 30 mg/
AGN-241689 30 mg
Oral (capsule)
AGN-241689 60 mg 
QD
Twice Daily
AGN-241689 60 mg/
Placebo
Oral (capsule)
AGN-241689 60 mg 
BID
Twice Daily
AGN-241689 60 mg/
AGN-241689 60 mg
Oral (capsule)
5.7 Storage of Investigational products/Treatments
The investigational product must be stored at room temperature in a securely locked cabinet. 
Further details regarding the storage of the investigational product are in the Study Reference 
Manual.
6.
Response Measures and Summary of Data Collection Methods
6.1 Efficacy Measures
Efficacy assessments will be based on information recorded by the patient.  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, 
probable migraine, and headache days per the criteria listed in Sections 6.1.1.  The HIT-6, 
ACM-I, EQ-5D-5L, PGIC, WPAI-SHP V2.0, and Patient Satisfaction with Study Medication
will be administered in an electronic tablet (eTablet) at the clinic visits.
6.1.1
Efficacy Measures
 
 
 


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6.3 Future Biomedical Research
Blood samples will be collected from all patients who consent to participate in the substudy, 
for the purposes for Future Biomedical Research. The samples will be obtained at the 
Screening Visit. All samples will be sent to the designated central laboratory and shipped to a 
biorepository for storage.  Please refer to the Central Laboratory Manual for the genetic 
blood sampling procedures, shipping instructions, and contact information. Anonymized
samples may be stored in the biorepository database for potential analysis under separate 
protocols for up to 15 years. Samples may be stored for a longer time if a regulatory or 
governmental authority has active questions that are being answered. In this special 
circumstance, samples will be stored until these questions have been adequately addressed.
The anonymized genetic material from the blood samples may also be used for future, 
unspecified research, not limited to the disease being studied in this particular clinical study.
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research substudy; however, participation is optional and will require a separate 
informed consent form. A patient who initially consents can withdraw that consent at any 
time and have his or her sample destroyed including any by-products of the sample whenever 
possible.


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6.4 Safety Measures
6.4.1
Adverse Events
Subjective AEs will be collected from the time of consent through the last visit. For all AEs, 
the Investigator must provide an assessment of the severity, causal relationship to the 
investigational product, start and stop date, and seriousness of the event (eg, serious adverse 
event [SAE]), document all actions taken with regard to the investigational product, and 
detail any other treatment measures taken for the AE. For events noted as serious adverse 
events (SAEs), the Sponsor must be notified immediately to meet their reporting obligations 
to appropriate regulatory authorities.
6.4.2
Events of Clinical Interest
Selected non-serious and serious events are of clinical interest and will require immediate 
reporting, recording and follow-up. The following events will be closely monitored:

Suicidal ideations with intent, with or without a plan, (ie, Type 4 or 5 on the C-SSRS) or 
any suicidal behaviors

Elevated ALT or AST lab value that is ≥ 3 x the ULN

Potential Hy’s law cases: elevated ALT or AST lab value that is ≥ 3 x the ULN and an 
elevated total bilirubin lab value that is ≥ 2 x the ULN and, at the same time, an alkaline 
phosphatase lab value that is < 2 x the ULN.
Reporting requirements for ALT or AST elevations and potential Hy’s law cases are outlined 
in Sections 9.5 and 9.5.1. Responses to the C-SSRS that meet the above criterion will 
captured in the eTablet and monitored by Allergan. Events that are determined to be AEs or 
SAEs must be reported appropriately via the designated eCRF pages and forms. 
6.4.3
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at the visits outlined in 
Table 1–1. Hematology, chemistry, and urinalysis will be conducted at these visits. Serology, 
coagulation parameters (INR), and the Urine drug screen will be conducted at Screening 
(Visit 1). The investigator will assess the clinical significance of any values outside the 
reference ranges provided by the central laboratory. Patients with abnormalities judged to be 
clinically significant at Screening (Visit 1) or with positive results on the urine drug screen 
will be excluded from the study. 


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Women of childbearing potential will be required to have a urine pregnancy test at all visits. 
A positive pregnancy test at Visit 1 or Visit 2 will exclude the patient from participation in 
the study.  
Investigators may also perform unscheduled clinical laboratory determinations at any time 
for the purpose of patient safety. 
Patients are not required to fast overnight before coming in for their appointments.
The clinical laboratory parameters to be measured are shown in Table 6–1.
Table 6–1
Clinical Laboratory Parameters
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, 
total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, creatine kinase, total protein, albumin, 
calcium, phosphorus, uric acid, total cholesterol. The estimated glomerular 
filtration rate will be calculated by the central laboratory.
Hematology
Hemoglobin; hematocrit; red blood cell count; red blood cell indices (mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration); white blood cell count, including differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils); platelet count
Urinalysis
Urine dipstick for specific gravity, pH, protein, glucose, ketones, bilirubin, and 
blood; microscopic exam including red blood cells/high-power field, white blood 
cells/high-power field, and casts/low-power field.
Coagulation
At Visit 1 only: international normalized ratio 
Serology
At Visit 1 only: anti-hepatitis A IgM antibody, hepatitis B surface antigen, anti–
hepatitis C antibody
Urine Drug Screen
Screening for drugs of abuse (eg, marijuana, cocaine, phencyclidine, 
amphetamines, benzodiazepines, barbiturates, opiates) will be conducted using a 
urine drug screen at Visit 1. If positive, the urine drug screen may be repeated with 
permission from Allergan; a negative result or an explanation of a positive result 
because of concomitant medication use (eg, opioids prescribed for migraine pain)
will be required for randomization.
A central laboratory will be used to evaluate all urine and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory.
6.4.4
Vital Signs
Vital sign measurements, including sitting and standing blood pressure (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 patient sits quietly for 
5 minutes, followed by a second set of measurements taken after the patient stands for at 
least 3 minutes (but no longer than 10 minutes).


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6.4.5
Physical Examination
A complete physical examination will be performed at the visits outlined in Table 1–1. A 
professionally trained physician or healthcare professional licensed to performed physical 
examinations will examine the patient for any detectable abnormalities of the following body 
systems:  general appearance; neck (including thyroid); head, eyes, ears, nose, and throat; 
lungs; heart/cardiovascular; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic; skin; and other. The neurologic examination should be conducted to detect the 
presence of any significant sensory/motor abnormalities.
6.4.6
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in Table 1–1. All ECGs should be 
performed after the patient has been supine for at least 5 minutes. A copy of the ECG 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 patient’s eCRF.
6.4.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation 
and behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 
2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods [not 
plan] without intent to act), 4 (active suicidal ideation with some intent to act, without 
specific plan), and 5 (active suicidal ideation with specific plan and intent). The C-SSRS also 
captures information about the intensity of ideation, specifically the frequency, duration, 
controllability, deterrents, and reasons for the most severe types of ideation. Suicidal 
behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or 
behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). More than 
1 classification can be selected provided they represent separate episodes. For actual attempts 
only, the actual or potential lethality is classified for the initial, most lethal, and most recent 
attempts. The C-SSRS will be completed at all study visits. At Visit 1 (Screening) the 
C-SSRS will be completed for the patient’s lifetime history of suicidal ideation and behavior. 
At all other visits the C-SSRS will be completed for ideation and behavior since the previous 
visit. The C-SSRS will be completed on the eTablet by the investigator or designee with 
current and valid training in administering the assessment. A patient should not be released 
from the study center until the results of C-SSRS are reviewed and it is confirmed that the 
patient is not considered to be at risk.


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6.5 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 
culture/sensitivity), and urine dipstick reagent strips

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 tablets
6.6 Summary of Methods of Data Collection
An IWRS will be used to randomize patients and manage investigational product inventory. 
All office visit data (ie, non-diary data) for this study will be collected by either the eTablet 
(eg, questionnaires for patient reported outcomes) or eCRFs via an electronic data capture 
system. Source documents will be used at the sites and may include a patient’s medical 
record, hospital charts, clinic charts, the investigator’s patient 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 Lab Procedure Manual.
Patients 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 8.  Training for 
the eDiary will be provided for qualified patients during the Screening/Baseline visit 
(Visit 1).
7.
Statistical Procedures
7.1 Analysis Populations
All safety analyses will be performed using the safety population, consisting of all patients 
who received at least one dose of the study treatment.  For safety data analyses, the patients 
will be analyzed according to actual treatment received (rather than as randomized).  The 
Intent-to-Treat (ITT) Population will consist of all randomized patients. All efficacy analyses 
will be performed using the modified intent-to-treat (ITT) population, consisting of all 


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randomized patients who received at least 1 dose of study treatment, had an evaluable 
baseline period of diary data, and had at least 1 evaluable post-baseline 4-week (Weeks 1-4, 
5-8, and 9-12) of diary data.  For efficacy data analyses, the patients will be analyzed 
according to randomization assignment, regardless of actual treatment received.
7.2 Collection and Derivation of Primary and Secondary Efficacy 
Assessments
For analysis purposes, four weeks (28 days) will be considered as one month. On a daily 
basis during the 28-day baseline period and throughout the double-blind treatment period, 
patients 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.  Patients will be able to report headache data, including absence 
of headache, for the day of the diary report and for the day immediately prior to the day of 
the diary report, as long as information reported is for a time subsequent to the patient’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 1-4, 5-8 and 9-12, corresponding to 
days 1-28, 29-56 and 57-84).  Therefore, for data analysis purposes, the number of 
migraine/probable migraine headache days during the first 28 days of the baseline phase, 
starting with the day of the screening visit, will serve as the “baseline”, and change from 
baseline will be calculated for consecutive 28-day periods beginning with Day 1.
In order to be randomized, a patient should be in the baseline phase for at least 28 days and 
must report diary data for at least 20 days (including missing recall) during the 28-day 
baseline period.  If less than 28 days of baseline data are reported, the number of headache 
days and other such counting variables for “baseline” will be prorated to standardize the 
count to a 28-day equivalent.  Subsequent to treatment start, the number of headache days 
will be counted in successive and non-overlapping 4-week (ie, 28-day) windows.  Headaches 
that continue into a subsequent 4-week period will be counted (with recorded severity and 
duration) as occurring in each period.  
If any diary window for a patient has at least 12 but less than 28 days of reported data, the 
prorated approach will be used.  If a patient reports less than 12 days of headache data, the 
patient’s observed counts in that particular 28-day dairy window will be set to missing for 


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that window.  These prorating rules will be applied to all efficacy analyses of diary data 
unless otherwise stated.  
7.2.1
Primary Efficacy Variable
The primary efficacy variable is the change from baseline in mean monthly MPM headache 
days across the 12-week treatment period. Baseline is defined as the number of MPM days 
during the first 28 days of the screening/baseline period, starting with the day of the 
screening visit.  
7.2.2
Secondary Efficacy Variables
The 3 secondary efficacy variables include:

Change from baseline in mean monthly headache days across the 12-week treatment 
period.

Proportion of patients with at least a 50% reduction in mean monthly MPM headache 
days across the 12-week treatment period.

Change from baseline in mean monthly acute medication use days across the 12-week 
treatment period
 
 
 
  
 
 


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7.3 Hypothesis and Methods of Analysis
7.3.1
Primary Efficacy Analyses
The primary efficacy analysis is on the change from baseline in the mean monthly MPM 
headache days across the 12-week treatment period. The primary null hypothesis is that 
AGN-241689 treatment doses 10 mg QD, 30 mg QD, 60 mg QD, 30 mg BID and 60 mg BID 
are each equally effective to placebo in decreasing from baseline the number of headache 
days per 4 weeks.  The alternative hypothesis is that at least one of those five doses of AGN-
241689 has a different effect than placebo.  
The primary comparison between treatment groups will be done by a mixed-effects model for 
repeated measures (MMRM) of the change from baseline.  The statistical model will include 
treatment group, visit and treatment group by visit interaction as categorical fixed effects.  It 
will also include the baseline score and baseline-by-visit interaction as covariates.  Pairwise 
contrasts in the MMRM model will be used to make the pairwise comparisons of each dose 
to placebo.   


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A sensitivity analysis will be performed on the primary endpoint to assess the robustness of 
the MMRM analysis to possible violation of the missing-at-random (MAR) assumption.  The
sensitivity analysis will be done using a pattern-mixture model (PMM), under which data 
could be missing-not-at-random (MNAR), with repeated analyses combined via the 
reference-based multiple imputation (MI) procedure. An additional sensitivity, MI in 
conjunction with robust regression, will be performed in case of non-normality for the 
primary efficacy endpoint.      
7.3.2
Secondary Efficacy Analyses 
The secondary efficacy variables are identified in rank order in Section 7.2.2.  The overall
type I error rate for multiple comparisons across active treatment doses and the primary and 
secondary efficacy parameters will be controlled at the 0.05 level using a graphical approach 
by Bretz et al (2011).  The weighting strategy of the multiple comparisons is designed to 
allocate initial alpha equally to the QD and BID dose regimens. Within each dosing regimen, 
individual AGN-241689 doses will be tested in a hierarchical order from high to low dose, 
i.e. for primary efficacy endpoint, low dose can be tested only if high dose comparison shows 
statistical significance. In addition, for a given dose comparison versus placebo, the strategy 
has the primary endpoint as gatekeeper to the secondary endpoints so that secondary 
endpoints can be tested only if primary hypothesis of the corresponding dose comparison 
reaches statistical significance. Weighted Bonferroni tests will be used for testing the 
hypotheses. A complete decision-flow graph and details of the graphical multiple comparison 
procedure will be presented in the statistical analysis plan of this study.
For continuous variables, pairwise comparisons will be analyzed using MMRM, with
baseline covariate.  For variables where data is binary, comparisons between treatment 
groups will be done by pairwise contrasts using logistic regressions for variables with only 
one postbaseline assessment or using generalized linear mixed model for variables with 
multiple postbaseline assessments.
 
  
 
 


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7.6 Subgroup Analyses
There are no planned subgroup analyses.
7.7 Sample Size Calculation
The assumptions and corresponding power assessments for the primary efficacy endpoint are 
shown in the table below. The treatment difference assumption is based on results from other 
episodic migraine prevention studies: the placebo-adjusted reduction in monthly migraine 
days ranged from 1.1 to 2 days (topiramate [Silberstein et al, 2004 and Brandes et al, 2004], 
telcagepant [Ho et al, 2014], and CGRP monoclonal antibodies Ph2 studies [Dodick et al, 
2014; Dodick et al, 2014; Bigal et al, 2015; Sun et al, 2016], and their Ph3 studies results 
reported from American Headache Society & American Academy of Neuroscience 2017). 
Common standard deviation is estimated based on blinded interim data assessments of this 
study. Power is calculated via 10,000 simulations based on multiplicity adjustment.
60mg BID 
(n=90)
30mg BID 
(n=90)
60mg QD 
(n=180)
30mg QD 
(n=180)
10mg QD 
(n=90)
Assumed Treatment
difference vs. placebo
(placebo n = 180)
-1.6
-1.5
-1.5
-1.4
-1.2
Effect size
(Common SD = 3.0)
0.53
0.5
0.5
0.47
0.4
Power
97.0%
91.4%
99.3%
98.1%
80.3%
QD = once daily; BID = twice daily; SD = standard deviation.
7.8 Interim Analyses
There is no interim analysis planned.


