A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Single Attack Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine
Phase: PHASE3
Conditions: Migraine, With or Without Aura
Sponsor: Allergan

NCT02828020 
 
Study ID: UBR‐MD‐01 
 
Title:  A Phase 3, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Single Attack Study to 
Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine 
 
Protocol Amendment 3 Date: 19 May 2017 
 
 
 

Allergan Confidential
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Title Page
ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information 
which is the property of Allergan
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED SINGLE ATTACK STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND TOLERABILITY OF ORAL UBROGEPANT 
IN THE ACUTE TREATMENT OF MIGRAINE
Protocol Number:  
UBR-MD-01 Amendment 3
Phase:
3
Name of Investigational Product:
Ubrogepant
Sponsor:
Allergan Pharmaceuticals 
International Limited
Clonshaugh Industrial Estate
Coolock
Dublin 17
Ireland
Authorized US Agent
Allergan Sales, LLC
2525 Dupont Drive
Irvine, California USA  92612
Emergency Telephone Number(s):
Refer to the Study Contacts Sheet
Serious Adverse Event 
Reporting Fax Number:
Allergan Medical Monitor
Contact Information:
Please see Study Contacts Sheet
Allergan Signatory:
Original Protocol Date:
29 Apr 2016
Protocol Amendment 1 Date:
09 Jun 2016
Protocol Amendment 2 Date:
04 Nov 2016
Protocol Amendment 3 Date:
19 May 2017
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The following information can be found on FDA Form 1572 and/or study contacts page:  
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
Investigator Signature Page ...................................................................................................... 3
Table of Contents ...................................................................................................................... 4
List of Tables............................................................................................................................. 7
List of Figures-.......................................................................................................................... 7
Protocol Summary .................................................................................................................... 8
1.
Background and Clinical Rationale ............................................................................ 15
2.
Study Objectives and Clinical Hypotheses................................................................. 17
2.1
Study Objectives ............................................................................................. 17
2.2
Clinical Hypotheses ........................................................................................ 17
3.
Study Design............................................................................................................... 17
3.1
Adjudication Committee and Data Safety Monitoring Board ........................ 18
4.
Study Population and Entry Criteria........................................................................... 19
4.1
Number of Patients ......................................................................................... 19
4.2
Study Population Characteristics.................................................................... 19
4.3
Inclusion Criteria ............................................................................................ 19
4.4
Exclusion Criteria ........................................................................................... 20
4.5
Permissible and Prohibited Medications/Treatments...................................... 23
4.5.1
Permissible Medications/Treatments.................................................. 23
4.5.1.1
Acute Treatment /Rescue Medication.................................. 24
4.5.1.2
Definition of Females of (Non-)Childbearing Potential 
and/or Acceptable Contraceptive Methods.......................... 24
4.5.2
Prohibited Medications/Treatments.................................................... 25
4.5.3
Special Diet or Activities.................................................................... 26
5.
Study Treatments ........................................................................................................ 26
5.1
Study Treatments and Formulations............................................................... 26
5.2
Control Treatment........................................................................................... 26
5.3
Methods for Masking/Blinding....................................................................... 26
5.4
Treatment Allocation Ratio and 
n................................................ 26
5.5
Method for Assignment to Treatment 
Groups/Randomization
............................................................. 27
5.6
Treatment Regimen and Dosing ..................................................................... 28
5.6.1
Treatment Administration................................................................... 28
5.6.3
Optional Second Dose and Rescue Medication.................................. 29
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5.7
Storage of Investigational Products/Treatments............................................. 30
6.
Response Measures and Summary of Data Collection Methods................................ 30
6.1
Efficacy Measures........................................................................................... 30
6.6
Other Study Supplies ...................................................................................... 37
6.7
Summary of Methods of Data Collection....................................................... 38
7.
Statistical Procedures.................................................................................................. 38
7.1
Analysis Populations....................................................................................... 38
7.1.1
Modified Intent-to-treat Population.................................................... 38
7.1.2
Safety Population................................................................................ 38
7.2
Collection and Derivation of Efficacy Assessments....................................... 38
7.2.1
Primary Efficacy Variables................................................................. 38
7.2.2
Secondary Efficacy Variables............................................................. 39
7.3
Hypothesis and Methods of Analysis ............................................................. 41
7.3.1
Efficacy Analyses ............................................................................... 41
7.3.1.1
Primary Efficacy Analyses .................................................. 41
7.3.1.2
Secondary Efficacy Analyses .............................................. 42
7.3.2
Pharmacokinetic Analyses.................................................................. 44
7.6
Interim Analyses ............................................................................................. 51
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8.
Patient Entry Procedures............................................................................................. 51
8.1.1
Overview of Entry Procedures............................................................ 51
8.1.2
Informed Consent and Patient Privacy ............................................... 51
8.2
Washout Intervals/Run-In............................................................................... 52
8.5
Instructions for the Patients ............................................................................ 58
8.6
Unscheduled Visits ......................................................................................... 59
8.7
Compliance with Protocol............................................................................... 59
8.8
Early Discontinuation of Patients ................................................................... 59
8.9
Withdrawal Criteria ........................................................................................ 60
8.11
Study Termination .......................................................................................... 60
9.
Adverse Events ........................................................................................................... 61
9.1
Definitions....................................................................................................... 61
9.1.1
Adverse Event..................................................................................... 61
9.1.2
Serious Adverse Event........................................................................ 61
9.1.3
Severity ............................................................................................... 62
9.1.4
Relationship to Study Drug or Study Procedure................................. 62
9.2
Procedures for Reporting Adverse Events...................................................... 62
9.3
Procedures for Reporting a Serious Adverse Event........................................ 63
9.4
Exposure to Investigational Product during Pregnancy.................................. 63
9.7
Procedures for Unmasking of Investigational Product................................... 66
10.
Administrative Items................................................................................................... 66
10.1
Protection of Human Patients ......................................................................... 66
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 
50) and Relevant Country Regulations............................................... 66
10.1.2 Compliance With IRB or IEC Regulations......................................... 66
10.1.3 Compliance With Good Clinical Practice........................................... 67
10.1.4 Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11)....................................................... 67
10.2
Changes to the Protocol .................................................................................. 67
10.3
Patient Confidentiality.................................................................................... 67
10.3.1 Patient Privacy .................................................................................... 67
10.4
Documentation................................................................................................ 68
10.4.1 Source Documents .............................................................................. 68
10.4.2 Electronic Case Report Form Completion.......................................... 69
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10.4.3 Study Summary................................................................................... 69
10.4.4 Retention of Documentation............................................................... 69
10.5
Labeling, Packaging, and Return or Disposal of Investigational 
Products/Treatments ....................................................................................... 70
10.5.1 Labeling/Packaging............................................................................. 70
10.5.2 Clinical Supply Inventory................................................................... 70
10.5.3 Return or Disposal of Investigational Products/Treatments and/or 
Supplies............................................................................................... 70
10.6
Monitoring by the Sponsor ............................................................................. 70
10.7
Handling of Biological Specimens/Samples................................................... 71
10.8
Publications..................................................................................................... 71
10.9
Coordinating Investigator ............................................................................... 71
11.
References................................................................................................................... 72
12.
Attachments ................................................................................................................ 74
12.1
Examination Procedures, Tests, Equipment, and Techniques ........................ 74
12.1.1 International Classification of Headache Disorders, 3rd Edition, 
Beta Version........................................................................................ 74
12.2
Examples of Prohibited Medications.............................................................. 89
12.3
Glossary of Abbreviations .............................................................................. 92
12.4
Protocol Amendment 1 Summary................................................................... 94
12.5
Protocol Amendment 2 Summary................................................................... 97
12.6
Protocol Amendment 3 Summary................................................................. 103
List of Tables
Table 2
Treatments Administered for Initial and Optional Second Dose.................... 28
Table 3
Clinical Laboratory Parameters ...................................................................... 35
Table 4
Assumed Response Rates and Estimated Power for Primary and Secondary 
Efficacy Endpoints.......................................................................................... 51
List of Figures
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Protocol Summary
Study Compound(s):  Ubrogepant
Phase:  3
Study Objective:  To evaluate the efficacy, safety, and tolerability of 2 doses of ubrogepant (50 mg and 
100 mg) compared to placebo for the acute treatment of a single migraine attack
Clinical Hypotheses:
1.  At least 1 ubrogepant dose is superior to placebo in the acute treatment of migraine.
2.  Ubrogepant is safe and tolerable.
Study Design
Structure:  Multicenter, randomized, double-blind, placebo-controlled, parallel-group, single attack study;
randomization to placebo, ubrogepant 50 mg, or ubrogepant 100 mg.
Duration:  The study includes a screening period of up to 14 days prior to randomization, a 60-day period in 
which to treat a single migraine attack, and a 4-week follow-up period.
Study Treatment Groups:  Ubrogepant 50 mg, ubrogepant 100 mg
Controls:  Ubrogepant placebo
Dosage/Dose Regimen:  Study participants will have up to 60 days to treat a single qualifying migraine attack of 
moderate or severe headache pain intensity at home. Patients have the option to take a second dose of 
investigational product (IP) or rescue medication if the patient has either a nonresponding migraine or a 
migraine recurrence. 
 
