Clinical trial NCT02828020
Conditions: Migraine, With or Without Aura
Sponsor: Allergan
Start date: 2016-07-22; Completion date: 2017-12-14
Enrollment: 1672 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will 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.

Detailed description:

Arms: arm 1: 1 ubrogepant 50 mg tablet and 1 placebo-matching ubrogepant 50 mg tablet, orally for treatment of a qualifying migraine attack. Participants had the option to take a second dose, 2 placebo-matching ubrogepant tablets or rescue medication, orally 2 to 48 hours after initial treatment. arm 2: 2 Ubrogepant 50 mg tablets, orally for treatment of a qualifying migraine attack. Participants had the option to take a second dose, 2 placebo-matching ubrogepant tablets or rescue medication, orally 2 to 48 hours after initial treatment. arm 3: 2 placebo-matching ubrogepant 50 mg tablets, orally for treatment of a qualifying migraine attack. Participants had the option to take 2-placebo-matching ubrogepant tablets or rescue medication, orally 2 to 48 hours after initial treatment.
Interventions: intervention 1: Ubrogepant intervention 2: Placebo-matching Ubrogepant
Intervention descriptions: intervention 1: 50 mg ubrogepant tablet(s) orally for the treatment of a qualifying migraine attack. intervention 2: Placebo-matching ubrogepant tablet(s) orally for the treatment of a qualifying migraine attack.

Protocol documents:
Prot_000.pdf: 
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
Protocol UBR-MD-01 Amendment 3
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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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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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Section
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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SAP_001.pdf: 
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 
 
Statistical Analysis Plan Amendment 2 Date: 22 Jan 2018 
 
 
 


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1.
Title Page
STATISTICAL ANALYSIS PLAN
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
Final: 2017-01-05
Amendment 1: 2017-05-17
Amendment 2: 2018-01-22
Protocol Number:
UBR-MD-01 Amendment 3
Development Phase:
3
Product Name:
Ubrogepant
Study Statistician:
Sponsor:
Allergan, Inc.
This document is the property of Allergan, Inc. and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, Inc.


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2.
Table of Contents
1.
Title Page ................................................................................................................................. 1
2.
Table of Contents..................................................................................................................... 2
2.1
List of Tables.................................................................................................................. 3
2.2
List of Figures ................................................................................................................ 5
3.
List of Abbreviations and Definition of Terms ........................................................................ 6
4.
Introduction.............................................................................................................................. 8
4.1
Study Design Summary ................................................................................................. 8
4.2
Study Objectives and Endpoints .................................................................................... 9
5.
Statistical Methodology and Study Endpoints....................................................................... 18
5.1
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 18
5.1.1
Statistical and Analytical Plans........................................................................ 18
5.1.1.1
Common Conventions....................................................................... 18
5.1.1.2
Demographics.................................................................................... 32
5.1.1.3
Efficacy and 
........................................... 36
5.2
Changes in the Conduct of the Study or Planned Analyses ......................................... 55
5.2.1
Changes in the Conduct of the Study............................................................... 55
5.2.2
Changes to Analyses Prior to Database Lock .................................................. 55
6.
Data Handling and Analysis Conventions ............................................................................. 56
6.1
Study Treatment Conventions...................................................................................... 56
6.1.1
Analysis Days .................................................................................................. 56
6.1.2
Missing/Incomplete Treatment End Date ........................................................ 56
6.2
Analysis Visit Windows ............................................................................................... 56
6.2.1
Efficacy ............................................................................................................ 56


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6.4
Imputed Value Listing Conventions............................................................................. 64
7.
References.............................................................................................................................. 65
2.1
List of Tables
Table 3-1
Abbreviations and Definitions of Terms ................................................................. 6
Table 4-1
Study Objectives and Corresponding Endpoints .................................................... 9
Table 5-1
Analysis Populations............................................................................................. 18
Table 5-2
Statistical Methodology ........................................................................................ 19
Table 5-3
Missing Data Handling by Endpoint Type............................................................ 21
Table 5-4
Analysis Population Summaries ........................................................................... 32
Table 5-5
Participant Disposition Summaries....................................................................... 32
Table 5-6
Protocol Deviation Summary................................................................................ 33
Table 5-7
Demographic Summaries...................................................................................... 33
Table 5-8
Baseline Characteristics Summaries..................................................................... 34
Table 5-9
Medical History Summary.................................................................................... 34