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8.
Study Visit Schedule and Procedures
Please see Table 1–1 for a schedule of visits and procedures and Figure 1 for a study visit 
flowchart.
8.1
Patient Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study.
8.1.2
Informed Consent and Patient Privacy
The study will be discussed with the patient and a patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The patient
must also give authorization and other written documentation in accordance with local 
privacy requirements (where applicable) prior to any study-related procedures or change in 
treatment.
Each patient who provides informed consent and/or assent will be assigned a patient number 
that will be used on patient documentation throughout the study.
The investigator or qualified designee will explain the PK and future biomedical research 
consents to the patient and answer all of his/her questions. Patients will sign separate consent 
forms to participate in the PK substudy and future biomedical research before performing 
any procedure related to the substudies, respectively.
8.2 Washout Intervals
This study will not include a washout period.  
8.3 Procedures for Final Study Entry 
At the Screening and Randomization visits (Visits 1 and 2), patients must meet all of the 
inclusion criteria and must not meet any of the exclusion criteria. Rescreening of patients 
may be considered with permission from Allergan. Also, all females 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 investigational product).


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Prior to randomization, confirm that the patient had 4 to 14 migraine/probable migraine 
headache days  and < 15 headache days during the 28-day baseline period (see Section 6.1.1
for definition) and completed the eDiary for at least 20 of the 28 days.
See Section 5.5 for the method for assignment to treatment groups/randomization.
 
 
 
 
 
 
 
 


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8.5 Instructions for the Patients
Section 4.4.4 provides diet and activity instructions for patients enrolled in the study.
Patients will be provided with instructions on daily completion of the eDiary. A practice 
session with a hypothetical scenario should be administered to ensure the patients’ 
comprehension of the questions and the information to be entered. In addition, prohibited 
medications should be reviewed with the patients. Patients will be instructed to bring their 
eDiary to each clinic visit and return their investigational product (used and unused).
Patients should be instructed to take investigational product twice daily at approximately the 
same times each day (approximately 12 hours between doses). For dosing on Day 1 (Visit 2), 
the first dose is to be taken at the study site, and patients should be advised to take the second 
dose depending on the time of the site visit and the patient’s usual routine. 
Patients should use appropriate contraceptive measures for the duration of their participation 
in the study. (See Section 4.4.3)


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8.6 Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to 
ensure the safety and well-being of the patients during the study period. Unscheduled visit 
eCRFs should be completed for each unscheduled visit.
8.7 Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1–1, and the 
timing of the visits should occur as close as possible to the day specified. At each visit, the 
patient will be asked if the patient 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. 
Investigational product compliance during any period will be closely monitored by counting 
the number of tablets dispensed and returned. Every effort will be made to collect all unused 
investigational product.
8.8 Early Discontinuation of Patients
A premature discontinuation will occur when a patient who signed the informed consent form 
(ICF) and has been randomized ceases participation in the study, regardless of circumstances, 
before completion of the study. Patients can be prematurely discontinued from the study for 
one of the following reasons:

Adverse event (AE)

Lack of efficacy

Withdrawal of consent (a clear reason must be documented)

Lost to follow-up (Every effort must be made to contact the patient; a 
certified/traceable letter must be sent.)

Pregnancy

Protocol violation

Non-compliance with study drug

Study terminated by Sponsor

Site terminated by Sponsor

Other 


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Patients may voluntarily withdraw from the study at any time. Notification of early patient 
discontinuation from the study and the reason for discontinuation will be clearly documented 
on the appropriate case report form. All randomized patients 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/Early 
Termination and Visit 8 Safety Follow-up, 4 weeks post the last dose of IP.
8.9 Withdrawal Criteria
Women who become pregnant (Section 9.4) and patients who meet investigational product 
discontinuation criteria related to abnormal liver function tests (Section 9.5) and advised not 
to be re-challenged will be withdrawn from the study and should refrain from taking 
investigational product. The patient should return to the clinic for early termination
procedures (Visit 7) and the Safety Follow-up Visit 8. Patients who reply with “yes” to 
questions 4 or 5 in the suicidal ideation section or “yes” to any question in the suicidal 
behavior section of the C-SSRS at Visits 3 through 6 must be withdrawn from the study and 
should receive appropriate follow-up as in routine clinical practice, including the Early 
Termination Visit 7 and the Safety Follow-Up Visit 8.
A patient with a condition and/or a situation that, in the investigator's opinion, may put the 
patient at significant risk, may confound the study results, or may interfere significantly with 
the patient's participation in the study may be withdrawn from treatment.
8.10 Withdrawal from Future Biomedical Research
A patient who initially consents can withdraw that consent at any time and have his or her 
sample destroyed, including any by-products of the sample whenever possible. If a patient 
withdraws consent, their physical sample will be destroyed and no new health information 
identifying the patient will be gathered after that date. However, once the genetic data is 
anonymized and placed into the biorepository database after study database lock, the 
information cannot be withdrawn.
8.11 Study Termination
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason, with appropriate notification.
9.
Adverse Events
AEs occurring during the study will be recorded on an AE case report form.  If AEs occur, 
the first concern will be the safety of the study participants.


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9.1 Definitions
9.1.1
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 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.  In addition, during the screening period, AEs will be assessed 
regardless of the administration of a pharmaceutical product.
Note:  AEs must be collected once informed consent has been obtained, regardless of 
whether or not the patient has been administered study drug.
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
AEs unless the disease progression is greater than anticipated in the natural course of the 
disease.
AEs will be assessed, documented, and recorded in the eCRF throughout the study (ie, after 
informed consent has been obtained).  At each visit, the investigator will begin by querying 
for AEs by asking each patient a general, non-directed question such as “How have you been 
feeling since the last visit?”  Directed questioning and examination will then be done as 
appropriate.  All reported AEs will be documented on the appropriate case report form.
9.1.2
Serious Adverse Event
An SAE is any AE occurring at any dose that results in any of the following outcomes: 
death, a life-threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  (See Section 9.3 for procedures for reporting an
SAE.)
Allergan considers all cancer adverse events as SAEs. In addition, Allergan considers any 
abortion (spontaneous or nonspontaneous) as an SAE.


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Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as an SAE.
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a SAE and reported to Allergan.
9.1.3
Severity
A clinical determination will be made of the intensity of an AE.  The severity assessment for 
a clinical AE must be completed using the following definitions as guidelines:
Mild
Awareness of sign or symptom, but easily tolerated.
Moderate
Discomfort enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or do usual activity.
9.1.4
Relationship to Study Drug or Study Procedure
A determination will be made of the relationship (if any) between an AE and the study drug
or study procedure, as applicable.  A causal relationship is present if a determination is made 
that there is a reasonable possibility that the AE may have been caused by the drug or study 
procedure.
9.2 Procedures for Reporting Adverse Events
Any adverse event must be recorded on the appropriate case report form.
All SAEs that are drug-related and unexpected (not listed as treatment-related in the current 
Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked ‘ongoing’ 
at the exit visit must be followed-up as appropriate.
9.3 Procedures for Reporting a Serious Adverse Event
Any SAE occurring during the study period (beginning with informed consent) and for at 
least 30 days after the last dose of study drug must be immediately reported but no later than 
24 hours after learning of an SAE.  SAEs must be reported to Allergan (or Agent of Allergan) 


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as listed on the Allergan Study Contacts Page and recorded on the SAE form.  All patients 
with an SAE must be followed up and the outcomes reported.  The investigator must supply 
the sponsor and the IRB/IEC with any additional requested information (eg, autopsy reports 
and discharge summaries).
In the event of an SAE, the investigator must:
1. Notify Allergan immediately by fax or email using the SAE form (contact details can 
be found on page 1 of the SAE form); phone numbers and relevant Allergan 
personnel contacts are also on the front page of protocol and Study Contacts Page.
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient.
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
SAE form describing the event chronologically, including any treatment given (eg, 
medications administered, procedures performed) for the adverse event(s).  
Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug.
4. Promptly inform the governing IRB/IEC of the SAE as required by the IRB/IEC, 
local regulations, and the governing health authorities.
9.4 Exposure to Investigational Product during Pregnancy
Study center personnel must report every pregnancy from the time he or she signs the ICF for 
the trial until 30 days after the last dose of investigational product on the Pregnancy Form as 
soon as possible (within 24 hours of learning of the pregnancy to the SAE/pregnancy fax 
number,
) even if no AE has occurred. Pregnancies in female partners of 
male patients must also be reported. The pregnancy must be followed to term and the 
outcome reported by completing a follow-up Pregnancy Form. If, however, the pregnancy is 
associated with a SAE (eg, if the mother is hospitalized for hemorrhage), in addition to the 
Pregnancy Form, a separate SAE Form must be filed as described in Section 9.3 with the 
appropriate serious criterion (eg, hospitalization) indicated.


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9.5 ALT or AST Elevations
A post treatment event of ALT or AST ≥ 3xULN is considered an Event of Clinical Interest.  
Any patient with this laboratory result after investigational product was taken must have 
repeat testing within 48 to 72 hours to confirm the abnormality.  For this repeat testing, the 
following labs must be drawn: hematology and chemistry panels, international normalized 
ratio (INR), and a toxicology screen for acetaminophen. In addition, the investigator will 
perform a complete history and exam to evaluate for possible liver disease. 
All Events of Clinical Interest must be reported to Allergan using the AE of Interest form and 
submitted within 24 hours of the time the Investigator becomes aware of the event. All new 
elements of history, physical exam, diagnostic testing results, and other relevant medical 
reports are to be reported for each event.
If an ALT or AST elevation ≥ 3 x ULN is confirmed and the patient meets any of the 
following criteria, close medical follow-up is required:

Patients with ALT or AST ≥ 3 x ULN and ≤5 x ULN and who are asymptomatic 
with regard to possible liver disease (ie. No fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia (> 5%))

Patients with ALT or AST ≥ 3 x ULN and ≤5 x ULN and (total bilirubin
< 2 x ULN and INR < 1.5)
Patients who meet these criteria must be followed clinically and further medical evaluation 
will be done per the judgment of the investigator and in conjunction with medical personnel 
at Allergan. The Chemistry panel will be repeated 1 to 2 times per week to follow the course 
of ALT/AST elevation. An extra blood serology sample must be collected and sent to the 
central laboratory for further diagnostic testing at a later date if needed.
If an ALT or AST elevation ≥ 3 x ULN is confirmed and the patient meets any of the 
following criteria, close medical follow-up is also required:

ALT or AST ≥3 x ULN and the patient is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (>5%)

ALT or AST ≥3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5)

ALT or AST ≥5 x ULN 
For these patients, possible etiologies for acute hepatic injury must be excluded. The 
following laboratory tests must be performed:  anti-hepatitis A IgM, hepatitis B surface 


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antigen, anti-hepatitis B core IgM, hepatitis C antibody, hepatitis C quantitative RNA by 
PCR, anti-hepatitis E IgM. An extra serology blood sample will be collected and sent to the 
central laboratory for further diagnostic testing at a later date if needed. The patient must be 
followed clinically and further medical evaluation should be done per the judgment of the 
investigator and in conjunction with medical personnel at Allergan. In general, the Chemistry 
panel should be repeated 1 to 2 times per week to follow the course of ALT/AST elevation. 
For procedural details on the medical evaluation of liver disease, please see the Study 
Reference Manual.
The investigator must contact the Allergan Medical Monitor to discuss all cases of confirmed 
ALT/AST elevation ≥ 3 x ULN. All ALT/AST elevations must be followed until ALT and 
AST return to < 1.5 x ULN and there is full clinical resolution
Investigational product must be discontinued if any of the following criteria are met: 

ALT or AST ≥3 x ULN and the patient is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (> 5%)

ALT or AST ≥3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5)

ALT or AST ≥5 x ULN for more than 2 weeks

ALT or AST ≥8 x ULN
The patient may be re-challenged with investigational product only after consultation with 
the Allergan Medical Monitor. For patients who are not re-challenged with investigational 
product, the patient should be discontinued from the study and complete the Early 
Termination Visit 7 and Safety Follow-Up Visit 8. Patients should receive appropriate follow-
up as per standard of care.
9.5.1
Potential Hy’s Law Cases
Sites must report every patient who meets the following potential Hy’s law criteria if this 
occurs within the time the patient signs the ICF until 30 days after the last dose of 
investigational product:

ALT or AST ≥ 3 x ULN AND

Total bilirubin ≥ 2 x ULN AND

Alkaline phosphatase < 2 x ULN


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A laboratory alert for potential Hy’s laws cases will be in place, and the investigators and 
Allergan will be notified immediately when the above criteria have been met. Any potential 
Hy’s laws case should be considered an SAE and also reported as an AE of Special Interest. 
Complete both an SAE and AE of Special Interest Form as soon as possible (within 24 hours 
of learning of the potential Hy’s law) and fax it to the SAE fax number. The eCRF pages 
associated with potential Hy’s law cases must be completed within 7 calendar days. Every 
effort to determine the cause of the liver abnormalities must be made, and close monitoring 
should be initiated in conjunction with the Allergan medical monitor and in accordance with 
the FDA “Guidance for Industry: Drug Induced Liver Injury - Pre-Marketing Clinical 
Evaluation” July 2009. For specific instructions, please refer to the Study Reference Manual.
9.6 Procedures for Unmasking of Investigational Product
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the Allergan Medical Monitor 
should be notified prior to unmasking investigational product.  The investigator must inform 
the Allergan Medical Monitor of the unmasking if there is no notification prior to the
unmasking.
The treatment assignment for the patient can be determined by designated site personnel 
logging into the IWRS system via password protected access.  The reason for breaking the 
code must be recorded in the patient’s source documents.
10.
Administrative Items
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH)
Guideline on GCP.
10.1 Protection of Human Patients
10.1.1
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study, and/or from the patient's legally authorized 
representative.


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10.1.2
Compliance With IRB or IEC Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan.
10.1.3
Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
10.1.4
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature.
10.2 Changes to the Protocol
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers).
10.3 Patient Confidentiality
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information.
10.3.1
Patient Privacy
Written authorization and other documentation in accordance with local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, 
and/or from the patient's legally authorized representative in accordance with the applicable 


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privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”).
In accordance with HIPAA requirements, additional purposes of this study may include
publishing of anonymous patient data from the study.
10.4 Documentation
10.4.1
Source Documents
Source documents may include a patient's medical records, hospital charts, clinic charts, the 
investigator's patient study files, the eDiary, as well as the results of diagnostic tests such as , 
laboratory tests and electrocardiograms. The investigator's copy of the case report forms 
serves as part of the investigator's record of a patient's study-related data.
The following information should be entered into the patient's medical record:

Patient’s name.

Patient’s contact information.

The date that the patient entered the study, patient number, and patient randomization 
[or medication kit] number.

The study title and/or the protocol number of the study and the name of Allergan.

A statement that informed consent was obtained (including the date).  A statement that 
written authorization or other local patient privacy required documentation for this 
study has been obtained (including the date).

Dates of all patient visits.

Patient’s medical history

Information regarding patient’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 adverse events.


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
The date the patient exited the study, and a notation as to whether the patient
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, Good Clinical Practice: 
Consolidated Guidance and ALCOA, i.e., records must be attributable, legible, 
contemporaneous, original and accurate.
10.4.2
Case Report Form Completion
The investigator is responsible for ensuring that data are properly recorded on each patient's 
eCRF and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the case report forms (as indicated in the case report forms) to 
ensure that the observations and findings are recorded on the case report forms correctly and 
completely.  The eCRFs are to be submitted to Allergan in a timely manner at the completion 
of the study, or as otherwise specified by Allergan and will be maintained in a central data 
repository.
10.4.3
Study Summary
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC.
10.4.4
Retention of Documentation
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of case report forms should be maintained on file.
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor.