  
 
 
 
 
 
 
Study Population Characteristics
Number of Patients:  Approximately 1650 patients will be randomized (550 per treatment arm)
Condition/Disease:  Migraine with or without aura
Key Inclusion Criteria:  To be eligible for study participation, patients must be 18 to 75 years of age (inclusive), 
have a history of migraine with or without aura for at least 1 year consistent with a diagnosis according to the
International Classification of Headache Disorders criteria, 3rd edition, beta version (ICHD-3 beta, 2013) and 
experience between 2 to 8 migraine attacks with moderate to severe headache pain in each of the 3 months prior 
to Screening (Visit 1).
Key Exclusion Criteria: 
 
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Response Measures
Efficacy:  Rating of headache severity, absence or presence of migraine-associated symptoms, use of rescue 
medication, use of optional second dose, and recurrence of headache pain
 
 
General Statistical Methods and Types of Analyses:  The efficacy analyses will be based on the Modified 
Intent-to-treat (mITT) Population. The last observation carried forward (LOCF) approach will be used to impute 
missing posttreatment values. Baseline for efficacy is defined as the last nonmissing efficacy assessment before 
the initial dose of study treatment. For each primary variable, the observed response proportions will be 
provided by treatment group. The primary efficacy variable of pain freedom at 2 hours after the initial dose will 
be analyzed using a logistic regression model with categorical terms for treatment group, historical triptan 
response (triptan responder, triptan insufficient responder, or triptan naïve), use of medication for migraine 
prevention (yes/no), and baseline headache severity (moderate or severe). The primary efficacy variable of 
absence of the most bothersome symptom at 2 hours after the initial dose will be analyzed using a similar 
logistic regression model with an additional categorical term for the underlying symptom that was identified as 
the most bothersome. The respective comparisons of the ubrogepant doses versus placebo, which are the formal 
tests of the efficacy hypotheses, will be conducted using the appropriate pairwise contrasts within the logistic 
regression model. For secondary and other efficacy endpoints related to migraine headache pain severity and/or 
recurrence, migraine-associated symptoms, or use of rescue medication (including the second dose of IP), the 
observed response proportions will be analyzed using the same methods used to analyze the primary efficacy 
variables. For secondary efficacy endpoints on migraine-associated symptoms, baseline presence/absence of the 
symptom will be included as an additional covariate for the logistic regression model. The proportion of 
patients reporting satisfaction with study medication at 2 and 24 hours after the initial dose, the proportion of 
patients able to function normally at 1, 2, 4, and 8 hours after the initial dose, and the proportion of patients 
assessed by the PGIC as “much better” or “very much better” at 2 hours after the initial dose will be analyzed 
using the same methods used to analyze the primary efficacy variables. The baseline functional disability score 
will also be included as a covariate for the analysis of the proportion of patients able to function normally. For 
the change from baseline in EQ-5D-5L index value at 24 hours after the initial dose, treatment comparisons of 
ubrogepant dose groups versus placebo will be performed using an analysis of covariance (ANCOVA) model 
with categorical terms for treatment group, baseline severity, historical triptan response, and use of medication 
for migraine prevention, and with the baseline EQ-5D-5L index value as a covariate. Descriptive statistics will 
be provided for the change from baseline in the EQ VAS score at 24 hours after the initial dose by treatment 
group.
 
 
 
 
 
 
 
 
 
