Clinical trial NCT04179474
Conditions: Migraine
Keywords: ubrogepant erenumab galcanezumab safety tolerability interaction
Sponsor: Allergan
Start date: 2019-09-26; Completion date: 2019-12-23
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the potential for a pharmacokinetic (PK) interaction and provide safety and tolerability information when ubrogepant and erenumab or ubrogepant and galcanezumab are co-administered.

Detailed description:

Arms: arm 1: Intervention A: Single oral dose of ubrogepant 100 mg tablet on Day 1 under fasted conditions; followed by Intervention B: Single subcutaneous (SC) injection of erenumab 140 mg on Day 8; followed by Intervention D: Ubrogepant 100 mg tablet orally once daily on Days 12, 13, 14 and 15 under fasted conditions. arm 2: Intervention A: Single oral dose of ubrogepant 100 mg tablet on Day 1 under fasted conditions; followed by Intervention C: Two SC injections of galcanezumab 120 mg on Day 8; followed by Intervention D: Ubrogepant 100 mg tablet orally once daily on Days 12, 13, 14 and 15 under fasted conditions.
Interventions: intervention 1: Ubrogepant intervention 2: Erenumab intervention 3: Galcanezumab
Intervention descriptions: intervention 1: Oral administration of 100 mg ubrogepant tablet once daily \[Intervention A=single dose and Intervention D=repeated daily dose\]. intervention 2: Single dose subcutaneous (SC) injection of erenumab 140 mg \[Intervention B\]. intervention 3: 2 SC injections of galcanezumab 120 mg \[Intervention C\].

Protocol documents:
Prot_001.pdf: 
NCT04179474 
 
Study ID: 3110‐108‐002 
 
 
Title:  A Phase 1b, Two‐Part, Open‐Label, Fixed‐Sequence, Safety, Tolerability and 
Drug‐Drug Interaction Study Between Single Dose Erenumab or Galcanezumab and Multiple 
Dose Ubrogepant in Participants with Migraine 
 
Protocol Date: 14Aug2019 


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Protocol 3110-108-002
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Title Page
Protocol Title: A Phase 1b, Two-Part, Open-Label, Fixed-Sequence, Safety, Tolerability and 
Drug-Drug Interaction Study Between Single Dose Erenumab or Galcanezumab and Multiple 
Dose Ubrogepant in Participants with Migraine
Protocol Number: 3110-108-002
Product: Ubrogepant (AGN-241688, MK-1602)
Brief Protocol Title: Drug-Drug Interaction Study of Ubrogepant with Erenumab or 
Galcanezumab
Study Phase: 1b
Sponsor Name and Legal Registered Address:
Allergan Pharmaceuticals International Limited, Clonshaugh Industrial Estate, Coolock, Dublin 
17, Ireland 
US Agent: Allergan Sales, LLC, 2525 Dupont Dr, Irvine, California 92612, USA
Regulatory Agency Identifying Number(s): IND #113924
SAE Reporting Fax Number/Email:
Business Unit
Email
Phone
Fax
Allergan
 
Approval Date: 14 August 2019


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Sponsor Signatories:
Date
Date
The signatures of the sponsor signatories are collected on the protocol approval page.


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Table of Contents
Title Page .........................................................................................................................................1
Table of Contents.............................................................................................................................3
List of Tables ...................................................................................................................................7
1.
Protocol Summary ..................................................................................................................8
1.1.
Synopsis ......................................................................................................................8
2.
Introduction...........................................................................................................................14
2.1.
Study Rationale.........................................................................................................14
2.2.
Background...............................................................................................................15
2.3.
Benefit/Risk Assessment ..........................................................................................17
3.
Objectives and Endpoints .....................................................................................................18
4.
Study Design.........................................................................................................................19
4.1.
Overall Design ..........................................................................................................19
4.2.
Scientific Rationale for Study Design.......................................................................20
4.3.
Justification for Dose ................................................................................................20
4.4.
End of Study Definition............................................................................................20
5.
Study Population...................................................................................................................21
5.1.
Inclusion Criteria ......................................................................................................21
5.2.
Exclusion Criteria .....................................................................................................23
5.3.
Lifestyle Considerations ...........................................................................................27
5.3.1.
Meals and Dietary Restrictions..................................................................27
5.3.2.
Caffeine, Alcohol, and Tobacco ................................................................27
5.3.3.
Activity ......................................................................................................28
5.4.
Screen Failures..........................................................................................................28
6.
Study Intervention.................................................................................................................29
6.1.
Study Intervention(s) Administered..........................................................................29
6.2.
Preparation/Handling/Storage/Accountability..........................................................31
6.3.
Measures to Minimize Bias: Randomization and Blinding ......................................31
6.4.
Study Intervention Compliance ................................................................................31
6.5.
Concomitant Therapy................................................................................................32
6.5.1.
Prohibited Interventions and Washout Before the 
Study ..........................................................................................................32
6.5.2.
Permitted Interventions..............................................................................33
6.5.3.
Rescue Medicine........................................................................................34
6.5.4.
Prohibited Interventions During the Study ................................................34
6.6.
Dose Modification ....................................................................................................34
6.7.
Intervention after the End of the Study.....................................................................34


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.................................................................................................35
7.1.
Discontinuation of Study Intervention......................................................................35
7.2.
Participant Discontinuation/Withdrawal from the Study..........................................36
7.3.
Lost to Follow Up .....................................................................................................36
8.
Study Assessments and Procedures ......................................................................................36
8.1.
Efficacy Assessments................................................................................................37
8.2.
Safety Assessments...................................................................................................37
8.2.1.
Physical Examinations...............................................................................37
8.2.2.
Vital Signs..................................................................................................37
8.2.3.
Electrocardiograms ....................................................................................38
8.2.4.
Clinical Safety Laboratory Assessments ...................................................38
8.2.5.
Suicidal Risk Monitoring...........................................................................39
8.3.
Adverse Events and Serious Adverse Events ...........................................................39
8.3.1.
Time Period and Frequency for Collecting AE and
SAE Information........................................................................................40
8.3.2.
Method of Detecting AEs and SAEs .........................................................40
8.3.3.
Follow-up of AEs and SAEs......................................................................40
8.3.4.
Regulatory Reporting Requirements for SAEs..........................................41
8.3.5.
Pregnancy...................................................................................................41
8.3.6.
AEs of Special Interest...............................................................................41
8.3.6.1.
Potential Hy’s Law Cases ...........................................................41
8.3.6.2.
ALT or AST Elevations..............................................................42
8.3.7.
Medication Errors ......................................................................................43
8.4.
Treatment of Overdose .............................................................................................43
8.5.
Pharmacokinetics ......................................................................................................44
8.5.1.
Blood PK Sampling Procedure ..................................................................44
8.5.3.
Plasma PK and 
 Bioanalysis ..................................................46
8.6.
Pharmacodynamics ...................................................................................................46
8.7.
Genetics.....................................................................................................................46
8.8.
Biomarkers and Other Assessments..........................................................................46
8.9.
Health Economics/Medical Resource Utilization and Health 
Economics.................................................................................................................47
9.
Statistical Considerations......................................................................................................48
9.1.
Statistical Hypotheses ...............................................................................................48
9.2.
Sample Size Determination.......................................................................................48
9.3.
Populations for Analyses ..........................................................................................48
9.4.
Statistical Analyses ...................................................................................................48
9.4.1.
Pharmacokinetic Analyses .........................................................................48
9.4.1.1.
Pharmacokinetic Parameters.......................................................48
9.4.1.2.
Statistical Analyses of Pharmacokinetic 
Data.............................................................................................49


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9.4.2.
Safety Analyses..........................................................................................49
9.4.2.1.
Adverse Events ...........................................................................49
9.4.2.2.
Clinical Laboratory Assessments................................................50
9.4.2.3.
Vital Signs...................................................................................50
9.4.2.4.
Electrocardiograms .....................................................................51
9.5.
Interim Analyses .......................................................................................................51
9.5.1.
Data Monitoring Committee......................................................................51
10.
Supporting Documentation and Operational Considerations ...............................................52
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...........................................................................................................53
10.1.1.
Regulatory and Ethical Considerations......................................................53
10.1.2.
Financial Disclosure...................................................................................53
10.1.3.
Informed Consent Process .........................................................................53
10.1.4.
Data Protection...........................................................................................54
10.1.5.
Data Quality Assurance .............................................................................54
10.1.6.
Source Documents .....................................................................................55
10.1.7.
Study and Site Closure...............................................................................55
10.1.8.
Publication Policy......................................................................................56
10.1.9.
Compliance with Protocol..........................................................................56
10.2.
Appendix 2: Clinical Laboratory Tests.....................................................................57
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...................................................58
Definition of AE .......................................................................................................58
Definition of SAE .....................................................................................................60
Recording and Follow-up of AEs and/or SAEs........................................................61
Reporting of SAEs ....................................................................................................63
10.4.
Appendix 4: Abbreviations.......................................................................................64
10.5.
Appendix 5: Standard Discontinuation Criteria........................................................67
10.6.
Appendix 6: Study Tabular Summary ......................................................................68
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information..............................................................................................70
Definitions: ...............................................................................................................70
Contraception Guidance: ..........................................................................................70
Pregnancy Testing:....................................................................................................71
Collection of Pregnancy Information: ......................................................................71
10.8.
Appendix 8: Study Schedule Supplement.................................................................73


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11.
References.............................................................................................................................82


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List of Tables
Table 6-1
Study Interventions ............................................................................................... 30
Table 9-1
Analysis Populations............................................................................................. 48
Table 10-1
Protocol-required Safety Laboratory Assessments............................................... 57


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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 1b, Two-Part, Open-Label, Fixed-Sequence, Safety, Tolerability and 
Drug-Drug Interaction Study Between Single Dose Erenumab or Galcanezumab and Multiple 
Dose Ubrogepant in Participants with Migraine
Protocol Number: 3110-108-002
Brief Title: Drug-Drug Interaction Study of Ubrogepant with Erenumab or Galcanezumab
Study Phase: 1b
Study Rationale:
Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist, currently 
seeking approval for the acute treatment of migraine. Migraine patients with episodic or chronic 
migraine are likely to be taking Aimovig® (erenumab) or Emgality® (galcanezumab) 
subcutaneously (SC) for the prevention of migraines. There is a high likelihood that physicians 
could prescribe ubrogepant for the acute treatment of breakthrough migraines in patients already 
taking migraine preventives. Ubrogepant is extensively metabolized in the liver by cytochrome 
P450 (CYP)3A4, while erenumab and galcanezumab are not metabolized by CYP enzymes. 
Although a significant metabolic interaction is not expected when ubrogepant and erenumab or 
ubrogepant and galcanezumab are co-administered, this study will evaluate the potential for a 
pharmacokinetic (PK) interaction and provide safety and tolerability information when 
ubrogepant and erenumab or ubrogepant and galcanezumab are co-administered.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary
To evaluate the effect of single dose erenumab 
or galcanezumab on the PK of multiple dose 
ubrogepant in participants with migraine 
Area under the plasma concentration versus 
time curve from time 0 to time t (AUC0-t) and 
from time 0 to infinity (AUC0-∞), and 
maximum plasma drug concentration (Cmax) of 
ubrogepant when ubrogepant and erenumab or 
ubrogepant and galcanezumab are administered 
together and when ubrogepant is administered 
alone