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Table 5-10
Migraine History Summary .................................................................................. 35
Table 5-11
Medication Summaries ......................................................................................... 35
Table 5-12
Efficacy Assessments............................................................................................ 36
Table 5-13
Efficacy Endpoint Baseline Definitions................................................................ 37
Table 5-14
US Analyses.......................................................................................................... 37
Table 5-15
EU Analyses.......................................................................................................... 41
Table 5-16
Multiple Comparisons Procedure Definitions for the US..................................... 45
Table 5-27
Assumed Response Rates and Estimated Power for Primary and Secondary 
Efficacy Endpoints................................................................................................ 54
Table 6-1
Analysis Day Definitions...................................................................................... 56
Table 6-2
Efficacy Analysis Visit Definitions....................................................................... 56


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2.2
List of Figures
Figure 5-5
Determination of sustained pain freedom from 2 to 24 hours after the initial dose
............................................................................................................................... 28
Figure 5-6
Determination of sustained pain relief from 2 to 24 hours after the initial dose .. 29
Figure 5-7
Determination of sustained pain freedom from 2 to 48 hours after the initial dose
............................................................................................................................... 30
Figure 5-8
Determination of sustained pain relief from 2 to 48 hours after the initial dose .. 31
Figure 5-9
Multiple Comparisons Procedure for the US........................................................ 45


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3.
List of Abbreviations and Definition of Terms
Table 3-1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
body mass index
C-SSRS
Columbia–Suicide Severity Rating Scale
CFB
change from baseline
CHD
coronary heart disease
CSR
clinical study report
CV
cardiovascular
DBS
dry blood spot
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
EQ VAS
European Quality of Life Visual Analogue Scale
EQ-5D-5L
European Quality of Life 5 Dimensional – 5 Level
EU
European Union
FDS
Functional Disability Scale
FWER
HEOR
familywise error rate
Health Economics and Outcomes Research
HR
hazard ratio
INR
international normalized ratio
IP
investigational product
IWRS
interactive web response system
kg
kilogram(s)
KM
Kaplan-Meier
LOCF
last observation carried forward
LS
least squares
m
meter(s)
MedDRA
Medication Dictionary for Regulatory Activities
mg
milligrams
mITT
modified intent-to-treat
PCS
potentially clinically significant
PF
pain free
PGIC
Participant Global Impression of Change
PO
Primary Objective
PR
pain relief
PT
preferred term
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)


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Abbreviation/Term
Definition
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SD
standard deviation
SE
standard error
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
SPF
sustained pain freedom
SPR
sustained pain relief
TBL
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States of America
WHO
World Health Organization


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4.
Introduction
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the protocol 
amendment #3 dated 17May2017 of Study UBR-MD-01. Specifications of tables, figures, and 
data listings are contained in a separate document. 
 
This document is organized into 3 main sections:
1. Study overview
2. Statistical Methodology and Study Endpoints
3. Data Handling and Analysis Conventions
4.1
Study Design Summary
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. Participants have the 
option to take a second dose of investigational product (IP) or rescue medication if the 
participant has either a nonresponding migraine or a migraine recurrence. Participants who are 
randomized to ubrogepant arms will be randomly assigned at the Randomization Visit (Visit 2) to 
active treatment or placebo (1:1) for the blinded optional second dose. Participants randomized 
to the placebo arm will receive placebo for their blinded optional second dose.
Randomization/
:  Participants will be randomized (1:1:1) to 1 of the following 
3 treatment groups:  placebo, ubrogepant 50 mg, or ubrogepant 100 mg. 
 
 
 
 


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Number of Participants:  Approximately 1650 participants will be randomized (550 per 
treatment arm).
4.2
Study Objectives and Endpoints
Each study objective is presented with corresponding endpoint(s) below:
Table 4-1
Study Objectives and Corresponding Endpoints
Objectives
Endpoints
Primary
[PO1] To compare the efficacy, 
safety, and tolerability of 2 doses of 
ubrogepant (50 and 100 mg) with 
placebo in participants with a single 
migraine attack
Primary Efficacy Endpoints
The coprimary efficacy parameters for the United 
States of America (US) are as follows:  

[P1] 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

[P2] Absence of the most bothersome 
migraine-associated symptom (the most 
bothersome migraine-associated symptom 
will be identified at baseline for each 
participant) at 2 hours after the initial 
dose. 
 