 
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Figure 1
Study Flow Diagram
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1.
Background and Clinical Rationale
What is Migraine and How Prevalent is It?
Migraine affects 18% of women and 6% of men in the United States with a peak prevalence 
occurring between the ages of 25 to 55 years. Approximately one-third of migraineurs have 
3 or more migraine headaches per month, and over half report severe impairment or the need 
for bed rest during an attack (Lipton et al, 2007). In the United States, 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 17.6% of women and 8% of men 
(Stovner and Andree, 2010). It is currently ranked by the World Health Organization 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, migraine headache 
may be preceded by focal neurological dysfunction (aura). Improving the diagnosis and 
optimizing treatments for migraine have been recognized as critically important to reduce the 
global burden of migraine (Katsarava et al, 2012).
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 is a syndrome diagnosis 
applied to patients with migraine (with or without aura) who have 1 to 14 headache days per 
month. Chronic migraine is a specific International Classification of Headache Disorders 
criteria, 3rd edition beta version (ICHD-3 beta) diagnosis applied to a subset of patients with 
≥15 headache days per month (ICHD-3 beta, 2013; Katsarava et al, 2012; 
Olesen et al, 2006). 
What is CGRP and What is its Relationship to Migraine?
CGRP (calcitonin gene-related peptide) is a neuropeptide implicated in the pathophysiology 
of migraine. CGRP levels in the cranial venous outflow (ie, external jugular vein) are
increased during a migraine attack (Goadsby and Edvinsson, 1993) 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 
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trigeminovascular system, with release of CGRP, may play a key role in migraine 
pathogenesis and that inhibition of CGRP function may yield a novel therapeutic approach to
treating migraine.
Establishment of CGRP Antagonism to Treat Migraine
The ability of CGRP antagonism to relieve pain in the acute treatment of migraine was
established by using an intravenous (IV) formulation of olcegepant (Olesen et al, 2004), 
and replicated by Merck & Co., Inc with an oral formulation of 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 et al, 2009). 
Serum alanine aminotransferase (ALT) increases were observed with telcagepant as well as 
with a second CGRP antagonist, MK-3207. For this reason, the development of these 
compounds was stopped. 
What is Ubrogepant?
Ubrogepant, a novel CGRP receptor antagonist that is chemically distinct from both 
telcagepant and MK-3207, is now being developed for the acute treatment of migraine. 
Preclinical and clinical studies conducted to date for ubrogepant have shown no evidence of 
hepatotoxicity.
A Phase 2b clinical study was conducted, which compared 1-, 10-, 25-, 50-, and 100-mg 
doses of ubrogepant to placebo in the acute treatment of migraine. Overall, all the ubrogepant 
doses tested were well tolerated and the adverse event (AE) profile of all ubrogepant doses 
did not differ significantly from placebo. For the primary efficacy endpoint of pain freedom
at 2 hours, ubrogepant doses of 1 and 10 mg did not differ from placebo, but doses of 25, 50, 
and 100 mg were better than placebo. For the primary efficacy endpoint of pain relief at 
2 hours none of the ubrogepant doses differed from placebo, probably due to a high placebo 
response rate.
The absence of migraine-associated symptoms of photophobia, phonophobia, and nausea was
assessed as key secondary endpoints. Ubrogepant doses of 50 and 100 mg were significantly 
better than placebo for absence of phonophobia and photophobia at 2 hours, whereas 25 mg 
did not differ from placebo. None of the ubrogepant doses differed from placebo for the 
endpoint of absence of nausea at 2 hours. Measures of sustained migraine headache relief 
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(2 to 24 hours and 2 to 48 hours sustained pain freedom and sustained pain relief) generally 
suggested that ubrogepant 50 mg and 100 mg were more effective than the 25-mg dose.
The purpose of this study will be to assess the safety and efficacy of 2 doses of ubrogepant, 
50 and 100 mg, versus placebo in the acute treatment of migraine with or without aura, in a 
randomized, double-blind, placebo-controlled Phase 3 study.
2.
Study Objectives and Clinical Hypotheses
2.1
Study Objectives
To evaluate the efficacy, safety, and tolerability of 2 doses of ubrogepant (50 and 100 mg) 
compared to placebo for the acute treatment of a single migraine attack.
2.2
Clinical Hypotheses
1. At least 1 ubrogepant dose is superior to placebo in the acute treatment of migraine.
2. Ubrogepant is safe and tolerable.
3.
Study Design
This multicenter, randomized, double-blind, placebo-controlled, parallel-group, single attack
study will enroll approximately 1650 patients from approximately 100 centers in the United 
States. Patients will be randomized (1:1:1) to 1 of the following 3 treatment groups: placebo, 
ubrogepant 50 mg, or ubrogepant 100 mg.
Study participants will have up to 60 days to treat a single qualifying migraine attack of 
moderate or severe intensity at home. Patients unable to treat a qualifying migraine within 
this time will be discontinued from the study.
 
 
 
 
 
 
The planned efficacy assessments are rating of headache severity, absence or presence of 
migraine-associated symptoms, use of rescue medication, use of optional second dose, and 
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recurrence of headache pain. A list and description of each efficacy assessment is in 
Section 6.1 and the efficacy analyses are presented in Section 7.3.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1
Adjudication Committee and Data Safety Monitoring Board
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 posttreatment elevations of ALT and/or aspartate aminotransferase (AST) ≥3 times the 
upper limit of normal (ULN) in the ubrogepant 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 ubrogepant.
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An independent Data Safety Monitoring Board (DSMB) will also 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 adverse events of treatment.
Details of the DSMB memberships, standard operational procedures for data 
monitoring/review, frequency of review, and other pertinent details will be provided in a 
separate DSMB Charter.
4.
Study Population and Entry Criteria
4.1
Number of Patients
Approximately 1650 patients will be randomized (550 patients per arm) from approximately 
100 centers in the United States.
4.2
Study Population Characteristics
This study will include adult patients with migraine with or without aura.
4.3
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
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. Migraine onset before age 50
5. By history, the patient’s migraines typically last between 4 and 72 hours if untreated or 
treated unsuccessfully and migraine episodes are separated by at least 48 hours of 
headache pain freedom
6. History of 2 to 8 migraine attacks per month with moderate to severe headache pain in 
each of the 3 months prior to Screening (Visit 1)
 
.
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8. Be able to read, understand and complete the study questionnaires and eDiary.
4.4
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the study:
 
 
2. Difficulty distinguishing migraine headache from tension-type or other headaches. 
 
 
 
 
 
 
4. Has taken medication for acute treatment of headache (including acetaminophen, 
nonsteroidal anti-inflammatory drugs [NSAIDs], triptans, ergotamine, opioids, or 
combination analgesics) on 10 or more days per month in any of the 3 months prior to 
Visit 1. 
5. Has a history of migraine aura with diplopia or impairment of level of consciousness, 
hemiplegic migraine, or retinal migraine as defined by ICHD-3 beta (Section 12.1.1)
6. Has a current diagnosis of new persistent daily headache, trigeminal autonomic 
cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by 
ICHD-3 beta (Section 12.1.1)
7. Required hospital treatment of a migraine attack 3 or more times in the 6 months prior 
to Visit 1.
 
 
 
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9. Has a chronic non-headache pain condition requiring daily pain medication (with the 
exception of pregabalin)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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
21. History of any prior gastrointestinal (GI) conditions (eg, diarrhea syndromes, 
inflammatory bowel disease) that may affect the absorption or metabolism of 
investigational product (IP); patients with prior gastric bariatric interventions (eg, Lap 
Band) which have been reversed are not excluded
22. 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 at Screening (Visit 1)
 
 
 
 
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4.5
Permissible and Prohibited Medications/Treatments
4.5.1
Permissible Medications/Treatments
Medications which are not specifically prohibited are allowed; however, there may be
clarifications and restrictions with certain medications.
The following medications are allowed during the study, but are prohibited within 48 hours 
prior to taking IP:

any triptan

any ergot derivative

any opioid

any NSAID

any other form of analgesic (including acetaminophen)

any antiemetic agent

any proton pump inhibitor
The following medications are allowed during the study, but are prohibited within 24 hours 
prior to taking IP:

any antacid

any H2 blocker
Examples of allowed but restricted medications listed above are displayed in 
Attachment 12.2.
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis.
Daily use of pregabalin is allowed. 
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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. SSRIs and 
SNRIs may not be started during the study.
Standard migraine prophylactic medications (eg, beta-blocker, tricyclic antidepressant, 
topiramate, valproic acid, botulinum toxin) will be permitted provided that the treatment is 
stable for at least 30 days prior to Visit 1, and continues without change in dose throughout 
the study. Prophylactic medications may not be started during 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.
4.5.1.1
Acute Treatment /Rescue Medication
Medications for acute treatment of migraine listed above may be taken during the study 
within the parameters noted in Section 4.5.1. 
 
 
 
 
For details regarding the requirements for 
treatment with rescue medication and optional second dose, please refer to Section 5.6.3.
 