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In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person.
10.5 Labeling, Packaging, and Return or Disposal of Investigational 
Products/Treatments
10.5.1
Labeling/Packaging
Investigational product 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. Immediately before dispensing 
the blister card, the investigator or designee will write the study center number, patient’s 
initials and patient number, and date on the blister card.
10.5.2
Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the patients, the number of units 
returned to the investigator by the patient (if applicable), and the number of units returned to 
Allergan during and at the completion of the study.  A detailed inventory must be completed 
for the investigational product.  The investigational product must be dispensed or 
administered only by an appropriately qualified person to patients in the study.  The 
medication is to be used in accordance with the protocol. 
10.5.3
Return or Disposal of Investigational Products/Treatments
and/or Supplies
All clinical investigational products/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction.
10.6 Monitoring by the Sponsor
A representative of the sponsor will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.


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Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions.
10.7 Handling of Biological Specimens 
Urine pregnancy test kits will be provided by the central lab; all urine pregnancy testing will 
be administered on site according to instructions in the central lab manual.  
Samples of blood and urine for evaluation of hematology, blood chemistry, urinalysis, and 
serology will be analyzed at a centralized clinical laboratory with certification from a 
recognized accreditation agency (eg, College of American Pathology or Clinical Laboratory 
Improvement Amendments certification).
DBS samples obtained from patients in the PK substudy will be stored at the centralized 
clinical laboratory until ready for PK analyses by Allergan’s Pharmacokinetics and Drug 
Distribution department using a validated method. This laboratory meets Good Laboratory 
Practice requirements.
All samples will be returned to Allergan or Allergan’s designee for destruction. Allergan shall 
have full ownership rights to any biological specimens/samples derived from the study.  For 
additional details regarding handling of biological specimens please refer to the Study 
Reference Manual.
10.8 Publications
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.
10.9 Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report.


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11.
References
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, and Yang R, et al. Safety, 
tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic 
migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 
Lancet Neurol. 2015 Nov;14(11):1081-90.
Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, 
Jacobs D. MIGR-002 Study Group. Topiramate for migraine prevention: a randomized 
controlled trial. JAMA. 2004 Feb 25;291(8):965-73.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer, Rohmeyer K. Graphical approaches 
for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biometrical Journal. 53 (2011) 6, 894–913.
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.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, and Ashina M. Safety and 
efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of 
frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory 
phase 2 trial. Lancet Neurol. 2014;13:1100-7.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and
efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the 
prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.
Lancet Neurol. 2014 Sep;13(9):885-92.
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 
2013;33(9):629–808.
Hewitt DJ, Martin V, Lipton RB, Brandes J, Ceesay P, Gottwald R, et al. Randomized 
controlled study of telcagepant plus Ibuprofen or acetaminophen in migraine. Headache. 
2011;51:533–543.
Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, 
Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist 
telcagepant for migraine prevention. Neurology. 2014 Sep 9;83(11):958-66.


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Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the 
United States. Arch Intern Med. 1999;159:813-818.
Katsarava Z, Buse DC, Manack AN, and Lipton RB. Defining the Differences Between 
Episodic Migraine and Chronic Migraine. Curr Pain Headache Rep. 2012:16:86–92
Li CC, Vermeersch S, Denney WS, Kennedy WP, Palcza J, and Gipson A. Characterizing the 
PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, 
an oral calcitonin gene related peptide receptor antagonist. Br J Clin Pharmacol.
2014;79;831-7.
Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. 
Headache. 2005;45(Suppl 1):S3-S13.
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.
Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. New appendix 
criteria open for a broader concept of chronic migraine. Cephalalgia. 2006:26;742-6.
Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-
related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.
N Engl J Med. 2004:350;1104-1110.
Silberstein SD, Neto W, Schmitt J, Jacobs D. MIGR-001 Study Group. Topiramate in 
migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61(4):490-5.
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010:11;289–299.
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon 
Y, Dietrich J, Lenz R. Safety and efficacy of AMG 334 for prevention of episodic migraine: a 
randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 
Apr;15(4):382-90.


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


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12.2 Examples of Prohibited Medications
The following medications are prohibited 30 days prior to screening and throughout the study 
period:

Strong OATP1B1 inhibitors e.g, Gemfibrozil (Lopid™)
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™)


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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
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 
(Depakote™)
Amitriptyline (Elavil™)
Nortriptyline (Pamelor™)
Metoprolol (Lopressor™, Toprol™)
Atenolol (Tenormin™)
Nadolol (Corgard™)
Propranolol (Inderal™)
Timolol (Apo-Timol™)
Venlafaxine (Effexor™)
Non-pharmacologic headache 
interventions:
Acupuncture
TENS (transcutaneous electrical nerve stimulation)
Cranial traction
Nociceptive trigeminal inhibition
Occipital nerve block treatments
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The following treatments are prohibited 6 months prior to screening and throughout 
the study period:

BOTOX injections into areas of the head, face, or neck
12.3 Classification of Migraine Preventive Medications
Below is a list of migraine preventive medications considered effective or probably effective 
sorted by mechanism of action.  Of note, topiramate and valproic acid derivatives are 
considered separate categories. A history of inadequate response to 3 or more of these 
medications (2 of which have different mechanisms of action) will exclude the patient from 
the study.
Pharmacologic Category
Drug Name
Anticonvulsant
Topiramate
Anticonvulsant
Valproic acid, sodium valproate, divalproex
Tricyclic Antidepressant
Amitriptyline
Nortriptyline
Beta-blockers
Metoprolol
Atenolol
Nadolol
Propranolol
Timolol
SNRI (serotonin norepinephrine 
reuptake inhibitor)
Venlafaxine


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12.4 Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
BID
aspartate aminotransferase
twice daily
BP
blood pressure
CGRP
CIDV
calcitonin gene-related peptide
capsaicin-induced dermal vasodilatation
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A4
cytochrome P450 3A4
DBS
dry blood spot
ECG
electrocardiogram
eCRF
eTablet
electronic case report form
electronic tablet
EQ-5D-5L
European Quality of Life – 5-Dimensional – 5-Level 
GCP
Good Clinical Practices
HIPAA
Health Insurance Portability and Accountability Act
HIT-6
Headache Impact Test
ICH
International Conference on Harmonisation
ICHD-3 beta
International Classification of Headache Disorders criteria, 3rd
edition (beta version, 2013)
IEC
Independent Ethics Committee
IgM
INR
immunoglobulin M
coagulation parameters
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
MI
MMRM
multiple imputation
mixed-effects model for repeated measures
NSAID
PGIC
nonsteroidal anti-inflammatory drug
Patient Global Impression of Change
PR
QD
pain relief
once daily


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QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
PK
pharmacokinetic
SAE
serious adverse event
SAP
statistical analysis plan
ULN
WPAI-SHP
upper limit of normal
Work Productivity and Activities Impairment-Specific Health 
Problem
12.5 Protocol Amendment 1 Summary
Title:  A Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study To Evaluate The Efficacy, Safety, And Tolerability Of Multiple Dosing 
Regimens Of Oral AGN-241689 In Episodic Migraine Prevention
Protocol CGP-MD-01
Date of Amendment:  11 Nov 2016
Amendment Summary
This amendment includes changes made to Protocol CGP-MD-01 (09 May 2016). The 
protocol was amended to: 1) update contact information; 2) correct or rephrase inaccurate
text; 3) update the Schedule of visits and procedures; 4) exclude patients who have used 
injectable monoclonal antibodies for CGRP; 5) modify exclusion criteria #21 and #24; 6) 
clarify use of SSRIs and SNRIs; 7) clarify childbearing potential, acceptable contraception, 
and male participation requirements; 8) clarify the timing of the PK sampling; 9) exclude 
patients who use benzodiazepines; 10) reorder the secondary efficacy variables for the EU; 
11) resort all the additional efficacy variables and the Health Outcomes Variables into 2 new 
sections; 12) make instructions for the management of patients with ALT or AST  elevations 
obligatory; and 13) clarify various study activities.
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized.


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Section
Revision
Rationale
Protocol Title Page
Revised the name of the US Agent from Allergan 
(North America) to Allergan Sales, LLC
Added the emergency contact number: +1-866-
438-8820
 
Removed the contact information for the Medical 
Monitor, and inserted: Refer to the Study 
Contacts Page
Added the “Protocol Amendment 1 Date” to the 
title page
The name of Allergan 
in the US has changed
To remove need to 
consult the study 
contacts page for this 
information
The number has 
changed
To preclude the need 
for amendment should 
the contact info 
change
To reflect the 
approval date of 
Amendment 1
Protocol Summary, 
Response Measures
Replaced acute medication use with triptan use. 
Corrected the text relating to the name of the
measure: Patient Satisfaction with Study 
Medication for Migraine Prevention. (in this 
section and throughout the protocol)
For accuracy
To use the correct 
name of the measure 
Protocol Summary, 
General Statistical 
Methods
Corrected the name of the MMRM: mixed-effects 
model for reported repeated measures (in this 
section and elsewhere in the protocol).
Reordered the secondary efficacy variables for the 
European Union
To use the correct 
name of the model
For accuracy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section
Revision
Rationale
 
 
 
 
 
 
 
 
 
 
 
 


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Section
Revision
Rationale
Section 1.2, Overview 
of AGN-241689
 
AGN-241689
For accuracy
Section 3.2 Efficacy 
Assessments
Deleted the full list of primary, secondary, and 
additional efficacy parameters (for the US and 
EU), and  added text regarding how assessments 
will be collected: Efficacy assessments will be 
based on information recorded by the patient.  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, 
probable migraine, and headache days per the 
criteria listed in Sections
 
 
 
 
To eliminate 
repetition of 
information already 
stated elsewhere 
(Section 7.2), and to 
describe the mode of 
data collection
 
 
 
 
Section 3.5 Drug Data 
Safety Monitoring 
Board
Changed the name of the Drug Safety Monitoring 
Board to Data Safety Monitoring Board
For accuracy
Section 4.3 Exclusion 
Criteria
Added text to criterion #8: (barbiturates are 
excluded during the baseline period and for the 
duration of the study [see Section 12.2 Examples 
of Prohibited Medications]).
 
 
 
 
 
#24
 
 
 
 
 
For clarity
To allow patients with 
reversions to be 
included
To exclude patients 
who have used 
injectable monoclonal 
antibodies for the 
CGRP pathway
Section 4.4.1 
Permissible 
Medications/Treatments
Inserted text regarding use of SSRIs and SNRIs: 
Selective serotonin reuptake inhibitors (SSRI) or 
serotonin norepinephrine reuptake inhibitors 
(SNRI) will be permitted provided that treatment 
To allow for patient 
use of stable-dose (at 
least 60 days prior to 
screening) SSRIs and 


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Section
Revision
Rationale
is stable for at least 60 days prior to screening 
(Visit 1) and continues without change in dose 
throughout the study.
SNRIs.
Section 4.4.3 Definition 
of Females of (Non-) 
Childbearing Potential 
and/or Acceptable 
Contraceptive Methods
Adjusted text that defines childbearing potential, 
acceptable contraception, and male participant 
requirements: For purposes of this study, females 
will be considered of childbearing potential unless 
they are naturally postmenopausal (ie, no menses 
for 2 years) or permanently sterilized (ie, bilateral 
tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy  or hysterectomy).  
For women of childbearing potential who may 
participate in the study, the following methods of 
contraception, if properly used, are generally 
considered reliable: hormonal contraceptives (ie, 
oral, patch, vaginal ring,  injection, implant), male 
condom with intravaginal spermicide, diaphragm 
or cervical cap with spermicide, vaginal 
contraceptive ring, intrauterine device, surgical 
sterilization (bilateral tubal ligation, bilateral 
salpingectomy), vasectomized partner, or sexual 
abstinence.
Male participants must also refrain from donating 
sperm during the course of the study.
For clarity regarding 
acceptable means of 
contraception , and to 
forbid sperm donation 
during the study.
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Section
Revision
Rationale
.  
 
 
 
 
 
 
 
6.3 Future Biomedical 
Research
Revised text to clarify possible uses of samples 
and to clarify destruction of by-products of the 
samples from patients who withdraw consent.
For clarity
Table 6–1 Clinical 
Laboratory Parameters
Added benzodiazepines to the list of urine drug 
screen parameters
To accurately reflect 
the urine drug screens 
being conducted
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Section 8.9 Withdrawal 
Criteria
The withdrawal criteria have been restated: 
Women who become pregnant (Section 9.4) and 
patients  who meet investigational product 
discontinuation criteria experience treatment-
emergent AEs related to abnormal liver function 
tests (Section 9.5) and advised not to be re-
challenged will be withdrawn from the study and 
should refrain from taking investigational 
product. The patient should return to the clinic for 
early termination procedures (Visit 7) and the 
Safety Follow-up Visit 8. 
For clarity
Section 8.10 
Withdrawal from 
Future Biomedical 
Research
Text regarding destruction of patient’s samples 
has been replaced with: A patient who initially 
consents can withdraw that consent at any time 
and have his or her sample destroyed, including 
any by-products of the sample whenever possible. 
If a patient withdraws consent, their physical 
For accuracy


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Section
Revision
Rationale
sample will be destroyed and no new health 
information identifying the patient will be 
gathered after that date. However, once the 
genetic data is anonymized and placed into the 
biorepository database after study database lock, 
the information cannot be withdrawn.
Section 9.5 ALT or 
AST Elevations
Throughout this section, the instructions for 
patients with ALT or AST  ≥ 3xULN, have been 
made obligatory. All previous instructions that 
indicated “should” have been replaced with 
“must” or “will” , and additional instructions have 
been added to paragraphs 4, 6, and 9: 
An extra blood serology sample should must be 
collected and sent to the central laboratory for 
further diagnostic testing at a later date if needed.
An extra serology blood sample should will be 
collected and sent to the central laboratory for 
further diagnostic testing at a later date if needed.
For patients that are not re-challenged with 
investigational product the patient should be 
discontinued from the study and complete the 
Early Termination Visit 7 and Safety Follow-Up 
Visit 8. Patients should receive appropriate 
follow-up as per standard of care.
For patient safety
Section 9.6 Procedures 
for Unmasking of 
Investigational Product
Text has been revised to make notification of the 
sponsor obligatory when there was no prior 
notification of unmasking
For clarity
Section 12.2 Examples 
of Prohibited 
Medications
Armodafinil (NuvigilTM) has been added to the 
“Others” row
For accuracy
Section 12.3 
Classification of 
Migraine Preventive 
Medications
Text has been added to Paragraph 1 to clarify that 
the list refers to medications that are effective or 
probably effective for prevention of migraine. 
Explanatory footnotes have been deleted.
For accuracy
12.6 Protocol Amendment 2 Summary
Title:  A Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study To Evaluate The Efficacy, Safety, And Tolerability Of Multiple Dosing 
Regimens Of Oral AGN-241689 In Episodic Migraine Prevention