Secondary Efficacy Endpoints
The secondary efficacy parameters for the US are:

[S1] Pain relief (PR) at 2 hours after the 
initial dose, defined as the reduction of a 


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Objectives
Endpoints
moderate/severe migraine headache to a 
mild headache or to no headache, at 
2 hours after the initial dose

[S2] 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

[S3] 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

[S4a] Absence of photophobia at 2 hours 
after the initial dose

[S4b] Absence of phonophobia at 2 hours 
after the initial dose

[S4c] Absence of nausea at 2 hours after 
the initial dose
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 


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5.
Statistical Methodology and Study Endpoints
5.1
Statistical Methods Planned in the Protocol and Determination of 
Sample Size
This statistical analysis plan (SAP) will be approved prior to database lock. The SAP expands the 
statistical section of the protocol and contains a detailed description of methods to analyze data 
collected in the study. The text portion of the SAP will be included in the clinical study report 
(CSR) report as Appendix 16.1.9. 
5.1.1
Statistical and Analytical Plans
Statistical analyses will be conducted using SAS Version 9.3 or newer.
5.1.1.1
Common Conventions
5.1.1.1.1
Analysis Populations
The analysis populations will consist of participants as defined below:
Table 5-1
Analysis Populations
Population
Definition
Study Treatment
Screened
All screened participants who signed informed consent
—
Intent-to-Treat (ITT)
All randomized participants.
Randomized assignment
Modified Intent-to-
Treat (mITT)
All randomized participants who received at least 1 dose of study 
treatment, recorded a baseline migraine headache severity 
measurement, and had ≥ 1 postdose migraine headache severity 
or migraine-associated symptom measurement at or before the 2-
hour timepoint.
Randomized assignment
Safety
All participants who received ≥ 1 dose of study treatment
Actual received
5.1.1.1.2
Study Treatments
The following treatment groups are defined for this study:

Placebo

Ubrogepant 50 mg

Ubrogepant 100 mg


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5.1.1.1.3
Statistical Methodology
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.
Table 5-2
Statistical Methodology
Methodology
Description
M1
Categorical 
counts

Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
M2
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category

N1 if proportion denominator ≠ number of participants in the population (standard 
percentage denominator)
o
N1 = participants with non-missing baseline value
 
 
 
 
 
 
 
M5
Continuous 
descriptives

N1, mean, standard deviation (SD), median, minimum, maximum

N1 = participants with non-missing value
M6
CFB 
descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
 
 
 
 
 
 
M8
Responder

Categorical descriptives using proportions for responders and nonresponders
o
Nonresponders include:

Participants who do not meet responder criteria

N1 = all participants unless otherwise specified
 


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Methodology
Description
M10
Logistic 
regression 
model

Measures the relationship between the binary categorical dependent variable
(responder or nonresponder) and independent variables 
o
Independent variables for initial dose:

treatment group (placebo, ubrogepant 50 mg, ubrogepant 100 mg)

historical triptan response (triptan responder, triptan insufficient 
responder, or triptan naïve)

use of medication for migraine prevention (yes, no)

baseline headache severity (moderate or severe)
Note: Historical triptan response and use of medication for migraine 
prevention are stratification factors for the study. 
For the analysis of individual migraine-associated symptoms, baseline 
presence/absence of the symptom will be included as an additional 
covariate in the logistic regression model.
For the analysis of the most bothersome symptom, the underlying symptom 
will be included as an additional covariate in the logistic regression model.
 
 
 
 
 
o
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 profile penalized likelihood approach (Heinze and Schemper, 
2002) will be used to make valid inference.

Formal test of efficacy hypothesis comparing 2 active treatments vs Placebo 
conducted using pairwise contrasts based on odds ratios and their 95% confidence 
intervals of the odds ratio
o
Calculate two-sided p-values
 
 
 
 
 
 
 
 
 
 


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Methodology
Description
 
 
CFB = change from baseline; ANCOVA = analysis of covariance.
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document.
5.1.1.1.4
Missing Data
General missing data handling conventions are specified for methodologies in Section 5.1.1.1.3 
and summarized as follows:
Table 5-3
Missing Data Handling by Endpoint Type
Parameter type
Timing
Missing Data Handling
 
Responder
Treatment Period

If missing headache severity, migraine-associated symptoms, 
satisfaction with study medication, or functional disability 
scale at scheduled postdose time points, use LOCF

Sensitivity analysis for the primary efficacy endpoints is to 
impute participants with missing data at 2 hours as non-
responders, provided that the participant has at least 1 
postdose value before 2 hours after the initial dose

 
 
 
A conservative approach will used to resolve the incompatibility between the answers to the 
headache recurrence questions at the 24- and 48-hour time points by setting the answer to the 
recurrence question at the 48-hour time point the same as the answer to the recurrence 
question at the 24-hour time point, when the 24-hour time point recurrence question indicates 
headache recurrence between 2 and 24 hours but the 48-hour time point recurrence question 
indicates either no or a less severe headache recurrence between 2 and 48 hours.