 
 
 
4.5.1.2
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, 
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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 investigational drug ubrogepant, 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.
4.5.2
Prohibited Medications/Treatments
The following medications are prohibited 30 days prior to Visit 1 and throughout the study 
period:

Strong and moderate cytochrome P450 3A4 (CYP3A4) inhibitors, including but not 
limited to: systemic (oral/IV) itraconazole, ketoconazole, fluconazole; erythromycin, 
clarithromycin, telithromycin; diltiazem, verapamil; aprepitant; cyclosporine;
nefazodone; cimetidine; quinine; and HIV protease inhibitors

Strong and moderate CYP3A4 inducers, including but not limited to barbiturates 
(eg, phenobarbital and primidone), systemic (oral/IV) glucocorticoids, nevirapine, 
efavirenz, pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and St. John’s 
wort

Inhibitors of the BCRP (breast cancer resistance protein) transporter (eg, rifampicin)

Drugs with narrow therapeutic margins (eg, digoxin, warfarin)
Examples of prohibited medications in the classes noted above are displayed in Section 12.2.
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.
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4.5.3
Special Diet or Activities
Patients must refrain from consuming grapefruit or grapefruit juice from the time the consent 
form is signed until completion of the study. In addition, patients will be asked to refrain 
from sleeping and consuming caffeine for at least 2 hours after they take IP.
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.
5.
Study Treatments
5.1
Study Treatments and Formulations
Ubrogepant 
 oral compressed tablets containing 50 mg of 
ubrogepant.
5.2
Control Treatment
Ubrogepant placebo 
 tablets.
5.3
Methods for Masking/Blinding
All study treatments will be provided in identical blister cards to maintain masking of the 
study. Tablets of ubrogepant 50 mg and placebo will be identical in appearance.
A modified double-dummy design will be utilized to maintain the study blind. All patients 
will be instructed to take 2 tablets to treat their migraine attack regardless of the dose group 
to which they are assigned. The treatments to be used in this study are outlined in Table 2.
5.4
Treatment Allocation Ratio 
Patients who meet all of the study entry criteria will be randomized and provided with IP to 
treat 1 migraine attack on an outpatient basis. Patients will be assigned randomly in a 
1:1:1 ratio to 1 of the following 3 treatment groups: placebo, ubrogepant 50 mg, or
ubrogepant 100 mg. 
 
 
 
 
 
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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.
An automated interactive web response system (IWRS) will be used to manage the 
randomization and treatment assignment. At the time of randomization (Visit 2), eligible 
patients will be randomly assigned to 1 of 3 treatment arms in a 1:1:1 ratio to placebo, 
ubrogepant 50 mg, or ubrogepant 100 mg
 
Allergan Biostatistics (randomization programmer) will prepare the randomization codes. 
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IP will be labeled with medication kit numbers. The IWRS will provide the site with the 
specific medication kit number(s) for each randomized patient at the time of randomization. 
Sites will dispense IP according to the IWRS instructions. 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
5.6.1
Treatment Administration
Table 2 presents the treatments that will be administered in this study. All patients will be 
instructed to take 2 tablets for their initial dose to treat their migraine attack regardless of the 
dose group to which they are assigned. If taking the optional second dose, patients will also 
be instructed to take 2 tablets. 
 
Table 2
Treatments Administered for Initial and Optional Second Dose
Drug/Dose
Route of 
Administration
Investigational 
Product
Administered for 
Initial Dose
 
 
Placebo
Oral (tablet)
50 mg placebo/
50 mg placebo
Ubrogepant 50 mg
Oral (tablet)
Ubrogepant 50 mg/
50 mg placebo
Ubrogepant 100 mg
Oral (tablet)
Ubrogepant 50 mg/
ubrogepant 50 mg
 
 
 
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5.6.3
Optional Second Dose and Rescue Medication
Two hours after initial treatment with IP, patients who did not adequately respond may take a 
blinded optional second dose, active treatment or placebo, as assigned at the Randomization 
Visit (Visit 2) or patients’ own rescue medication, or may elect to take no further medication. 
Inadequate response to the initial dose of IP is defined as meeting 1 of the following:

Continues to have a headache that is either moderate or severe; OR

After initial pain relief at 2 hours (defined as a headache severity rating of no pain or 
mild pain), moderate or severe headache returns within 2 to 48 hours after the initial 
dose
 
 
 
 
 
 
 
 
 
 
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5.7
Storage of Investigational Products/Treatments
IP at the site must be stored at room temperature in a securely locked cabinet. Further details 
regarding the storage of the IP are in the Study Reference Manual.
6.
Response Measures and Summary of Data Collection Methods
6.1
Efficacy Measures
Efficacy measurement assessments are based on information recorded by the patient in an 
eDiary.
Rating of Headache Severity
Headache severity will be subjectively rated by the patient at predefined timepoints (predose 
and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours after the initial dose) on a scale from no pain to 
severe pain:

No pain

Mild pain

Moderate pain

Severe pain
Migraine Associated Symptoms
The patient will record whether the following associated symptoms were present or absent at 
predefined timepoints (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours after the initial 
dose):

Photophobia

Phonophobia

Nausea

Vomiting
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Use of Rescue Medication
Patients will record in their eDiary any rescue medication taken within 48 hours after treating 
their migraine attack with IP, in addition documenting the date and time that the rescue 
medication was taken.
Use of Optional Second Dose and Recurrence of Headache Pain
Patients will record in their eDiary use of the optional second dose of IP due to inadequate 
response to their initial dose of IP. Date and time of the second dose will be reported, as well 
as pain severity and absence or presence of migraine-associated symptoms at the time the 
second dose is taken and 2 hours after taking the second dose. The incidence of recurrence in 
patients who had pain relief and pain freedom at 2 hours after the initial dose will be 
collected.
 
 
 
 
 
 
 
 
 
  
 
 
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6.6
Other Study Supplies
The following will be provided by Allergan:

All supplies needed for blood and urine sampling (central laboratory analysis, urine 
culture/sensitivity) and urine dipstick reagent strips


Shipping materials for shipment of laboratory samples to central laboratory

All supplies needed for ECG assessment including ECG machine

Electronic diaries (eDiary)

Electronic tablets (eTablet)
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6.7
Summary of Methods of Data Collection
An IWRS will be used to randomize patients and manage IP inventory. Data for this study 
will be collected using eCRFs via an electronic data capture system, eDiaries, and eTablets.
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. Centralized vendors will be used for the 
analysis of all blood/urine samples and ECG assessments. Additional information on the 
collection and handling of samples is detailed in the respective laboratory manuals.
Patients will use an eDiary to record details associated with their migraine attack, including, 
but not limited to the date and time of dosing, efficacy assessments (eg, pain severity, 
absence or presence of migraine-associated symptoms), and other important study
information at designated timepoints post-dose. Training for the eDiary will be provided for 
qualified patients during the Randomization Visit (Visit 2). For details regarding eDiary 
instructions to patients, see the eDiary manual.
The C-SSRS will be conducted as a clinical interview at each visit and recorded by qualified
site staff via an eTablet.
7.
Statistical Procedures
7.1
Analysis Populations
7.1.1
Modified Intent-to-treat Population
The Modified Intent-to-treat (mITT) Population will consist of all randomized patients who 
received at least 1 dose of study treatment, recorded a baseline migraine headache severity 
measurement, and had at least 1 postdose migraine headache severity or migraine-associated 
symptom measurement at or before the 2-hour timepoint.
7.1.2
Safety Population
The Safety Population will consist of all randomized patients who received at least 1 dose of 
study treatment.
7.2
Collection and Derivation of Efficacy Assessments
7.2.1
Primary Efficacy Variables
The coprimary efficacy parameters for the United States are as follows:  
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
Pain freedom (PF) at 2 hours after the initial dose, defined as a reduction in headache 
severity from moderate/severe at baseline to no pain, at 2 hours after the initial dose

