Clinical trial NCT04492020
Conditions: Migraine
Keywords: Migraine
Sponsor: AbbVie
Start date: 2020-08-21; Completion date: 2022-04-19
Enrollment: 518 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine When Administered During the Prodrome

Detailed description:

Arms: arm 1: Participants randomized to Treatment Sequence A will receive placebo to treat their first qualifying prodrome event and ubrogepant 100 mg to treat their second qualifying prodrome event arm 2: Participants randomized to Treatment Sequence B will receive ubrogepant 100 mg to treat their first qualifying prodrome event and placebo to treat their second qualifying prodrome event
Interventions: intervention 1: Ubrogepant 100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: For each qualifying prodrome event, 2 compressed tablets containing 50 mg of ubrogepant will be taken orally when the participant is confident that a headache will follow within 1-6 hours intervention 2: For each qualifying prodrome event, 2 compressed tablets containing placebo will be taken orally when the participant is confident that a headache will follow within 1-6 hours

Protocol documents:
Prot_000.pdf: 


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
2
Table of Contents
Title Page...................................................................................................................................1
List of Tables.............................................................................................................................5
List of Figures............................................................................................................................5
1.
Protocol Summary......................................................................................................6
1.1.
Synopsis.......................................................................................................................6
1.2.
Schema.........................................................................................................................8
1.3.
Schedule of Activities (SoA) ........................................................................................9
2.
Introduction..............................................................................................................14
2.1.
Study Rationale ..........................................................................................................14
2.2.
Background ................................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................................18
3.
Objectives and Endpoints.........................................................................................19
4.
Study Design .............................................................................................................23
4.1.
Overall Design............................................................................................................23
4.2.
Scientific Rationale for Study Design .........................................................................27
4.3.
Justification for Dose..................................................................................................27
4.4.
End of Study Definition..............................................................................................27
5.
Study Population ......................................................................................................28
5.1.
Inclusion Criteria........................................................................................................28
5.2.
Exclusion Criteria.......................................................................................................30
5.3.
Lifestyle Considerations .............................................................................................32
5.3.1.
Meals and Dietary Restrictions ...................................................................................32
5.3.2.
Alcohol.......................................................................................................................32
5.3.3.
Activity ......................................................................................................................33
5.4.
Screen Failures...........................................................................................................33
6.
Study Intervention....................................................................................................34
6.1.
Study Intervention(s) Administered ............................................................................34
6.2.
Preparation/Handling/Storage/Accountability.............................................................34
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................35
6.3.1.
Qualifying Prodrome Event ........................................................................................35
6.3.2.
Breaking the Blind......................................................................................................36
6.4.
Study Intervention Compliance...................................................................................36
6.5.
Concomitant Therapy .................................................................................................37
6.5.1.
Prohibited Interventions and Washout Before Study ...................................................37
6.5.2.
Permitted Interventions...............................................................................................38
6.5.3.
Rescue Medicine ........................................................................................................38
6.5.4.
Prohibited Interventions During the Study ..................................................................39
6.6.
Dose Modification......................................................................................................39
6.7.
Intervention after the End of the Study........................................................................39
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................40


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Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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7.1.
Discontinuation of Study Intervention ........................................................................40
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................41
7.3.
Lost to Follow up .......................................................................................................42
8.
Study Assessments and Procedures .........................................................................43
8.1.
Efficacy Assessments .................................................................................................50
8.2.
Safety Assessments ....................................................................................................50
8.2.1.
Physical Examinations................................................................................................51
8.2.2.
Vital Signs..................................................................................................................51
8.2.3.
Electrocardiograms.....................................................................................................51
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................51
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring.........................................................52
8.3.
Adverse Events and Serious Adverse Events ..............................................................53
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................53
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................53
8.3.3.
Follow-up of AEs and SAEs.......................................................................................54
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................54
8.3.5.
Pregnancy...................................................................................................................54
8.3.6.
Adverse Events of Special Interest..............................................................................55
8.4.
Treatment of Overdose ...............................................................................................55
8.5.
Pharmacokinetics........................................................................................................55
8.6.
Pharmacodynamics.....................................................................................................55
8.7.
Genetics .....................................................................................................................55
8.8.
Biomarkers and Other Assessments ............................................................................56
8.9.
Immunogenicity Assessments.....................................................................................56
8.10.
Health Economics Outcomes Assessments .................................................................56
9.
Statistical Considerations.........................................................................................57
9.1.
Statistical Hypotheses.................................................................................................57
9.2.
Sample Size Determination.........................................................................................57
9.3.
Populations for Analyses ............................................................................................58
9.4.
Statistical Analyses.....................................................................................................58
9.4.1.
Efficacy Analyses.......................................................................................................58
9.4.1.1.
Analysis Endpoints.........................................................................................58
9.4.1.2.
Primary Analyses ...........................................................................................60
9.4.1.3.
Secondary Analyses........................................................................................61
9.4.1.4.
Other Efficacy Analyses .................................................................................62
9.4.2.
Safety Analyses ..........................................................................................................62
9.4.2.1.
Adverse Events...............................................................................................62
9.4.2.2.
Clinical Laboratory Assessments ....................................................................63
9.4.2.3.
Vital Signs......................................................................................................64
9.4.2.4.
Electrocardiograms.........................................................................................64
9.4.2.5.
Suicidality Assessment ...................................................................................64
9.4.2.6.
Potential Hy's Law..........................................................................................64
9.4.3.
PK Analyses...............................................................................................................65
9.4.3.1.
PK Parameters................................................................................................65


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
4
9.4.3.2.
Statistical Analyses of PK Data ......................................................................65
9.4.4.
Other Analyses ...........................................................................................................65
9.4.4.1.
Subgroup Analyses.........................................................................................65
9.5.
Interim Analyses.........................................................................................................65
10.
Supporting Documentation and Operational Considerations ................................66
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................67
10.1.1.
Regulatory and Ethical Considerations........................................................................67
10.1.2.
Financial Disclosure ...................................................................................................67
10.1.3.
Informed Consent Process ..........................................................................................67
10.1.4.
Data Protection...........................................................................................................68
10.1.5.
Committees Structure .................................................................................................68
10.1.6.
Dissemination of Clinical Study Data .........................................................................68
10.1.7.
Data Quality Assurance ..............................................................................................69
10.1.8.
Source Documents......................................................................................................69
10.1.9.
Study and Site Start and Closure.................................................................................70
10.1.10. Publication Policy.......................................................................................................70
10.1.11. Compliance with Protocol...........................................................................................71
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................72
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................73
10.3.1.
Definition of AE.........................................................................................................73
10.3.2.
Definition of SAE.......................................................................................................75
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................76
10.3.4.
Reporting of SAEs......................................................................................................79
10.4.
Appendix 4: Abbreviations .........................................................................................80
10.5.
Appendix 5: Standard Discontinuation Criteria...........................................................82
10.6.
Appendix 6: Study Tabular Summary.........................................................................84
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................85
Definitions: ...............................................................................................................................85
Contraception Guidance:...........................................................................................................85
Pregnancy Testing:....................................................................................................................87
10.8.
Appendix 8: International Classification of Headache Disorders, 
3rd Edition, 2018........................................................................................................89
10.9.
Appendix 9: Examples of Prohibited Medications and Allowed 
Medications (with Restrictions) ................................................................................109
11.
References...............................................................................................................112
12.
Protocol Amendment 2 Summary..........................................................................114


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
5
List of Tables
Table 1-1
Schedule of Activities.......................................................................................9
Table 6-1
Study Interventions.........................................................................................34
Table 6-2
Study Interventions Administered for Each Treatment Sequence ....................35
Table 10-1
Protocol-required Clinical Laboratory Tests....................................................72
Table 10-2
Highly Effective and Acceptable Contraceptive Methods ...............................86
List of Figures
Figure 2-1
Phases of Migraine .........................................................................................15
Figure 4-1
Overall Study Design......................................................................................23
Figure 4-2
Screening Period.............................................................................................26
Figure 4-3
Double-blind Treatment Period.......................................................................26




AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
7
Objectives
Endpoints
3:
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
prevention of the headache phase 
3:
Absence of a headache of any intensity within 
24 hours after taking double-blind study 
intervention during the prodrome 
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, crossover study to compare 
the efficacy, safety, and tolerability of ubrogepant 100 mg to placebo in the acute treatment of 
migraine when administered during the prodrome.
To be eligible for study participation, participants must be 18 to 75 years of age (inclusive) at 
Visit 1, have at least a 1-year history of migraine with or without aura consistent with a diagnosis 
according to the International Classification of Headache Disorders criteria, 3rd edition 
(ICHD-3) (2018), and experience 2 to 8 migraine attacks with moderate to severe headache per 
month by history in each of the 3 months prior to the Screening Visit (Visit 1). Participants must 
be able to identify their prodrome symptom(s) and demonstrate that they reliably experience 
headache after experiencing prodrome symptom(s).  
The study includes a 60-day screening period (between Visit 1 and Visit 2) during which 
participants will demonstrate that they reliably develop headache after experiencing qualifying 
prodrome events. After meeting eligibility criteria, participants will be randomized at Visit 2 and 
dispensed double-blind study intervention to treat their first qualifying prodrome event. Four 
days after taking double-blind study intervention for their first qualifying prodrome event, 
participants will have Visit 3 at which time double-blind study intervention will be provided to 
treat a second qualifying prodrome event. Visit 4 will occur 4 days after taking double-blind 
study intervention for their second qualifying prodrome event. In summary, participants will 
have up to 60 days (double-blind treatment period between Visit 2 and Visit 4) to treat a total of 
2 qualifying prodrome events with study intervention. 
Disclosure Statement: This is a crossover treatment study with 2 sequences that is participant 
and investigator blinded.
Number of Participants: Approximately 516 participants will be randomized (258 participants 
per sequence). Section 9.2 describes the sample size determination.
Intervention Groups and Duration:
Approximately 516 eligible participants will be randomized (1:1) to treatment sequences A or B 
in this crossover study. Participants randomized to Treatment Sequence A will receive placebo to 
treat their first qualifying prodrome event and ubrogepant 100 mg to treat their second qualifying 
prodrome event. For those randomized to Treatment Sequence B, they will receive the reverse: 
ubrogepant 100 mg to treat their first qualifying prodrome event and placebo to treat their second 
qualifying prodrome event.


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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For each qualifying prodrome event, a single dose (2 tablets) of double-blind study intervention 
will be taken at the time the prodrome event qualifies to be treated.
The study duration will be approximately 4 months: 60 days for the screening period, and up to 
60 days for double-blind treatment period.
Data Monitoring Committee: No
1.2.
Schema
Please refer to the figures provided in Section 4.1.


AbbVie  CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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1.3.
Schedule of Activities (SoA)
Table 1-1
Schedule of Activities
Study Period
Screening Period
(60 days)
Double-blind Treatment Period
(up to 60 days)
Visit
Visit 1
Screening
Phone 
Calla
Visit 2
Randomization
First Qualifying 
Prodrome 
Event 
Treatment Day
Visit 3
Posttreatment
Second 
Qualifying 
Prodrome Event 
Treatment Day
Visit 4
Posttreatment/
ETb
Scheduled day/week
30 days 
after 
Visit 1
60 days after 
Visit 1
4 days after 
dose of study
interventionc
≥7 days after 
taking study 
intervention for 
first qualifying 
prodrome event 
4 days after dose 
of study 
interventionc
Scheduling window
± 7 days
+ 7 days
-2/+4 days
-2/+4 days
Informed consent 
X
Access IWRS
X
X
X
X
Demographic information
X
Duplicate Participation 
Identification consent and 
verification
X
Inclusion and exclusion 
criteria
X
X
Medical history (including 
CV disease and risk factors)
X
Conduct comprehensive 
structured interview to 
confirm migraine diagnosis 
and assess 
prodrome symptomsd
X
Prior medicatione
X


AbbVie  CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
10
Study Period
Screening Period
(60 days)
Double-blind Treatment Period
(up to 60 days)
Visit
Visit 1
Screening
Phone 
Calla
Visit 2
Randomization
First Qualifying 
Prodrome 
Event 
Treatment Day
Visit 3
Posttreatment
Second 
Qualifying 
Prodrome Event 
Treatment Day
Visit 4
Posttreatment/
ETb
Scheduled day/week
30 days 
after 
Visit 1
60 days after 
Visit 1
4 days after 
dose of study
interventionc
≥7 days after 
taking study 
intervention for 
first qualifying 
prodrome event 
4 days after dose 
of study 
interventionc
Scheduling window
± 7 days
+ 7 days
-2/+4 days
-2/+4 days
Concomitant medication
X
X
X
X
X
Migraine treatment history 
(eg, prior migraine 
preventative medication
response and historical triptan 
response) 
X
Vital sign measurementsf
X
X
X
X
ECGg
X
X
X
Physical examination
X
X
Clinical laboratory 
determinationsh
X
X
X
Urine pregnancy testi
X
X
X
X
Drug screen
X
C-SSRSj
X
X
X
X
Allodynia (ASC-12) 
questionnaire
X
eDiary training
X
X


AbbVie  CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
11
Study Period
Screening Period
(60 days)
Double-blind Treatment Period
(up to 60 days)
Visit
Visit 1
Screening
Phone 
Calla
Visit 2
Randomization
First Qualifying 
Prodrome 
Event 
Treatment Day
Visit 3
Posttreatment
Second 
Qualifying 
Prodrome Event 
Treatment Day
Visit 4
Posttreatment/
ETb
Scheduled day/week
30 days 
after 
Visit 1
60 days after 
Visit 1
4 days after 
dose of study
interventionc
≥7 days after 
taking study 
intervention for 
first qualifying 
prodrome event 
4 days after dose 
of study 
interventionc
Scheduling window
± 7 days
+ 7 days
-2/+4 days
-2/+4 days
Dispense eDiary to 
participantk
X
Randomization
X
Dispense study intervention; 
review dosing instructions 
X
X
Provide side-effects diary to 
participant 
Xl
Xl
Participant takes study 
intervention
Xm
Xm
Participant completes 
assessments in eDiary
------------------ Xn,o----------------
(during the screening period)
Xo,p
Xo,p
Collect study intervention 
and review compliance
X
X
Review eDiary data and 
compliance
X
Xq
X
X
Collect eDiary from 
participant
X
Review and assess AEs
X


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Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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Study Period
Screening Period
(60 days)
Double-blind Treatment Period
(up to 60 days)
Visit
Visit 1
Screening
Phone 
Calla
Visit 2
Randomization
First Qualifying 
Prodrome 
Event 
Treatment Day
Visit 3
Posttreatment
Second 
Qualifying 
Prodrome Event 
Treatment Day
Visit 4
Posttreatment/
ETb
Scheduled day/week
30 days 
after 
Visit 1
60 days after 
Visit 1
4 days after 
dose of study
interventionc
≥7 days after 
taking study 
intervention for 
first qualifying 
prodrome event 
4 days after dose 
of study 
interventionc
Scheduling window
± 7 days
+ 7 days
-2/+4 days
-2/+4 days
For Participants Who Consent to Participating in Optional PK Substudy
Obtain informed consent for 
optional PK substudy
X
Provide DBS training
X
Participant collects DBS 
sample to ensure 
comprehension of process
Xr
Provide participant with 
supplies for PK sample 
collections
X
X
Participant collects DBS 
samples and records date and 
time in eDiary
Xt
Xt
Collect DBS samples from 
participant
X
X