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For sustained efficacy endpoints (sustained pain freedom and sustained pain relief from 2 to 24 
and 48 hours after the initial dose), the primary analysis will only include participants for whom 
the sustained efficacy endpoint in question can be determined based on all available data on 
headache severity, headache recurrence, use of rescue medication, and use of optional second 
dose. Figure 5-5 to Figure 5-8 show the diagrams for determining the sustained efficacy 
endpoints based on all available data. 


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Figure 5-5
Determination of sustained pain freedom from 2 to 24 hours after the initial dose
Observed or LOCFed 
headache severity at 2, 
3, 4, 6, 8, 24 hours 
= No Pain?
Nonresponder
No
No rescue medication 
and no optional second 
dose taken between 2 
and 24 hours?
Yes
No
Recurrence response at 
24 hours missing?
Yes
No worsening to 
mild/moderate/severe 
pain?
No
No
Responder
Yes
Recurrence response at 
48 hours missing?
Yes
Indeterminable
Yes
No worsening to 
mild/moderate/severe 
pain?
No
Yes
No


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Figure 5-6
Determination of sustained pain relief from 2 to 24 hours after the initial dose
Observed or LOCFed 
headache severity at 2, 
3, 4, 6, 8, 24 hours 
= No or mild Pain?
Nonresponder
No
No rescue medication 
and no optional second 
dose taken between 2 
and 24 hours?
Yes
No
Recurrence response at 
24 hours missing?
Yes
No worsening to 
moderate/severe 
pain?
No
No
Responder
Yes
Recurrence response at 
48 hours missing?
Yes
Indeterminable
Yes
No worsening to 
moderate/severe 
pain?
No
Yes
No


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Figure 5-7
Determination of sustained pain freedom from 2 to 48 hours after the initial dose
Observed or LOCFed 
headache severity at 2, 
3, 4, 6, 8, 24, 48 hours 
= No Pain?
Nonresponder
No
No rescue medication 
and no optional second 
dose taken between 2 
and 48 hours?
Yes
No
Recurrence response at 
48 hours missing?
Yes
No worsening to 
mild/moderate/severe 
pain?
No
No
Responder
Yes
Recurrence response at 
24 hours missing?
Yes
Indeterminable
Yes
No worsening to 
mild/moderate/severe 
pain?
No
No
Yes


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Figure 5-8
Determination of sustained pain relief from 2 to 48 hours after the initial dose
Observed or LOCFed 
headache severity at 2, 
3, 4, 6, 8, 24, 48 hours 
= No or mild Pain?
Nonresponder
No
No rescue medication 
and no optional second 
dose taken between 2 
and 48 hours?
Yes
No
Recurrence response at 
48 hours missing?
Yes
No worsening to 
moderate/severe 
pain?
No
No
Responder
Yes
Recurrence response at 
24 hours missing?
Yes
Indeterminable
Yes
No worsening to 
moderate/severe 
pain?
No
No
Yes


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5.1.1.2
Demographics
5.1.1.2.1
Analysis Populations 
The distribution of participants within the analysis populations will be summarized as follows:
Table 5-4
Analysis Population Summaries
Population 
Description
Timing
Methodology
Screened Population
Distribution overall and within sites in 
total
—
Categorical counts
ITT, mITT, and Safety 
populations
Distribution overall and within sites in 
total and by treatment group
—
Categorical counts
5.1.1.2.2
Participant Disposition
Participant disposition encompasses the distribution of participants who enter, complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Participant disposition will be summarized as follows:
Table 5-5
Participant Disposition Summaries
Parameter
Description
Timing
Methodology
Screening disposition1
Distribution in the Screened Population in 
total
Screening Period
Categorical 
descriptives
Double blind 
disposition1
Distribution in the Safety Population and 
ITT Population in total and by treatment 
group
Double Blind Period
Categorical 
descriptives
4 Week Safety Follow-
up disposition1
Distribution in the Safety Population and 
ITT Population in total and by treatment 
group
Post-treatment 
Period
Categorical 
descriptives
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5.1.1.2.3
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, including 
importance classification. Protocol deviations will be summarized as follows:
Table 5-6
Protocol Deviation Summary
Parameter
Description
Timing
Methodology
Major protocol 
deviations1
Distribution in the ITT Population in total 
and by treatment group
—
Categorical 
descriptives
1 Protocol deviations will be listed.
5.1.1.2.4
Demographics 
Demographics will be summarized in total and by treatment group for the ITT, Safety, and mITT 
populations, as follows:
Table 5-7
Demographic Summaries
Parameter
Description
Timing
Methodology
Age1
Age (years) relative to informed consent 
date
Informed consent
Continuous 
descriptives
Age group