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Protocol CGP-MD-01
Date of Amendment 2:  11 Sep 2017
Amendment Summary
This amendment includes changes made to original Protocol CGP-MD-01 (09 May 2016) as 
amended with Amendment 1 (11 Nov 2016). The protocol was amended to: 1) allow 
participation of patients with history of hemiplegic migraine; 2) revise the primary and 
secondary efficacy endpoints for the US and EU; 3) revise the multiple comparisons 
procedure; 4) update the sample size calculation; 5) define “one month” for the efficacy 
analysis; 6) revise the additional efficacy variables for the US and EU; and 7) clarify the 
section on early discontinuation of patients.
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  In this summary, added text is shown
underlined, and deleted text is shown as strikethrough. Minor editorial and document 
formatting revisions have not been summarized.
Section
Revision
Rationale
Protocol Summary, 
Clinical Hypotheses, 
and Section 2.2 
Clinical Hypotheses
Rewrite the Clinical Hypotheses: In individuals with 
episodic migraine, at least one of the following 
doses (10-mg QD,  30-mg QD, 30-mg BID, 60- mg 
QD, and 60-mg BID) dose active treatment arm, 60 
mg QD or 60 mg BID is superior to placebo as 
measured by the change from baseline in mean
monthly number of migraine/probable migraine 
(MPM) headache days across the 12-week treatment 
period in the last 28 days of the treatment period 
ending with week 12.
Per discussion 
with regulatory 
authority
Protocol Summary, 
Study Population 
Characteristics, Key 
Exclusion Criteria, 
Section 4.3 (criterion 
#2)
Remove the exclusion of participants with history of 
hemiplegic migraine: 
Has a history of migraine with accompanied by diplopia 
or decreased level of consciousness or, hemiplegic 
migraine, and retinal migraine as defined by ICHD-3 beta 
version, 2013 
Per discussion 
with regulatory 
authority
Protocol Summary, 
Response Measures
Revise the efficacy measure for triptan use: 
Frequency of migraine or probable migraine 
headache days, headache days, and triptan use acute 
medication use days
Per discussion 
with regulatory 
authority
Protocol Summary, 
General Statistical 
Methods, and Section 
Revise the primary efficacy endpoint: 
The primary efficacy endpoint is the change from 
baseline in mean monthly MPM headache days 
across the 12-week treatment period the frequency 
Per discussion 
with regulatory 
authority


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Revision
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7.3.1 Primary Efficacy 
Analyses
of migraine/probable migraine headache days per 4 
weeks, the primary measurement time is the 28 days 
ending with diary week 12, and the primary analysis 
is on the change from baseline.  Comparisons 
between each dose group and placebo will be done 
by a mixed-effects model for repeated measures 
(MMRM) of the change from baseline.  The 
statistical model will include treatment group, visit 
and treatment group by visit interaction as 
categorical fixed effects.  It will also include the 
baseline score and baseline-by-visit interaction as 
covariates.  Pairwise contrasts in the MMRM model 
will be used to make the pairwise comparisons of 
dose to placebo. A sensitivity analysis will be 
performed on the primary endpoint to assess the 
robustness of the MMRM analysis to possible 
violation of the missing-at-random (MAR) 
assumption.  The sensitivity analysis will be done 
using a pattern-mixture model (PMM), under which 
data could be missing-not-at-random (MNAR), with 
repeated analyses combined via the multiple 
imputation procedure (MI). An additional 
sensitivity, multiple imputation in conjunction with 
robust regression, will be performed in case of non-
normality for the primary efficacy endpoint.      
Protocol Summary, 
General Statistical 
Methods 
Revise the secondary efficacy endpoints: 
Secondary efficacy endpoints will be analyzed 
separately for the United States (US) and Europe 
(EU) submissions. Secondary efficacy endpoints for 
the US include: (1) Change from baseline in mean 
monthly headache days across the 12-week 
treatment period Change from baseline in number of 
headache days to the last 28 days of the treatment 
period ending with week 12; (2) Proportion of 
patients with at least a 50% reduction in mean 
monthly MPM days across the 12-week treatment 
period migraine/probable migraine headache days in 
the last 28 days of the treatment period ending with 
week 12; (3) Change from baseline in mean monthly 
acute medication use days across the 12-week 
treatment period Change from baseline in the 
activities of daily living (ADL) domain score of the 
ACM-I (Assessment of Chronic Migraine Impact)  
at week 12; (4) Proportion of patients “satisfied” or 
“extremely satisfied” with study medication for 
migraine prevention at week 12. Secondary efficacy 
endpoints for the EU include: (1) Change from 
baseline in number of headache days to the last 28 
Per discussion 
with regulatory 
authority


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Revision
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days of the treatment period ending with week 12; 
(2) Proportion of patients with at least a 50% 
reduction in migraine/probable migraine headache 
days per 28 day period at the end of the 12 week 
treatment period; (3) Change from baseline in 
number of triptan use days to the last 28 days of the 
treatment period ending with week 12; (4) Change 
from baseline in the HIT-6 total score (Headache 
Impact Test)  at week 12.
Protocol Summary, 
General Statistical 
Methods
Revise the multiple comparisons procedure: 
The overall type I error rate for multiple 
comparisons across active treatment doses and the 
primary and four secondary efficacy parameters will 
be controlled at the 0.05 level using a graphical 
approach by Bretz et al (20112009).  The weighting 
strategy of the multiple comparisons is designed to 
allocate initial alpha equally to the QD and BID 
dose regimens. Within each dosing regimen, 
individual AGN-241689 doses will be tested in a 
hierarchical order from high to low dose, i.e. for 
primary efficacy endpoint, low dose can be tested 
only if high dose comparison shows statistical 
significance. In addition, for a given dose 
comparison versus placebo, the strategy has the 
primary endpoint as gatekeeper to the secondary 
endpoints so that secondary endpoints can be tested 
only if primary hypothesis of the corresponding 
dose comparison reaches statistical significance.   
allocates ¼ weight to each of 30 mg QD, 30 mg 
BID, 60 mg QD and 60 mg BID comparisons versus 
placebo for the primary hypothesis.  If any of those 
comparisons is rejected, 20% of the corresponding 
weight will be propagated to test 10 mg QD versus 
placebo for the primary hypothesis and 80% of the 
weight will be propagated to test the first secondary 
hypotheses in the corresponding dose versus 
placebo. Then for the comparison of each dose 
versus placebo, 100% of the weight will be 
propagated sequentially for the remaining secondary 
endpoints. Finally, if for one of the doses efficacy 
can be shown for primary and all the secondary 
endpoints, the associated weight is passed on to 
other doses. This weighting strategy implies that the 
10 mg QD versus placebo comparison can only be 
tested if at least one of the 30 mg QD, 30 mg BID, 
60 mg QD and 60 mg BID versus placebo 
comparisons for the primary hypothesis is rejected 
and a small amount of weight is to be allocated to 
the 10 mg QD versus placebo comparison, since it is 
Per discussion 
with regulatory 
authority


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selected as a likely suboptimal dose.  Similarly, 
under this strategy, no secondary hypothesis can be 
rejected until a primary hypothesis of the 
corresponding dose comparison is rejected.  The 
primary endpoint will serve as the gatekeeper for the 
secondary endpoints. Weighted Simes Bonferroni 
tests will be used for testing the hypotheses. within 
each endpoint as the associated test statistics are 
positively correlated, and a Bonferroni mixture will 
be used to combine test results across different 
endpoints. A complete decision-flow graph and 
details of the graphical multiple comparison 
procedure will be presented in the statistical analysis 
plan of this study.
Protocol Summary, 
General Statistical 
Methods, Sample Size 
Calculation; and 
Section 7.7
Revise the Sample Size Calculation: 
The assumptions and corresponding power 
assessments for the primary efficacy endpoint are 
shown in the table below (Note: the revised table is 
not included here). The treatment difference 
assumption is based on results from other episodic 
migraine prevention studies: the placebo-adjusted 
reduction in monthly migraine days ranged from 1.1 
to 2 days (topiramate [Silberstein et al. 2004 and 
Brandes et al. 2004], telcagepant [Ho et al., 2014], 
and CGRP monoclonal antibodies Ph2 studies 
[Dodick et al., 2014; Dodick et al., 2014; Bigal et 
al., 2015; Sun et al 2016], and their Ph3 studies 
results reported from American Headache Society & 
American Academy of Neuroscience 2017). 
Common standard deviation is estimated based on 
blinded interim data assessments of this study. 
Power is calculated via 10,000 simulations based on 
multiplicity adjustment.
The following table displays the power calculations 
for treatment comparisons of 30 mg or 60 mg QD 
versus placebo and 30 mg or 60 mg BID versus 
placebo, respectively. The differences between 
treatment groups in the mean number of 
migraine/probable migraine headache days change 
from baseline at the primary timepoint (Week 12) is 
assumed to be 1.5 for the comparison of 30 mg or 
60 mg QD versus placebo (assumed equally 
effective for 30 mg QD and 60 mg QD), and be 1.75 
for the comparison of 30 mg or 60 mg BID versus 
placebo (assumed equally effective for 30 mg BID 
and 60 mg BID). With the allocated ¼ weight, each 
of the hypotheses will be tested at alpha level of 
Updated to reflect 
revised primary 
endpoint and 
multiplicity 
strategy


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Revision
Rationale
0.0125 using the Bonferroni approach for power 
calculation. This is a more conservative power 
assessment compared to the weighted Simes test 
used in the final analysis. The statistical power 
calculations are focused on doses of 30 mg QD, 30 
mg BID, 60 mg QD and 60 mg BID, because the 10 
mg QD is considered to likely be a suboptimal dose 
and is only tested if at least one of the 4 doses 
comparison is significant. For critical alpha level 
0.0125, the powers are displayed based on a 
standard deviation estimate of 4.0.
Section 6.1.1.4 Acute 
Medication Use Day 
and Triptan Use Day
Describe the allowed medications for headache 
pain: 
The allowed medications include the following 
categories of drugs: triptans, ergots, opioids, 
analgesics (including acetaminophen), NSAIDs 
(including aspirin), and antiemetics.
For clarity
 
 
 
 
 
 
 
 
 
Section 7.2 Collection 
and Derivation of 
Primary and 
Secondary Efficacy 
Assessments
Revise section to define “one month”. For analysis 
purposes, four weeks (28 days) will be considered 
as one month.
For clarity
Section 7.2.1 Primary 
Efficacy Variable
Revise the primary efficacy variable: The primary 
efficacy variable is the change from baseline in 
mean monthly MPM headache days across the 12-
week treatment period. the frequency of 
migraine/probable migraine headache days to the 
28-day period ending with Week 12 (ie, Day 57 to 
Day 84 inclusive, relative to the day 1 treatment 
start).
Per discussion 
with regulatory 
authority


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Section
Revision
Rationale
Section 7.2.2
Secondary Efficacy 
Variables for the 
United States
Revise the secondary efficacy variables: 
The 34 secondary efficacy variables for the US 
include:

Change from baseline in mean monthly number 
of headache days across the 12-week treatment 
period to the last 28 days of the treatment period 
ending with week 12.

Proportion of patients with at least a 50% 
reduction in mean monthly migraine/probable 
migraine headache days across the 12-week 
treatment period in the last 28 days of the 
treatment period ending with week 12.

Change from baseline in mean monthly acute 
medication use days the activities of daily living 
(ADL) domain score of the ACM-I (Assessment 
of Chronic Migraine Impact)  at week 12

Proportion of patients “satisfied” or “extremely 
satisfied” with study medication for  migraine 
prevention at week 12.
Per discussion 
with regulatory 
authority
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section
Revision
Rationale
 
 
.
Section 7.3.2 
Secondary Efficacy 
Analyses
Revise this section: 
The secondary efficacy variables are identified in 
rank order for the US and EU, respectively, in 
Sections 7.2.2 and 7.2.3.  To control the type 1 error 
rate for multiple secondary endpoints, a gatekeeping 
approach will be used for these secondary variables 
at the primary visit (week 12) according to the rank 
order specified.  
Specifically, t The overall type I error rate for 
multiple comparisons across active treatment doses 
and the primary and secondary efficacy parameters 
will be controlled at the 0.05 level using a graphical 
approach by Bretz et al. (2011).  The weighting 
strategy of the multiple comparisons is designed to 
allocate initial alpha equally to the QD and BID 
dose regimen. Within QD or BID dose regimen, 
AGN-241689 doses will be tested in a hierarchical 
order from high to low dose, i.e. for primary 
efficacy endpoint, low dose can be tested only if 
high dose comparison shows statistical significance. 
In addition, for a given dose comparing versus 
placebo, the strategy has the primary endpoint as 
gatekeeper to the secondary endpoints so that 
secondary endpoints can be tested only if primary 
hypothesis of the corresponding dose comparison 
reaches statistical significance.allocates ¼ weight to 
each of 30 mg QD, 30 mg BID, 60 mg QD and 60 
mg BID comparisons versus placebo for the primary 
hypothesis.  If any of those comparisons is rejected, 
20% of the corresponding weight will be propagated 
to test 10 mg QD versus placebo for the primary 
hypothesis and 80% of the weight will be 
propagated to test the first secondary hypotheses in 
the corresponding dose versus placebo. Then for the 
comparison of each dose versus placebo, 100% of 
the weight will be propagated sequentially for the 
remaining secondary endpoints. Finally, if for one 
of the doses efficacy can be shown for primary and 
all the secondary endpoints, the associated weight is 
passed on to other doses. This weighting strategy 
implies that the 10 mg QD versus placebo 
comparison can only be tested if at least one of the 
30 mg QD, 30 mg BID, 60 mg QD and 60 mg BID 


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Revision
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versus placebo comparisons for the primary 
hypothesis is rejected and a small amount of weight 
is to be allocated to the 10 mg QD versus placebo 
comparison, since it is selected as a likely 
suboptimal dose.  Similarly, under this strategy, no 
secondary hypothesis can be rejected until a primary 
hypothesis of the corresponding dose comparison is 
rejected.  The primary endpoint will serve as the 
gatekeeper for the secondary endpoints. Weighted 
Simes Bonferroni tests will be used for testing the 
hypotheses within each endpoint as the associated 
test statistics are positively correlated, and a 
Bonferroni mixture will be used to combine test 
results across different endpoints. A complete 
decision-flow graph and details of the graphical 
multiple comparison procedure will be presented in 
the statistical analysis plan of this study.
 
 
 
 
 
 
 
 
 
.
Section 8.8 Early 
Discontinuation of 
Patients
Revise the last paragraph of this section: 
Patients may voluntarily withdraw from the study at 
any time. Notification of early patient 
discontinuation from the study and the reason for 
discontinuation will be clearly documented on the 
appropriate case report form. All randomized 
patients who prematurely discontinue from the 
study, regardless of cause, should be seen for a final 
study assessments. The final assessments will be 
defined as completion of the evaluations scheduled 
for Visit 7/Early Termination and Visit 8 Safety 
Follow-up, 4 weeks post the last dose of IP.
For clarity
Section 11. References
Additional references added.
To support revised 
sample size 
calculation

SAP_001.pdf: 
NCT02848326 
 
Study ID: CGP‐MD‐01 
 
Title:  A PHASE 2/3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND TOLERABILITY OF MULTIPLE DOSING REGIMENS OF ORAL AGN-
241689 IN EPISODIC MIGRAINE PREVENTION 
 
 
STATISTICAL ANALYSIS PLAN Amendment 2 Date: 22 May 2018 


Allergan Confidential 
SAP CGP-MD-01 
 
1 
 
1. 
Title Page 
 
STATISTICAL ANALYSIS PLAN 
 
A PHASE 2/3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND TOLERABILITY OF MULTIPLE DOSING REGIMENS OF ORAL 
AGN-241689 IN EPISODIC MIGRAINE PREVENTION 
 
Final: 2017-01-05 
Amendment 1: 2017-10-09 
Amendment 2: 2018-05-22 
Protocol Number: 
CGP-MD-01 
Development Phase: 
2/3 
Product Name: 
Atogepant (AGN-241689) 
Study Statistician: 
 
Sponsor: 
Allergan, Inc. 
Clonshaugh Industrial Estate, Coolock, Dublin 17, 
Ireland 
 
 
 
 
This document is the property of Allergan, Inc. and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, Inc.