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Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
13
a
The follow-up check-in phone call is required 30 days after the Screening Visit (Visit 1). The site must check in with the participant via telephone call to review concomitant 
medications, assess any AEs, and review the data collected in the eDiary, including compliance in answering all questions.  
b
Randomized participants who are withdrawn or prematurely discontinue from the study, regardless of whether or not they took study intervention, will complete the 
assessments for the Visit 4/ET Visit.
c
Participants will return to the clinic for Visit 3 after treating their first qualifying prodrome event as soon as possible after completing their assessments (the last assessment 
will be at the 48-hour timepoint). Similarly, participants will return to the clinic for Visit 4 after treating their second qualifying prodrome event as soon as possible after 
completing their assessments. 
d
A detailed comprehensive structured interview will be conducted to confirm diagnosis of migraine and collect migraine history. In addition, collect information such as 
participant's individual prodrome symptom(s) and the reliability of a headache following these symptom(s). Please use the guide/worksheet provided.  
e
Review of prior medications includes all migraine medications taken in the past, including any medications for the prevention of migraine.
f
Collection of vital signs includes sitting and standing systolic and diastolic blood pressure, sitting and standing pulse rate, respiration rate, temperature, height (only at 
Visit 1), and weight (Section 8.2.2).
g
Only one ECG is required for each assessment at each specified visit. If multiple ECGs are completed, all ECGs (readable and unreadable) must be transmitted to the central 
ECG vendor (Section 8.2.3). 
h
Clinical laboratory tests include chemistry, hematology, and urinalysis; coagulation are performed at Visit 1 only (Section 8.2.4).
i
For WOCBP only.
j
At Visit 1, the Screening/baseline assessment of the C-SSRS will be completed. At all other visits, the Since the Last Visit C-SSRS will be completed (Section 8.2.5).
k
After being dispensed an eDiary device, participants should bring the eDiary to all visits and review with study site personnel. For participants who terminate prematurely 
after the eDiary is dispensed, the eDiary should be collected at the next visit. eDiary will need to be collected from those who discontinue the study as well as screen failure 
participants.
l
Participant records side effects (if any) within 48 hours of taking study intervention in side-effects diary (paper diary). Side-effects diary should be collected at the following 
visits and reviewed with the participant per Section 8.
m
Participant will take study intervention to treat 2 qualifying prodrome events during the double-blind treatment period (between Visit 2 and Visit 4) (up to 60 days). It is 
recommended to treat qualifying prodrome events that occur in the morning or early afternoon so that assessments can be collected in the eDiary during waking hours.
n
During the 60-day screening period (between Visit 1 and Visit 2) participants will record their qualifying prodrome events and any headache (if it develops) in the eDiary.
o
HEOR assessments will be completed by the participant in the eDiary during the screening period and double-blind treatment period as outlined in Section 8.10. 
p
During the double-blind treatment period (between Visit 2 and Visit 4) (up to 60 days), the participant will record in the eDiary 2 qualifying prodrome events and any 
headache (if it develops). 
q
Data collected on the eDiary during the screening period must be reviewed to determine if participant meets eligibility to be randomized. See inclusion criteria 2.06 and 2.07 
(Section 5.1).
r
If DBS sample collection unsuccessful during the training, the participant may not participate in the optional PK substudy.
s
Review collection timing, handling, and storage of DBS samples that will be collected at home before providing the participant with the supplies for PK sample collection.
t
Participants will collect 3 DBS samples at home after treating each qualifying prodrome event and record the date and time in their eDiary. Collection times are outlined in 
Section 8.5.


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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2.
Introduction
Ubrogepant (Ubrelvy™) is a CGRP receptor antagonist approved for the acute treatment of 
migraine with or without aura in adults. The recommended dose is 50 mg or 100 mg, taken 
orally, with a second dose available to be taken, at least 2 hours later, if needed. Pivotal studies
demonstrated the efficacy of ubrogepant for the treatment of moderate or severe headache and 
nonheadache migraine symptoms (Dodick 2019; Lipton 2019). 
Optimizing the treatment of acute migraine has been a goal of the medical community for many 
years and one way to do this would be to treat early, ideally before the headache begins. The 
CGRP receptor antagonist mechanism, a mechanism that is intrinsically preventive, suggests that 
ubrogepant may be a good candidate to study when administered during the prodrome, the 
earliest clinical manifestation of the acute migraine attack. This study is designed to examine the 
potential of ubrogepant, when administered during the prodrome, to prevent or attenuate the 
headache phase.
2.1.
Study Rationale
Migraine is a multiphasic, episodic disease of the nervous system with 4 generally recognized 
phases: prodrome/premonitory phase, aura phase, headache phase, and postdrome/postheadache 
phase (Karsan 2018; Figure 2-1). Per the recently updated ICHD-3 (2018), the term prodrome
has replaced premonitory phase as the preferred terminology.


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Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
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Figure 2-1
Phases of Migraine
Source: Karsan 2018
Although demonstration of efficacy for the treatment of a migraine headache of moderate to 
severe intensity is necessary for regulatory approval, this treatment paradigm is not optimal from 
the patient perspective. The FDA guidance acknowledges this and specifically states that drug 
administration as early as practicable during the course of acute migraine is recommended by 
migraine experts and additional trials assessing drug response after treatment of acute migraine 
at the mild pain stage can be conducted and described in the label (FDA Guidance 2018). 
Support for early treatment can also be found in the current treatment guidelines from the 
American Headache Society which recommend treating acute migraine as early as possible after 
the onset of headache pain, as delayed treatment may increase pain severity and disability 
(Marmura 2015). Early treatment of a migraine headache has been shown to improve rates of 
pain freedom and pain relief, and to reduce headache recurrence and rescue medication use when 
compared with treatment of a moderate to severe migraine headache (Dowson 2006).
Although treating a migraine at the beginning of the headache phase has advantages over 
delaying treatment until the headache is moderate to severe, this may still be suboptimal. Ideally, 
treatment should be initiated at the beginning of the migraine, before the headache starts, with 
the goal of either preventing or attenuating the headache phase and reducing nonheadache
migraine symptoms. The possibility of treating a migraine attack with a triptan in the 
preheadache phases (ie, prodrome or aura) has been investigated previously with mixed results 
(Aurora 2009, Bates 1994, Dowson 1996, Luciani 2000, Olesen 2004). It is difficult to draw any 
definitive conclusions regarding the efficacy of triptans when administered during the prodrome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 