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Objectives
Endpoints
Secondary
To evaluate secondary PK parameters of 
ubrogepant following administration of 
ubrogepant and erenumab or ubrogepant and 
galcanezumab and when ubrogepant is 
administered alone
Secondary
Time of maximum plasma drug concentration 
(Tmax), terminal elimination rate constant (λz), 
terminal elimination half-life (T½), apparent 
total body clearance of drug from plasma after 
extravascular administration (CL/F), and 
apparent volume of distribution during the 
terminal phase after extravascular 
administration (Vz/F) of ubrogepant when 
ubrogepant and erenumab or ubrogepant and 
galcanezumab are co-administered and when
ubrogepant is administered alone
To evaluate the safety and tolerability profiles 
when ubrogepant and erenumab or ubrogepant 
and galcanezumab are administered in 
combination and when administered alone in
participants with a history of 2 or more 
migraine attacks per month
 
 
Changes from baseline in vital signs, clinical 
laboratory measurements, physical 
examinations, and electrocardiograms (ECGs)
Incidence of adverse events (AEs) including 
severity and causality of AEs, as well as AEs 
leading to discontinuation
 
 
Overall Study Design:  
This study will be a Phase 1b, 2-part, multi-center, open-label, fixed-sequence drug interaction 
study in 40 male and female participants who have been diagnosed with migraine for at least 
1 year and are aged 18 through 50 years. In Part 1, 20 participants will receive a single oral dose 
of 100 mg ubrogepant alone (Study Intervention A) on Day 1, a single SC injection of 140 mg 
erenumab alone (Study Intervention B) on Day 8, followed by once daily oral doses of 100 mg 
ubrogepant on Days 12 through 15 (Study Intervention D) under fasted conditions. Similarly, in 
Part 2, a separate cohort of 20 participants will receive a single oral dose of 100 mg ubrogepant 
alone (Study intervention A) on Day 1, 2 consecutive SC injections of 120 mg galcanezumab 
alone (Study intervention C) on Day 8, followed by once daily oral doses of 100 mg ubrogepant 
on Days 12 through 15 (Study Intervention D) under fasted conditions. 


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If all doses are well tolerated, the duration of participation in the study will be 46 ± 3 days 
(Day –1 through the safety Follow-up visit on Day 45), not including the Screening Visit.

Duration: 
o
Screening: Up to 21 days (Day -21 to Day -1) 
o
Intervention Period: Up to a total of 17 days (Day -1 to Day 16) 
o
Follow-up period: 30 (±3) days after the last dose

PK and Biomarker Sampling
In Part 1 and Part 2, PK and biomarker blood samples for the analysis of ubrogepant and 
CGRP concentrations will be collected at 0 hour (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 
14, and 24 hours postdose on Days 1 and 12. 

Safety Measurements
The safety and tolerability profiles when ubrogepant and erenumab or ubrogepant and 
galcanezumab are co-administered and when each study intervention is administered 
alone in participants with migraine will be evaluated by clinical assessment of AEs,
physical examinations, safety 12-lead ECGs, standard laboratory safety tests (hematology, 
serum chemistry, and urinalysis), and by measurements of vital signs at specified time 
points after each study intervention.
Number of Participants:  
A total of 40 participants will be enrolled in the study; 20 participants in Part 1 and a separate 
cohort of 20 participants in Part 2. Part 1 and Part 2 will enroll in parallel. 
 
Participants who prematurely 
discontinue from the study may be replaced at the discretion of the sponsor.
Number of Sites: Up to 3 sites in the United States
Intervention Groups and Study Duration:  
Study Intervention A:
Single oral 100-mg dose of ubrogepant tablet on Day 1
Study Intervention B:
Single subcutaneous injection of 140-mg erenumab on Day 8
Study Intervention C:
Two consecutive subcutaneous injections of 120-mg galcanezumab
on Day 8
Study Intervention D:
Repeated once daily oral doses of 100-mg ubrogepant on Days 12,
13, 14, and 15
If all doses are well tolerated, the duration of participation in the study will be 46 ± 3 days 
(Day –1 through the safety Follow-up Visit on Day 45), not including the Screening Visit.
Data Monitoring Committee: No


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2.
Introduction
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 those with migraine 
have 3 or more migraines 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 affecting 17.6% of women and 8% of men (Stovner and Andree, 2010). The Global 
Burden of Disease Study 2010 (Vos et al, 2012) estimated the global prevalence of migraine to 
be 14.7%, making it the third most common disease in the world in both males and females. 
Migraine was ranked seventh highest among specific causes of disability globally (Steiner 2013).
Calcitonin gene-related peptide (CGRP) is a neuropeptide implicated in the pathophysiology of 
migraine. CGRP levels in the cranial venous outflow (ie, external jugular vein) are increased 
during a migraine attack (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 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.
This study will evaluate the safety, tolerability, and PK of ubrogepant, a CGRP antagonist, when 
administered to participants with migraine receiving erenumab or galcanezumab.
2.1.
Study Rationale
Ubrogepant is a novel, oral CGRP receptor antagonist, currently seeking approval for the acute 
treatment of migraine. Migraine patients with episodic or chronic migraine are likely to be taking 
Aimovig (erenumab) or Emgality (galcanezumab) subcutaneously (SC) for the prevention of 
migraines. There is a high likelihood that physicians could prescribe ubrogepant for the acute 
treatment of breakthrough migraines in patients already taking migraine preventives. Ubrogepant 
is extensively metabolized in the liver by cytochrome P450 (CYP)3A4, while erenumab and 
galcanezumab are not metabolized by CYP enzymes. Although a significant metabolic 
interaction is not expected when ubrogepant and erenumab or ubrogepant and galcanezumab are 
co-administered, this study will evaluate the potential for a PK interaction and provide safety and 
tolerability information when ubrogepant and erenumab or ubrogepant and galcanezumab are 
co-administered.


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2.2.
Background
Ubrogepant 
Ubrogepant, a novel oral CGRP receptor antagonist, that is chemically distinct from both 
telcagepant and MK-3207, is being developed for the acute treatment of migraine. Current 
standard of care for the acute treatment of migraines includes triptans, NSAIDs, and ergots. 
Ubrogepant has completed Phase 3 evaluation for the acute treatment of migraine.
Preclinical and clinical studies conducted to date for ubrogepant have shown no evidence of 
hepatotoxicity. The toxicity studies conducted to date have demonstrated considerable safety 
margins over the projected efficacious clinical exposure. For the highest anticipated dose used in 
clinical studies of 100 mg with potential redosing in the same day (AUC 4.4 μM•hr for a total 
dose of 200 mg), the safety margins are 3.5- and 74-fold over the rat NOAEL and monkey 
NOEL exposures, respectively. The nonclinical toxicity profile of ubrogepant via the oral route 
of administration supports the continuation of dosing via the oral route in appropriately designed 
clinical trials. The findings from the developmental toxicology studies in rats and rabbits and a 
fertility study in rats support inclusion of women of childbearing potential (WOCBP) in clinical 
trials in compliance with the study protocol and applicable regulatory guidelines. 
In Phase 1 studies, single doses of 1 to 400 mg ubrogepant and multiple doses of ubrogepant up 
to 400 mg once daily (QD) for 10 consecutive days and 150 mg QD for 28 consecutive days 
have been evaluated. Ubrogepant was generally safe and well tolerated in these studies. In the 
multiple dose safety and tolerability studies evaluating hepatic effects of 150 mg QD for 28 days 
and high frequency, intermittent dosing of 100 mg (2 days ubrogepant followed by 2 days 
placebo) for 56 days, no signs of drug-induced liver injury (DILI) were observed based on a 
systematic measurement of serum ALT and aspartate aminotransferase (AST). The most 
frequently reported clinical AEs in these Phase 1 studies include nasopharyngitis, headache, and 
nausea. Adverse events have generally been transient and mild to moderate in intensity. 
Dose-proportional PK was noted in the dose range of 1 to 400 mg. Ubrogepant is rapidly 
absorbed with maximum plasma concentrations achieved in 0.5-1.5 hours. Ubrogepant is 
metabolized to an inactive metabolite almost exclusively by CYP3A4 with subsequent 
glucuronidation. Ubrogepant has a short terminal elimination half-life (T½) of 5 to 7 hours with 
no accumulation after QD repeated dosing. 
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 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. 
Further efficacy and safety of ubrogepant were established in 2 randomized, double-blind, 
placebo-controlled, single-attack, Phase 3 studies (UBR-MD-01 and UBR-MD-02). The results 
from these studies demonstrated that both ubrogepant 50 mg and 100 mg are superior to placebo 
in the acute treatment of migraine based on the coprimary efficacy endpoints (pain freedom and 


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absence of the most bothersome migraine-associated symptom at 2 hours after the initial dose of 
investigational product). Study UBR-MD-02 demonstrated that ubrogepant 25 mg was superior 
to placebo for the coprimary endpoint pain freedom at 2 hours after the initial dose; however, 
statistical significance was not achieved for the coprimary endpoint absence of the most 
bothersome migraine-associated symptom at 2 hours after the initial dose. The efficacy in each 
study was supported by the prospectively defined secondary and additional endpoints. A 
long-term safety extension study, UBR-MD-04, was conducted and supported the safety of 
ubrogepant evidenced in the 2 pivotal studies. 
Additional information and a detailed description of the chemistry, pharmacology, toxicology, 
efficacy, and safety of ubrogepant can be found in the ubrogepant Investigator’s Brochure, 
(Edition 6, 2019). Rationale for dose selection is described in Section 4.3.
Erenumab 
Erenumab-aooe (Aimovig®) is a human immunoglobulin G2 (IgG2) monoclonal antibody 
(MAB) that has high affinity binding to the CGRP receptor and antagonizes CGRP receptor 
function. Erenumab is indicated for the preventive treatment of migraine in adults. Erenumab is 
produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. It is 
composed of 2 heavy chains, each containing 456 amino acids, and 2 light chains of the lambda 
subclass, each containing 216 amino acids, with an approximate molecular weight of 150 kDa. 
Erenumab exhibits non-linear kinetics as a result of binding to the CGRP receptor. Less than 
2-fold accumulation was observed in trough serum concentrations (Cmin) for episodic and chronic 
migraine patients following SC administration of 70 mg once monthly and 140 mg once monthly 
doses. Serum trough concentrations approached steady state by 3 months of dosing. The 
effective half-life of erenumab is 28 days. Median peak serum concentrations were attained in 
approximately 6 days, and estimated absolute bioavailability was 82%. Two elimination phases 
were observed for erenumab. At low concentrations, the elimination is predominantly through 
saturable binding to target (CGRP receptor), while at higher concentrations the elimination of 
erenumab is largely through a non-specific, non-saturable proteolytic pathway. Erenumab is not 
metabolized by CYP enzymes; therefore, interactions with concomitant medications that are 
substrates, inducers, or inhibitors of CYP enzymes are unlikely.
Additional information for erenumab can be found in the Aimovig® USPI.
Galcanezumab 
Galcanezumab-gnlm (Emgality®) is a humanized immunoglobulin G4 (IgG4) MAB that binds to 
CGRP ligand and blocks its binding to the receptor. Galcanezumab is produced in CHO cells by 
recombinant DNA technology. Galcanezumab is composed of 2 identical immunoglobulin kappa 
light chains and 2 identical immunoglobulin gamma heavy chains and has an overall molecular 
weight of approximately 147 kDa. 
Galcanezumab exhibits linear PK and exposure increases proportionally with doses between 1 
and 600 mg. A loading dose of 240 mg achieved the serum galcanezumab steady-state 
concentration after the first dose. The time to maximum concentration is 5 days, and the 
elimination half-life is 27 days. Following a SC injection of galcanezumab, the time to maximum 