Absence of the most bothersome migraine-associated symptom (the most bothersome 
migraine-associated symptom will be identified at baseline for each patient) at 2 hours 
after the initial dose. 
7.2.2
Secondary Efficacy Variables
The secondary efficacy parameters for the United States are:

Pain relief (PR) at 2 hours after the initial dose, defined as the reduction of a 
moderate/severe migraine headache to a mild headache or to no headache, at 2 hours 
after the initial dose

Sustained pain relief (SPR) from 2 to 24 hours after the initial dose, defined as pain 
relief with no administration of either rescue medication or the second dose of IP, and 
with no occurrence thereafter of a moderate/severe headache during the relevant 
number of hours after dosing with the IP

Sustained pain freedom (SPF) from 2 to 24 hours after the initial dose, defined as pain 
freedom with no administration of either rescue medication or the second dose of IP, 
and with no occurrence thereafter of a mild/moderate/severe headache during the 
relevant number of hours after dosing with the IP

Absence of photophobia at 2 hours after the initial dose

Absence of phonophobia at 2 hours after the initial dose

Absence of nausea at 2 hours after the initial dose
 
 
 
 
 
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7.3
Hypothesis and Methods of Analysis
The efficacy analyses will be based on the mITT Population. The last-observation-carried-
forward (LOCF) approach will be used to impute missing posttreatment values. Baseline for 
efficacy is defined as the last nonmissing efficacy assessment before the initial dose of study 
treatment. 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.
7.3.1
Efficacy Analyses
7.3.1.1
Primary Efficacy Analyses
For each primary variable, the observed response proportions will be provided by treatment 
group. The primary efficacy variable of pain freedom at 2 hours after the initial dose will be 
analyzed using a logistic regression model with categorical terms for treatment group, 
historical triptan response (triptan responder, triptan insufficient responder, or triptan naïve), 
use of medication for migraine prevention (yes/no), and baseline headache severity 
(moderate or severe). The primary efficacy variable of absence of the most bothersome 
symptom at 2 hours after the initial dose will be analyzed using a similar logistic regression 
model with an additional categorical term for the underlying symptom that was identified as 
the most bothersome. If the logistic regression model fails to converge due to complete or 
quasi-complete separation, Firth’s penalized likelihood method (Firth, 1993) will be used. 
The logistic regression model will be referred to as the primary model. 
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The respective comparisons of the ubrogepant doses versus placebo, which are the formal 
tests of the efficacy hypotheses, will be conducted using the appropriate pairwise contrasts 
within the logistic regression model. Treatment comparisons will be based on the model-
derived odds ratios and their associated 95% confidence intervals. Two-sided p-values will 
also be provided. 
, the study will be considered a success if at least 1 ubrogepant dose is 
demonstrated to be superior to placebo on both coprimary variables after multiplicity 
adjustment. 
 
 
.
7.3.1.2
Secondary Efficacy Analyses 
For each secondary efficacy endpoint, the observed response proportions will be analyzed 
using the same methods used to analyze the primary efficacy variables. The respective 
comparisons of the ubrogepant doses versus placebo will be conducted using model-derived 
odds ratios, 95% confidence intervals and p-values from the logistic regression model. For 
secondary efficacy endpoints on migraine-associated symptoms, baseline presence/absence 
of the symptom will be included as an additional covariate for the logistic regression model.
A graphical approach by Bretz et al (2009) will be used to control the overall type I error rate 
for multiple comparisons across the ubrogepant doses and the primary and secondary 
efficacy endpoints. The coprimary efficacy endpoints will serve as the gatekeepers of the 
secondary endpoints. The secondary endpoints will be tested in the same order as they appear 
in the list of secondary endpoints, except for the 3 migraine-associated symptoms which will 
be treated at the same level to allow the recycling of weights among the 3 symptom 
endpoints. Recycling of weights between the 2 doses is also allowed. The details of the 
multiple comparison procedure will be provided in the statistical analysis plan (SAP).
.
 
 
 
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Table 4
Assumed Response Rates and Estimated Power for Primary and Secondary Efficacy 
Endpoints
Endpoint
Assumed Response 
Rate for Placebo
Assumed Response Rate for 
Ubrogepant Groups
Power After Multiplicity 
Adjustment
PF 2h
10%
24%
>99%
Absence of the Most 
Bothersome Symptom 2h
26.7%
37.7%
88%
PR 2h
34%
56%
88%
SPR 2 to 24h
19%
38%
88%
SPF 2 to 24h
6.5%
14.5%
83%
Absence of Photophobia 2h
32%
44%
78%
Absence of Phonophobia 2h
43%
57%
81%
Absence of Nausea 2h
59%
70%
71%
; h = hours; PF = pain freedom; PR = pain relief; SPF = sustained pain freedom; SPR = 
sustained pain relief
7.6
Interim Analyses
No interim analysis is planned for this study.
8.
Patient Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the inclusion and exclusion criteria in Sections 4.3 and 4.4
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 
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privacy requirements (where applicable) prior to any study-related procedures or change in 
treatment.
Each patient that provides informed consent will be assigned a patient number that will be 
used on patient documentation throughout the study.
 
 
8.2
Washout Intervals/Run-In
This study will not include a washout period.
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5
Instructions for the Patients
Section 4.5.3 provides diet and activity instructions for patients enrolled in the study.
Patients will be provided with instructions on the use of the eDiary to complete when they 
experience a qualifying migraine. 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, criteria for a qualifying migraine to be treated as well as prohibited 
medications should be reviewed with the patients. Patients will be instructed to bring their 
eDiary at the next clinic visit and return their IP (used and unused).
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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. For all parameters not measured, 
indicate “not done”.
8.7
Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1, and the
timing of the visits should occur as close as possible to the specified day. 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. 
Patients will record the requested information regarding their migraine attack and the IP
taken in the eDiary. IP compliance will be closely monitored by counting the number of 
tablets dispensed and returned. Every effort will be made to collect all unused IP.
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)

Protocol violation

Noncompliance with IP

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.)

Lack of Qualifying Event (a qualifying migraine is not treated within 60 days from 
Randomization [Visit 2])

Pregnancy
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
Other reasons
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 eCRF. All randomized patients who prematurely discontinue from the 
study, regardless of cause, should be seen for a final assessment. A final assessment will be 
defined as completion of the evaluations scheduled for Visit 3/Early Termination
 
 
. If the patient discontinues after IP is 
taken, the patient is also expected to return for the Safety Follow-up Visit (Visit 4) 4 weeks 
postdose.
8.9
Withdrawal Criteria
Women who become pregnant will be withdrawn from the study (see Section 4.5.1.2) and 
should refrain from taking IP. The patient should return to the clinic for early termination
procedures (Visit 3), including the safety follow-up visit (Visit 4) if IP was taken. 
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 Visit 3 
 
nd should receive appropriate follow-up as in routine clinical practice, 
including the safety follow-up visit (Visit 4) if IP was taken.
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.
 