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2. 
Table of Contents 
1. 
Title Page ................................................................................................................................. 1 
2. 
Table of Contents ..................................................................................................................... 2 
2.1 
List of Tables .................................................................................................................. 3 
2.2 
List of Figures ................................................................................................................ 5 
3. 
List of Abbreviations and Definition of Terms ........................................................................ 6 
4. 
Introduction .............................................................................................................................. 8 
4.1 
Study Design Summary .................................................................................................. 8 
4.2 
Study Objectives and Endpoints .................................................................................... 9 
4.3 
Schedule of Activities .................................................................................................. 10 
5. 
Statistical Methodology and Study Endpoints ....................................................................... 12 
5.1 
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 12 
5.1.1  Statistical and Analytical Plans ........................................................................ 12 
5.1.1.1  Common Conventions ....................................................................... 12 
5.1.1.2  Demographics .................................................................................... 15 
5.1.1.3  Efficacy and Pharmacokinetic Analyses ........................................... 18 
5.1.1.4  Safety Analyses ................................................................................. 25 
5.1.1.5  Subgroup Analyses ............................................................................ 31 
5.1.1.6  Interim Analyses ................................................................................ 31 
5.1.2  Determination of Sample Size ......................................................................... 31 
5.2 
Changes in the Conduct of the Study or Planned Analyses ......................................... 32 
5.2.1  Changes in the Conduct of the Study ............................................................... 32 
5.2.2  Changes to Analyses Prior to Database Lock .................................................. 32 
6. 
Data Handling and Analysis Conventions ............................................................................. 32 
6.1 
Study Treatment Conventions ...................................................................................... 32 
6.1.1  Analysis Days .................................................................................................. 32 
6.1.2  Missing/Incomplete Treatment End Date ........................................................ 32 
6.2 
Analysis Visit Windows ............................................................................................... 32 
6.2.1  Efficacy ............................................................................................................ 32 
6.2.2  Safety ............................................................................................................... 33 
6.3 
Missing/Incomplete Date Conventions ........................................................................ 33 
6.3.1  Missing/Incomplete AE Start Date ................................................................... 34 
6.3.2  Missing/Incomplete Medication Start Date ..................................................... 34 
6.3.3  Missing/Incomplete AE/Medication End Date ................................................ 34 


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6.4 
Efficacy Endpoint Conventions ................................................................................... 34 
6.4.1  Derivation of Efficacy Endpoints Based on eDiary Data ................................ 34 
6.4.2  Primary Efficacy Analysis ................................................................................ 36 
6.4.3  Sensitivity Analysis .......................................................................................... 36 
6.4.3.1  Pattern-Mixture Model ...................................................................... 36 
6.4.3.2  Robust Regression ............................................................................. 37 
6.5 
Safety Endpoint Conventions ....................................................................................... 38 
6.5.1  Adverse Events ................................................................................................ 38 
6.5.1.1  Missing Intensity or Relationship ...................................................... 38 
6.5.2  Clinical Laboratory Assessments ..................................................................... 38 
6.5.2.1  Potentially Clinically Significant Criteria ......................................... 38 
6.5.2.2  Hepatic Laboratory Abnormalities .................................................... 40 
6.5.2.3  Continuous Descriptives and Shift Table Parameters ....................... 41 
6.5.2.4  Character Values ................................................................................ 41 
6.5.3  Vital Signs ........................................................................................................ 42 
6.5.3.1  Potentially Clinically Significant Criteria ......................................... 42 
6.5.3.2  Continuous Descriptives and Shift Table Parameters ....................... 42 
6.5.4  Electrocardiograms .......................................................................................... 42 
6.5.4.1  QTc Derivation .................................................................................. 42 
6.5.4.2  Potentially Clinically Significant Criteria ......................................... 43 
6.5.4.3  Continuous Descriptives and Shift Table Parameters ....................... 43 
6.6 
Imputed Value Listing Conventions ............................................................................. 43 
7. 
References .............................................................................................................................. 43 
 
2.1 
List of Tables 
Table 3–1 
Abbreviations and Definitions of Terms ................................................................. 6 
Table 4–1 
Study Objectives and Corresponding Endpoints .................................................... 9 
Table 4–2 
Schedule of Activities ........................................................................................... 10 
Table 5–1 
Analysis Populations ............................................................................................. 12 
Table 5–2 
Statistical Methodology ........................................................................................ 13 
Table 5–3 
Missing Data Handling by Endpoint Type ............................................................ 15 
Table 5–4 
Analysis Population Summaries ........................................................................... 15 
Table 5–5 
Participant Disposition Summaries ....................................................................... 15 


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Table 5–6 
Protocol Deviation Summary ................................................................................ 16 
Table 5–7 
Demographic Summaries ...................................................................................... 16 
Table 5–8 
Baseline Characteristics Summaries ..................................................................... 16 
Table 5–9 
Medical History Summary .................................................................................... 17 
Table 5–10 
Medical History Summary .................................................................................... 17 
Table 5–11 
Medication Summaries ......................................................................................... 18 
 
 
Table 5–13 
Efficacy Endpoint Baseline Definitions ................................................................ 20 
Table 5–14 
Efficacy Analysis .................................................................................................. 20 
Table 5–15 
Multiple Comparisons Procedure Definitions ...................................................... 23 
Table 5–16 
Safety Endpoint Baseline Definitions ................................................................... 25 
Table 5–17 
Study Treatment Summaries ................................................................................. 25 
Table 5–18 
AE Terms .............................................................................................................. 26 
Table 5–19 
AE Summaries ...................................................................................................... 27 
Table 5–20 
Clinical Laboratory Summaries ............................................................................ 28 
Table 5–21 
Potential Hy’s Law Summaries ............................................................................. 29 
Table 5–22 
Vital Signs Summaries .......................................................................................... 30 
Table 5–23 
ECG Summaries.................................................................................................... 30 
Table 5–24 
Suicidality Summaries .......................................................................................... 31 
Table 5–25 
Assumed Effect Size and Estimated Power for Primary Efficacy Endpoint ........ 31 
Table 6–1 
Analysis Day Definitions ...................................................................................... 32 
Table 6–2 
Efficacy Analysis Visit Definitions for eDiary data .............................................. 32 
Table 6–3 
Safety Analysis Visit Definitions .......................................................................... 33 
Table 6–4 
Imputation Scenarios ............................................................................................ 33 
Table 6–5 
Initial Imputed Date Algorithm ............................................................................. 34 


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Table 6–6 
Missing AE Intensity and Relationship Imputation Algorithms ........................... 38 
Table 6–7 
Clinical Laboratory PCS Criteria .......................................................................... 38 
Table 6–8 
Criteria for Hepatic Laboratory Abnormalities ..................................................... 40 
Table 6–9 
Clinical Descriptive and Shift Table Parameters .................................................. 41 
Table 6–10 
Vital Sign PCS Criteria ......................................................................................... 42 
Table 6–11 
Vital Sign Descriptive and Shift Table Parameters ............................................... 42 
Table 6–12 
QTc Derivation ...................................................................................................... 42 
Table 6–13 
ECG PCS Criteria ................................................................................................. 43 
Table 6–14 
ECG Descriptive and Shift Table Parameters ....................................................... 43 
 
2.2 
List of Figures 
Figure 5-1 
Multiple Comparisons Procedure ......................................................................... 25 


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3. 
List of Abbreviations and Definition of Terms 
Table 3–1 
Abbreviations and Definitions of Terms 
Abbreviation/Term 
Definition 
ACM-I 
Assessment of Chronic Migraine Impact 
AE 
ALP 
ALT 
adverse event 
alkaline phosphatase 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
BID 
BMI 
Anatomical Therapeutic Chemical 
twice daily 
body mass index 
CFB 
change from baseline 
C-SSRS 
DBS 
DDE 
Columbia-Suicide Severity Rating Scale 
dry blood spot 
Drug Dictionary Enhanced 
eCRF 
electronic case report form 
ECG 
EQ-5D-5L 
EU 
electrocardiogram, electrocardiographic 
European Quality of Life-5 Dimensional 
European Union 
FWER 
familywise error rate 
HEOR 
HIT-6 
INR 
health economics and outcomes research 
Headache Impact Test 
international normalized ratio 
ITT 
intent-to-treat 
LS 
LOCF 
MAR 
least squares 
last observation carried forward 
missing-at-random 
MedDRA 
MCMC 
MI 
Medication Dictionary for Regulatory Activities 
Markov Chain Monte Carlo 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
MPM 
mixed-effects model for repeated measures 
migraine/probable migraine 
OR 
odds ratio 
PCS 
PGIC 
potentially clinically significant 
Patient Global Impression of Change 
PK 
pharmacokinetics 
PID 
participant identification 
PT 
QD 
preferred term 
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 
SI 
Le Système International d’Unités (International System of Units) 


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Abbreviation/Term 
Definition 
SOC 
TBL 
system organ class 
total bilirubin 
TEAE 
US 
treatment-emergent adverse event 
United States 
WHO 
WPAI-SHP 
World Health Organization  
Work Productivity and Activity Impairment Questionnaire – Specific Health Problem 


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4. 
Introduction 
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the protocol 
amendment #2 dated 11Sep2017 of Study CGP-MD-01. Specifications of tables, figures, and 
data listings are contained in a separate document. The SAP for pharmacokinetic (PK) and health 
economics and outcomes research (HEOR) data will be prepared separately. 
This document is organized into 3 main sections: 
1. Study overview 
2. Statistical Methodology and Study Endpoints 
3. Data Handling and Analysis Conventions 
4.1 
Study Design Summary 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel group study 
conducted at approximately 75 sites in the United States. Approximately 810 participants will be 
randomized to one of six treatment arms (placebo, 10-mg once daily [QD], 30-mg QD, 30-mg 
twice daily [BID], 60-mg QD, and 60-mg BID) in a 2:1:2:1:2:1 ratio as follows: 
 Placebo (n = 180) 
 Atogepant 10-mg QD (n = 90) 
 Atogepant 30-mg QD (n = 180) 
 Atogepant 30-mg BID (n = 90) 
 Atogepant 60-mg QD (n = 180) 
 Atogepant 60-mg BID (n = 90) 
To maintain the blind, investigational product will be administered orally BID for 12 weeks to all 
participants. Participants, therefore, will receive either placebo twice daily, a morning dose of 
atogepant with an evening dose of placebo, or atogepant twice daily.   
Subject 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. 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 (Safety Follow-up). For details, please see Table 4–2, Schedule 
of Visit and Procedures. 


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4.2 
Study Objectives and Endpoints 
Each study objective is presented with corresponding endpoint(s) below: 
Table 4–1 
Study Objectives and Corresponding Endpoints  
Objectives 
Endpoints 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 To prospectively test for 
superiority of the following doses 
and dose regimens of atogepant 
(10-mg QD, 30-mg QD, 30-mg 
BID, 60-mg QD, and 60-mg BID) 
versus placebo for the prevention 
of episodic migraine in this 
pivotal trial 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
Primary Efficacy Endpoint 
P1. Change from baseline in the mean monthly migraine/probable 
migraine (MPM) headache days across the 12-week treatment period 
Secondary Efficacy Endpoints 
S1. Change from baseline in mean monthly headache days across the 12-
week treatment period 
S2. Proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 
S3. Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period 
 


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5. 
Statistical Methodology and Study Endpoints 
5.1 
Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
This statistical analysis plan (SAP) will be approved prior to database lock. The SAP expands the 
statistical section of the protocol and contains a detailed description of methods to analyze data 
collected in the study. The text portion of the SAP will be included in the CSR report as 
Appendix 16.1.9.  
5.1.1 
Statistical and Analytical Plans 
Statistical analyses will be conducted using 
. 
5.1.1.1 
Common Conventions 
5.1.1.1.1 
Analysis Populations 
The analysis populations will consist of participants as defined below: 
Table 5–1 
Analysis Populations 
Population 
Definition 
Study Treatment 
Screened 
All screened participants who sign informed consent
—
Intent-to-Treat (ITT) 
All randomized participants
Randomized assignment
Modified Intent-to-
Treat (mITT) 
All randomized participants who received ≥ 1 dose of study 
treatment, had an evaluable baseline period of diary data, and had 
≥ 1 evaluable post-baseline 4-week (Weeks 1-4, 5-8, and 9-12) of 
diary data 
 
For baseline, evaluable is defined as having at least 
20 days of diary data during the 4-week baseline period 
 
For each post-baseline 4-week treatment period, 
evaluable is defined as having at least 12 days of diary 
data for that particular period
Randomized assignment 
Safety 
All participants who received ≥ 1 dose of study treatment
Actual received1
1 Participants will be summarized according to the study treatment received for majority of treatment period. 
 
5.1.1.1.2 
Study Treatments 
The following treatment groups are defined for this study: 
 Placebo 
 Atogepant 10-mg QD 
 Atogepant 30-mg QD 
 Atogepant 30-mg BID 
 Atogepant 60-mg QD 


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 Atogepant 60-mg BID 
5.1.1.1.3 
Statistical Methodology 
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise. 
Table 5–2 
Statistical Methodology 
Methodology 
Description 
R1 
Categorical counts 
 
Number of participants in individual categories 
o 
Participants with ≥ 1qualifying event counted once per individual category
R2 
Categorical 
descriptives 
 
Number and percentage of participants in individual categories 
o 
Participants with ≥ 1qualifying event counted once per individual category 
 
N1 if percentage denominator ≠ number of participants in the population (standard 
percentage denominator) 
o 
N1 = participants with non-missing baseline value 
R3 
PCS descriptives 
 
Number and percentage of participants meeting potentially clinically significant 
(PCS) criteria 
o 
Participants with ≥ 1qualifying event counted once per PCS category  
 
Percentage denominator = number of participants with non-missing non-PCS 
baseline and >=1 non-missing postbaseline assessment 
o 
Unevaluable assessments considered missing
R4 
Shift analysis 
 
Number and percentage of participants in individual baseline and postbaseline 
categories 
 
Percentage denominator = number of participants in individual baseline categories 
 
N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
R5 
Continuous 
descriptives 
 
N1, mean, standard deviation (SD), median, minimum, maximum 
 
N1 = participants with non-missing value
R6 
CFB descriptives 
 
Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values 
 
N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
R7 
CFB ANCOVA 
 
Continuous descriptives and standard error (SE) for baseline, postbaseline, and 
CFB values 
 
Estimates derived from mixed model for CFB value controlling for factors 
(treatment group) and covariates (baseline value) 
o 
Least squares (LS) means and standard errors 
o 
LS mean differences, standard errors, and confidence intervals vs Placebo 
o 
P-values from contrast t-test comparing atogepant treatment groups vs 
Placebo 
 
N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
R8 
CFB MMRM 
 
Continuous descriptives and SE for baseline, postbaseline, and CFB values at each 
analysis visit 
o 
N1 = participants with non-missing values at both baseline and the 
specified postbaseline analysis visit 
 
Estimates derived from mixed model for CFB value controlling for fixed factors 
(treatment group, analysis visit), covariates (baseline value), and interactions 


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Methodology 
Description 
(treatment group by analysis visit, baseline value by analysis visit), with an 
unstructured covariance matrix (compound symmetry covariance matrix if 
convergence fails) 
o 
LS means and standard errors 
o 
LS mean differences, standard errors, and confidence intervals vs Placebo 
o 
P-values from contrast t-test comparing atogepant treatment groups vs 
Placebo 
o 
N1 = participants with non-missing values at both baseline and at least one 
postbaseline analysis visit 
o 
When the time point of interest is across overall 12-week treatment 
period, the contrast is constructed to estimate the mean difference in 
average change from baseline of Month 1 – 3 in the model.  
R9 
CFB figure 
 
Plot of CFB LS means and SE bars for Weeks 1-4, 5-8, and 9-12 
R10 
Responder 
 
Categorical descriptives for responders and nonresponders 
o 
Nonresponders include: 
 
Participants who do not meet responder criteria 
 
N1 = all participants unless otherwise specified
R11 
CDF Figure 
 
Plot of proportions of participants achieving a range of 0% to 100% reduction 
from baseline (i.e. improvement) in mean monthly MPM headache days across 
12-week treatment period by treatment group 
o 
The figure is cumulative, so that participants whose change from 
baseline is, for example, 50%, are also included at every level of 
improvement below 50%
R12 
GLMM  
 
Measures the relationship between the binary dependent variable with repeated 
measures and independent variables  
 
Estimates derived from generalized linear mixed model (GLMM) for repeated 
measures which assumes a binomial distribution for the response and uses a logit 
link.  
 