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concentration was about 5 days. Galcanezumab is expected to be degraded into small peptides 
and amino acids via catabolic pathways in the same manner as endogenous IgG. Galcanezumab 
is not metabolized by CYP enzymes; therefore, interactions with concomitant medications that 
are substrates, inducers, or inhibitors of CYP enzymes are unlikely.
Additional information for galcanezumab can be found in the Emgality® USPI.
2.3.
Benefit/Risk Assessment
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of ubrogepant may be found in the ubrogepant Investigator’s Brochure. Based on 
the observed nonclinical and clinical safety profile of ubrogepant, evaluation of ubrogepant in 
large Phase 3 trials was supported and these trials are currently completed with a potentially 
favorable risk/benefit. Since ubrogepant is an investigational product currently being considered 
for approval by the US FDA, the benefit/risk assessment of the product has not yet been 
completed by the FDA.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
Primary
To evaluate the effect of single dose erenumab 
or galcanezumab on the PK of multiple dose 
ubrogepant in participants with migraine 
Area under the plasma concentration versus 
time curve from time 0 to time t (AUC0-t) and 
from time 0 to infinity (AUC0-∞), and 
maximum plasma drug concentration (Cmax) of 
ubrogepant when ubrogepant and erenumab or 
ubrogepant and galcanezumab are administered 
together and when ubrogepant is administered 
alone
Secondary
To evaluate secondary PK parameters of
ubrogepant following administration of 
ubrogepant and erenumab or ubrogepant and 
galcanezumab and when ubrogepant is 
administered alone
Secondary
Time of maximum plasma drug concentration 
(Tmax), terminal elimination rate constant (λz), 
terminal elimination half-life (T½), apparent 
total body clearance of drug from plasma after 
extravascular administration (CL/F), and 
apparent volume of distribution during the 
terminal phase after extravascular 
administration (Vz/F) of ubrogepant when 
ubrogepant and erenumab or ubrogepant and 
galcanezumab are co-administered and when
ubrogepant is administered alone
To evaluate the safety and tolerability profiles 
when ubrogepant and erenumab or ubrogepant 
and galcanezumab are administered in 
combination and when administered alone in 
participants with a history of 2 or more 
migraine attacks per month
Changes from baseline in vital signs, clinical 
laboratory measurements, physical 
examinations, and ECGs 
Incidence of AEs including severity and 
causality of AEs, as well as AEs leading to 
discontinuation
 
 


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4.
Study Design
4.1.
Overall Design
This study will be a Phase 1b, 2-part, multi-center, open-label, fixed-sequence drug interaction 
study in 40 male and female participants who have been diagnosed with migraine for at least 1 
year and are aged 18 through 50 years. In Part 1, 20 participants will receive a single oral dose of 
100 mg ubrogepant alone (Study Intervention A) on Day 1, a single SC injection of 140 mg 
erenumab alone (Study Intervention B) on Day 8, followed by once daily oral doses of 100 mg 
ubrogepant on Days 12 through 15 (Study Intervention D) under fasted conditions. Similarly, in 
Part 2, a separate cohort of 20 participants will receive a single oral dose of 100 mg ubrogepant 
alone (Study intervention A) on Day 1, 2 consecutive SC injections of 120 mg galcanezumab 
alone (Study intervention C) on Day 8, followed by once daily oral doses of 100 mg ubrogepant 
on Days 12 through 15 (Study Intervention D) under fasted conditions. 
If all doses are well tolerated, the duration of participation in the study will be 46 ± 3 days 
(Day –1 through the safety Follow-up Visit on Day 45), not including the Screening Visit.

Duration: 
o
Screening: Up to 21 days (Day -21 to Day -1)
o
Intervention Period: Up to a total of 17 days (Day -1 to Day 16)
o
Follow-up period: 30 (±3) days after the last dose

PK and Biomarker Sampling
In Part 1 and Part 2, PK blood samples for the analysis of ubrogepant and CGRP 
concentrations will be collected at 0 hour (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 14, and 
24 hours postdose on Days 1 and 12. 
 

Safety Measurements
The safety and tolerability profiles when ubrogepant and erenumab or ubrogepant and 
galcanezumab are co-administered and when each study intervention is administered 
alone in participants with migraine will be evaluated by clinical assessment of AEs,  
physical examinations, safety 12-lead ECGs, standard laboratory safety tests (hematology, 
serum chemistry, and urinalysis), and by measurements of vital signs at specified time 
points after each study intervention.

Number of Participants
A total of 40 participants at up to 3 sites in the United States will be enrolled in the study; 
20 participants in Part 1 and a separate cohort of 20 participants in Part 2. Part 1 and Part 
2 will enroll in parallel.
 


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. Participants who prematurely discontinue from the study may be replaced at 
the discretion of the sponsor.
4.2.
Scientific Rationale for Study Design
The multi-center, open-label, fixed-sequence design is considered adequate to assess the 
potential effect on the safety and PK of ubrogepant when ubrogepant and erenumab or 
ubrogepant and galcanezumab are co-administered. Considering the long half lives of erenumab 
and galcanezumab (about 28 days), the fixed-sequence design allows for the evaluation of the 
effect of erenumab/galcanezumab on the PK of ubrogepant. The washout period of 7 days 
between Study Intervention A and Study Intervention B (Part 1) or Study Intervention C (Part 2) 
is adequate given ubrogepant’s short T½ of 5-7 hours. 
 
Multiple dose 
administration of ubrogepant following erenumab or galcanezumab administration will help to 
assess the safety/tolerability of the combinations in a potential real world setting of administering 
ubrogepant to acutely treat an acute migraine attack in participants who are already on a 
preventive medication, either erenumab or galcanezumab.
4.3.
Justification for Dose

The ubrogepant dose of 100 mg (administered as one 100 mg tablet) is the highest 
clinical dose of ubrogepant for which approval is being sought. 

A multiple-dose once daily administration of ubrogepant will provide a dosing regimen 
similar to the potential real-world use of ubrogepant in combination with migraine 
preventive MABs and is considered adequate to satisfy the objectives of the study.

140 mg erenumab and 240 mg galcanezumab are the highest approved doses of the 
CGRP receptor MAB (erenumab) and CGRP ligand MAB (galcanezumab), respectively.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit (Follow-up) of the last participant in 
the study on Day 45 (± 3 days), or at early termination.
A participant is considered to have completed the study if he/she has not been terminated early 
and has completed all phases of the study through the last visit (Follow-up) on 
Day 45 ± 3 (30 [± 3] days after the last dose of study intervention).


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5.
Study Population
Study participants will be individuals with at least a 1-year history of migraine with or without 
aura, consistent with a migraine diagnosis according to the International Classification of
Headache Disorders, 3rd edition, (ICHD-3, 2018). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
2.
Type of Participant and Migraine Characteristics
2.01
At least a 1-year history of migraine with or without aura consistent with a diagnosis 
according to the International Classification of Headache Disorders, 3rd edition, 
(ICHD-3, 2018)
2.02
By history, the participant’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
2.03
History of at least 2 migraine attacks per month in the 2 months prior to Screening
2.04
Have a sitting pulse rate ≥ 45 beats per minute (bpm) and ≤ 100 bpm during the vital 
sign assessment at the Screening Visit. Clinical site may perform a maximum of 
2 repeats of vital sign measurements if the initial measurement is out of range.
2.05
Negative test results for benzoylecgonine (cocaine), methadone, barbiturates, 
amphetamines, benzodiazepines, cannabinoids, opiates, and phencyclidine at the 
Screening Visit and Day -1; unless explained by concomitant medication use 
(eg, opioids prescribed for migraine pain)
 


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4.
Sex
 
 
 
5.02
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period
 
 
 
 
 
 
 


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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions and History
1.01
Difficulty distinguishing migraine headache from tension-type or other headaches
1.02
Has a history of migraine aura with diplopia or impairment of level of 
consciousness, hemiplegic migraine, or retinal migraine as defined by ICHD-3
1.03
Has a current diagnosis of new persistent daily headache, trigeminal autonomic 
cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by 
ICHD-3
1.04
Required hospital treatment of a migraine attack 3 or more times in the 6 months 
prior to Screening
1.05
Has a chronic non-headache pain condition requiring daily pain medication (with the 
exception of pregabalin)
 
 
 
 


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3.02
Participation in any other clinical investigation using an experimental drug within 
30 days prior to study intervention administration
3.03
Participation in a blood or plasma donation program within 60 or 30 days, 


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respectively, prior to study intervention administration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
1. Water can be allowed as desired except for 1 hour before and after oral study intervention 
administration. Participants will be required to undergo a 10-hour overnight fast prior to 
dosing on Days 1, 12, 13, 14, and 15 and will maintain a fasted condition for an additional 
4 hours following oral dose administration on these days. The oral study intervention will 
be administered with 240 mL of water. Following each dose administration, participants 
will continue their fast and remain seated upright and awake for 4 hours.
2. Participants will be served meals at appropriate times on admission days. On dosing days 
with study intervention administration (Days 1, 8, 12, 13, 14, and 15); no breakfast will be 
provided, but a standard lunch, dinner, and snack will be provided at approximately 
4 hours postdose, 10 hours postdose, and 13 hours postdose, respectively. On all other 
days of confinement, breakfast, lunch, dinner, and snack will be served at approximately 
0800, 1200, 1800, and 2100 hours, respectively.
3. Seville oranges, beverages or food containing quinine (bitter lemon, tonic water), poppy 
seeds, or taken dietary supplements or other foods or beverages that may affect various 
drug-metabolizing enzymes and transporters (eg, grapefruit, grapefruit juice, grapefruit-
containing beverages), vegetables from the mustard green family (eg, kale, broccoli, 
watercress, collard greens, kohlrabi, brussel sprouts, mustard), or charbroiled meats must 
not be consumed within 14 days prior to dosing and throughout the duration of the study.
4. A copy of the menu with the total nutritional content (fat, protein, carbohydrates, and 
calories) of each component of each meal and snack will be made available to the sponsor 
at the start of the study. Participants will be instructed to consume the entire contents of 
each meal and snack, if possible. Study center personnel will document the percentage or 
the amount of consumed food for each participant.
5. While admitted in the study center, participants will be provided with standardized low-fat 
(< 20 g) meals. 
6. Participants must refrain from implementing drastic changes in their diet or start a new 
diet during the study. 
5.3.2.
Caffeine, Alcohol, and Tobacco
1. Participants will abstain from ingesting caffeine- or xanthine-containing products 
(eg, coffee, tea, cola drinks, and chocolate) for at least 2 hours before dosing and at least 
4 hours after dosing.
2. Alcohol intake should be limited to no more than 1 drink per day throughout the study. A 
drink is defined as a 12-ounce can/bottle of beer, a 4-ounce glass of wine, or 1 ounce of 
liquor.