<20

20 to 29

30 to 39

40 to 49

50 to 59

60 to 69

>= 70
Informed consent
Categorical 
descriptives
Sex, race, and ethnicity1

eCRF categories

Race group
o
White
o
Non-white
Screening Period
Categorical 
descriptives
1 Participant demographics will be listed.
5.1.1.2.5
Baseline Characteristics
Baseline characteristics will be summarized in total and by treatment group for the ITT, Safety, 
and mITT populations as follows:


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Table 5-8
Baseline Characteristics Summaries
Parameter
Description
Timing
Methodology
Baseline characteristics1

Height (m)

Weight (kg)

Body mass index (BMI)
o
Weight (kg) / height (m)2
Latest assessment in 
Screening Period
Continuous 
descriptives
Randomization strata2

Previous response to triptans
(Triptan Responder, Triptan 
Insufficient Responder, Triptan 
Naïve)

Current use of prophylactic 
concomitant medication for 
migraine (Yes, No)
Randomization date
Categorical 
descriptives
Baseline efficacy
Endpoints and timing fully described in 
Section 5.1.1.3

migraine headache severity 

migraine-associated symptom

most bothersome migraine-
associated symptom by symptom
Summary for mITT Population only 
Predose
Categorical 
descriptives
Cardiovascular risk

Cardiovascular risk factor 
subgroup (low risk, moderate 
risk, high risk)
Summary for Safety Population only
Randomization date
Categorical 
descriptives
1 Participant baseline characteristics will be listed.
2 Participant randomization scheme and codes will be listed.
5.1.1.2.6
Medical History
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.0 or newer. Unique participants who report medical history events will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) in total and by 
treatment group for the Safety Population as follows:
Table 5-9
Medical History Summary
Parameter
Description
Timing
Methodology
Medical history1
Abnormalities and surgeries occurring 
before the Screening Visit
Screening Period
Categorical 
descriptives
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group.
1 Participant medical history will be listed.
5.1.1.2.7
Migraine History
Migraine history, including diagnosis, duration of disorder, previous use of prophylaxis 
treatment, average frequency of moderate to severe migraines per month in past 3 months, and 


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acute treatments will be reported in total and by treatment group for the Safety Population as 
follows:
Table 5-10
Migraine History Summary
Parameter
Description
Timing
Methodology
Migraine Diagnosis1
With Aura, Without Aura, Both
Screening Period
Categorical 
descriptives
Previous Prophylaxis 
Migraine Treatment1
Yes or No
Screening Period
Categorical 
descriptives
Acute Migraine 
Treatment1
Categorize as Yes or No, and 
subcategorize the Yes by:

Triptan

Ergot or Ergot Combinations

NSAID

Opiate or Opiate Combination

Antiemetic Agent

Barbiturates

Other
Screening Period
Categorical 
descriptives
Migraine Disorder 
Duration1
In the Table summarize in Years, in the 
Listing show original data in Years and 
Months
Screening Period
Continuous 
descriptives
Average Frequency of 
Moderate to Severe 
Migraines per Month in 
Last 3 Months
N/A
Screening Period
Continuous 
descriptives
1 Participant migraine history will be listed.
5.1.1.2.8
Prior and Concomitant Medications
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version March 2016 or newer. Unique participants who reported medications will be summarized 
by Anatomical Therapeutic Chemical (ATC) 4 class and PT in total and by treatment group for 
the Safety Population as follows:
Table 5-11
Medication Summaries
Parameter
Description
Timing
Methodology
Prior medications1
Medications taken ≥ 1 time before the 
study treatment start date, regardless of 
medication end date
Screening Period
Categorical 
descriptives
Concomitant 
medications1
Medications taken ≥ 1 time on or after the 
study treatment start date, regardless of 
medication start date
Treatment Period
Categorical 
descriptives
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group.
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5.1.1.3
Efficacy and Pharmacokinetic Analyses
Efficacy analyses will be based on the mITT Population.
The following efficacy assessments and terms are defined:
Table 5-12
Efficacy Assessments
Assessment/Term
Description
Rating of Headache Severity1 Headache severity will be subjectively rated by the participant 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
Use of Rescue Medication1
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.