For the responder analysis in MPM headache days, the model includes: 
o 
Fixed factors (treatment group, analysis visit), covariates (baseline MPM 
headache days), and interactions (treatment group by analysis visit, baseline 
MPM headache days by analysis visit), with an unstructured covariance 
matrix (compound symmetry covariance matrix if convergence fails).  
o 
Odds ratios, confidence intervals, and p-values comparing atogepant 
treatment groups vs Placebo 
o 
When the time point of interest is across overall 12-week treatment 
period, the contrast is constructed to estimate the geometric mean of 
odds ratio of Month 1 – 3 in the model. 
 
Include participants with non-missing values at both baseline and at least one 
postbaseline analysis visit
CDF = cumulative distribution function; CFB = change from baseline; ANCOVA = analysis of covariance;  
MMRM = mixed model for repeated measures; GLMM = generalized linear mixed model. 
 
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document. 
5.1.1.1.4 
Missing Data 
General missing data handling conventions are specified for methodologies in Section 5.1.1.1.3 
and summarized as follows: 


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Table 5–3 
Missing Data Handling by Endpoint Type 
Parameter type 
Timing 
Missing Data Handling 
Responder 
Treatment Period 
 
Responder rate: 
o 
All participants included 
 
GLMM: 
o 
If missing covariates (including baseline if 
applicable) or missing values at all postbaseline 
analysis visits: Participant excluded 
o 
If ≥1 non-missing value at any postbaseline analysis 
visit: Participant included
CFB ANCOVA 
Treatment Period 
 
If missing covariates (including baseline if applicable)  
o
Participant excluded
CFB MMRM 
Treatment Period 
 
If missing covariates (including baseline if applicable) or 
missing values at all postbaseline analysis visits 
o 
Participant excluded 
 
If ≥1 non-missing value at any postbaseline analysis visit: 
o 
Participant included 

Missing at random assumed 
Pattern-mixture 
model (PMM) 
Treatment Period 
 
Sensitivity analysis for the primary efficacy endpoint to assess 
the robustness of the primary MMRM analysis to possible 
violation of the missing-at-random (MAR) assumption.  
 
A pattern-mixture model approach based on the “copy 
reference” method (Carpenter et al, 2013) will be used for 
missing value imputation. Refer to Section 6.4.3.1 for details.
CFB = change from baseline; ANCOVA = analysis of covariance;  
MMRM = mixed model for repeated measures; GLMM = generalized linear mixed model. 
 
5.1.1.2 
Demographics 
5.1.1.2.1 
Analysis Populations 
The distribution of participants within the analysis populations will be summarized as follows: 
Table 5–4 
Analysis Population Summaries 
Population  
Description 
Timing 
Methodology 
ITT, mITT, and Safety 
populations 
Distribution in total and by treatment 
group 
— 
Categorical counts 
 
5.1.1.2.2 
Participant Disposition 
Participant disposition encompasses the distribution of participants who complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Participant disposition will be summarized as follows: 
Table 5–5 
Participant Disposition Summaries 
Parameter 
Description 
Timing 
Methodology 
Screening disposition 1 
Number of screened participants in total
Screening Period 
Categorical 
descriptives
Treatment Period 
Distribution in the ITT Population in total 
Treatment Period 
Categorical 


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Parameter 
Description 
Timing 
Methodology 
disposition 1 
and by treatment group
descriptives
Follow-up period 
disposition1 
Distribution in the ITT Population in total 
and by treatment group
Safety Follow-up 
Period 
Categorical 
descriptives
1 Participant disposition will be listed and participants who prematurely discontinued will be listed. 
 
5.1.1.2.3 
Protocol Deviations 
Protocol deviations will be defined in Protocol Deviation Requirement Specification, including 
importance classification. Protocol deviations will be summarized as follows: 
Table 5–6 
Protocol Deviation Summary 
Parameter 
Description 
Timing 
Methodology 
Major protocol 
deviations1 
Distribution in the ITT Population in total 
and by treatment group
— 
Categorical 
descriptives
1 Protocol deviations will be listed. 
 
5.1.1.2.4 
Demographics 
Demographics will be summarized by treatment group for the Safety and mITT populations, as 
follows: 
Table 5–7 
Demographic Summaries 
Parameter 
Description 
Timing 
Methodology 
Age1 
Age (years) relative to informed consent 
date 
Informed consent 
Continuous 
descriptives
Age group 
 
<20 
 
20 – 29 
 
30 – 39 
 
40 – 49 
 
50 – 59 
 
60 – 69 
 
>=70 
Informed consent 
Categorical 
descriptives 
Sex, race, and ethnicity1 
 
eCRF categories 
 
Race group 
o 
White 
o 
Non-white
Screening Period 
Categorical 
descriptives 
1 Participant demographics will be listed. 
 
5.1.1.2.5 
Baseline Characteristics 
Baseline characteristics will be summarized in total and by treatment group for the Safety and 
mITT populations as follows: 
Table 5–8 
Baseline Characteristics Summaries 
Parameter 
Description 
Timing 
Methodology 
Baseline characteristics1 
 
Height (m) 
Latest assessment in 
Screening Period 
Continuous 
descriptives


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Parameter 
Description 
Timing 
Methodology 
 
Weight (kg) 
 
Body mass index (BMI) 
o 
Weight (kg) / height (m)2
Baseline efficacy 
Endpoints and timing fully described in 
Section 5.1.1.3 
 
Number of MPM headache days  
 
Number of headache days 
 
Number of acute medication use 
days 
Summary for mITT Population only 
The first 28 days of 
the screening 
period, starting with 
the day of the 
screening visit 
Continuous 
descriptives 
1 Participant baseline characteristics will be listed. 
MPM = migraine/probable migraine.  
 
5.1.1.2.6 
Medical History 
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 19.0 or newer. Unique participants who report medical history events will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) in total and by 
treatment group for the Safety Population as follows: 
Table 5–9 
Medical History Summary 
Parameter 
Description 
Timing 
Methodology 
Medical history1 
Abnormalities and surgeries occurring 
before the Screening Visit
Screening Period 
Categorical 
descriptives
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
1 Participant medical history will be listed. 
 
5.1.1.2.7 
Migraine History 
Migraine history, including diagnosis, duration of disorder, previous use of prophylaxis treatment, 
average frequency of migraines or headache days per month in past 3 months, and acute 
treatments will be reported in total and by treatment group for the Safety Population as follows: 
Table 5–10 
Medical History Summary 
Parameter 
Description 
Timing 
Methodology 
Migraine Diagnosis1 
With Aura, Without Aura, Both 
Screening Period 
Categorical 
descriptives
Duration of migraine1  
In the Table summarize in Years, 
in the Listing show original data 
in Years and Months
Screening Period 
Continuous 
descriptives 
Previous Prophylaxis Migraine 
Treatment1 
Yes or No 
Screening Period 
Categorical 
descriptives
Average number of migraine days 
per month in the last 3 months1 
 
Screening Period 
Continuous 
descriptives
Average number of headache days 
per month in the last 3 months1 
 
Screening Period 
Continuous 
descriptives


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Parameter 
Description 
Timing 
Methodology 
Acute Migraine Treatment1 
 
Categorize as Yes or No, and 
subcategorize the Yes by: 
 
Triptan 
 
Ergot or ergot 
combinations 
 
NSAID 
 
Opiate or opiate 
combination 
 
Antiemetic agent 
 
Barbituates 

Other 
Screening Period 
Categorical 
descriptives 
1 Participant migraine history will be listed. 
 
5.1.1.2.8 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary 
Enhanced (DDE), version MAR2016 or newer. Unique participants who reported medications 
will be summarized by Anatomical Therapeutic Chemical (ATC) 4 class and PT in total and by 
treatment group for the Safety Population as follows: 
Table 5–11 
Medication Summaries 
Parameter 
Description 
Timing 
Methodology 
Prior medications1 
Medications taken ≥ 1 time before the 
study treatment start date, regardless of 
medication end date
Screening Period 
Categorical 
descriptives 
Concomitant 
medications1 
Medications taken ≥ 1 time on or after the 
study treatment start date, regardless of 
medication start date 
 
Medications starting 1 day after 
treatment end date will be listed 
but excluded from analysis
Treatment Period 
Categorical 
descriptives 
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
1 Participant prior and concomitant medication will be listed. 
 
5.1.1.3 
Efficacy and Pharmacokinetic Analyses 
Efficacy analyses will be based on the mITT Population. 
The following efficacy assessments and terms are defined: 
 
 
 
 
 
 
 
 


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Assessment/Term 
Description 
 
 
.
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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For analyses of headache characteristics and acute medication use, the first 28 days of the 
screening period, starting with the day of the screening visit, will serve as the “baseline”. 
Baseline assessments for applicable efficacy endpoints defined as follows: 
Table 5–13 
Efficacy Endpoint Baseline Definitions 
Endpoint 
Description 
Timing 
Baseline number of MPM 
headache days 
The total number of reported MPM headache 
days divided by the total number of days with 
non-missing eDiary records during the 4-week 
baseline period and multiplied by 28. Refer to 
Section 6.4.1 for details. 
The first 28 days from screening 
visit to the day before 
randomization 
Baseline number of 
headache days 
The total number of reported headache days 
divided by the total number of days with non-
missing eDiary records during the 4-week 
baseline period and multiplied by 28. Refer to 
Section 6.4.1 for details. 
The first 28 days from screening 
visit to the day before 
randomization 
Baseline average headache 
day pain intensity 
Baseline average headache day pain intensity is 
calculated for days with non-missing eDiary 
data during baseline period. Refer to Section 
6.4.1 for details.
The first 28 days from screening 
visit to the day before 
randomization 
Baseline cumulative 
headache hours 
Average daily headache hours are calculated 
for days with non-missing eDiary data during 
baseline period. Baseline cumulative headache 
hours are calculated as average daily headache 
hours multiplied by 28. Refer to Section 6.4.1 
for details. 
The first 28 days from screening 
visit to the day before 
randomization 
Baseline number of acute 
medication use days 
The total number of reported acute medication 
use days divided by the total number of days 
with non-missing eDiary records during the 4-
week baseline period and multiplied by 28. 
Refer to Section 6.4.1 for details.
The first 28 days from screening 
visit to the day before 
randomization 
Baseline number of triptan 
use days 
The total number of reported triptan use days 
divided by the total number of days with non-
missing eDiary records during the 4-week 
baseline period and multiplied by 28. Refer to 
Section 6.4.1 for details.
The first 28 days from screening 
visit to the day before 
randomization 
MPM = migraine/probable migraine.  
 
5.1.1.3.1 
Efficacy Endpoints  
The efficacy endpoints are summarized in the table below. Analyses of HEOR endpoints (ACM-I 
total and domain scores, PGIC, WPAI-SHP V2.0, patient satisfaction with study medication, 
HIT-6, and EQ-5D-5L) will be specified in a separate HEOR SAP. 
Table 5–14 
Efficacy Analysis 
Endpoint 
Description 
Timing 
Methodology 
Endpoint 1 
P1 
Change from baseline in mean monthly MPM 
headache days across the 12-week treatment period 
Treatment 
period 
CFB MMRM 
Sensitivity Analyses: 
 
PMM 
 
Robust regression 


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Endpoint 
Description 
Timing 
Methodology 
(Refer to Section 6.4.3 
for details) 
Endpoint 2 
S1 
Change from baseline in mean monthly headache 
days across the 12-week treatment period
Treatment 
Period 
CFB MMRM 
Endpoint 3 
S2 
Proportion of participants with at least a 50% 
reduction in mean monthly MPM headache days 
across the 12-week treatment period
Treatment 
Period 
Responder 
GLMM 
Endpoint 4 
S3 
Change from baseline in mean monthly acute 
medication use days across the 12-week treatment 
period 
Treatment 
Period 
CFB MMRM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Analysis visits defined in Section 6.2.1.  
MPM = migraine/probable migraine. CFB = change from baseline; MMRM = mixed model for repeated measures; 
GLMM = generalized linear mixed model. 
P1: primary efficacy parameter; S1-S3: secondary efficacy parameters. Endpoint 5 – 12: additional efficacy 
parameters 
 
5.1.1.3.2 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be described in a separate SAP. 
5.1.1.3.3 
Multiple Comparisons Procedure for Primary and Secondary 
Endpoints 
The primary and secondary efficacy endpoints are identified as follows: 
 Primary (P1): Change from baseline in mean monthly MPM headache days across the 12-
week treatment period 
 1st Secondary (S1): Change from baseline in mean monthly headache days across the 12-
week treatment period  
 2nd Secondary (S2): Proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 


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 3rd Secondary (S3): Change from baseline in mean monthly acute medication use days 
across the 12-week treatment period 
The overall familywise error rate (FWER) will be controlled at α = 0.05 for each set of primary 
and secondary endpoint comparisons between each dose level of atogepant vs placebo. 
Specifically, the overall type I error rate for multiple comparisons across atogepant doses and the 
primary and secondary efficacy endpoints will be controlled at the 0.05 level using a graphical 
approach by Bretz et al (2011). The overall graphic approach procedure is defined in the Table 
5–15 and Figure 5-1. In the graph, each of the nodes is corresponding to one null hypothesis, 
for example, 60BID/P1 represents the null hypothesis that there is no statistically significant 
difference comparing 60 mg BID versus placebo on the primary endpoint. The number inside 
each node is the proportion of overall alpha initially allocated to that hypothesis. The number 
on the edge between two nodes represents the proportion of local alpha propagated from one 
hypothesis to the other given the former null hypothesis is rejected. 
It is of Sponsor’s interest to develop a QD regimen for registration unless the BID regimen 
provides meaningful additional benefit. Therefore, this study is designed to identify the dose 
regimen of QD or BID for the future development along with using its results for registration. 
To accomplish that objective, the weighting strategy is designed to allocate initial alpha 
equally to the QD and BID dose regimen. Within QD or BID dose regimen, atogepant doses 
will be tested in a hierarchical order from high to low dose. Specifically, for QD regimen, 50% 
of overall alpha (i.e. 0.025) is allocated to 60QD/P1. If 60QD/P1 is statistically significant, 3/5 
of the local alpha (i.e. 0.015) will be propagated to test the lower dose on primary endpoint 
(30QD/P1); and the other 2/5 of the local alpha (i.e. 0.01) will be passed to the same dose 
comparison for the secondary endpoint (60QD/S1). The proportion of weights are chosen to 
first ensure sufficient power for the lower dose comparison on primary hypothesis and then 
reserve the rest of the alpha for the corresponding secondary endpoints so that their data can 
be used as part of the registration along with primary data. Then if 30QD/P1 is significant, 1/3 
of the local alpha (i.e. 0.005) will be propagated to test 10QD/P1; and the other 2/3 of the local 
alpha (i.e. 0.01) will be passed to 30QD/S1. Similar weighting strategy applies to the BID 
regimen (60 mg BID and 30 mg BID).  
Following statistical significance of primary endpoint for 60 mg QD and 30 mg QD, if 
60QD/S1, 30QD/S1, 10QD/P1, or 10QD/S1 is significant, 100% of the local alpha will then be 
passed sequentially for the remaining secondary endpoints. Finally, if 60 mg QD or 30 mg QD 
can be shown significant across primary and all secondary endpoints, the associated alpha will 
be recycled to the primary hypothesis comparing the next lower dose. Similar alpha 
propagation applies to the secondary endpoints of BID regimen (60 mg BID and 30 mg BID). 
By this weighting strategy, secondary endpoints would be tested at the same alpha level of 0.01 