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3. Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit.
5.3.3.
Activity
Maintaining a consistent lifestyle when participating in a clinical trial is vital. Participants will 
abstain from strenuous exercise or starting an intense exercise regimen for at least 7 days before 
blood collection for clinical laboratory tests on Day 1 and throughout the duration of the study, 
including the follow-up period. Participants may participate in light recreational activities during 
the study conduct (eg, watching television, reading).
5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened unless the reason for screen failure was a positive urine drug screen. A participant 
who is rescreened will be assigned a new identification number and must sign the informed 
consent at the time of re-screening.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol.
6.1.
Study Intervention(s) Administered
Study Intervention A:
Single oral 100-mg dose of ubrogepant tablet on Day 1
Study Intervention B:
Single SC injection of 140-mg erenumab on Day 8
Study Intervention C:
Two consecutive SC injections of 120-mg galcanezumab on Day 8
Study Intervention D:
Repeated once daily oral doses of 100-mg ubrogepant on Days 12, 13, 
14, and 15
Migraine participants will be randomized to either Part 1 or 2 and will receive study 
interventions in a fixed sequence. Parts 1 and 2 could be conducted in parallel. In Part 1, 
20 participants will receive a single oral dose of 100 mg ubrogepant alone (Study Intervention A) 
on Day 1, a single SC injection of 140 mg erenumab alone (Study Intervention B) on Day 8, 
followed by once daily oral doses of 100 mg ubrogepant on Days 12 through 15 (Study 
Intervention D) under fasted conditions. Similarly, in Part 2, a separate cohort of 20 participants
will receive a single oral dose of 100 mg ubrogepant alone (Study Intervention A) on Day 1, 
2 consecutive SC injection of 120 mg galcanezumab alone (Study Intervention C) on Day 8, 
followed by once daily oral doses of 100 mg ubrogepant on Days 12 through 15 (Study 
Intervention D) under fasted conditions. There will be a 7-day washout period between the 
administration of Study Intervention A and Study Intervention B (Part 1) or Study Intervention A 
and Study Intervention C (Part 2) and an 11-day washout period between ubrogepant doses.


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Table 6-1
Study Interventions
Study Intervention 
Name
Ubrogepant 
(Intervention A)
Ubrogepant 
(Intervention D)
Aimovig 
(Erenumab)
(Intervention B)
Emgality 
(galcanezumab)
(Intervention C)
Dose Formulation
Tablet
Tablet
Solution for
injection
Solution for 
injection
Identity of Formulation
100 mg ubrogepant
100 mg ubrogepant
140 mg/mL 
erenumab aooe
120 mg/mL 
galcanezumab 
gnlm
Device Configuration
NA
NA
Single-dose 
prefilled 
SureClick 
autoinjector 
or single-dose 
prefilled syringe 
(
Single-dose 
prefilled pen 
 
 or 
single-dose 
prefilled syringe 
Route of 
Administration 
Oral
Oral
Subcutaneous 
injection
Subcutaneous 
injection
Dosing Instructions
1 tablet to be 
administered with 
240 mL of water, 
under fasted 
conditions on Day 1
1 tablet to be 
administered with 
240 mL of water, 
under fasted 
conditions on 
Days 12, 13, 14, 
and 15
Single 
subcutaneous 
injection of 
140-mg erenumab 
in the abdomen, 
thigh, or upper 
arm on Day 8
Two consecutive
subcutaneous 
injections of 
120-mg 
galcanezumab in 
the abdomen, 
thigh, back of the 
upper arm, or 
buttocks on Day 8
Packaging and 
Labeling
Study intervention 
will be provided in 
bottles, each 
containing 
35 tablets. Each
bottle will be 
labeled as required 
per country 
requirement.
Study intervention 
will be provided in 
bottles, each
containing 
35 tablets. Each 
bottle will be 
labeled as required 
per country 
requirement.
Study intervention 
will be provided 
as either single-
dose prefilled 
SureClick 
autoinjector or 
single-dose 
prefilled syringe. 
Each 
autoinjector/pre-
filled syringe will 
be labeled as 
required per 
country 
requirement.
Study intervention 
will be provided as 
either single-dose 
prefilled pen or 
single-dose 
prefilled syringe. 
Each pre-filled 
pen/pre-filled 
syringe will be 
labeled as required 
per country 
requirement.
Manufacturer
Allergan plc, 
Clonshaugh, Ireland
Allergan plc, 
Clonshaugh, 
Ireland
Amgen Inc, 
Thousand Oaks, 
CA
Eli Lilly and 
Company, 
Indianapolis, IN


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6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. All unused study intervention and empty kits and bottles must be returned to the sponsor 
at the termination of the study. Unit counts will be performed when the study intervention
is returned, and all study intervention must be accounted for. Used syringes and pens 
should be discarded at the site.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Participants will be randomized to 1 of 2 parts: Part 1 or Part 2. Participants randomized to 
Part 1 will receive Study Intervention A on Day 1, Study Intervention B on Day 8, and Study 
Intervention D once daily on Days 12 through 15. Participants randomized to Part 2 will receive 
Study Intervention A on Day 1, Study Intervention C on Day 8, and Study Intervention D once 
daily on Days 12 through 15. 
 
 
 
 
 
 
 
 
 
This is an open-label study; no blinding of assigned study intervention will occur.
6.4.
Study Intervention Compliance
Participants will receive all doses under the direct supervision of study center personnel. Each 
participant’s mouth and hands will be checked to ensure that the oral study interventions A and 


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D have been taken. Subcutaneous injections for study interventions B and C will be administered 
by site staff. Study intervention compliance will be assumed to be 100% when oral and 
subcutaneous dosing has been recorded in the eCRF.
Dosing should occur at the same time each dosing day for a participant; differences in dosing 
times > 60 minutes will be noted as protocol deviations, and the reason for deviation must be 
recorded in the source documents and eCRFs.
Galcanezumab injections should be administered consecutively with no more than 5 minutes 
between injections. A difference in injection times > 5 minutes will be noted as protocol 
deviations, and the reason for deviation must be recorded in the source documents and eCRFs.
The study center will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter, prescription medicines, vitamins, herbal 
supplements, and/or cannabis or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
At screening, upon admission to and discharge from the study center, EOD, and the Follow-up 
Visit, study center staff will question each participant specifically on the use of concomitant 
medications. Study center staff must notify the sponsor immediately if a participant consumes 
any concomitant medications not permitted by the protocol. Participants who admit to using 
prohibited concomitant medications may be discontinued from the study at the discretion of the 
investigator or the sponsor.
6.5.1.
Prohibited Interventions and Washout Before the Study
Participants must discontinue any of the medications listed in the table below for the specified 
period prior to Day -1. These medications are prohibited for the duration of the study. Other 
stable medications being used at screening may be continued. A medication will be considered 
stable if the dose and frequency remain unchanged for at least 14 days prior to screening.


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The investigator or sponsor reserves the right to exclude a participant from participation in the 
study if a medication taken 14 or more days before the study start may interfere with the study 
outcome (eg, a drug with prolonged half-life).
Any hormonal product taken within 30 days or any other medication taken within 14 days before 
the first dose of study intervention will be recorded in the eCRF as a prior medication.
The decision to administer a prohibited medication/intervention during the study period is done 
with the safety of the study participant as the primary consideration. When possible, the sponsor
should be notified before the prohibited medication/intervention is administered.
6.5.2.
Permitted Interventions
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific concomitant medication or prior 
medication/intervention is in question, please contact the sponsor. All concomitant/prior 
medication use must be reviewed by the investigator in consultation with the sponsor prior to 
enrollment.
The following medications are allowed during the study, but are prohibited within 48 hours prior 
to taking oral study intervention:

any triptan

any ergot derivative

any opioid

any NSAID

any other form of analgesic (including acetaminophen and Excedrin®)

any antiemetic agent

any proton pump inhibitor


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The following medications are allowed during the study, but are prohibited within 24 hours prior 
to taking oral study intervention:

any antacid

any H2 blocker
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis. Daily use of gabapentin/pregabalin 
is allowed.
Selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine reuptake inhibitors 
(SNRI) will be permitted provided that treatment is stable at Screening and continues without 
change in dose throughout the study. SSRIs and SNRIs may not be started during the study. 
For medications taken for migraine, all past and current medications will be recorded in the 
eCRF. Any medication taken during the study between the date of the first dose of study 
intervention and the date of the EOD visit will be recorded in the eCRF as a concomitant 
medication; any medication started after the EOD visit will not be considered a concomitant 
medication and should not be captured in the eCRF.
6.5.3.
Rescue Medicine
The study site will supply rescue medication that will be obtained locally. Rescue medication 
includes medications for the acute treatment of migraine. The following rescue medications may 
be used: triptans, ergotamines, NSAIDs, acetaminophen or combination analgesics 
(ie Excedrin®), opioids, or other medications that are not explicitly prohibited and may be taken 
during the study. In the Screening period, rescue medication can be taken if headache of any 
severity develops. 
Although the use of rescue medications is allowable at any time during the study, the use of 
rescue medications should be delayed, if possible, for at least 2 hours following the 
administration of study intervention. The date and time of rescue medication administration as 
well as the name and dosage regimen of the rescue medication must be recorded.
6.5.4.
Prohibited Interventions During the Study
Interventions that are prohibited during the entire study, including the duration of the Follow-up 
Visit, are described in Table 6-2.
6.6.
Dose Modification
No dose modification is allowed through the duration of the study
6.7.
Intervention after the End of the Study
There will be no study intervention administered after the end of the study.


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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and receives study 
intervention ceases participation in the study, regardless of circumstances, before the completion 
of the protocol-defined study procedures.
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
case report form.
Reasons for discontinuation from the study treatment and/or the study may include the following
commonly used or other acceptable terms:
Commonly Used Terms
Other Acceptable Terms
Adverse event
Death
Lost to follow-up
Technical problems
Non-compliance with study drug
Other
Physician decision
Pregnancy
Protocol deviation
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by subject
7.1.
Discontinuation of Study Intervention
Criteria for discontinuation of the participant from study intervention are described above. 
Participants who discontinue study intervention must be discontinued from the study and should 
undergo EOD evaluations at early termination. 
Discontinuation of study intervention due to any clinically significant findings in clinical 
laboratory determinations, vital sign or ECG measurements should be considered by the 
investigator if the investigator believes that it is in best interest of the participant. Any new 
clinically relevant finding should be reported as an AE.
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined in Section 8.3.6 or if the 
investigator believes that it is in best interest of the participant.
See the SoA in Section 1.2 for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.


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7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.

See the SoA (Section 1.2) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts will be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.

Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.

Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.


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
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

A detailed listing of study assessments by day is presented in Appendix 8.

Study center staff will admit participants into a nonsmoking environment on Days -1, and 7. 
Participants will remain in the study center until 24 hours following study intervention 
administration on Day 1 and on Days 7 through 16 for a total of 11 overnight stays 
(2 overnight stays on Days -1 and 1; and 9 overnight stays on Days 7 through 15). 
Participants will be released from the study center on Day 2 after the 24-hour postdose PK 
blood draw and on Day 16 after completion of the 96-hour or EOD assessments. Participants 
will be administered doses of Study Intervention B or Study Intervention C on Day 8, and 
ubrogepant doses (Study Intervention A and D) on Days 1 and 12 through 15 at the study 
center. 

The amount of blood collected from each participant over the duration of the study will be 
approximately 194 mL. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples.
8.1.
Efficacy Assessments
No applicable.
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

Physical examinations should be completed by a professionally trained physician or health 
professional listed on Form FDA 1572 and licensed to perform physical examinations.
8.2.2.
Vital Signs
Vital signs will be assessed as follows:

Screening: Blood pressure (BP), pulse rate, respiratory rate, height, weight, and temperature

Interim: BP and pulse rate


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
EOD: BP, pulse rate, respiratory rate, weight, and temperature

Blood pressure and pulse measurements will be assessed in a sitting position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (eg, television, cell phones).