Recorded by participants in e-diary
Use of Optional Second Dose 
and Recurrence of Headache 
Pain1
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 participants who 
had pain relief and pain freedom at 2 hours after the initial dose will be collected.

Recorded by participants in e-diary
Migraine-associated 
symptoms1
Absence or presence of migraine-associated symptoms: photophobia, phonophobia, 
nausea, and vomiting

Completed by the participant in e-diary
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Baseline assessments for applicable efficacy endpoints are defined as follows:
Table 5-13
Efficacy Endpoint Baseline Definitions
Endpoint
Description
Timing
Baseline rating of headache 
severity
Headache severity rating (Moderate, Severe)
pre-dose
Baseline migraine-
associated symptom
Migraine-associated symptom

Photophobia (Yes, No)

Phonophobia (Yes, No)

Nausea (Yes, No)

Vomiting (Yes, No)
pre-dose
5.1.1.3.1
Endpoints for US
The efficacy endpoints for the United States analyses are described as follows.
 
 
y.
Table 5-14
US Analyses
Endpoint
Description
Timing
Methodology
P1
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
2 hours after the 
initial dose
Logistic regression 
model
P2
Absence of the most bothersome migraine-
associated symptom (the most bothersome 
migraine-associated symptom will be identified 
at baseline for each participant) at 2 hours after 
the initial dose.
2 hours after the 
initial dose
Logistic regression 
model
S1
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
2 hours after the 
initial dose
Logistic regression 
model
S2
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
2 to 24 hours after 
the initial dose
Logistic regression 
model
S3
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
2 to 24 hours after 
the initial dose
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Endpoint
Description
Timing
Methodology
S4a
Absence of photophobia at 2 hours after the 
initial dose
2 hours after the 
initial dose
Logistic regression 
model
S4b
Absence of phonophobia at 2 hours after the 
initial dose
2 hours after the 
initial dose
Logistic regression 
model
S4c
Absence of nausea at 2 hours after the initial 
dose
2 hours after the 
initial dose
Logistic regression 
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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
dose.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A summary of the number and percentage of participants who took both the optional second dose 
and rescue medication within 24 (48) hours after the initial dose will also be provided by 
treatment sequence (placebo/placebo, ubrogepant 50 mg/50 mg, ubrogepant 50 mg/placebo, 
ubrogepant 100 mg/100 mg, ubrogepant100 mg/placebo). The denominator is the number of 
participants who took the optional second dose.
5.1.1.3.4
Multiple Comparisons Procedure for Primary and Secondary 
Endpoints
The overall familywise error rate (FWER) will be controlled at α = 0.05 for the set of primary 
and secondary endpoint comparisons between each dose level of ubrogepant vs. placebo both for 
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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. For the US analyses, 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. 
Using graphical approach with the weighted Bonferroni-based closed test procedure, the 
endpoints are represented by circles with associated weights inside the circle. The weight is the 
fraction of α, representing local significance levels. The fraction in the rectangle, associated with 
a line connecting two circles, indicates the fraction of the local significance level of the circle at 
the beginning of the line which is added to the local significance level of the circle at the end of 
the line, if the null hypothesis at the beginning circle is rejected.
Figure 5-9
Multiple Comparisons Procedure for the US
Table 5-16
Multiple Comparisons Procedure Definitions for the US
Circle
Alternative Hypothesis
Objective
Weight
Local Significance 
Level
50mgP1
Primary Efficacy Endpoint 1 for 50 mg ubrogepant is 
significantly different from placebo
PO1
1/2
α*(1/2) = α/2
50mgP2
Primary Efficacy Endpoint 2 for 50 mg ubrogepant is 
significantly different from placebo
PO1
0
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50mgS1
Secondary Efficacy Endpoint 1 for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
50mgS2
Secondary Efficacy Endpoint 2 for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
50mgS3
Secondary Efficacy Endpoint 3 for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
50mgS4a
Secondary Efficacy Endpoint 4a for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
50mgS4b
Secondary Efficacy Endpoint 4b for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
50mgS4c
Secondary Efficacy Endpoint 4c for 50 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mgP1
Primary Efficacy Endpoint 1 for 100 mg ubrogepant
is significantly different from placebo
PO1
1/2
α*(1/2) = α/2
100mgP2
Primary Efficacy Endpoint 2 for 100 mg ubrogepant
is significantly different from placebo
PO1
0
α*0 = 0
100mgS1
Secondary Efficacy Endpoint 1 for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mgS2
Secondary Efficacy Endpoint 2 for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mgS3
Secondary Efficacy Endpoint 3 for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mgS4a
Secondary Efficacy Endpoint 4a for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mgS4b
Secondary Efficacy Endpoint 4b for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
α*0 = 0
100mS4c
Secondary Efficacy Endpoint 4c for 100 mg 
ubrogepant is significantly different from placebo
PO1
0
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5.1.1.4.1
Study Treatment Exposure and Compliance
Study treatment exposure and compliance will be listed for the Safety Population.
A summary of treatment compliance to the first dose of study medication in terms of the number 
and percentage of participants who took 2 tablets instead of only 1 tablet will be provided by 
treatment group. 
The listing of treatment exposure will indicate whether the participant took the optional second 
dose and PK dose in addition to the first dose. 
:


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5.1.1.5
Subgroup Analyses
A pooled analysis among triptan insufficient responders across ubrogepant pivotal studies will be 
conducted to demonstrate statistically significant efficacy in the triptan insufficient responders’ 
population.
5.1.1.6
Interim Analyses
Not applicable.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.2
Changes in the Conduct of the Study or Planned Analyses
Prior to database lock, there were no changes in study conduct or planned analyses from what 
was described in the protocol and detailed in the SAP. 
5.2.1
Changes in the Conduct of the Study
Not applicable.
5.2.2
Changes to Analyses Prior to Database Lock
Not applicable.


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6.
Data Handling and Analysis Conventions
6.1
Study Treatment Conventions
6.1.1
Analysis Days
Treatment day is defined as follows:
Table 6-1
Analysis Day Definitions
Term
Description
Treatment Day
Relative to treatment start date
If analysis date ≥ treatment start date:

Day = analysis date – treatment start date + 1
o
Day 1 = treatment start date
If analysis date < treatment start date:

Day = analysis date – treatment start date
o
Day -1 = day before treatment start date
o
There is no Day 0
6.1.2
Missing/Incomplete Treatment End Date
If the investigator is unable to provide the treatment end date, treatment end date will be imputed 
to the last available dosing record date.
6.2
Analysis Visit Windows
6.2.1
Efficacy
The analysis visit windows for efficacy endpoints are defined as follows:
Table 6-2
Efficacy Analysis Visit Definitions
Analysis Phase
Analysis Visit (Derived)
Study Hour (eDiary)
Window
Pretreatment
Baseline
Pre-dose
Based on nominal timepoints 
recorded in eDiary
Treatment
0.5 hour post-dose
0.5 hour post-dose
1 hour post-dose
1 hour post-dose
1.5 hours post-dose
1.5 hours post-dose
2 hours post-dose
2 hours post-dose
3 hours post-dose
3 hours post-dose
4 hours post-dose
4 hours post-dose
6 hours post-dose
6 hours post-dose
8 hours post-dose
8 hours post-dose
24 hours post-dose
24 hours post-dose
48 hours post-dose
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6.4
Imputed Value Listing Conventions
In general, listings will present the actual partial or missing values rather than the imputed values 
that may be used in endpoint derivation. In instances where imputed values will be presented, 
imputed values will be flagged. Actual rules will be fully defined in the table, figure, and data 
listing specification document.


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7.
References
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586–604.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, 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.
Heinze G, Schemper M. A solution to the problem of separation in logistic regression. Stat Med. 
2002;21:2409-2419.
Hewitt DJ, Martin V, Lipton RB, Brandes J, Ceesay P, Gottwald R, et al. Randomized controlled 
study of telcagepant plus Ibuprofen or acetaminophen in migraine. Headache. 2011;51:533–543.
Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of 
an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 
2008;70:1304-1312.
Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of 
MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, 
compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-
treatment trial. Lancet. 2008a;372:2115–2123.
Ho AP, Dahlof CG, Silberstein SD, Saper JR, Ashina M, Kost JT, et al. Randomized, controlled 
trial of telcagepant over four migraine attacks. Cephalalgia. 2010;30:1443–1457.
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


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Harborside Financial Center, Plaza V
Jersey City, NJ 07311
UBR-MD-01
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
STATISTICAL ANALYSIS PLAN AMENDMENT
SUMMARY OF CHANGES
Original SAP Date:
5 Jan 2017
Amendment #1:
17 May 2017
Amendment #2:
22 Jan 2018
Confidentiality Statement
This document is the property of Allergan, Inc. and may not, in full or part, be passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, Inc.