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for all 5 atogepant doses after the corresponding primary hypothesis is rejected (without 
considering alpha recycling). Under this strategy, no secondary hypothesis can be rejected 
until a primary hypothesis of the corresponding dose comparison is rejected. The primary 
endpoint will serve as the gatekeeper for the secondary endpoints. Weighted Bonferroni tests 
will be used for testing the hypotheses in the graph. 
In addition, 10 mg QD dose comparison is tested with control of type I error. In case the other 
four higher doses are all rejected, 10QD/P1 will be tested at alpha level of 0.01. A lower 
expected alpha level is allocated to the 10QD/P1 is because this dose is included in the study as 
a potentially sub-optimal dose.   
Table 5–15 
Multiple Comparisons Procedure Definitions 
Nodes 
Alternate Hypothesis 
Weight 
Initial Local 
Significance 
Level 
60mgBID P1 
60 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly MPM headache days across 
the 12-week treatment period (P1) 
1/2 
 α*(1/2) = α/2 
30mgBID P1 
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly MPM headache days across 
the 12-week treatment period (P1) 
0 
α*0 = 0 
60mgQD P1 
60 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly MPM headache days across the 12-
week treatment period (P1) 
1/2 
 α*(1/2) = α/2 
30mgQD P1 
30 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly MPM headache days across the 12-
week treatment period (P1) 
0 
α*0 = 0 
10mgQD P1 
10 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly MPM headache days across the 12-
week treatment period (P1) 
0 
α*0 = 0 
60mgBID S1 
60 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 12-
week treatment period (S1) 
0 
α*0 = 0 
30mgBID S1 
30 mg BID atogepant is significantly different from placebo in 
change from baseline in mean monthly headache days across the 12-
week treatment period (S1) 
0 
α*0 = 0 
60mgQD S1 
60 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly headache days across the 12-week 
treatment period (S1) 
0 
α*0 = 0 
30mgQD S1 
30 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly headache days across the 12-week 
treatment period (S1) 
0 
α*0 = 0 
10mgQD S1 
10 mg QD atogepant is significantly different from placebo in change 
from baseline in mean monthly headache days across the 12-week 
treatment period  (S1) 
0 
α*0 = 0 
60mgBID S2 
60 mg BID atogepant is significantly different from placebo in 
proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 
0 
α*0 = 0 


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Nodes 
Alternate Hypothesis 
Weight 
Initial Local 
Significance 
Level 
30mgBID S2 
30 mg BID atogepant is significantly different from placebo in 
proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 
0 
α*0 = 0 
60mgQD S2 
60 mg QD atogepant is significantly different from placebo in 
proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 
0 
α*0 = 0 
30mgQD S2 
30 mg QD atogepant is significantly different from placebo in change 
from baseline in proportion of patients with at least a 50% reduction in 
mean monthly MPM headache days across the 12-week treatment 
period 
0 
α*0 = 0 
10mgQD S2 
10 mg QD atogepant is significantly different from placebo in 
proportion of patients with at least a 50% reduction in mean monthly 
MPM headache days across the 12-week treatment period 
0 
α*0 = 0 
60mgBID S3 
60 mg BID atogepant 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 
30mgBID S3 
30 mg BID atogepant 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 
60mgQD S3 
60 mg QD atogepant 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 
30mgQD S3 
30 mg QD atogepant 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 
10mgQD S3 
10 mg QD atogepant 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 
 


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Figure 5-1 
Multiple Comparisons Procedure 
 
 
 
5.1.1.4 
Safety Analyses 
Safety analyses will be based on the Safety Population. 
Baseline assessments for applicable safety endpoints defined as follows: 
Table 5–16 
Safety Endpoint Baseline Definitions 
Parameter 
Description 
Timing 
 
Clinical laboratory evaluations 
 
Vital signs 
 
Electrocardiograms (ECGs) 
eCRF- or (standardized) vendor-provided 
assessments 
Latest non-missing 
assessment before 
the first dose of 
study medication
 
5.1.1.4.1 
Study Treatment Exposure and Compliance 
Study treatment exposure and compliance will be summarized by treatment group for the Safety 
Population as follows: 
Table 5–17 
Study Treatment Summaries 
Parameter 
Description 
Timing 
Methodology 


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Parameter 
Description 
Timing 
Methodology 
Study treatment 
exposure (days)1 
Treatment end date - treatment start date + 1 
Treatment Period 
Continuous 
descriptives
Participant-years of 
study treatment 
exposure (years) 
Sum over participants of study treatment 
exposure 
Treatment Period 
— 
Categorical study 
treatment exposure 
 
1 day 
 
2-7 days 
 
8-14 days 
 
15-21 days 
 
22-28 days 
 
29-35 days 
 
36-42 days 
 
43-49 days 
 
50-56 days 
 
57-63 days 
 
64-70 days 
 
71-77 days 
 
78-84 days 
 
> 84 days 
 
Treatment Period 
Categorical 
descriptives 
Study treatment 
compliance (%)2 
Summary by visit interval and overall 
 
100 × 
Number of treatment units 
actually taken
Number of treatment units 
expected to be taken
 
Day 1 – Week 2, 
Week 2 – Week 4, 
Week 4 – Week 6, 
Week 6 – Week 8, 
Week 8 – Week 12, 
Overall during 
Treatment Period 
Continuous 
descriptives 
Categorical study 
treatment compliance 
(%) 
Summary by the following compliance 
categories: 
 
< 80% 
 
80% - 120% 
 
> 120% 
Day 1 – Week 2, 
Week 2 – Week 4, 
Week 4 – Week 6, 
Week 6 – Week 8, 
Week 8 – Week 12, 
Overall during 
Treatment Period 
Categorical 
descriptives 
1 Treatment dosing data will be listed. 
2 Treatment duration and compliance will be listed. 
 
5.1.1.4.2 
Adverse Events 
The following adverse event (AE) terms are defined: 
Table 5–18 
AE Terms 
Term 
Description 
Treatment-
emergent  
An event that initially occurs or increases in severity on or after the treatment start date, where: 
 
Treatment start date ≤ event start date ≤ (treatment end date + 30 or Visit 8, whichever 
comes later) 
On-therapy 
An event where: 
 
Treatment start date ≤ event start date ≤ (treatment end date + 30 or Visit 8, whichever 
comes later) 
Newly 
emergent 
An event that initially occurs or increases in severity on or after the start date of safety follow-up 
period, where  


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Term 
Description 
 
Start date of the safety follow-up period ≤ event start date ≤ (treatment end date + 30 or 
Visit 8, whichever comes later)
 
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.0 or newer. Unique participants reporting AEs in the 
following AE categories will be summarized by treatment group for the Safety Population as 
follows: 
Table 5–19 
AE Summaries 
Parameter 
Description 
Timing 
Methodology 
Overall summary 
Overall summary only for the following 
categories: 
 
Treatment-emergent AEs 
(TEAEs) 
 
Treatment-related TEAEs 
 
On-therapy serious adverse events 
(SAEs) 
 
On-therapy fatal SAEs 
 
AEs leading to discontinuation
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later 
Categorical 
descriptives 
TEAEs 
Overall summary and by SOC and PT 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
Common TEAEs 
Summary by PT 
 
Includes TEAEs occurring in ≥ 
2% of participants in any 
treatment group 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
TEAEs by severity 
Overall summary and by SOC, PT, and 
severity 
 
Participants categorized overall 
and within each SOC and PT for 
the most severe occurrence 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
TEAE by relationship 
Overall summary and by SOC, PT, and 
relationship 
 
Participants categorized overall 
and within each SOC and PT for 
the most related occurrence 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
Newly emergent AE 
Overall summary and by SOC and PT 
From safety follow-
up start date until 30 
days after treatment 
end date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
On-therapy SAE1 
Overall summary and by PT 
From treatment start 
date until 30 days 
Categorical 
descriptives


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Parameter 
Description 
Timing 
Methodology 
after treatment end 
date or Visit 8, 
whichever comes 
later
Newly emergent SAE 
Overall summary and by PT 
From safety follow-
up start date until 30 
days after treatment 
end date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
On-therapy fatal SAE1 
Overall summary and by PT 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
Newly emergent fatal 
SAE 
Overall summary and by PT 
From safety follow-
up start date until 30 
days after treatment 
end date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
AEs leading to 
discontinuation1 
Overall summary and by PT 
From treatment start 
date until 30 days 
after treatment end 
date or Visit 8, 
whichever comes 
later
Categorical 
descriptives 
1 Participants who report ≥ 1 AE in the AE category and all AEs for those participants will be listed. 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2
 
 
5.1.1.5 
Subgroup Analyses 
Not applicable. 
5.1.1.6 
Interim Analyses 
Not applicable. 
5.1.2 
Determination of Sample Size 
With this multiplicity strategy as described in Section 5.1.1.3.3, the assumptions and 
corresponding power assessments for the primary efficacy endpoint are shown in Table 5–25. 
The treatment differences are assumed based on results from other episodic migraine 
prevention studies. The placebo-adjusted reduction in monthly migraine days observed from 
other episodic migraine prevention studies ranged from 1.1 to 2 days [topiramate (Silberstein 
2004 and Brandes 2004), telcagepant (Ho 2014), and CGRP monoclonal antibodies Ph2 
studies (Dodick 2014; Dodick 2014; Sun 2016), and their Ph3 studies results reported from 
American Headache Society & American Academy of Neuroscience 2017]. Power is calculated 
via 10,000 simulations based on multiplicity adjustment as described in Figure 5-1 for the 5 
doses and primary and secondary endpoints.    
Table 5–25 
Assumed Effect Size and Estimated Power for Primary Efficacy Endpoint 
 
60 mg BID 
(n=90) 
30 mg BID 
(n=90) 
60 mg QD 
(n=180) 
30 mg QD 
(n=180) 
10 mg QD 
(n=90) 
Assumed Treatment 
difference vs. placebo 
(placebo n = 180) 
-1.6 
-1.5 
-1.5 
-1.4 
-1.2 
Effect size  
(Common SD1 = 3.0) 
0.53 
0.5 
0.5 
0.47 
0.4 
Power 
97.0% 
91.4% 
99.3% 
98.1% 
80.3% 
 1 Common standard deviation is estimated based on blinded interim data assessments.  
QD = once daily; BID = twice daily; SD = standard deviation. 


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5.2 
Changes in the Conduct of the Study or Planned Analyses 
5.2.1 
Changes in the Conduct of the Study 
Not applicable.  
5.2.2 
Changes to Analyses Prior to Database Lock 
Not applicable.  
6. 
Data Handling and Analysis Conventions 
6.1 
Study Treatment Conventions 
6.1.1 
Analysis Days 
Treatment day is defined as follows: 
Table 6–1 
Analysis Day Definitions 
Term 
Description 
Treatment Day 
 
Relative to treatment start date 
If analysis date ≥ treatment start date: 
 
Day = analysis date – treatment start date + 1 
o 
Day 1 = treatment start date 
If analysis date < treatment start date: 
 
Day = analysis date – treatment start date 
o 
Day -1 = day before treatment start date 
o 
There is no Day 0
 
6.1.2 
Missing/Incomplete Treatment End Date 
If the investigator is unable to provide the treatment end date, treatment end date will be imputed 
to the last available dosing record date. 
6.2 
Analysis Visit Windows 
6.2.1 
Efficacy 
The analysis visit windows for efficacy endpoints based on daily eDiary data are defined as 
follows: 
Table 6–2 
Efficacy Analysis Visit Definitions for eDiary Data 
Analysis Phase 
Analysis Visit (Derived) 
eDiary Window 
Pretreatment 
Baseline 
The first 28 days from screening visit
Treatment 
Weeks 1 – 4
Treatment Day [1, 28] 
 
Weeks 5 – 8
Treatment Day [29, 56] 
 
Weeks 9 – 12
Treatment Day [57, 84] 


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6.2.2 
Safety 
The analysis visit windows for safety endpoints are defined as follows: 
Table 6–3 
Safety Analysis Visit Definitions 
Analysis Phase 
Analysis Visit 
(Derived) 
Scheduled Study 
Visit (eCRF) 
Window 
Pretreatment 
Baseline 
Visit 2 
(Randomization)
Treatment Day ≤ 1 
Treatment 
Week 2 
Visit 3
Treatment Day [2, 20] 
 
Week 4 
Visit 4
Treatment Day [21,34] 
 
Week 6 
Visit 5
Treatment Day [35, 48] 
 
Week 8 
Visit 6
Treatment Day [49, 69] 
 
Week 12 
Visit 7/ET
Treatment Day [70, the last double-blind visit]
 
End of treatment 
 
Last available assessment during double blind 
treatment period 
 
Week 16 (Safety 
follow-up) 
Visit 8 
Treatment Day [the last double-blind visit +1, the 
last study visit] 
End of study 
 
Last available assessment after treatment start date, 
i.e. occurs at final visit (expected Day 112) or ET
Safety follow-up visit will be presented in analysis tables for clinical laboratory values and vital signs. 
End of Treatment is defined as the last available assessment during double-blind treatment period, i.e. on or before the treatment end date. End of 
Treatment results will be presented in analysis tables for clinical laboratory values and vital signs.    
End of Study is defined as the last available assessment during the study, including double-blind and safety follow-up period. End of Study 
results will be presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical laboratory values, and 
vital signs. 
ET = early termination. 
 
The following general conventions for repeated or unscheduled assessments will apply unless 
otherwise specified: 
 The latest non-missing assessment within any analysis window will be flagged as the 
analysis value for any summaries by analysis visit 
 All postbaseline assessments will be considered for PCS categorization 
 All assessments will be included in respective listings 
 
6.3 
Missing/Incomplete Date Conventions 
Dates may be imputed with year, month, and day values under certain scenarios: 
Table 6–4 
Imputation Scenarios 
 
 
Complete
 
Scenario 
Year 
Month 
Day 
Imputable 
1 
Yes 
Yes
Yes
Complete
2 
Yes 
Yes
—
Yes
3 
Yes 
—
Yes
No1
4 
Yes 
—
—
Yes
5 
— 
Yes
Yes
No1


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Complete
 
Scenario 
Year 
Month 
Day 
Imputable 
6 
— 
Yes
—
No1
7 
— 
—
Yes
No1
8 
— 
—
—
Yes
1 Not allowed per database design. 
 
Dates will be imputed initially toward a specified target date for imputable scenarios 2, 4, and 8, 
and adjusted against the latest reasonable dates. The initial imputed date is determined by the 
following algorithm: 
Table 6–5 
Initial Imputed Date Algorithm 
Available Year 
Available Month (MM) 
(YYYY) 
Missing 
< Target Month 
= Target Month 
> Target Month 
Missing 
Target Date 
—
< Target Year 
YYYY-12-31 
YYYY-MM-LD 
= Target Year 
Target Date 
YYYY-MM-LD
Target Date
YYYY-MM-01
> Target Year 
YYYY-01-01 
YYYY-MM-01 
YYYY = available start date year; MM = available start date month; LD = last day of the month. 
 