Study center staff will assess vital signs at the nominal times (relative to the dosing time) or 
within 30 minutes prior to the nominal times (see Section 1.2, SoA, for additional details on 
assessment timepoints). Assessments performed outside this window will be noted as 
protocol deviations, and the reason for deviation must be documented in the source 
documents. Predose vital signs must be assessed within 120 minutes prior to the dosing time.

For interim and EOD assessments, participants who have a sitting systolic BP ≥160 mm Hg 
or ≤90 mm Hg or who have a sitting diastolic BP ≥100 mm Hg or ≤45 mm Hg will undergo 
at least 2 BP reassessments within 15 minutes of the original. Participants who have a pulse 
rate > 100 bpm or < 45 bpm will undergo at least 2 pulse rate reassessments within 15 
minutes of the original. If the second repeat of BP and/or pulse rate continues to be out of 
range, the investigator or subinvestigator must assess its clinical significance. Participants 
should be discontinued from the study if interim BP or pulse rate values are deemed 
clinically significant. If this occurs at screening, participants will be excluded from the study.
8.2.3.
Electrocardiograms

A standard 12-lead ECG will be performed in the supine position at the nominal times 
(relative to the dosing times) or within 45 minutes prior to the nominal times as outlined in 
the SoA (see Section 1.2). Assessments performed outside this window will be noted as 
protocol deviations, and the reason for deviation must be documented in the source 
documents. Predose ECGs must be performed within 120 minutes prior to the dosing time.

The paper speed will be a standard 25 mm/sec; the ECG tracing will be kept at the study 
center. Measurements will be recorded for the following parameters in lead II or lead III: 
heart rate, PR interval, QRS duration, QT interval, QTcB, and QTcF. All ECGs will be 
clinically interpreted by the investigator or subinvestigator.

For interim and EOD ECGs, participants who have an abnormal QT result (QTcF ≥450 msec 
for male participants or ≥470 msec for female participants or uncorrected QT ≥500 msec) 
will undergo at least 2 ECG reassessments within 15 minutes of the original. If the second 
repeat of ECG results continues to be out of range, the investigator or subinvestigator must 
assess its clinical significance. Participants should be discontinued from the study if interim 
ECG results are deemed clinically significant.
8.2.4.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency.


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
At screening, the investigator or subinvestigator will assess the clinical significance of any 
values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significant during participation in the 
study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical safety physician.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA.

Urine dipstick kits may be used to conduct drugs-of-abuse screens and pregnancy tests  at the 
study center at screening and on admission days. 

Study center local laboratories may be used to conduct drugs-of-abuse screens and pregnancy 
tests on admission days. Local laboratories may also be used to conduct safety or eligibility 
tests that require quick results (which the central laboratory is unable to provide) only if the 
test sample is split and sent to the central laboratory in addition to the local laboratory. Prior 
to using a local laboratory, the study center must ensure that the laboratory is listed on the 
Form FDA 1572 and that copies of the laboratory certificates and reference ranges are 
provided to the sponsor.
8.2.5.
Suicidal Risk Monitoring
Not applicable.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and any other study-specific terms as 
relevant and remain responsible for following up AEs that are serious, considered related to the 
study intervention or study procedures, or that caused the participant to discontinue the study 
intervention and/or study (see Section 7).


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8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs, including SAEs, from the signing of the ICF until the Follow-up Visit/30 days after the 
last dose of study intervention will be collected at the timepoints specified in the SoA
(Section 1.2), and as observed or reported spontaneously by study participants.
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF and will be considered 
pretreatment AEs.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs and AEs of special interest (as defined in 
Section 8.3.6) will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor or designee with a copy of any postmortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information.


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8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs, and investigators. 

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure or state other documents and will notify 
the IRB, if appropriate according to local requirements.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.3.5.
Pregnancy

Details of all pregnancies in female participants, and if indicated, female partners of male 
participants will be collected from the signing of the ICF and until 33 days for female and 
93 days for male participants.

If a pregnancy is reported, the investigator should inform the sponsor or designee within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an elective 
abortion or not) are considered SAEs.
8.3.6.
AEs of Special Interest
AEs of special interest (AESI) that warrant ongoing monitoring and rapid communication by the 
investigator to the sponsor are potential Hy’s Law cases and ALT/AST elevations, and are 
outlined below.
8.3.6.1.
Potential Hy’s Law Cases
Criteria for potential Hy’s Law cases are as follows:

ALT or AST ≥ 3 × upper limit of normal (ULN) AND 

Total bilirubin ≥ 2 × ULN AND 

Alkaline phosphatase < 2 × ULN
Study site personnel must report every participant who meets these potential criteria. Typically, 
all 3 analytes will be obtained from the same sample, but they may come from multiple samples 


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taken within a 24-hour period. This requirement applies from the time the participant signs the 
ICF for the study until 30 days after the final protocol-defined study procedure or the last known 
dose of study intervention (if the final visit does not occur).
Investigators must inform the sponsor when the above criteria have been met. A possible Hy’s 
law case must be faxed to the sponsor on an AE of Special Interest Form as soon as possible 
(within 24 hours of learning of the possible Hy’s law case) to the SAE/Pregnancy fax number, 
even if no AE has occurred. The eCRF for potential Hy’s law cases must be completed within 
7 calendar days. Every effort to determine the cause of the liver enzyme abnormalities must be 
made, and close monitoring should be initiated in conjunction with the medical safety physician 
and in accordance with the FDA Guidance for Industry, Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009. The participant should return to the study site and 
be evaluated as soon as possible, preferably within 48 hours from the time the investigator 
becomes aware of the abnormal results. This evaluation should include laboratory tests, detailed 
history, and physical assessment.
8.3.6.2.
ALT or AST Elevations
A treatment-emergent ALT or AST ≥ 3 × ULN is considered an AESI. Any participant with this 
laboratory result after the study intervention was taken must have repeat testing within 48 to 
72 hours to confirm the abnormality. For this repeat testing, the following labs must be drawn: 
hematology and chemistry panels, international normalized ratio (INR), serum acetaminophen
level, urine drugs of abuse screen, and blood alcohol level. An extra blood serology sample must 
be collected and sent to the central laboratory for further diagnostic testing at a later date, if 
needed. In addition, the investigator will perform a complete history and examination to evaluate 
the participant for possible liver disease.
All AESIs must be reported to Allergan within 24 hours of the time the investigator becomes 
aware of the event using the abnormal liver function reporting form and the AE eCRF. All new 
elements of history, physical examination, diagnostic testing results, and other relevant medical 
reports are to be reported for each AESI.
If an ALT or AST elevation ≥ 3 × the ULN is confirmed, close medical follow-up is 
required: For these participants, the following laboratory tests may be performed following 
consultation with the medical personnel at Allergan: anti-hepatitis A IgM, hepatitis B surface 
antigen, anti-hepatitis B core IgM, hepatitis C antibody, hepatitis C quantitative ribonucleic acid 
by polymerase chain reaction, anti-hepatitis E IgM, anti-hepatitis E IgG, Cytomegalovirus IgM 
antibody, and Epstein-Barr Virus IgM antibody. The participant must be followed clinically, and 
further medical evaluation (for other causes of acute hepatic injury) should be done per the 
judgment of the investigator and in conjunction with medical personnel at Allergan. In general, 
the chemistry panel should be repeated 1 to 2 times per week to follow the course of ALT/AST 
elevation.


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Study interventions must be discontinued if any of the following criteria are met:

ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain, or tenderness, fever, rash, or 
eosinophilia (> 5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN

ALT or AST ≥ 3 × ULN and INR > 1.5

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
The participant may be rechallenged with study intervention only after consultation with the 
Allergan Medical Monitor. For participants who are not rechallenged with study intervention, 
they should be discontinued from the study and complete an EOD Visit and Follow up Visit. 
Participants should receive appropriate follow-up as per standard of care.
The investigator must contact the Allergan Medical Monitor to discuss all cases of 
confirmed ALT/AST elevation ≥ 3 × ULN. All ALT/AST elevations must be followed until 
ALT and AST return to < 1.5 × ULN and there is full clinical resolution.
8.3.7.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study drug/device

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration, including wrong site of administration (eg, wrong eye)

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is above the maximum recommended dose according to the 
reference safety information or protocol for the study intervention or comparator as applicable. 
This also takes into account cumulative effects due to overdose. 
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol.
8.4.
Treatment of Overdose
Ubrogepant: Single or multiple doses of up to 400 mg of ubrogepant once daily have been 
administered to participants in completed Phase 1 studies. Ubrogepant was found to be safe and 
well tolerated at the doses studied. There has been no evidence of clinically significant safety 


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findings in routine clinical laboratory tests, ECGs, or vital signs, and no observed drug-related 
liver enzyme elevations at the highest doses studied.
For this study, any dose of ubrogepant greater than 400 mg within a 24-hour time period will be 
considered an overdose.
Single doses of up to 210 mg of Aimovig have been studied in participants; any doses higher 
than 210 mg will be considered as an overdose.
Single doses of up to 600 mg of Emgality have been studied in participants; any doses higher 
than 600 mg will be considered as an overdose.
At present, specific information regarding treatment of overdose for ubrogepant is unavailable. 
In case of an acute overdose, it is recommended that the stomach be emptied and oral gavage 
with activated charcoal be used to help reduce absorption of ubrogepant.
The sponsor does not recommend specific intervention for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical safety physician immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 2 days).
3. Obtain a plasma sample for PK analysis (within 1 day from the date of the last dose of oral 
study intervention and within 5 days of SC injected study intervention) if requested by the 
medical safety physician (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical safety physician based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
8.5.1.
Blood PK Sampling Procedure
Starting on Days 1 and 12, PK blood samples to determine ubrogepant plasma concentrations 
will be collected at 0 hour (predose) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 14, and 24 hours postdose.
These samples may also be used to determine CGRP concentrations.
PK blood samples should be drawn at the nominal times specified above, relative to the dosing 
time, and the actual time of the blood draw must be recorded in the source documents and eCRFs. 
Samples taken more than ± 5 minutes from the nominal time will be noted as protocol deviations, 
and the reason for deviation must be recorded in the source documents and eCRFs. Predose 
samples must be drawn within 30 minutes of the dosing time.
Study center staff will record the atomic clock times of all blood draws for each participant and 
will label Vacutainer and polypropylene tubes with a coded label that corresponds to the 


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participant number and blood draw time. The study center will supply the coded labels. The 
study center will be responsible for Vacutainer, polypropylene tubes, and all other supplies.
Any changes in the timing or addition of timepoints for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the sponsor 
and site study files but will not constitute a protocol amendment. The IRB will be informed of 
any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF.
A qualified phlebotomist will collect each participant’s blood via an indwelling catheter or 
venipuncture from either arm into prechilled 4-mL Vacutainer tubes containing K2EDTA as an 
anticoagulant (Appendix 9). 
Blood Volume Collected per Participant

Total: approximately 194 mL

PK and biomarker blood samples: 104 mL (26 blood samples, 4 mL each)

Screening and end-of-study clinical laboratory analysis: 90 mL
Within 30 minutes from the time of the blood draw, blood samples must be centrifuged at no less 
than 2500g for 10 minutes at approximately 4°C. After centrifugation, the plasma samples will 
be harvested and transferred into 2 prechilled, coded polypropylene tubes. The samples will then 
be flash-frozen in a dry ice and alcohol bath (with isopropyl alcohol, ethanol, isopropanol, or 
methanol) and stored at approximately -20°C.
Study center staff will send plasma samples to the BA laboratory for bioanalysis as directed by 
the Allergan study team (see Appendix 9 for shipping instructions). Before shipment and on the 
day of shipment, the sponsor and BA laboratory will be notified by email as to the time and 
method of shipment.