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1.0
AMENDMENT #2 TO STATISTICAL ANALYSIS PLAN FOR 
UBR-MD-01
1.1
INTRODUCTION
Amendment #2 specifies the following changes to the Statistical Analysis Plan (SAP)
Amendment #1 for Study UBR-MD-01, dated 7 May 2017: 

Adding 3 other effiacy endpoints in Table 4-1 Study Objectives and Corresponding 
Endpoints

Adding proportional odds model anaylsis in Table 5-2 Statistical Methodology

Updating missing data handling for the analysis of sustained efficacy endpoints

Adding 3 endpoints in Table 5-14 US Analyses and 
 

Updating the Table 5-27 Assumed Response Rates and Estimated Power for Primary 
and Secondary Efficacy Endpoints

Minor editorial changes 
1.2
GLOBAL CHANGES
None.
1.3
SECTIONS DELETED
None.


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1.4
SECTIONS ADDED
None.
1.5
REVISIONS
1.5.1
Table 4-1, Study Objectives and Corresponding Endpoints (Pages 11-
14)
Rationale: This section has been amended to reflect adding 3 other efficacy endpoints to 
the list of other efficacy endpoints.


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1.5.2
Table 5-2, Statistical Methodology (Page 20-21)
Rationale: This table has been amended to add the proportional odds model for the 
analysis of pain severity at 2 hours after the initial dose. 
This proportional odds model analysis now reads as follows:


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1.5.3
Section 5.1.1.1.4, Missing Data (Pages 21-31)
Rationale: This section has been amended to update the missing data handling of 
sustained efficacy endpoints. 
The missing data section now reads as follows:
General missing data handling conventions are specified for methodologies in Section 
5.1.1.1.3 and summarized as follows:
Table 5-3
Missing Data Handling by Endpoint Type
Parameter type
Timing
Missing Data Handling
 

Responder
Treatment Period

If missing headache severity, migraine-associated symptoms, 
satisfaction with study medication, or functional disability 
scale at scheduled postdose time points, use LOCF

Sensitivity analysis for the primary efficacy endpoints is to 
impute participants with missing data at 2 hours as non-
responders, provided that the participant has at least 1 
postdose value before 2 hours after the initial dose

 
 
 


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A conservative approach will used to resolve the incompatibility between the answers to 
the headache recurrence questions at the 24- and 48-hour time points by setting the 
answer to the recurrence question at the 48-hour time point the same as the answer to the 
recurrence question at the 24-hour time point, when the 24-hour time point recurrence 
question indicates headache recurrence between 2 and 24 hours but the 48-hour time 
point recurrence question indicates either no or a less severe headache recurrence 
between 2 and 48 hours.
 


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Figure 5-51
Determination of sustained pain freedom from 2 to 24 hours after the initial dose


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Figure 5-62
Determination of sustained pain relief from 2 to 24 hours after the initial dose


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Figure 5-73
Determination of sustained pain freedom from 2 to 48 hours after the initial dose


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Figure 5-84
Determination of sustained pain relief from 2 to 48 hours after the initial dose


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1.5.4
Table 5-14, US Analyses and 
 (Pages 37-44)
Rationale: These tables has been amended to reflect adding 3 other efficacy endpoints.
The US Analyses 
 tables now reads as follows:
Table 5-14
US Analyses
Endpoint
Description
Timing
Methodology
P1
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
2 hours after the 
initial dose
Logistic regression 
model
P2
Absence of the most bothersome migraine-associated 
symptom (the most bothersome migraine-associated 
symptom will be identified at baseline for each 
participant) at 2 hours after the initial dose.
2 hours after the 
initial dose
Logistic regression 
model
S1
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
2 hours after the 
initial dose
Logistic regression 
model
S2
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
2 to 24 hours 
after the initial 
dose
Logistic regression 
model
S3
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
2 to 24 hours 
after the initial 
dose
Logistic regression 
model
S4a
Absence of photophobia at 2 hours after the initial 
dose
2 hours after the 
initial dose
Logistic regression 
model
S4b
Absence of phonophobia at 2 hours after the initial 
dose
2 hours after the 
initial dose
Logistic regression 
model
S4c
Absence of nausea at 2 hours after the initial dose
2 hours after the 
initial dose
Logistic regression 
model
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.5.8
Table 5-27, Assumed Response Rates and Estimated Power for 
Primary and Secondary Efficacy Endpoints (Pages 54-55)
Rationale: This table has been amended to update the power after multiplicity 
adjustment based on new sample size and new assumptions. 
 
 
 
 
 
 
 h = hours; PF = pain freedom; PR = pain relief; SPF = sustained pain freedom; SPR = 
sustained pain relief


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