AbbVie CONFIDENTIAL
Protocol 3110-304-002 Amendment 2
Ubrogepant
GRD-CLN-T-01-01 v5.0
16
or aura because of significant design limitations with these studies (eg, small sample sizes, 
open-label design, and short timeframe from aura to headache).
The prodrome is the earliest clinical manifestation of a migraine attack. Therefore, treating 
during the prodrome is an attractive therapeutic option. Prodrome symptoms can be broadly 
grouped into 4 categories: cognitive and mood changes (eg, concentration change, difficulties 
reading, memory complaints, confusion, disorientation, and mood changes); homeostatic and 
hormonal changes (eg, food cravings, thirst, polyuria, yawning, altered sleep-wake cycle, and 
changes in alertness); migrainous and sensory sensitivities (mild head discomfort, photophobia, 
phonophobia, osmophobia, neck discomfort, allodynia, and nausea); and cranial autonomic 
symptoms (lacrimation, nasal stuffiness, rhinorrhea, aural fullness, abnormal taste, and sensation 
of throat swelling) (Karsan 2018).
How common are prodrome symptoms? Historically, a handful of small studies have attempted 
to quantify the proportion of patients with migraine who experience a clinically identifiable 
prodrome. These studies reported widely varying estimates from 8% to 87% of the adult 
population with migraine. Recently a large, cross-sectional study was conducted with 
approximately 2700 patients with migraine to specifically address this question. Among patients 
diagnosed with migraine, 77% reported a clinically identifiable prodrome (Laurell 2016). This 
proportion is consistent with feedback that the sponsor received from clinical migraine experts 
during consultation for this study. These experts noted that patients often do not spontaneously 
report prodromal symptoms and physicians often do not ask about these symptoms. However, 
when patients are educated about the prodrome and then asked directly if they experience these 
symptoms, it was estimated that approximately 70% to 80% of patients experience a clinically 
identifiable prodrome and can describe it in detail.
The prodrome represents the beginning of a migraine attack and there is evidence for alterations 
in hypothalamic and brainstem function during the prodrome, which can be demonstrated by 
functional imaging and electrophysiological methods (Karsan 2018). The headache phase is due 
to activation of trigeminal sensory neurons, many of which express CGRP, that innervate pain 
sensitive intracranial structures including the eye, dura, meningeal vessels, and dural venous 
sinuses. During the headache phase, CGRP is released pathologically from these sensory nerves 
in the meninges and from their central projections to the spinal trigeminal nucleus, and this can 
be detected as increased levels of CGRP in the cranial venous outflow (Goadsby 2017,
Messlinger 2018).
The goal of this study is to administer ubrogepant during the prodrome so that it is 'on board' as 
the headache phase pathophysiology emerges, with the ultimate objective of preventing or 
ameliorating the headache phase. The pharmacokinetics of ubrogepant are well suited to do this. 
Ubrogepant is rapidly absorbed and long-acting. Based on an EC90 of 13 ng/mL for the inhibition 
of capsaicin-induced dermal blood flow (a pharmacodynamic measure of CGRP blockade), 
potentially effective concentrations of ubrogepant are achieved within 15 minutes and last 
15 hours after a single dose of ubrogepant 100 mg (AHS poster presentation, Dodick 2019).
Treating a migraine during the prodrome may also be optimal from a practical perspective, as 
prodromal symptoms start well before the headache phase, thus providing patients with ample 
time to identify these symptoms and administer treatment, while also allowing the treatment 
sufficient time to act to reverse the neurobiological mechanisms that cause migraine. Ubrogepant 


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may be particularly well suited for administration during the prodrome for reasons including the 
unique role of CGRP in migraine pathophysiology, favorable tolerability profile, and no defined 
risk for medication overuse.
Tolerability is important when considering drug administration before the headache begins. 
Whereas patients may not be willing to take an acute treatment with significant side effects until 
a headache begins, ubrogepant has been shown to be extremely well tolerated and is a good 
candidate to be used in the preheadache phase. In addition, there is a concern that treatment 
during the prodrome phase may increase overall acute medication use and lead to medication 
overuse headache (Marmura 2015). While medication overuse headache is a recognized 
complication of excessive triptan use, ubrogepant does not share this risk given its mechanism of 
action.
In summary, treating migraine during the prodrome has the potential to transform the current 
treatment paradigm and may prove to be the optimal way to treat migraine in some patients. The 
ability to administer a treatment at the beginning of the migraine and potentially prevent or 
attenuate the headache phase has the potential to vastly improve patient outcomes (ie, symptoms 
and functional impairment of migraine). Ubrogepant's mechanism of action as a CGRP-RA, 
excellent tolerability, and low risk for the negative consequences of medication overuse make it 
particularly well-suited for the acute treatment of migraine when administered during the 
prodrome.
2.2.
Background
Migraine affects 18% of women and 6% of men in the United States with peak prevalence 
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 2007). In the United States, work loss due to migraine is estimated to 
cost ~ $13 billion annually (Hu 1999). Prevalence is similar in Europe, with migraine affecting 
17.6% of women and 8% of men (Stovner 2010). The Global Burden of Disease Survey 
(Vos 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. According to the 2016 Global Burden 
of Disease study, migraine ranked second only to low back pain as the leading cause of years 
lived with disability (GBD 2016).
Migraine is typically characterized by attacks of throbbing, headache of moderate or severe pain 
intensity, associated with nausea, vomiting, and/or sensitivity to light (photophobia) and sound 
(phonophobia). In about 25% of individuals, the headache phase of migraine may be preceded by 
focal cerebral dysfunction (aura). Improving the diagnosis and optimizing treatments for 
migraine have been recognized as critically important to reduce the global burden of migraine 
(Katsarava 2012).
Because there are no biological markers for migraine, diagnosis is based on clinical history, 
exam, and the exclusion of other headache disorders. Physicians apply clinical criteria to guide 
diagnosis and treatment. Episodic migraine is a syndrome diagnosis applied to patients with 
migraine (with or without aura) who have 1 to 14 headache days per month. Chronic migraine is 
an ICHD-3 diagnosis (2018) applied to a subset of patients with ≥15 headache days per month 
(Katsarava 2012, Olesen 2006).


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2.3.
Benefit/Risk Assessment
Ubrogepant is FDA-approved for the acute treatment of migraine with or without aura in adults. 
Efficacy has been demonstrated for the acute treatment of migraine headache of moderate/severe 
intensity as well as for nonheadache migraine symptoms (ie, photophobia, phonophobia, and 
nausea). Ubrogepant has been shown to be safe and well tolerated (Ubrelvy™Package Insert-
Prescribing Information).
This study will assess the efficacy and safety of ubrogepant 100 mg when administered during 
the prodrome phase of migraine. Treatment with ubrogepant during the prodrome is consistent 
with the Indications and Usage section of the FDA Prescribing Information; that is, the 
Prescribing Information allows for treatment of acute migraine with ubrogepant during the 
prodrome. In addition, the dosing schedule of ubrogepant in this study is consistent with the US 
Prescribing Information.
The ability to administer a treatment at the beginning of the migraine and potentially prevent or 
attenuate the headache phase has the potential to vastly improve patient outcomes (ie, symptoms 
and functional impairment of migraine).
Overall, the benefit/risk assessment supports the study of ubrogepant in this clinical trial.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse effects of ubrogepant may be found in the US Prescribing Information and the 
investigator's brochure.


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3.
Objectives and Endpoints
The overall study objective is to evaluate the efficacy, safety, and tolerability of ubrogepant 
100 mg compared to placebo for the acute treatment of migraine when administered during the 
prodrome.
The clinical hypotheses are:
1. Ubrogepant 100 mg is superior to placebo in the acute treatment of migraine when 
administered during the prodrome.
2. Ubrogepant 100 mg is safe and tolerable.
Objectives
Endpoints
Efficacy Objectives and Endpoints
Primary
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
attenuation of the headache phase 
Absence of a headache of moderate/severe 
intensity within 24 hours after taking 
double-blind study intervention during the 
prodrome
Secondary
1:
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
attenuation of the headache phase 
1: 
Absence of a headache of moderate or severe 
intensity within 48 hours after taking double-
blind study intervention during the prodrome
2:
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on ability 
to function normally
2:
Ability to function normally over 24 hours 
after taking double-blind study intervention 
during the prodrome
3:
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
prevention of the headache phase 
3:
Absence of a headache of any intensity within 
24 hours after taking double-blind study 
intervention during the prodrome 


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Objectives
Endpoints
Additional Objectives and Endpoints
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
attenuation of the headache phase

Absence of headache of any intensity 
by timepoint (excluding the endpoints 
that are already captured as primary 
and secondary endpoints)

Absence of moderate/severe headache 
by timepoint (excluding the endpoints 
that are already captured as primary 
and secondary endpoints)

Absence of severe headache by 
timepoint

Time to development of headache of 
any intensity within 48 hours after 
taking double-blind study intervention 
during the prodrome (Kaplan-Meier 
analysis)

Time to development of headache of 
moderate/severe intensity within 48 
hours after taking double-blind study 
intervention during the prodrome 
(Kaplan-Meier analysis)