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8.5.3.
Plasma PK
 Bioanalysis
Concentrations of ubrogepant in plasma 
es will be determined using validated 
and qualified liquid chromatography-tandem mass spectrometry methods, respectively.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers and Other Assessments
Measurement of CGRP concentrations in plasma 
 will be attempted from the 
PK samples at the timepoints specified in Sections 8.5.1 and 8.5.2. These samples will be 
collected, processed, and shipped as described in Sections 8.5.1 and 8.5.2 above.
Biomarker blood samples should be drawn at the nominal times specified above, relative to the 
dosing time, and the actual time of the blood draw must be recorded in the source documents and 
eCRFs. Samples taken more than ± 5 minutes from the nominal time will be noted as protocol 
deviations, and the reason for deviation must be recorded in the source documents and eCRFs. 
Predose samples must be drawn within 30 minutes of the dosing time.
 
 


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8.9.
Health Economics/Medical Resource Utilization and Health 
Economics
Health economics/Medical resource utilization and health economics parameters are not 
evaluated in this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
Not applicable.
9.2.
Sample Size Determination
This is a study to evaluate the safety, tolerability and PK of ubrogepant when co-administered 
with CGRP MABs. Although the sample size is not based on a statistical calculation, inclusion 
of 40 participants (20 participants in each part
 
s considered reasonable to achieve the objectives of the study.
9.3.
Populations for Analyses
The analysis populations will consist of participants as defined below:
Table 9-1
Analysis Populations
Population
Definition
Pharmacokinetic (PK1)
All participants who have evaluable PK parameters of ubrogepant for both 
ubrogepant alone and ubrogepant in combination with erenumab or galcanezumab
Safety
All participants who received ≥ 1 administration of study intervention
9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of PK and safety 
data.
9.4.1.
Pharmacokinetic Analyses
The principal parameters describing the PK of ubrogepant will be derived from plasma 
concentrations using noncompartmental analysis with the software program
 
 Plasma concentrations below the limit of quantification will be treated as 
zero for all PK calculations. The actual sampling times will be used in the calculations of PK 
parameters in this study. 
9.4.1.1.
Pharmacokinetic Parameters
The following PK parameters for ubrogepant will be calculated based on standard 
 
equations: area under the plasma concentration versus time curve from time 0 to 
time t (AUC0-t) and from time 0 to infinity (AUC0-∞), maximum plasma drug concentration 


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(Cmax), time of maximum plasma drug concentration (Tmax), terminal elimination rate constant 
(λz),  terminal elimination half-life (T½), apparent total body clearance of drug from plasma after 
extravascular administration (CL/F), and apparent volume of distribution during the terminal 
phase after extravascular administration (Vz/F).
The AUC0-t will be calculated by using the linear-log trapezoidal rule. 
Estimates of T½ will be calculated based on λz. The λz will be determined by performing a 
regression analysis on the terminal linear phase of semilogarithmic plots of individual 
ubrogepant concentration-time data using a minimum of three concentration-time points in the 
elimination phase excluding Cmax. λz will be considered to be valid if r2 > 0.8.
9.4.1.2.
Statistical Analyses of Pharmacokinetic Data
Details of the statistical analyses of ubrogepant PK data (concentrations and parameters) will be 
described in the PK analysis plan finalized before database lock. 
Descriptive statistics will be provided for all PK parameters of ubrogepant for participants in the 
Pharmacokinetic PK1 population by study part and by study intervention. PK parameters (Cmax, 
AUC0-t, and AUC0-∞) for ubrogepant will be compared using a linear mixed-effects model with 
study intervention as fixed effect and participant as a random effect.
Statistical analysis will be based on log-transformed values for the Cmax and AUC parameters of 
ubrogepant. The 2-sided 90% CI for each study part will be constructed for the ratio of least 
squares geometric means of Cmax, AUC0-t, and AUC0-∞of ubrogepant in combination with CGRP 
MAB on Day 12 versus ubrogepant alone on Day 1. No effect of co-administration with CGRP 
MABs on the PK of ubrogepant will be concluded if the 90% CIs for the ratios of ubrogepant PK 
parameters for test study intervention versus reference study intervention are within the limits of 
80% to 125%.
Descriptive statistics will be reported for the plasma concentrations of ubrogepant by study part 
at each nominal time point for all participants in the Pharmacokinetic PK1 population.
 
 
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, clinical laboratory parameters, vital signs, and 
ECG parameters. Safety analyses will be reported for each study part separately.
9.4.2.1.
Adverse Events
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date (and time, if known) of the first dose of study intervention. However, 
an AE that occurs more than 30 days after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion.


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The number and percentage of participants with TEAEs in each study intervention group will be 
tabulated by system organ class and preferred term and by system organ class, preferred term, 
and severity. The number and percentage of participants with study intervention-related TEAEs 
in each study intervention group will be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Summary tables will be provided for participants with TESAEs and participants with TEAEs
leading to discontinuation if 5 or more participants reported such events. Listings of all AEs, 
SAEs, and AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 3.
An AE will be assigned to the study intervention when it occurred on or after the first dose of the 
study intervention or the subsequent washout period in which the AE occurred, before the first 
dose of the next study intervention. An AE will be assigned to the last study intervention of the 
study intervention sequence if it occurred on or after the first dose of the last study intervention 
administration.
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline, EOD, Follow-up 
visit, and changes from baseline at each assessment will be presented overall for each clinical 
laboratory parameter in each part of the study.
Descriptive statistics for interim clinical laboratory values at predose, postdose, and changes 
from predose at postdose will be presented by study intervention in each part of the study.
The criteria for potentially clinically significant (PCS) laboratory values will be detailed in the 
SAP. The number and percentage of participants who have PCS postbaseline clinical laboratory 
values will be tabulated overall for EOD assessment and Safety Follow-up visit and by study 
intervention for interim assessments. The percentages will be calculated relative to the number of 
participants who have available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of participants mentioned prior with at least 1 PCS 
postbaseline value. A supportive listing of participants with PCS postbaseline values will be 
provided for the safety population. 
9.4.2.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, weight, respiration rate, 
and temperature) at baseline (screening), EOD, and changes from baseline at EOD will be 
presented overall in each study part.
Descriptive statistics for interim vital signs (systolic and diastolic BP, pulse rate) at predose, 
postdose, and changes from predose at postdose will be presented by study intervention in each 
part of the study.


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Vital signs values will be considered to be PCS if they meet both the observed-value criteria and 
the change-from-baseline-value criteria that will be detailed in the SAP. The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated overall 
for EOD and by study intervention for interim assessment. The percentages will be calculated 
relative to the number of participants who have available non-PCS baseline values and at least 
1 postbaseline assessment. The numerator will be the total number of participants mentioned 
prior with at least 1 PCS postbaseline value. A supportive listing of participants with PCS 
postbaseline values will be provided for the safety population.
9.4.2.4.
Electrocardiograms
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, QT interval, 
and QTc) at baseline, EOD, and changes from baseline at EOD will be presented overall in each 
study part. 
Descriptive statistics for interim ECG parameters at predose, postdose, and changes from 
predose at postdose will be presented by study intervention in each part of the study.
The criteria for PCS ECG values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline ECG values will be tabulated overall for EOD and by 
study intervention for interim assessments. The percentages will be calculated relative to the 
number of participants who have available non-PCS baseline values and at least 1 postbaseline 
assessment. The numerator will be the total number of participants mentioned prior with at least 
1 PCS postbaseline value. A supportive listing of participants with PCS postbaseline values will 
be provided for the safety population.
9.5.
Interim Analyses
No interim analysis is planned for this study.
9.5.1.
Data Monitoring Committee
Not applicable.


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Supporting Documentation and Operational Considerations


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


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
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB or 
study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information that would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities.
10.1.5.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 


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
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.1.6.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
10.1.7.
Study and Site Closure
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If a study is prematurely terminated or suspended due to safety issues, the sponsor shall inform 
all investigators and the regulatory authorities of the termination or suspension and the reason(s) 
for the termination or suspension. The IRB is also to be informed promptly and provide the 
reason(s) for the termination or suspension by the sponsor or by the investigator, as specified by 
the applicable regulatory requirements. If a premature termination or suspension occurs, the 
sponsor shall remain responsible for providing resources to fulfill the protocol obligations and 
existing agreements for follow-up of participants enrolled in the study, and each investigator or 
authorized designee shall promptly inform enrolled participants, if applicable.


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10.1.8.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. Authorship will be established 
prior to the writing of the manuscript. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.9.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB according to the IRB’s reporting requirements.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10-1 will be performed by the central laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10-1
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
WBC count with differential
(absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical 
Chemistrya
BUN
Potassium
AST
Total, direct, and 
indirect bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Cholesterol, chloride, 
albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

Drugs of abuseb: Benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, and phencyclidine 

Serum human chorionic gonadotropin (β-hCG) pregnancy test at screening and serum or 
urine test on admission daysb

Serology: anti-HIV type 1 and type 2 antibody, hepatitis B surface antigen (HbsAg), and 
anti-hepatitis C virus

Coagulation: prothrombin time (PT), activated partial thromboplastin time (aPTT), and 
international normalized ratio (INR)

Postmenopausal females: FSH to confirm postmenopausal state.
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are provided in Section 8.3.6. All events of ALT ≥3 × upper limit of normal (ULN) and 
bilirubin  ≥  2 × ULN (> 35% direct bilirubin) or ALT  ≥  3 × ULN and international normalized ratio (INR) 
>1.5, if INR is measured, which may indicate severe liver injury (possible Hy’s law- Section 8.3.6.1), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
b
Urine dipstick kits may be used to conduct drugs-of-abuse screens and pregnancy tests at the study center on 
admission days.
Investigators must document their review of each laboratory safety report.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention.

An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention.
Adverse Event of Special Interest (AESI)
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
sponsor’s study intervention or program, which warrants ongoing monitoring and rapid 
communication by the investigator to the sponsor. Such an event might warrant further 
investigation in order to characterize and understand it. 
The following AESIs have been identified for the study intervention(s) in this protocol: potential 
Hy’s law cases (see Section 8.3.6.1) and AST or ALT elevations (see Section 8.3.6.2).
Serious AESIs should be reported to the sponsor within 24 hours. The AESI form, along with a 
targeted questionnaire, if applicable, should be used for reporting the AESI, even if a serious 
outcome may not apply. 


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Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease); for 
example:
o
The test result is associated with accompanying symptoms, and/or
o
The test result requires additional diagnostic testing or medical/surgical intervention,
and/or
o
The test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy, and/or
o
The test result is considered to be an AE by the investigator or sponsor.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition

New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an AE or 
SAE unless it is an intentional overdose taken with possible suicidal/ self-harming intent. 
Such overdoses should be reported regardless of sequelae.