6.3.1 
Missing/Incomplete AE Start Date 
AE start dates will be imputed as the minimum of the following: 
 Initial imputed date, where target date = Treatment start date 
 Complete end date  
6.3.2 
Missing/Incomplete Medication Start Date 
Medication start dates will be imputed as the minimum of the following: 
 Initial imputed date, where target date = Treatment start date – 1 
 Complete end date  
6.3.3 
Missing/Incomplete AE/Medication End Date 
AE and medication end dates will be imputed as the minimum of the following: 
 Initial imputed date, where target date = Treatment end date + 30 
 Death date 
6.4 
Efficacy Endpoint Conventions 
6.4.1 
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 


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and symptoms, the pain severity, and use of any acute headache pain medication. Daily headache 
diary data consists of data from “today’s dairy” completed on that day and “yesterday’s diary” 
completed on the following day. Participants are to report headache data in “today’s diary” in the 
evening 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 are able to 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 MPM headache 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 analysis purpose endpoint, the number of headache days during the first 28 days of the 
baseline phase, starting with the day of the screening visit, will serve as the “baseline”, and 
change from baseline will be calculated for consecutive 28-day periods beginning with Day 1 
(ie, Weeks 1-4, 5-8 and 9-12, corresponding to Days 1-28, 29-56 and 57-84). In order to be 
randomized, a participant should be in the baseline phase for at least 28 days and must report 
diary data for at least 20 days during the 28-day baseline period.   
The 4-week (monthly) MPM headache days is defined as the total number of reported MPM 
headache days in the diary divided by the total number of days with diary records during each 4-
week period and multiplied by 28. A minimum of 12 days’ diary data during each postbaseline 4-
week treatment period is required in order for the MPM headache migraine days to be evaluable 
for that particular period. If a subject does not have at least 12 days of diary data for any 4-week 
treatment period, the MPM headache days for that particular period will be considered as 
missing. MPM headache days will be derived for each participant at baseline and for each 
postbaseline 4-week treatment period (Weeks 1-4, 5-8, 9-12). The same method to derive MPM 
headache days will be used to derive headache days, acute medication use days, and triptan use 
days. 


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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. 
 
6.4.2 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline in mean monthly MPM headache 
days across the 12-week treatment period. The endpoint will be analyzed using MMRM. The 
response variable is the change from baseline to each postbaseline month in monthly MPM 
headache days. The model will include baseline monthly MPM headache days as a covariate, 
treatment group and visit (month) as fixed factors, and treatment group-by-visit and baseline-
by-visit as interaction terms. The analysis will be performed based on evaluable postbaseline 
data using only the observed cases without imputation of missing values. 
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 
compound symmetry covariance structure will be used. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. Contrasts will be constructed to 
obtain the average treatment effects across the 12-week treatment period to compare each 
atogepant treatment group versus the placebo group. Each treatment effect and treatment 
comparisons will be estimated by the LS Means and their differences in LS Means, along with 
their SE and 95% confidence intervals, and the p-value corresponding to the between-
treatment group difference.  
6.4.3 
Sensitivity Analysis 
6.4.3.1 
Pattern-Mixture Model 
The sensitivity analysis will use a pattern-mixture model (PMM) approach based on the 
reference-based copy reference method (Carpenter et al, 2013) for missing value imputation. 
This approach considers a missing-not-at-random (MNAR) mechanism for missing data and 
is to assess the impact of potential deviation of MAR assumption in the primary analysis.  
Note that the missingness is assumed monotonic. Any intermediate missing values, if any, will 
be imputed at first. If the intermediate missing value exists at the first postbaseline month, it is 
imputed using the average of baseline and next available postbaseline values; otherwise, 
intermediate missing values are imputed using last observation carried forward (LOCF) 
approach.  
The details of missing data imputation using the copy reference method are as follows: 


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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.  
2. For atogepant treatment groups, missing values are imputed based on the distribution 
estimated from the reference group (from Step 1).  
3. The MI (Step 1 and 2) will be performed 20 times and result in 20 imputed datasets. 
Each of the 20 imputed datasets will be analyzed using ANCOVA model. For a given 
imputed dataset, the average change from baseline in monthly MPM headache days is 
calculated across the 3 post-baseline months and is used as the response variable in the 
model. The model includes treatment group as a fixed factor and baseline monthly 
MPM headache 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.   
 
4. The ANCOVA analysis results from 20 completed datasets are combined for overall 
estimation and inference using Rubin’s rule (1987) 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.  
 
 
6.4.3.2 
Robust Regression 
The sensitivity analysis uses MI in conjunction with robust regression to assess the robustness 
of the primary MMRM analysis to the possible violation of normality assumption. This method 
has been described and referred as ADAP [R] in Mehrotra et al. 2012. The details of method 
are as follows.  
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 (K-S) test for normality is 
applied to the de-correlated and scaled residuals and normality test is rejected if p-value from 
the K-S test is less than 0.01.  
If the normality test is rejected, sensitivity analysis below will be performed: 


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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 MPM headache 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 as a fixed factor and baseline monthly MPM 
headache days as a covariate. The mean difference and corresponding SE is estimated 
from the model comparing each 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 rule (1987) to produce a pooled estimate of 
treatment difference, its SE, and corresponding p-value for the test of null hypothesis 
of no treatment effect.  
 
6.5 
Safety Endpoint Conventions 
6.5.1 
Adverse Events 
6.5.1.1 
Missing Intensity or Relationship 
If the investigator is unable to provide the actual values, the following imputations will be 
applied: 
Table 6–6 
Missing AE Intensity and Relationship Imputation Algorithms 
Missing Value 
Imputation 
Timing 
Intensity 
Mild
Screening Period
 
Severe
Treatment Period
Relationship 
—
Screening Period
 
Related
Treatment Period
 
6.5.2 
Clinical Laboratory Assessments 
6.5.2.1 
Potentially Clinically Significant Criteria 
Laboratory assessments values meeting any of the following PCS low or PCS high criteria will 
be categorized as PCS: 
Table 6–7 
Clinical Laboratory PCS Criteria 
 
 
PCS Criteria 
Category 
Parameter 
SI Unit 
PCS Low 
PCS High 


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PCS Criteria 
Category 
Parameter 
SI Unit 
PCS Low 
PCS High 
Chemistry 
Albumin 
g/L
< 0.8 × LLN 
> 1.2 × ULN
 
Alanine aminotransferase 
U/L
—
≥ 3.0 × ULN
 
Alkaline phosphatase 
U/L
—
≥ 3.0 × ULN
 
Aspartate aminotransferase 
U/L
—
≥ 3.0 × ULN
 
Bicarbonate
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Bilirubin, total 
μmol/L
—
≥ 1.5 × ULN
 
Blood urea nitrogen 
mmol/L
—
> 1.5 × ULN
 
Calcium 
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Chloride 
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Cholesterol, total 
mmol/L
—
> 1.6 × ULN
 
Creatinine 
μmol/L
—
> 1.5 × ULN
 
Creatine kinase 
U/L
—
> 2.0 × ULN
 
Estimated glomerular filtration rate
mL/min/1.73m2
< 0.8 × LLN 
—
 
Glucose, nonfasting 
mmol/L
< 0.8 × LLN 
> 2.0 × ULN
 
Lactate dehydrogenase (LDH)
U/L
—
> 3.0 × ULN
 
Phosphorus 
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Potassium 
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Protein, total  
g/L
< 0.9 × LLN 
> 1.1 × ULN
 
Sodium 
mmol/L
< 0.9 × LLN 
> 1.1 × ULN
 
Triglycerides 
mmol/L
—
> 2.0 × ULN
Uric acid  
μmol/L
—
> 1.2 × ULN
Hematology 
Basophils, absolute cell count
109/L
—
> 2.0 × ULN
Eosinophils, absolute cell count
109/L
—
> 2.0 × ULN
Hematocrit 
Ratio
< 0.9 × LLN 
> 1.1 × ULN
Hemoglobin 
g/L
< 0.9 × LLN 
> 1.1 × ULN
Lymphocytes, absolute cell count
109/L
< 0.7 × LLN 
> 1.3 × ULN
Monocytes, absolute cell count
109/L
< 0.5 × LLN 
> 2.0 × ULN
Neutrophils, absolute cell count
109/L
< 0.7 × LLN 
> 1.3 × ULN
Platelet count 
109/L
< 0.5 × LLN 
> 1.5 × ULN
Red blood cell count 
1012/L
< 0.9 × LLN 
> 1.1 × ULN
White blood cell count 
109/L
< 0.9 × LLN 
> 1.5 × ULN
Urinalysis 
pH 
pH
< 0.9 × LLN 
> 1.1 × ULN
Glucose 
mmol/L
—
Positive 1
Protein  
g/L
—
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 negative will be considered as positive. 
2 Any results other than trace or negative will be considered as positive. 
 
 


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6.5.2.2 
Hepatic Laboratory Abnormalities 
The following laboratory parameters will be summarized: 
Table 6–8 
Criteria for Hepatic Laboratory Abnormalities 
Laboratory Parameter 
Categories 
ALT 
≥ 1 × ULN 
≥ 1.5 × ULN 
≥ 2 × ULN 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 10 × ULN 
≥ 20 × ULN 
AST 
≥ 1 × ULN 
≥ 1.5 × ULN 
≥ 2 × ULN 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 10 × ULN 
≥ 20 × ULN 
ALT or AST 
≥ 1 × ULN 
≥ 1.5 × ULN 
≥ 2 × ULN 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 10 × ULN 
≥ 20 × ULN 
Bilirubin Total 
≥ 1 × ULN 
≥ 1.5 × ULN 
≥ 2 × ULN 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 10 × ULN 
≥ 20 × ULN 


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Laboratory Parameter 
Categories 
Alkaline Phosphatase 
≥ 1 × ULN 
≥ 1.5 × ULN 
≥ 2 × ULN 
≥ 3 × ULN 
≥ 5 × ULN 
≥ 10 × ULN 
≥ 20 × ULN 
Concurrent Elevations1 
ALT or AST >= 3 × ULN AND Bilirubin Total  ≥ 1.5 × ULN 
ALT or AST >= 3 × ULN AND Bilirubin Total ≥ 2 × ULN 
Potential Hy’s Law1 
ALT or AST ≥ 3 × ULN AND Bilirubin Total ≥ 2 × ULN AND 
ALP < 2 × ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ALP = alkaline 
phosphatase; ULN = upper limit of normal (value provided by the laboratory). 
1 Elevations are from the same day 
 
6.5.2.3 
Continuous Descriptives and Shift Table Parameters 
The following laboratory parameters will be summarized: 
Table 6–9 
Clinical Descriptive and Shift Table Parameters 
Category 
Parameters 
Hematology 
Hemoglobin; hematocrit; red blood cell count; red blood cell indices (mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); white blood cell 
count, including differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils); 
platelet count 
Chemistry 
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, 
creatine kinase, total protein, albumin, calcium, phosphorus, uric acid, total cholesterol. The 
estimated glomerular filtration rate will be calculated by the central laboratory. 
Urinalysis 
Urine dipstick for specific gravity, pH
 
6.5.2.4 
Character Values 
Character values (eg, < 5, negative) will be reviewed prior to database lock and converted to 
numeric for analysis as appropriate. These conversions will be documented in the ADaM 
specifications. 


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6.5.3 
Vital Signs 
6.5.3.1 
Potentially Clinically Significant Criteria 
Vital sign values meeting both the actual value and change from baseline PCS criteria will be 
categorized as PCS: 
Table 6–10 
Vital Sign PCS Criteria 
 
 
 
PCS Criteria 
Parameter 
Unit 
PCS Category 
Actual Value 
Change from Baseline 
Systolic BP 
mmHg 
High
≥ 180
Increase ≥ 20
 
 
Low
≤ 90
Decrease ≥ 20
Diastolic BP 
mmHg 
High
≥ 105
Increase ≥ 15
 
 
Low
≤ 50
Decrease ≥ 15
Pulse rate 
bpm 
High
≥ 120
Increase ≥ 15
 
 
Low
≤ 50
Decrease ≥ 15
Weight 
kg 
High
—
Increase ≥ 7%
 
 
Low
—
Decrease ≥7%
Orthostatic SBP change 
mm Hg
Low
≤ -20
 
Orthostatic DBP change 
mm Hg
Low
≤ -15
 
Orthostatic Pulse rate change 
bpm 
High
≥ 25
 
BP = blood pressure; bpm = beats per minute. 
Orthostatic pulse rate change equals standing pulse rate minus sitting pulse rate; orthostatic systolic blood pressure change 
equals standing systolic blood pressure minus sitting systolic blood pressure; and orthostatic diastolic blood pressure change 
equals standing diastolic blood pressure minus sitting diastolic blood pressure. 
 
6.5.3.2 
Continuous Descriptives and Shift Table Parameters 
The following vital sign parameters will be summarized: 
Table 6–11 
Vital Sign Descriptive and Shift Table Parameters 
Parameters 
Systolic BP 
Respiratory rate
Weight 
Diastolic BP 
Temperature
BMI 
Pulse rate 
Orthostatic SBP
Orthostatic DBP 
Orthostatic Pulse rate 
 
BP = blood pressure. 
Orthostatic pulse rate change equals standing pulse rate minus sitting pulse rate; orthostatic systolic blood pressure change 
equals standing systolic blood pressure minus sitting systolic blood pressure; and orthostatic diastolic blood pressure change 
equals standing diastolic blood pressure minus sitting diastolic blood pressure. 
 
6.5.4 
Electrocardiograms 
6.5.4.1 
QTc Derivation 
QTc Bazett (QTcB) and QTc Fridericia (QTcF) are derived as follows: 
Table 6–12 
QTc Derivation 
Parameter 
Derivation if RR available 
Derivation if RR unavailable 


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Parameter 
Derivation if RR available 
Derivation if RR unavailable 
QTcB 
QT
square root of RR
QT 
square root of 60/HR
 
QTcF 
QT
cubic root of RR
QT 
cubic root of 60/HR
 
QTcB = QTc Bazett; QTcF = QTcF Fridericia. 
 
6.5.4.2 
Potentially Clinically Significant Criteria 
ECG values meeting either the actual value or change from baseline PCS high criteria will be 
categorized as PCS: 
Table 6–13 
ECG PCS Criteria 
 
 
PCS High Criteria 
Parameter 
Unit 
Actual Value 
Change from Baseline 
QRS interval 
msec
≥ 150
— 
PR interval 
msec
≥ 250
— 
QTcB, QTcF 
msec
> 500
Increase > 60
QTcB = QTc Bazett; QTcF = QTcF Fridericia.
6.5.4.3 
Continuous Descriptives and Shift Table Parameters 
The following ECG parameters will be summarized: 
Table 6–14 
ECG Descriptive and Shift Table Parameters 
Parameters 
Heart rate 
QRS interval
QT interval 
 
PR interval
QTcB
 
RR interval
QTcF
 
QTcB = QTc Bazett; QTcF = QTcF Fridericia. 
 
6.6 
Imputed Value Listing Conventions 
In general, listings will present the actual partial or missing values rather than the imputed values 
that may be used in endpoint derivation. In instances where imputed values will be presented, 
imputed values will be flagged. Actual rules will be fully defined in the table, figure, and data 
listing specification document. 
7. 
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