Time to development of headache of 
severe intensity within 48 hours after 
taking double-blind study intervention 
during the prodrome (Kaplan-Meier 
analysis)


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Objectives
Endpoints
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
prodrome symptoms, nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, and dizziness), and aura
For each of the 5 most common individual 
prodrome symptoms:

Absence of any intensity at each 
timepoint 

Absence of moderate/severe intensity 
at each timepoint

Absence of severe intensity at each 
timepoint

Time to absence of any intensity
After a headache of any intensity is reported:

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of any intensity at 
each timepoint 

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of moderate/severe 
intensity at each timepoint

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of severe intensity at 
each timepoint
Other:

Absence of aura at each timepoint 
To evaluate the effect of a single dose of 
ubrogepant (100mg) versus placebo on use of 
rescue medication

Rescue medication use within 24 and 
48 hours after taking double-blind
study intervention

Time to rescue medication use within 
48 hours after taking double-blind
study intervention (Kaplan-Meier 
analysis)


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Objectives
Endpoints
Additional HEOR Objectives and Endpoints
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
satisfaction with study medication

Satisfaction with study medication at 
8 and 24 hours after taking double-
blind study intervention during the 
prodrome
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on 
Activity Limitation 

Activity Limitation over 24 hours after 
taking double-blind study intervention 
during the prodrome
Safety Objective and Endpoint
To compare the safety of ubrogepant versus 
placebo in participants with migraine

AEs, clinical laboratory tests, ECGs, 
vital signs, and the C-SSRS


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4.
Study Design
4.1.
Overall Design
This multicenter, randomized, double-blind, placebo-controlled, crossover study will enroll 
approximately 516 participants from approximately 75 centers in the United States.
The study includes a 60-day screening period during which participants will demonstrate that 
they reliably develop headache after experiencing qualifying prodrome events. After meeting 
eligibility criteria, randomized participants will treat 2 qualifying prodrome events with study 
intervention during the double-blind treatment period (between Visit 2 and Visit 4) (up to 
60 days), separated by a clinic visit (Visit 3) to ensure a minimum 7-day washout period. 
A posttreatment visit (Visit 4) will follow 4 days after the last treatment is taken.
To be eligible for study participation, participants must be 18 to 75 years of age (inclusive) at 
Visit 1, have at least a 1-year history of migraine with or without aura consistent with a diagnosis 
according to the ICHD-3 (2018; Section 10.8), and experience 2 to 8 migraine attacks with 
moderate to severe headache per month by history in each of the 3 months prior to screening. 
The overall study design is displayed below in Figure 4-1.
Figure 4-1
Overall Study Design
PBO = placebo; UBR = ubrogepant
Screening Visit (Visit 1)
At the Screening Visit (Visit 1), as part of the eligibility assessment, the investigator will conduct 
a detailed medical history which includes a comprehensive structured interview with the 
potential participant inquiring about their migraines, including prodrome symptoms and 
headache. This interview will confirm, per the investigator's judgment and based on participant 
history, that the participant can identify and routinely experiences prodrome symptom(s) that are 
reliably followed by headache (of any intensity) within 1 to 6 hours after experiencing the 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
        
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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prodrome symptoms (at least 3 out of 4 times, or 75% of the time). In addition, a description of 
the course of the participant's typical migraine will be documented, including a list of specific 
prodrome symptom(s) that the participant experiences and the usual timeframe from onset of 
prodrome symptom(s) to onset of the headache.
Screening Period
Participants who meet all eligibility criteria at the Screening Visit (Visit 1) will be asked to 
objectively demonstrate that their prodrome symptoms are reliably followed by headache. An 
eDiary will be dispensed and the participant asked to record all qualifying prodrome events 
during the full 60 day screening period (between Visit 1 and Visit 2). For both the screening and 
double-blind treatment periods, a qualifying prodrome event is defined as an event in which the 
participant experiences a clinically identifiable prodrome with ALL the following conditions 
met:
Definition of a Qualifying Prodrome Event

Headache is not currently present 

The participant has not had a headache in the previous 48 hours

Treatments for acute headache (eg, ibuprofen, acetaminophen, triptan, Excedrin®) have 
not been taken in the previous 48 hours 

The participant is confident that a headache will inevitably follow within 1 to 6 hours after 
experiencing the qualifying prodrome event

The participant is able to complete the eDiary for the next 8 hours
A follow-up check-in phone call is required 30 days after the Screening Visit (Visit 1). The site 
should check in with the participant via telephone call to review the qualifying prodrome events 
and headaches (if any) reported on their eDiary, review any changes to concomitant medications 
or AEs. 
Criteria for Randomization
Participants must record 3 to 16 qualifying prodrome events during the screening period.
Each prodrome event will be categorized as positive or negative depending on whether or not a 
headache of any severity (mild, moderate, severe) is reported within 1 to 6 hours after the start of 
the qualifying prodrome event.
For participants who record only 3 qualifying prodrome events, all events must be categorized as 
positive to be eligible for randomization (ie, 3 out of 3 positive events).
For participants who record 4 to 16 qualifying prodrome events, at least 75% of events must be 
categorized as positive to be eligible for randomization.
Randomization Visit (Visit 2)
At Visit 2, participants who meet all eligibility criteria will be randomized (1:1) to 1 of 2 
treatment sequences, A or B, in this crossover study. A full list of inclusion criteria can be found 
in Section 5.1 and exclusion criteria can be found in Section 5.2.


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Double-Blind Treatment Period
During the double-blind treatment period (between Visit 2 and Visit 4), participants will have up 
to 60 days to treat 2 qualifying prodrome events, as defined above, with study intervention. 
Participants should treat as soon as they are confident that a headache will inevitably follow their 
prodrome symptoms. 
eDiary Assessments
During both the screening and double-blind treatment periods, the participant will report 
information in the eDiary at the time of each qualifying prodrome event:

Confirmation that the participant is experiencing a qualifying prodrome event

Identification and intensity of individually specific prodrome symptom(s)

Headache pain and intensity (if it occurs) 

Nonheadache symptoms (photophobia, phonophobia, nausea, dizziness) including 
intensity (mild, moderate, severe)

Presence or absence of aura

Health Outcomes assessments
Participants will be asked to complete their eDiary at prespecified timepoints (1, 2, 3, 4, 6, 8, 24, 
and 48 hours) and on an event-driven basis (ie, when a headache occurs). In addition, in the 
double-blind treatment period, the date and time of when double-blind study intervention is taken 
will be captured, as well as rescue medication use.
Visit Schedule
In addition to the Screening Visit (Visit 1) and Randomization Visit (Visit 2) described above, 
participants will return to the clinic for the Posttreatment Visit (Visit 3) after the first qualifying 
prodrome event is treated, 4 days after taking double-blind study intervention. The first and 
second qualifying prodrome events must be 2 separate and distinct events that are at least 7 days 
apart. Participants unable to treat 2 qualifying prodrome events during the double-blind treatment 
period will be discontinued from the study.
Participants will return to the clinic for Visit 4 after the second qualifying prodrome event is 
treated, 4 days after taking double-blind study intervention. Visit 4 will be conducted for 
randomized participants who prematurely discontinue during the double-blind treatment period, 
regardless of whether or not they took study intervention. For additional information on study 
visits and procedures, please see the SoA (Section 1.3). The sequence of events during the 
screening and double-blind treatment periods are displayed below in Figure 4-2.