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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. Merely 
repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
recording as an AE.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen
Definition of SAE
SAEs must meet both the AE criteria described above and the seriousness criteria listed below.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event that hypothetically 
might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 


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significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive intervention in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Recording and Follow-up of AEs and/or SAEs
AE and SAE Recording

When an AE or SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE or SAE information in the participant’s 
medical records, in accordance with the investigator’s normal clinical practice and on the 
appropriate form of the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the sponsor or designee AE or 
SAE eCRF page.

There may be instances when copies of medical records for certain cases are requested by
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission 
to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.


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Assessment of Intensity
MILD
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living.
MODERATE
A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
SEVERE
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention.
An event is defined as serious when it meets at least one of the predefined outcomes as described 
in the definition of an SAE NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE or SAE.

A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed products,
in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.


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Follow-up of AEs and SAEs

See Section 8.3.3.
Reporting of SAEs
SAE Reporting within 24 hours

Email is the preferred method to transmit SAE information. The email address is 
IR-Clinical-SAE@allergan.com.

Facsimile transmission of the SAE information is also acceptable. The fax number is 
+1-714-796-9504 (backup number is +1-714-246-5295). 

In rare circumstances and in the absence of facsimile equipment, notification by telephone
(see the study contact list) is acceptable with a copy of the SAE form, sent by overnight mail 
or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE form within the designated reporting time frames.

Contacts for SAE reporting can be found on the protocol title page.


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10.4.
Appendix 4: Abbreviations
Abbreviation
Definition
λz
terminal elimination rate constant
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
aPTT
activated partial thromboplastin time
AUC
area under the curve
AUC0-∞
area under the plasma concentration-vs-time curve from time 0 to infinity
AUC0-t
area under the plasma concentration-vs-time curve from time 0 to time t
BA
bioanalytical
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CGRP
calcitonin gene-related peptide
CHO
Chinese hamster ovary
CDISC
Clinical Data Interchange Standards Consortium
CIOMS
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences
CL
clearance
CL/F
apparent total body clearance of drug from plasma after extravascular administration
Cmax
maximum plasma drug concentration
Cmin
trough serum concentrations
CRF
case report form
CYP3A4
cytochrome P450
DILI
drug-induced liver injury
CRO
contract research organization
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
EOD
end of dosing
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GC-MS
gas chromatography-mass spectrometry
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin


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Abbreviation
Definition
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council on Harmonisation
ICHD
International Classification of Headache Disorders
ID
identification 
IgG
immunoglobin
IgG2
immunoglobulin G2
IgG4
immunoglobulin G4
IgM
immunoglobulin M
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
MAB
monoclonal antibodies
MCV
mean corpuscular volume
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
NOAEL
no observable adverse effect level
NOEL
no observable effect level
NSAID
nonsteroidal anti-inflammatory drug
PCS
potentially clinically significant
PT
prothrombin time
PK
pharmacokinetic
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)1/3)
RBC
red blood cell
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SNRI
serotonin norepinephrine reuptake inhibitors
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
SSRI
selective serotonin reuptake inhibitors
T½
terminal elimination half-life
Tmax
time of maximum plasma drug concentration
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event


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Abbreviation
Definition
ULN
upper limit of normal
USPI
United States package insert
Vz/F
apparent volume of distribution during the terminal phase after extravascular 
administration
WBC
white blood cell
WOCBP
woman of childbearing potential


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10.5.
Appendix 5: Standard Discontinuation Criteria
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable.  
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Death
The absence of life or state of being dead (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)


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Appendix 6: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).
Parameter Group
Parameter
Value
Trial information
Trial Title
A Phase 1b, Two-Part, Open-Label, Fixed-
Sequence, Safety, Tolerability and Drug-
Drug Interaction Study Between Single Dose 
Erenumab or Galcanezumab and Multiple 
Dose Ubrogepant in Participants with 
Migraine 
Clinical Study Sponsor
Allergan Pharmaceuticals International 
Limited, Clonshaugh Industrial Estate, 
Coolock, Dublin 17, Ireland 
US Agent: Allergan Sales, LLC, 2525 
Dupont Ave, Irvine, California 92612, USA
Trial Phase Classification
Phase 1b
Trial Indication
NA
Trial Indication Type
NA
Trial Type
Drug-Drug interaction
Trial Length
45 ± 3 days
Planned Country of Investigational Sites
United States
Planned Number of Subjects
40
FDA-regulated Device Study
No
FDA-regulated Drug Study
IND #113924
Pediatric Study
No
Subject information
Diagnosis Group
Participants with migraine for at least 1 year
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18
Planned Maximum Age of Subjects
50
Sex of Participants
Both male and female
Stable Disease Minimum Duration
1 year


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Parameter Group
Parameter
Value
Treatments
Investigational Therapy or Treatment
Ubrogepant
Intervention Type
Drug interaction
Pharmacological Class of Investigational
Therapy
CGRP receptor antagonist
Dose per Administration
Study Intervention A: Single oral 100-mg 
dose of ubrogepant tablet on Day 1
Study Intervention B: Single SC injection of 
140-mg erenumab on Day 8
Study Intervention C: Two consecutive SC 
injections of 120-mg galcanezumab on Day 8
Study Intervention D: Repeated once daily 
oral doses of 100-mg ubrogepant on Days 12, 
13, 14, and 15
Dose Units
mg
Dosing Frequency
Single and daily
Route of Administration
Oral (ubrogepant)
Current Therapy or Treatment
Erenumab and galcanezumab
Added on to Existing Treatments
No
Control Type
active
Comparative Treatment Name
Erenumab or galcanezumab, single dose; 
subcutaneous administration
Trial design
Study Type
Interventional
Intervention Model
Parallel
Planned Number of Arms
2 arms per study part, 2 study parts
Trial Is Randomized
Yes
Randomization Quotient
Randomization by study intervention in each 
part (erenumab in Part 1, galcanezumab in 
Part 2)
Trial Blinding Schema
Open-label
Stratification Factor
None
Adaptive Design
No
Study Stop Rules
None


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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Supporting documentation from the physician who performed the surgery is 
needed.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to the following during the protocol-defined timeframe in Section 5.1
(during the intervention period and for at least 93 days after the last dose of study intervention): 

Agree to use a male condom with spermicide when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant
In addition, nonvasectomized male participants must refrain from donating sperm during the 
intervention period and for at least 93 days after the last dose of study intervention.
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during intervention period and for at least 93 days after the last dose of study 
intervention.


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Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use an 
acceptable method of contraception consistently and correctly during the study intervention 
period and for at least 33 days after the last dose of study intervention.
Acceptable birth control methods include:

Male or female condom with or without spermicide 

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device

Hormonal contraceptives

Bilateral tubal ligation

Bilateral tubal occlusion (eg, Essure®)
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double 
barrier methods) are also considered acceptable, birth control methods.
Pregnancy Testing:

WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test at screening and also a negative urine or serum test on Day -1.

Additional pregnancy testing should be performed during the study intervention period on 
Day 7.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female Participants Who Become Pregnant 


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
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate, and the information 
will be forwarded to the sponsor. Generally, follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or genetic abnormalities 
(whether leading to an elective abortion or not) are always considered to be SAEs and will be 
reported as such. Any poststudy pregnancy-related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.


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10.8.
Appendix 8: Study Schedule Supplement
Study procedures are shown in the following sections for participants after enrollment in the 
study. When procedure times coincide, assess the ECG first, measure vital signs, draw PK and 
biomarker blood samples at the scheduled time, collect the PK 
 sample, and 
then serve the meal, unless otherwise specified. With the exception of the fasting requirements 
prior to study intervention dosing, meal times are approximate and may be adjusted by the study 
center as needed, with documentation provided to the sponsor before the start of the study.


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References
Aimovig® USPI. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/aimovig/aimovig_pi_hcp_english.ashx. Accessed 03Jun2019.
Emgality® USPI. https://pi.lilly.com/us/emgality-uspi.pdf. Accessed 03Jun2019.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M. et al.Years lived with 
disability (YLD) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–2196.
Goadsby PJ and Edvinsson L. The Trigeminovascular System and Migraine: Studies 
Characterizing Cerebrovascular and Neuropeptide Changes Seen in Humans and Cats. Ann 
Neurol. 1993;33:48-56.
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. Cephalalgia. International 
Headache Society. 2018;38(1):1-211.
Lipton RB, Bigal ME, Diamond M, Fretag F, Reed ML, and Steward WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
Steiner TJ, Stover LJ, and Birbeck GL. Migraine: the seventh disabler. J Headache Pain. 
2013:14:1.
Stovner LJ and Andree C. Prevalence of headache in Europe: a review for the Eurolight project. 
J Headache Pain. 2010;11:289–299.
US Food and Drug Administration. Guidance for industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009. available at 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf. Accessed 01 February 2018.

SAP_000.pdf: 
NCT04179474 
 
Study ID: 3110‐108‐002 
 
 
Title:  A Phase 1b, Two‐Part, Open‐Label, Fixed‐Sequence, Safety, Tolerability and 
Drug‐Drug Interaction Study Between Single Dose Erenumab or Galcanezumab and Multiple 
Dose Ubrogepant in Participants with Migraine 
 
Statistical Analysis Plan Date: 18Mar2020 


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NON-CLINICAL AND TRANSLATIONAL SCIENCES
CLINICAL PHARMACOLOGY
A Pharmacokinetic Data Analysis Plan (DAP) for Study 3110-108-002 Entitled “A 
Phase 1b, Two-Part, Open-Label, Fixed-Sequence, Safety, Tolerability and
Drug-Drug Interaction Study Between Single Dose Erenumab or Galcanezumab 
and Multiple Dose Ubrogepant in Participants with Migraine”
Document Number
3110-108-002 DAP
Project Name and Number:
Ubrogepant (AGN-241688, MK-1602)
Protocol Number:
3110-108-002
Phase:
1
Clinic Start Date:
26 September 2019
Study Clinical Pharmacologist:
Sponsor:
Version:
Date:
 
Allergan plc
Final
18 March 2020


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Table of Contents
Table of Contents .....................................................................................................2
List of Abbreviations................................................................................................3
Introduction..............................................................................................................4
Objectives ................................................................................................................4
Methods....................................................................................................................4
5.1
Study Design................................................................................................4
5.2
Analysis Populations....................................................................................9
5.3
Sample Size Considerations.........................................................................9
5.4
Software.......................................................................................................9
5.5
Methodology of Measurements ...................................................................9
5.5.1
Pharmacokinetic Methodology........................................................9
5.5.2
Biomarker Methodology................................................................10
5.6
Data Handling and Storage ........................................................................11
Data Analysis .........................................................................................................12
6.1
Pharmacokinetics .......................................................................................12
6.2
Biomarkers.................................................................................................13
Data Summarization and Statistical Analysis ........................................................13
7.1
Data Summarization...................................................................................13
7.2
Statistical Analysis.....................................................................................14
Presentation of Final Results .................................................................................14
Changes to Analysis Plan.......................................................................................15
References..............................................................................................................15


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List of Abbreviations
AUC0-t
area under the plasma concentration versus time curve, from time 0 to 
time t, time of last measurable concentration
AUC0-∞
area under the plasma concentration versus time curve, from time 0 to 
infinity
BLQ
below limit of quantitation
CDISC
Clinical Data Interchange Standards Consortium 
CI
confidence interval
Clast
last measurable concentration
CL/F
apparent total body clearance of drug from plasma after extravascular 
administration
Cmax
maximum plasma drug concentration
CRF
case report form
CSF
cerebrospinal fluid
CSR
clinical study report
DAP
data analysis plan
ECG
electrocardiogram
EOD
end of dosing
λz
terminal phase rate constant
ln
natural logarithm
PK
pharmacokinetic 
PKS
Phoenix Knowledgebase Server
sFTP
secure file transfer protocol
T ½ 
apparent terminal-phase half-life
Tmax
time of maximum plasma drug concentration
Vz/F
apparent volume of distribution during the terminal phase after 
extravascular administration


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Introduction
The data analyses outlined in this document are to support clinical study 3110-108-002. 
In this study, measurements will be made for ubrogepant and CGRP concentrations in 
plasma
. This data analysis plan (DAP) outlines how data 
analyses of these measurements will be conducted. Additional analysis may be 
conducted, if necessary. Safety analyses are described separately in the Statistical 
Analysis Plan.
Objectives
The primary objective of this study is to evaluate the effect of single dose erenumab or 
galcanezumab on the PK of ubrogepant in participants with migraine. The secondary 
objectives of the study are to evaluate secondary pharmacokinetic (PK) parameters of 
ubrogepant following administration of ubrogepant and erenumab, or ubrogepant and 
galcanezumab, and when ubrogepant is administered alone as well as the safety and 
tolerability profiles when ubrogepant and erenumab or ubrogepant and galcanezumab are 
administered in combination and when administered alone in participants with a history 
of 2 or more migraine attacks per month.
 