 
 
 
 
.
8.11
Study Termination
Allergan may stop the study (and/or the study site) for any reason with appropriate 
notification.
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9.
Adverse Events
Adverse events occurring during the study will be recorded on an adverse event eCRF. If 
adverse events occur, the first concern will be the safety of the study participants.
9.1
Definitions
9.1.1
Adverse Event
An adverse event 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 adverse event 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, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.
Note:  Adverse events 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 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease.
Adverse events 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 adverse events 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 adverse events will be documented on the 
appropriate case report form.
9.1.2
Serious Adverse Event
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, 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 serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient and may require 
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medical or surgical intervention to prevent one of the outcomes listed in this definition. (See 
Section 9.3 for procedures for reporting a serious adverse event.)
Allergan considers all cancer adverse events as serious adverse events. In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event.
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event.
Any preplanned 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 serious adverse event and reported to Allergan.
9.1.3
Severity
A clinical determination will be made of the intensity of an adverse event. The severity 
assessment for a clinical adverse event 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 adverse event 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 adverse event 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 serious adverse events 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.
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9.3
Procedures for Reporting a Serious Adverse Event
Any serious adverse event 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 a serious adverse event. Serious adverse 
events must be reported to Allergan or Agent of Allergan (eg, contract research organization 
[CRO]) and recorded on the serious adverse event form. All patients with a serious adverse 
event must be followed up and the outcomes reported. The investigator must supply Allergan
and the IRB/IEC with any additional requested information (eg, autopsy reports and 
discharge summaries).
In the event of a serious adverse event, the investigator must:
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol.
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 
serious adverse event 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 serious adverse event 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 IP 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 
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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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9.7
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 IP. The investigator should 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 on to the IWRS 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 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.
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 
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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 21 CFR 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 
privacy requirements (eg, HIPAA).
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study.
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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 ECGs. 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 nonprescription medications being 
taken at the time of enrollment; at each subsequent visit, changes to the list of 
medications should be recorded)

Occurrence and status of any adverse events

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, ie, records must be attributable, legible, 
contemporaneous, original, and accurate.
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10.4.2
Electronic 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, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the 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.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person.
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10.5
Labeling, Packaging, and Return or Disposal of Investigational 
Products/Treatments
10.5.1
Labeling/Packaging
IP will be supplied in blister cards and will be labelled 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 
of all used and unused IP and packaging. The IP 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 IPs/treatments and/or supplies will be returned to Allergan or Allergan designee 
for destruction.
10.6
Monitoring by the Sponsor
A representative of Allergan will monitor the study on a periodic basis. The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents. These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions.
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10.7
Handling of Biological Specimens/Samples
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, 
coagulation, serology, and the urine drug screen will be analyzed at a centralized clinical 
laboratory with certification from a recognized accreditation agency (eg, College of 
American Pathology [CAP] or Clinical Laboratory Improvement Amendments [CLIA] 
certification).
 
 
 
All samples will be returned to Allergan or Allergan’s designee for destruction. Allergan shall 
have full ownership rights to any biological specimens/samples derived from the study. For 
additional details regarding handling of biological samples please refer to the Laboratory 
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
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586–604.
Cady RK, McAllister PJ, Spierings ELH, Messina J, Carothers J, Djupesland PG, et al. A
randomized, double-blind, placebo-controlled study of breath powered nasal delivery of
sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study).
Headache 2015;55:88-100.
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.
Firth D. Bias reduction of maximum likelihood estimates. Biometrika.1993;80:27–38.
Food and Drug Administration Guidance for Industry. Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation (UCM174090) July, 2009.
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies 
characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann 
Neurol. 1993;33(1):48-56.
Grundy SM, Cleeman JI, Bairey Merz CN, Brewer Jr HB, Clark LT, Hunninghake DB, 
Pasternak RC, Smith Jr SC, and Stone NJ. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll of 
Cardiology. 2004;44:720-732.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the 
United States. Arch Intern Med. 1999;159:813-818.
International Classification of Headache Disorders, 3rd edition (beta version). Headache 
Classification Committee of the International Headache Society (IHS). Cephalalgia. 
2013;33(9):629–808. http://www.ihs-classification.org/_downloads/mixed/International-
Headache-Classification-III-ICHD-III-2013-Beta.pdf
Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic 
migraine and chronic migraine. Curr Pain Headache Rep. 2012;16(1):86-92.
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Lipton RB, Bigal ME, Diamond M, Freitag F, Reed MI, Stewart WF, on behalf of the AMPP 
advisory group. Migraine prevalence, disease burden, and the need for preventive therapy. 
Neurol. 2007;68(5):343-349.
National Cholesterol Education Program Adult Treatment Panel III Guidelines.
NIH Publication No. 01-3670, May 2001. 
http://www.scymed.com/en/smnxdj/edzr/edzr9610.htm
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(11):1104-1110.
Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. Headache 
Classification Committee. New appendix criteria open for a broader concept of chronic 
migraine. Cephalalgia. 2006;26(6):742-746.
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010;11:289–299. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917556/pdf/10194_2010_Article_217.pdf 
Accessed 05Apr2016
Tepper SJ, Cady RK, Silberstein S, Messina J, Mahmoud RA, Djupesland PG, et al. AVP-825 
breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg 
oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative 
randomized clinical trial across multiple attacks. Headache. 2015;55(5):621-635.
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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
Prohibited Medications
The following medications are prohibited 30 days prior to Screening and throughout the 
study period:
Strong/Moderate CYP3A4 Inducers
Strong/Moderate CYP3A4 Inhibitors
Antidepressant/ 
Antianxiety
Barbiturates 

Amobarbital (Amytal®)

Aprobarbital (Alurate®)

Butalbital (Fiorinal®, 
Fioricet®)

Butabarbital (Busodium®, 
Butisol®)

Mephobarbital (Mebaral®)

Pentobarbital (Nembutal®)

Phenobarbital (Luminal®,
Solfoton®)