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Figure 4-2
Screening Period
Figure 4-3
Double-blind Treatment Period
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Efficacy, Safety, and Pharmacokinetic Assessments
The key efficacy assessments to be collected are ratings of prodrome symptom(s), headache, and 
nonheadache symptoms. A list and description of each efficacy assessment is in Section 8.1 and 
the efficacy analyses are presented in Section 9.4.1. The planned safety assessments are AEs, 
clinical laboratory tests, ECGs, vital signs, physical examination, and the C-SSRS. Details 
regarding safety assessments are described in Section 8.2 and the safety analyses are presented in 
Section 9.4.2.
A separate optional PK substudy will be conducted on a subset of participants who consent to 
participate in the optional PK substudy. These participants will undergo serial PK sample 
collection at home. PK samples will be collected using DBS methodology after taking the dose 
of double-blind study intervention (for details, please see Section 8.5).
4.2.
Scientific Rationale for Study Design
The double-blind study design was adopted to minimize systematic bias resulting from the 
investigator, participant, and sponsor knowing the treatment being administered. Randomization 
is expected to minimize participant selection bias and increase baseline comparability among the 
treatment groups. Placebo was included as an ineffective agent against which to compare the 
response to ubrogepant. A crossover design was used to increase the efficiency for treatment 
comparisons. 
The study was designed with a rigorous screening period to ensure that the appropriate 
participants who routinely have headaches after experiencing prodrome symptoms are selected to 
participate in the study. This select group of participants are required to test the hypothesis that 
ubrogepant is effective given at the beginning of the migraine before the participant develops a 
headache.
Treatment with the first dose is to test the efficacy of ubrogepant versus placebo in disrupting the 
usual course of the migraine and therefore attenuating the development of a headache. This 
design was implemented to reflect how ubrogepant could be utilized in practice.
4.3.
Justification for Dose
This study will test 1 dose of ubrogepant versus placebo, with participants themselves also being 
the control, which was selected based on the safety and efficacy results in Phase 2b and Phase 3 
studies. The highest tested dose in the Phase 3 pivotal studies, 100 mg, was selected because it 
was demonstrated to be the most efficacious dose and was well tolerated and without safety 
concerns. 
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has not been terminated early 
and has completed the study, including treating 2 qualifying prodrome events as well as the last 
visit or the last scheduled procedure shown in the SoA (Section 1.3).
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study.


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5.
Study Population
Approximately 516 participants will be randomized (258 participants per sequence) from 
approximately 75 centers in the United States. 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 and Sex
1.01
Male or female participants ages 18 to 75 years, inclusive, at Visit 1
2.
Type of Participant and Migraine Characteristics
2.01
At least a 1-year history of migraine with or without aura consistent with a 
diagnosis according to the ICHD-3 (2018; Section 10.8)
2.02
Migraine onset before age 50 years
2.03
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.
2.04
History of 2 to 8 migraine attacks per month with moderate to severe headache in 
each of the 3 months prior to the Screening Visit (Visit 1)
2.05
By history and per investigator's judgment, the participant routinely experiences 
prodrome symptom(s) that are reliably followed (≥75% of the time) by a 
headache of any intensity within 1 to 6 hours after experiencing the prodrome 
symptoms.
2.06
Participant records ≥3 to ≤16 qualifying prodrome events in the eDiary during 
the screening period (Visit 1 to Visit 2).
2.07
Based on data collected during the screening period, demonstrated that the 
participant reliably experiences headache pain of any intensity within 1 to 6 hours 
following a qualifying prodrome event recorded in the eDiary. Participant may be 
eligible for randomization at Visit 2 if: 

3 qualifying prodrome events are recorded and headache develops within 
1 to 6 hours following all three qualifying prodrome events (ie, headache 
develops after experiencing 100% of qualifying prodrome events).

4 to 16 qualifying prodrome events are recorded and headache develops 
within 1 to 6 hours after at least 75% of qualifying prodrome events 
(eg, participant records 4 qualifying prodrome events in the eDiary and 
headache develops in 3 out of 4 qualifying prodrome events).


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2.08
Current or past use of at least one prescription medication for the acute treatment 
of migraine (eg, triptan, opioid, prescription NSAID, barbiturate combination) or a 
prescription medication for preventive medication for migraine (eg, topiramate, 
amitriptyline, onabotuliumtoxin A)
3.
Weight and Body Mass Index
3.01
BMI ≤ 40 kg/m2 at Visit 1 and Visit 2
4.
Contraceptives
4.01
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period.
A female participant is eligible to participate if she is not pregnant (ie, has a 
negative urine pregnancy result at the Screening Visit [Visit 1] and Randomization 
Visit [Visit 2]; see Section 1.3), is not breastfeeding, and fulfills at least one of the 
following conditions:

Not a woman of child bearing potential as defined in Section 10.7.

OR A woman of child bearing potential who agrees to follow the 
contraceptive guidance in Section 10.7 for the duration of the study
4.02
Male participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period. A male participant must agree 
to use contraception as detailed in Section 10.7 of this protocol for the duration of 
the study and refrain from donating sperm during the course of the study. 
5.
Informed Consent
5.01
Written informed consent and participant privacy information 
(eg, Written Authorization for Use and Release of Health and Research Study 
Information) obtained from the participant prior to initiation of any 
study-specific procedures.
6.
Other
6.01
Be able to read, understand and complete the study questionnaires and eDiary.


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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Any clinically significant hematologic, endocrine, pulmonary, renal, hepatic, 
gastrointestinal, or neurologic disease.

If there is a history of such disease, but the condition has been stable for more 
than 1 year prior to Visit 1 and is judged by the investigator as not likely to 
interfere with the participant's participation in the study, the participant may be 
included.
o
Participants on dialysis for renal failure are excluded.
1.02
In the opinion of the investigator, other confounding pain syndromes, confounding 
psychiatric conditions, dementia, epilepsy or other significant neurological disorders 
other than migraine
1.03
History of malignancy in the 5 years prior to Visit 1, except for adequately treated 
basal cell or squamous cell skin cancer, or in situ cervical cancer
1.04
History of any prior gastrointestinal conditions (eg, diarrhea syndromes, inflammatory 
bowel disease) that, per investigator judgment, may affect the absorption or 
metabolism of the study intervention; participants with prior gastric bariatric 
interventions (eg, Lap Band) which have been reversed are not excluded
1.05
Clinically significant cardiovascular or cerebrovascular disease per the investigator's 
opinion including, but not limited to:

Clinically significant ischemic heart disease (eg, unstable angina pectoris)

Clinically significant cardiac rhythm or conduction abnormalities (eg, atrial 
fibrillation, second- or third-degree heart block) or risk factors for Torsade de 
Pointes (eg, heart failure, hypokalemia, bradycardia)

Myocardial infarction, transient ischemic attack, or stroke within 6 months 
prior to Visit 1

Heart failure defined as New York Heart Association functional classification 
system, Class III or IV
1.06
Significant risk of self-harm, based on clinical interview and responses on the C-SSRS, 
or of harm to others in the opinion of the investigator; participants must be excluded if 
they report suicidal ideation with intent, with or without a plan, (ie, Type 4 or 5 on the 
C-SSRS) in the past 6 months or report suicidal behavior in the last 6 months prior to 
Visit 1 or Visit 2 assessments (see Section 9.4.2.5 for details)
1.07
At Visit 1, current alcohol or drug abuse or dependence per investigator's judgment


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2.
Migraine Characteristics
2.01
A current diagnosis of chronic migraine as defined by ICHD-3 (2018; Section 10.8), or 
a history of 15 or more headache days per month on average in the 6 months prior to 
Visit 1 in the investigator's judgment. A headache day is defined as a day in which 
there was any occurrence of a headache of a minimum duration of 2 hours or a 
headache of any duration for which acute medication was taken.