 
Methods
5.1
Study Design
This study is a Phase 1b, 2-part, multi-center, open-label, fixed-sequence drug interaction 
study in 40 male and female participants who have been diagnosed with migraine for at 
least 1 year and are aged 18 through 50 years. In Part 1, 20 participants will receive a 
single oral dose of 100 mg ubrogepant alone (Study Intervention A) on Day 1, a single 
SC injection of 140 mg erenumab alone (Study Intervention B) on Day 8, followed by 
once daily oral doses of 100 mg ubrogepant on Days 12 through 15 (Study Intervention 
D) under fasted conditions. Similarly, in Part 2, a separate cohort of 20 participants will 
receive a single oral dose of 100 mg ubrogepant alone (Study intervention A) on Day 1, 2 
consecutive SC injections of 120 mg galcanezumab alone (Study intervention C) on Day 
8, followed by once daily oral doses of 100 mg ubrogepant on Days 12 through 15 (Study 
Intervention D) under fasted conditions.


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5.2
Analysis Populations
The analysis populations will consist of participants as defined below:

The safety population includes all participants who receive/take ≥ 1 administration of 
study intervention 

The PK1 population includes all participants who have evaluable plasma PK parameters 
of ubrogepant for both ubrogepant alone and ubrogepant in combination with erenumab 
or galcanezumab
 
 

The PK3 population includes all participants who have at least 1 CGRP concentration 
measurement in plasma
5.3
Sample Size Considerations
This is a study to evaluate the safety, tolerability and PK of ubrogepant when co-
administered with CGRP MABs. Although the sample size is not based on a statistical 
calculation, inclusion of 40 participants (20 participants in each part 
 
 is considered reasonable to achieve the objectives of the 
study.
5.4
Software
Pharmacokinetic analysis, summarization of concentration-time data and PK parameter 
values, and statistical analysis of PK parameter values will be performed using Phoenix®
WinNonlin® (Version 8.0 or newer). Tabulations will be exported into Word 2016 (or 
newer) for formatting. Plotting of concentration-time profiles and scatter graphs (if 
applicable) will be performed using Phoenix WinNonlin (Version 8.0 or newer), Excel 2016 
(or newer) or SigmaPlot 14 (or newer).
5.5
Methodology of Measurements
5.5.1
Pharmacokinetic Methodology
A qualified phlebotomist will collect each participant’s blood via an indwelling catheter or 
venipuncture from either arm into prechilled 4-mL vacutainer tubes containing K2EDTA as 
an anticoagulant. In Part A and Part B, PK blood samples to determine ubrogepant plasma 
concentrations will be collected at 0 hour (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 


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14, and 24 hours postdose on Days 1 and 12. These samples will also be used for the 
determination of CGRP concentrations.
A total of 52 venous blood samples (26 in Part A and 26 in Part B) per participant will be 
collected for PK and biomarker analysis. Within 30 minutes from the time of the blood draw, 
blood samples must be centrifuged at no less than 2500g for 10 minutes at approximately 
4°C. After centrifugation, the plasma samples will be harvested and transferred into 2
prechilled, coded polypropylene tube(s). The samples will then be flash-frozen in a dry ice 
and alcohol bath (with isopropyl alcohol, ethanol, isopropanol, acetone, or methanol) and 
stored at approximately –20°C or colder. 
Total blood volume collected per participant for PK samples is 104 mL (26 blood samples, 4
mL each) in Part A and Part B, respectively. 
Plasma concentrations of ubrogepant will be determined using a validated liquid 
chromatography-tandem mass spectrometry method
 
 
5.5.2
Biomarker Methodology
In Part A and Part B, PK blood samples to determine ubrogepant plasma concentrations will 
be collected at 0 hour (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 14, and 24 hours 
postdose on Days 1 and 12. These samples will also be used for the determination of 
biomarker (CGRP) concentrations.  
 
 
. Plasma and 
 of CGRP will be determined using a qualified 
ELISA assay.


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5.6
Data Handling and Storage
A source data file from
will be transferred to Data Management via secure File 
Transfer Protocol (sFTP). Data Management will use the data for reconciliation against case 
report form (CRF) data and general cleaning.
Data Management shall provide the data file to Statistical Programming who will add the
data to the 
 
software for the calculation of PK parameters. Once the 
 is 
created, Statistical Programming will notify the Allergan Clinical Pharmacology
representative via email and transfer it to the relevant group via a shared study-specific 
repository, in the
.
Pharmacokinetic analysis and statistical analysis of pharmacokinetic data will be performed 
using 
 or 
other appropriate software.
Unless otherwise specified in subsequent sections, these general data handling instructions 
will be followed:

All measured data will be used in analysis initially unless it may be excluded in 
accordance to regulatory guidances. Measured data not used and the reasons for its 
exclusion from the final analysis will be documented in the clinical study report 
(CSR).

The actual sampling times will be used in the calculations of PK parameter values, 
nominal sample times will be used in the calculation of descriptive statistics.

All postdose time points for which no sample is collected will be treated as missing. 
No value will be imputed for these missing values.

Concentration data below the lower limit of quantitation (BLQ) will be defaulted to 
0.00.
A data file (‘.xpt’ or ‘.xls’ format) containing PK parameter values will be generated by the 
Clinical Pharmacology representative and added to the shared study-specific repository for 
retrieval by Statistical Programming and for archival. If necessary, a document defining the 
content and CDISC parameter names will also be provided. Other files necessary to 
reproduce the analysis of PK parameter values, e.g., the WinNonlin Project file, will be 
archived in PKS or another appropriate study-specific repository.


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Data Analysis  
6.1
Pharmacokinetics
The following pharmacokinetic parameters for ubrogepant determined from plasma 
concentration data for each part of the study will be calculated using noncompartmental 
analysis:
AUC0-t
Area under the plasma concentration-time curve from time 0 to t hours post-
dose, calculated by the linear-log trapezoidal rule
AUC0-
Area under the plasma concentration-time curve from time 0 to infinity, as 
calculated by Phoenix WinNonlin (AUC0-). AUC0-∞values will be 
calculated and reported for all participants, however values will only be 
included in the summary statistics and statistical analysis if the % 
extrapolated area (AUC%) is ≤ 20%.
AUC%
Percent of AUC extrapolated from the last measurable concentration to 
infinity: [AUC% = (((AUC0-∞- AUC0-t)/AUC0-∞) *100)]
Cmax
Maximal observed plasma concentration
CL/F
Apparent oral clearance is the oral dose divided by AUC0-∞
λz
Apparent terminal-phase rate constant, determined by performing a 
regression analysis on the terminal linear phase of semi-logarithmic plots of 
individual concentration-time data using a minimum of three concentration-
time points in the elimination phase excluding Cmax. λz will be considered to 
be valid if r2 > 0.80. The values included in the regression analyses will be 
determined by WinNonlin and will be reviewed and revised as necessary by 
the Clinical Pharmacologist.
Tmax
Time corresponding to maximal plasma concentration
T½
Apparent terminal-phase half-life, calculated as 0.693/λz
Vz/F
Apparent volume of distribution during the terminal phase after extravascular 
administration
If the extrapolated AUC is > 20%, the AUC0-∞, CL/F, and Vz/F values will be listed by 
participant but excluded from descriptive statistics.
The PK parameter values will be reported up to at least 2 decimal places.
 


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6.2
Biomarkers
The percent change from baseline in plasma CGRP levels will be calculated using Excel 
2016 (or newer) and will be presented by study intervention and nominal timepoint for each 
part of the study for the PK3 population.
 
 
 
 
 
 
.
Data Summarization and Statistical Analysis
7.1
Data Summarization
PK1 Population
Descriptive statistics (arithmetic mean, standard deviation, relative standard deviation, 
maximum, minimum) will be reported for the plasma concentrations of ubrogepant at each 
nominal time point for all participants in the PK1 Population by study part and by study 
intervention. Descriptive statistics (arithmetic mean, standard deviation, relative standard 
deviation, maximum, median, minimum) will be calculated for ubrogepant PK parameters for 
each study part by study intervention for all participants in the PK1 Population. Additionally, 
the geometric mean will be reported for ubrogepant Cmax, AUC0-t, AUC0-, CL/F, and Vz/F 
parameters.


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PK3 Population
For each part of the study, individual values and descriptive statistics will be reported for the 
plasma CGRP concentrations at each nominal time point for all participants in the PK3 
population. Changes at postdose from baseline by study intervention will be reported for the 
plasma CGRP concentrations at each nominal time point by study part for all participants in 
the PK3 population.
7.2
Statistical Analysis
Plasma PK parameters (Cmax, AUC0-t, and AUC0-∞) for ubrogepant will be compared using a 
linear mixed-effects model with study intervention as fixed effect and participant as a random 
effect in each part of the study for the PK1 population. Statistical analysis will be based on 
log-transformed values for the Cmax and AUC parameters of ubrogepant. For each study part, 
the 2-sided 90% CI will be constructed for the ratio of least squares geometric means of Cmax, 
AUC0-t, and AUC0-∞ of ubrogepant in combination with CGRP MAB (Test, Day 12) versus 
ubrogepant alone (Reference, Day 1). No effect of co-administration with CGRP MABs on 
the PK of ubrogepant will be concluded if the 90% CIs for the ratios of ubrogepant PK 
parameters for test study intervention versus reference study intervention are within the limits 
of 80% to 125%. 
Presentation of Final Results
Presentation of data will be performed using the software described in Section 5.4.

Ratios, coefficient of variation, and confidence intervals will be presented as percentages.

Percentages will be presented to 2 decimal places.

Descriptive statistics presented in summary tables in the study report will be presented to 
a number of decimal places (at least 2) that is consistent with the data from which the 
statistics were derived.

Participants will be identified in the listings using their participant number.


GRD-SSP-T-01-01 NTS Data Analysis Plan Template v2.0
15
All data used, and results will be presented in data tables and listings. 
Changes to Analysis Plan
None
 
References
None


Electronic Signatures