Secobarbital (Seconal®)
Nefazodone (Serzone®)
Antiseizure
Carbamazepine (Atretol®, Carbatrol®, 
Epitol®, Equetro®, Tegretol®)
Oxcarbazepine (Trileptal®)
Phenytoin (Dilantin®, Phenytek®)
Primidone (Myidone®, Mysoline®)
Diabetes
Pioglitazone (Actos®)
Troglitazone (Rezulin®, Resulin®)
Antiemetic
Aprepitant (Emend®)
Antihypertension
Diltiazem (Cardizem®)
Verapamil (Calan®, Calan SR®)
Glucocorticoid
(Systemic)
Betamethasone (Celestone®)
Dexamethasone (Baycadron®, 
DexPak®)
Hydrocortisone (Cortef®)
Methylprednisolone (Medrol®)
Prednisolone (Prelone®)
Prednisone (Deltasone®)
Triamcinolone (Kenalog®)
Antibiotics
Rifabutin (Mycobutin®) 
Rifampicin/ Rifampin (Rifadin®, 
Rifater®, Rimactane®) 
Erythromycin ( Benzamycin®, 
EryTab®)
Clarithromycin (Biaxin®)
Telithromycin (Ketek®)
Antifungal
Fluconazole (Diflucan®, Trican®)
Itraconazole (Sporanox®)
Ketoconazole (Nizoral®)
Anti-HIV
Efavirenz (Stocrin®, Sustiva®) 
Nevirapine (Viramune®)
Indinavir (Crixivan®)
Nelfinavir (Viracept®) 
Ritonavir (Norvir®)
Saquinavir (Fortovase®, Invirase®)
Immunosuppressant
Cyclosporine - oral/IV only (Neoral®, 
Sandimmune®)
Other
St John’s Wort
Enzalutamide (Xtandi®)
Modafinil (Provigil®)
Buprenorphine (Cizol®, Subutex®, 
Suboxone®), Quinine, armodafinil 
(Nuvigil TM)
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Drugs with Narrow Therapeutic Margins
Warfarin (Coumadin®)
Digoxin (Digitek®, Lanoxin®, Digox®)
Cisapride (Prepulsid®, Propulsid®)
Pimozide (Orap®)
The following medications are allowed during the study; however, they are prohibited within 
48 hours prior to taking IP:
Triptan
Almotriptan (Axert®)
Eletriptan (Relpax®)
Frovatriptan (Frova®)
Naratriptan (Amerge®)
Rizatriptan (Maxalt®)
Sumatriptan (Imitrex®) 
Zolmitriptan (Zomig®)
Ergot Derivative
Dihydroergotamine (DHE 45®, Migranal®)
Ergotamine (Cafergot®, Ergomar®, Wigraine®)
Opioid
Tramadol (eg, Ultracet®, Ultram®)
Butorphanol (Stadol®)
Codeine-containing analgesics (eg, Tylenol with Codeine #3®)
Hydrocodone (Zohydro ER™ )/Hydrocodone-containing analgesics 
(eg, Vicodin®)
Oxycodone (Oxycontin®, Roxicodone®)/Oxycodone-containing 
analgesics (eg, Percocet®)
Morphine (MS Contin®)
NSAID
Aspirin 
Combination medicines with NSAIDs (eg, Excedrin®)
Diclofenac (Arthrotec®, Cataflam®, Voltaren®)
Ibuprofen (eg, Advil®, Excedrin IB®, Motrin®)
Ketoprofen (eg, Orudis®) 
Naproxen (eg, Aleve®, Naprosyn®)
Analgesic
Acetaminophen (eg, Tylenol® or any combination drug Tylenol®)
Antiemetic agent
Chlorpromazine (Thorazine®)
Hydroxyzine (Vistaril®)
Metoclopramide (Reglan®)
Ondansetron (Zofran®)
Prochlorperazine (Compazine®)
Promethazine (Phenergan®, Mepergan®)
Proton Pump Inhibitor
Esomeprazole (Nexium®)
Lansoprazole (Prevacid®, Zoton®)
Omeprazole (Losec®, Prilosec®, Zegerid®)
Pantoprazole (Pantoloc®, Pantozol®, Protonix®, Somac®, Zurcal®)
Rabeprazole (Aciphex®, Pariet®, Rabecid®)
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The following medications are allowed during the study; however, they are prohibited within 
24 hours prior to taking IP:
Antacid
Aluminum Carbonate Gel (Basaljel®)
Aluminium Hydroxide (AlternaGEL®, Amphojel®)
Aluminium Hydroxide and magnesium hydroxide (Maalox®, Mylanta®)
Bismuth Subsalicylate (Pepto-bismol®)
Calcium Carbonate (Alcalak®, Quick-Eze®, Rennie®, Rolaids®, Titralac®, 
TUMS®)
Hydrotalcite (Talcid®)
Magaldrate plus Simethicone (Pepsil®)
Magnesium Hydroxide (Phillips' Milk of Magnesia®)
Sodium Bicarbonate (Alka-Seltzer®, Bicarbonate of Soda®)
H2 Blocker
Famotidine (Pepcid®)
Nizatidine (Axid®)
Ranitidine (Zantac®)
Cimetidine (Tagamet®) 
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12.3
Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
ALCOA
attributable, legible, contemporaneous, original, and accurate
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
BP
blood pressure
C2hr
plasma concentration at 2 hours postdose
CAP
College of American Pathology
CGRP
calcitonin gene-related peptide
CGRP RA
CGRP receptor antagonist
CHD
coronary heart disease
CLIA
Clinical Laboratory Improvement Amendments
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
cardiovascular
CYP3A4
cytochrome P450 3A4
DBS
dry blood spot
DSMB
Data Safety Monitoring Board
EC50
half-maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eDISH
evaluation of drug-induced serious hepatotoxicity
EMA
European Medicines Agency
Emax
maximum drug effect
eTablet
electronic tablet
EU
European Union
FDS
Functional Disability Scale
EQ-5D-5L
European Quality of Life – 5-Dimensional – 5-Level 
FDA
US Food and Drug Administration
GCP
Good Clinical Practices
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
ICF
informed consent form
ICH
International Council on Harmonisation
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ICHD-3 beta
International Classification of Headache Disorders criteria, 3rd
edition (beta version, 2013)
IEC
Independent Ethics Committee
IETD
investigator emergency treatment disclosure
IgM
immunoglobulin M
INR
international normalized ratio (blood-clotting test)
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
LOCF
last observation carried forward
mITT
Modified Intent-to-treat
NCEP
National Cholesterol Education Program
NSAID
nonsteroidal anti-inflammatory drug
PCS
potentially clinically significant
PF
pain freedom
PGIC
Patient Global Impression of Change
PR
pain relief
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SSRI
selective serotonin reuptake inhibitors
SNRI
serotonin norepinephrine reuptake inhibitors
SPF
sustained pain freedom
SPR
sustained pain relief
TBL
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
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12.4
Protocol Amendment 1 Summary
Title:  A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Single Attack 
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute 
Treatment of Migraine
Protocol UBR-MD-01 Amendment 1
Date of Amendment:  09 June 2016
Amendment Summary
This summary includes changes made to Protocol UBR-MD-01 (29 April 2016). This 
protocol was amended to:  1) revise title page, key responder definitions, health outcomes 
measures, and efficacy variables, and 2) 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.
Section
Revision
Rationale
Protocol Title Page
Revised name of the Authorized 
US Agent from Allergan, Inc. to 
Allergan Sales, LLC
The name of Allergan in the US has 
changed
Added Emergency Telephone 
Number
To remove need to consult the study 
contacts page
Added “Protocol Amendment 1 
Date” to the title page
To reflect the approval date of 
Amendment 1
Deleted Name and contact 
information of Allergan study 
personnel and
To reflect change in study contacts 
page
Protocol Summary, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section
Revision
Rationale
 
 
 
 
 
 
 
 
Section 3.1, 
Adjudication 
Committee and Drug 
Safety Monitoring 
Board
Added Drug to title and text for 
DSMB, and added that details of 
the DSMB will be provided in a 
separate Charter
Clarification
 
 
 
Section 4.5.1.2, 
Definition of Females 
of (Non-) Childbearing 
Potential and/or 
Acceptable 
Contraceptive Methods
Added to description of male 
contraception methods:  Male 
participants should also refrain 
from donating sperm during the 
course of the study.
To clarify that since male study 
participants should use contraception 
during the study, they should also 
refrain from donating sperm per central 
IRB request
Section 5.3, Methods 
for Masking/Blinding
Added to description of study 
treatments: Tablets of 
ubrogepant 50 mg and placebo 
will be identical in appearance.
To clarify that ubrogepant and placebo 
tablets will be indistinguishable to 
maintain blinding
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 
 
Section 7.4, Subgroup 
 
 
 
 
 
 
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Revision
Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.5
Protocol Amendment 2 Summary
Title:  A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Single Attack 
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute 
Treatment of Migraine
Protocol UBR-MD-01 Amendment 2
Date of Amendment:  04 Nov 2016
Amendment Summary
This summary includes changes made to Protocol UBR-MD-01 Amendment 1, 
(09 June 2016). This protocol was amended to: 1) update health outcomes measures and 
efficacy variables; and 2) clarify several exclusion criteria 
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.
Section
Revision
Rationale
Global Change
In reference to the Satisfaction With 
Study Medication assessment, instances 
of “migraine treatment” were changed to 
“study medication”
Based on input from patient 
qualitative interviews, expert panel 
suggested rephrasing “migraine 
treatment” to “study medication”
Global Change
Revised SAE/Pregnancy Reporting Fax 
Number
Administrative update
Protocol Title Page 
 
Administrative update
Protocol Summary –
General Statistical 
Methods and Types of 
Analyses
Revised to note that PGIC will be 
completed 2 hours after the initial dose: 
…the proportion of patients assessed by 
the PGIC as “much better” or “very 
much better” at 2 24hours after the 
initial dose will be analyzed using the 
same methods used to analyze the 
primary efficacy variables.
Expert input recommended a change 
in PGIC assessment from 24 hours 
to 2 hours after the initial dose to 
increase the probability of 
differentiating between treatment 
and placebo
 
 
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Section
Revision
Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.1, Adjudication 
Committee and Data 
Safety Monitoring Board
Section title and in-text change updated 
to Data Drug Safety Monitoring Board
Clarification
Section 4.4,
 
 
 
 
 
 
 
 
 
 
Section 4.4, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section
Revision
Rationale
Section 4.4, 
 
 
Section 4.4, 
Exclusion 21
History of gastric or small intestinal 
surgery (including gastric bypass 
surgery or banding), or has a disease that 
causes malabsorption (eg, Crohn’s 
disease) any prior gastrointestinal (GI) 
conditions (eg, diarrhea syndromes, 
inflammatory bowel disease) that may 
affect the absorption or metabolism of 
investigational product (IP); patients 
with prior gastric bariatric interventions
(eg, Lap Band) which have been
reversed are not excluded
Clarification on excluded GI 
procedures and conditions including 
inclusion of patients with reversal of 
certain procedures.
Section 4.4, 
 
 
 
 
 
 
 
 
Section 4.5.1 Permissible 
Medications/Treatments
Deleted “any proton pump inhibitor” 
from list of medications prohibited 
within 24 hours prior to taking IP and 
added it to list of medications prohibited 
within 48 hours prior to IP dosing
Amended per FDA request
Section 4.5.1.2 
Definition of Females of 
(Non-) Childbearing 
Potential and/or 
Acceptable 
Contraceptive Methods
Moved surgical sterilization from a 
method of contraception to defining 
women of childbearing potential:
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).
Clarification
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Section
Revision
Rationale
Section 4.5.1.2 
Definition of Females of 
(Non-) Childbearing 
Potential and/or 
Acceptable 
Contraceptive Methods
Updated acceptable contraceptive 
methods:
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 should must also refrain 
from donating sperm during the course 
of the study.
Clarification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section
Revision
Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section
Revision
Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 12.2 Examples 
of Prohibited 
Medications
Added “(Systemic)” to Glucocorticoid 
class
Clarification that only systemic 
glucocorticoids are excluded
Added to “Others” category: armodafinil 
(NuvigilTM)
Clarification
Deleted the following Proton Pump 
Inhibitors from the list of medications 
prohibited within 24 hours prior to IP 
dosing and added them to the list of 
medications prohibited within 48 hours 
prior to IP dosing:
Esomeprazole (Nexium®)
Lansoprazole (Prevacid®, Zoton®)
Omeprazole (Losec®, Prilosec®, 
Zegerid®)
Pantoprazole (Pantoloc®, Pantozol®, 
Protonix®, Somac®, Zurcal®)
Rabeprazole (Aciphex®, Pariet®, 
Rabecid®)
Amended per FDA request
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12.6
Protocol Amendment 3 Summary
Title:  A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Single Attack 
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute 
Treatment of Migraine
Protocol UBR-MD-01 Amendment 3
Date of Amendment:  19 May 2017
Amendment Summary
This summary includes changes made to Protocol UBR-MD-01 Amendment 2, (04 Nov 
2016). This protocol was amended to: 1) increase sample size from 450 to 550 patients per 
arm; 2) revise statistical methods to include an additional categorical term to the logistic 
regression analysis for the primary efficacy variable of absence of the most bothersome 
symptom at 2 hours after the initial dose; 3) revise statistical methods to include an additional 
categorical term to the logistic regression analysis for the secondary efficacy endpoints on 
migraine-associated symptoms; 4) reorder the secondary endpoints, 5) 
 
 
 6) remove the 35% triptan insufficient responder 
requirement.
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.
Section
Revision
Rationale
Title Page
Replaced Emergency Telephone Number and 
Allergan Medical Monitor Contact Information 
with instructions to refer to Study Contacts
Sheet.
Administrative update
Protocol Summary, 
Section 3 Study Design, 
Section 4.1 Number of 
Patients
Increased number of patients to be randomized 
to approximately 1650 (550 patients per 
treatment arm).
Sample size re-estimate based 
on updated assumptions
Section 5.5 Method for 
Assignment to Treatment
Groups/Randomization/ 
 
 
 
 
Section 7.2.2 Secondary 
Efficacy Variable
Reordered the secondary efficacy parameters for 
both the US 
 so that SPF from 2 to 24 
(48) hours is listed third, after PR at 2 hours and 
The re-ordering of the 
secondary efficacy endpoints is 
based on new assumptions. The 
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Section
Revision
Rationale
SPR from 2 to 24 (48) hours. Removed 
satisfaction with study medication and ability to 
function normally at 2 hours from the secondary 
efficacy parameters.
 
 
Protocol Summary,
Section 7.3.1.1 Primary 
Efficacy Analyses
Revised logistic regression model as follows:
For each primary variable, the observed 
response proportions will be provided by 
treatment group. The primary efficacy variable 
of pain freedom at 2 hours after the initial dose 
will be analyzed using a logistic regression 
model with categorical terms for treatment 
group, historical triptan response (triptan 
responder, triptan insufficient responder, or 
triptan naïve), use of medication for migraine 
prevention (yes/no), and baseline headache 
severity (moderate or severe). The primary 
efficacy variable of absence of the most 
bothersome symptom at 2 hours after the initial 
dose will be analyzed using a similar logistic 
regression model with an additional categorical 
term for the underlying symptom that was 
identified as the most bothersome. 
The treatment response on the 
most bothersome symptom 
varies according to which 
symptom is identified as the 
most bothersome
Protocol Summary,
Section 7.3.1.2 Secondary 
Efficacy Analyses
Revised logistic regression model to include:
For secondary efficacy endpoints on migraine-
associated symptoms, baseline presence/absence 
of the symptom will be included as an additional 
covariate for the logistic regression model.
The treatment response on 
migraine-associated symptoms 
is different depending on 
whether the patient had the 
symptom at predose baseline.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
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Section
Revision
Rationale
 
 
 
 
 
 
 
 
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