Participants with a diagnosis of chronic migraine who, in the opinion of the 
investigator, currently have fewer than 15 headache days per month due to 
concomitant prophylactic treatment are allowed in the study.
2.02
Participants who overuse medication for migraine defined as use of opioids or 
barbiturates > 2 days/month, triptans or ergots ≥ 10 days/month, or simple analgesics 
(eg, aspirin, NSAIDs, acetaminophen) ≥ 15 days/month in the 3 months prior to Visit 1 
per investigator's judgment
2.03
Difficulty distinguishing migraine headache from tension-type or other headaches
2.04
Has a history of migraine aura with diplopia or impairment of level of consciousness, 
hemiplegic migraine, or retinal migraine as defined by ICHD-3 (2018; Section 10.8).
2.05
Has a current diagnosis of new persistent daily headache, trigeminal autonomic 
cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3 
(2018; Section 10.8).
2.06
Required hospital treatment of a migraine attack 3 or more times in the 6 months prior 
to Visit 1.
3.
Prior/Concomitant Therapy
3.01
Requirement for any medication (eg, barbiturates) or diet (eg, grapefruit juice) that is 
on the list of prohibited concomitant medications (see Section 6.5.1 and Section 5.3.1) 
that cannot be discontinued or switched to an allowable, alternative medication before 
entering the double-blind treatment portion of this study.

Certain medications require stable dosing throughout the study; for these 
medications and requirements, please refer to Section 6.5.2.
Examples of prohibited medications and allowed medications with restrictions are 
listed in Section 10.9. 
3.02
Has a chronic nonheadache pain condition requiring daily pain medication (with the 
exception of pregabalin).
3.03
Previous exposure to:

Injectable monoclonal antibodies blocking the CGRP pathway within the last 
3 months (eg, Aimovig™, Emgality™, Ajovy®)
3.04
History of hypersensitivity or clinically significant adverse reaction to a CGRP-RA
4.
Prior/Concurrent Clinical Study Experience
4.01
Currently participating or has participated in a study with an investigational compound 
or device within 30 days prior to Visit 1 (this includes studies using marketed 
compounds or devices).


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5.
Diagnostic Assessments
5.01
Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or sitting 
diastolic blood pressure > 100 mm Hg at Visits 1 or 2. Vital sign measurements 
that exceed these limits may be repeated only once.
5.02
Abnormal ECG results thought to be potentially clinically significant according to the 
investigator or designee 
5.03
Clinically significant abnormalities (as determined by the investigator) in clinical 
laboratory safety test(s) or physical examination at Visit 1
5.04
Clinical laboratory results at Visit 1 (or before randomization) with the following:

ALT or AST > 1.5 × ULN OR

Total bilirubin > 1.5 mg/dL (except for participants with a diagnosis of 
Gilbert's disease) OR

Serum albumin < 2.8 g/dL
5.05
Positive result on the urine drug screen at Visit 1 unless explained by concomitant 
medication use (eg, opioids prescribed for migraine pain) 

A positive urine drug screen for cannabinoids will exclude the participant from 
the study however one repeat urine drug screen will be allowed.
5.06
History of acute hepatitis within 6 months of the Screening Visit (Visit 1) or chronic 
hepatitis (including nonalcoholic steatohepatitis). Participants with severe hepatic 
impairment (ie, Child-Pugh C) are excluded from participation. 
6.
Other
6.01
Employed by or is an immediate family member (parents, spouses, siblings, or 
children) of one of the investigators, study staff, or the sponsor.
6.02
Any medical or other reasons (eg, unlikely to adhere to the study procedures, keep 
appointments, or is planning to relocate during the study) that, in the investigator's 
opinion, might indicate that the participant is unsuitable for the study
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
Participants must refrain from consuming grapefruit or grapefruit juice during the double-blind 
treatment period of the study (Visit 2 through Visit 4). 
5.3.2.
Alcohol
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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5.3.3.
Activity
Maintaining a consistent lifestyle when participating in a clinical study is vital. Participants must 
refrain from implementing drastic changes in their diet or starting a new diet during the study. 
Participants should not engage in intense exercise (eg, running a marathon) or start an intense 
exercise regimen during the course of the study.
After taking double-blind study intervention, participants should refrain from sleeping for at least 
8 hours to ensure the eDiary assessments are completed.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes indicating screen failure as reason for 
ending the study, demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened with permission from the sponsor. A participant who is rescreened will be screened 
again in the IWRS and given a new participant number.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s) or placebo intended to be 
administered to a study participant according to the study protocol.
6.1.
Study Intervention(s) Administered
Table 6-1
Study Interventions
Study Intervention Name
Ubrogepant 100 mg
Placebo
Dose Formulation
Compressed tablets containing 
50 mg of ubrogepant
Compressed tablets containing 
placebo
Route of Administration 
oral
oral
Dosing Instructions
For each qualifying prodrome event, 
2 tablets will be taken as soon as the 
participant is confident that a headache 
will inevitably follow within 1 to 6 hours. 
Study intervention can be taken with or 
without food.
For each qualifying prodrome event, 
2 tablets will be taken as soon as the 
participant is confident that a headache 
will inevitably follow within 1 to 6 hours. 
Study intervention can be taken with or 
without food.
Packaging and Labeling
Study intervention will be provided in 
blister cards. Each blister card will 
contain a total of 2 tablets to treat 
1 qualifying prodrome event.
The cards will be labeled as required per 
country requirement.
Study intervention will be provided in 
blister cards. Each blister card will 
contain a total of 2 tablets to treat 
1 qualifying prodrome event.
The cards will be labeled as required per 
country requirement.
Manufacturer
Allergan
Allergan
Immediately before dispensing the double-blind study intervention, the investigator (or 
appropriately trained designee) will write the participant's identification number and the date on 
the label.
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 randomized in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual or other specified location.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
Prior to initiation of study treatment, each participant who provides informed consent will be 
assigned a participant number that will serve as the participant identification number on all study 
documents.
An automated IWRS will be used to manage the randomization and assignment to study 
intervention. Before the study is initiated, log-in information and directions for the IWRS will be 
provided to each site. Study intervention will be dispensed at Visit 2 (one blister card) and 
Visit 3 (one blister card) as summarized in the SoA (Section 1.3).
At the time of randomization (Visit 2), eligible participants will be randomly assigned either 
Treatment Sequence A or B in a 1:1 ratio in this crossover study. All participants will be 
instructed to take 2 tablets for each dose of study intervention regardless of the treatment 
sequence they are assigned. As this is a crossover study, the study intervention for the first and 
second qualifying prodrome event will be the reverse for the two treatment sequences. Table 6-2
below outlines the study intervention administered for each treatment sequence.
Table 6-2
Study Interventions Administered for Each Treatment Sequence
Treatment Sequence
First Qualifying Prodrome Event
Second Qualifying Prodrome Event
Single Dose (2 tablets)
Single Dose (2 tablets)
Treatment Sequence A
placebo/
placebo
ubrogepant 50 mg/
ubrogepant 50 mg
Treatment Sequence B
ubrogepant 50 mg/
ubrogepant 50 mg
placebo/
placebo
The sponsor's biostatistics (randomization programmer) will prepare the randomization codes. 
Each blister card containing study intervention will be labeled with medication kit numbers. 
IWRS will provide the site with the specific medication kit number(s) for each randomized 
participant at the time of randomization (Visit 2) and at Visit 3. Sites will dispense study 
intervention according to the IWRS instructions at these 2 visits. Sites will receive the IWRS 
confirmation notifications for each transaction. All notifications are to be maintained with the 
study source documents.
All study interventions will be provided in identical blister cards to maintain masking of the 
study. Tablets of ubrogepant 50 mg and placebo will be identical in appearance.
Once a randomization number has been assigned, it must not be reassigned. Withdrawn study 
participants will not be replaced. Returned study intervention should not be redispensed to the 
participants.
6.3.1.
Qualifying Prodrome Event
For both the screening and double-blind treatment periods, a qualifying prodrome event is 
defined as an event in which the participant experiences a clinically identifiable prodrome with 
all the following conditions met:


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
Headache is not currently present 

The participant has not had a headache in the previous 48 hours

Treatments for acute headache (eg, ibuprofen, acetaminophen, triptan, Excedrin®) have 
not been taken in the previous 48 hours

The participant is confident that a headache will inevitably follow within 1 to 6 hours after 
experiencing the qualifying prodrome event

The participant is able to complete the eDiary for the next 8 hours
Participants who meet all of the initial study entry criteria at the Screening Visit (Visit 1) will be 
dispensed an eDiary to record their qualifying prodrome events within 60 days. At Visit 2, if they 
qualify, participants will be randomized, provided with double-blind study intervention to treat 
the first qualifying prodrome event, and redispensed the eDiary to record the first qualifying 
prodrome event. At Visit 3, participants will be provided with double-blind study intervention to 
treat the second qualifying prodrome event and redispensed the eDiary to record the second 
qualifying prodrome event.
For the double-blind treatment period, it is recommended to treat qualifying prodrome events 
that occur in the morning or early afternoon so that assessments can be collected in the eDiary 
during waking hours. 
Study participants will have up to 60 days to treat 2 qualifying prodrome events at home with 
study intervention during the double-blind treatment period (between Visit 2 and Visit 4). 
Participants unable to treat 2 qualifying prodrome events within this time will be discontinued 
from the study.
Please refer to Section 6.5.3 for details regarding rescue medication use.
6.3.2.
Breaking the Blind
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant's study 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a participant's 
study intervention assignment unless this could delay emergency treatment of the participant. If a 
participant's study intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation.
6.4.
Study Intervention Compliance
At the clinic visits, study intervention compliance will be closely monitored by counting the 
number of tablets dispensed and returned. Before dispensing new study intervention at the study 
visits, study center personnel will make every effort to collect all unused study intervention and 
empty blister cards. Participants will be instructed to record in their eDiaries the date and time 
study intervention was taken.


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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, and 
herbal supplements) that the participant is receiving at the time of enrollment or takes during the 
study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
At every visit and phone call, study center staff will question each participant specifically on the 
use of concomitant medications. 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 Study
The following classes of medications below are not allowed to be taken during the double-blind 
treatment period only, between Visit 2 and Visit 4/ET. Participants taking these medications at 
the Screening Visit (Visit 1) will need to discontinue them prior to randomization at Visit 2. 
Participants who cannot or should not be taken off these medications should not be enrolled. If a 
participant requires concomitant treatment with these medications at any time during the study, 
the participant must be discontinued. An extended list of examples of prohibited medications are 
displayed in Section 10.9.

Strong/moderate CYP3A4 inducers, including but not limited to: barbiturates 
(eg, phenobarbital and primidone), systemic (oral/intravenous) glucocorticoids 
(eg, methylprednisolone, prednisolone, prednisone), nevirapine, efavirenz, 
pioglitazone, carbamazepine, phenytoin, rifampin, rifabutin, and St. John's wort

Strong/moderate CYP3A4 inhibitors, including but not limited to: systemic 
(oral/intravenous) itraconazole, ketoconazole, fluconazole; erythromycin, clarithromycin, 
telithromycin; diltiazem, verapamil; aprepitant; cyclosporine (oral/intravenous only); 
nefazodone; cimetidine; quinine; and HIV protease inhibitors.

Inhibitors of the BCRP transporter (eg, rifampicin)
The following medications are prohibited for the entire duration of the study (Visit 1 through 
Visit 4). 

Oral gepants (eg, Ubrelvy™[ubrogepant], Nurtec™[rimegepant])

All injectable migraine prophylactic medications like botulinum toxin (Botox®) and 
injectable monoclonal antibodies blocking the CGRP pathway (eg, Aimovig™, Emgality™, 
Ajovy®) 

Cannabinoids (ie, marijuana), CBD oil (systemically used)


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The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, the sponsor should be notified before 
the prohibited medication/treatment 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 medication/intervention is in question, please 
contact the sponsor.
Medications which are not specifically prohibited are allowed; however, there may be 
clarifications and restrictions with certain medications.
The following medications are allowed during the study, but are prohibited within 48 hours prior 
to taking study intervention:

any triptan or ditan

any ergot derivative

any opioid

any NSAID

any other form of analgesic (including acetaminophen and Excedrin®)

any antiemetic agent
In regard to the permissibility of these medications after taking study intervention, please refer to 
the following section below on rescue medication use.
Examples of allowed but restricted medications listed above are displayed in Section 10.9.
Aspirin up to 325 mg/day is allowed for cardiac prophylaxis. Daily use of gabapentin/pregabalin 
is allowed.
SSRI or SNRI use will be permitted provided that treatment is stable at the Screening Visit 
(Visit 1) and continues without change in dose/frequency throughout the study. SSRIs and 
SNRIs may not be started during the study.
Standard oral migraine prophylactic medications (eg, amitriptyline, topiramate, propranolol, 
valproic acid) and nondrug therapies (eg, acupuncture, TENS, cranial traction, nociceptive 
trigeminal inhibition, occipital nerve block) will be permitted provided that the treatment is 
stable at the Screening Visit (Visit 1) and continues without change in dose/frequency 
throughout the study. New prophylactic medications may not be started during the study. 
Any medication taken 6 months prior to Visit 1 and during the study between Visit 1 and the date 
of the EOS visit will be recorded in the eCRF. For medications taken for migraine, all past and 
current medications will be recorded in the eCRF. Any medication started after the EOS visit 
will not be considered a concomitant medication and should not be captured in the eCRF.
6.5.3.
Rescue Medicine
Rescue medication refers to the participants' own medications used for the acute treatment of 
migraine headache. Rescue medications may include NSAIDs, acetaminophen, triptans, ditans, 


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ergotamines, analgesic or combination analgesics (eg, Excedrin®), opioids, or antiemetics; these 
may be taken during the study within the parameters noted in Section 6.5.2.
Screening Period:

If a headache of any intensity develops following a qualifying prodrome event, then 
rescue medication can be taken to treat the headache. 
Double-blind Treatment Period:

If a moderate or severe headache develops following a qualifying prodrome event, 
rescue medication can be taken at any time.

If a mild headache develops following a qualifying prodrome event, rescue medication 
cannot be taken within 24 hours after taking the dose of double-blind study intervention.
Rescue medication will not be supplied by the sponsor. Use of rescue medication, and all 
allowable medication, must conform to the prescribing information of the product and the 
restrictions of this protocol.
6.5.4.
Prohibited Interventions During the Study
Refer to Section 10.9 for examples of prohibited medications and allowed medications (with 
restrictions). Refer to Section 6.5.1 for examples of prohibited medications and washout before 
study.
6.6.
Dose Modification
This protocol does not allow for any modification from the currently outlined dosing schedule as 
this is an event-driven study.
6.7.
Intervention after the End of the Study
There is no intervention following the end of the study or optional PK substudy.


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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 has been 
randomized to receive study intervention ceases participation in the study, regardless of 
circumstances, before the completion of the protocol-defined study procedures.
Participants may voluntarily withdraw from the study at any time.
Notification of early discontinuation from the study and the reason for discontinuation will be 
clearly documented on the appropriate eCRF. All randomized participants who prematurely 
discontinue from the study, regardless of cause, should be seen for a final assessment. A final 
assessment will be defined as completion of the evaluations scheduled for Visit 4/ET. If no study 
intervention is taken, Visit 4/ET will be the last study visit.
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms:

Adverse event

Completed

Lack of efficacy

Lost to follow-up

Non-compliance with study drug

Other

Pregnancy

Protocol deviation

Screen failure

Site terminated by sponsor

Study terminated by sponsor

Withdrawal by subject 

Lack of qualifying events
7.1.
Discontinuation of Study Intervention
A participant with a condition and/or a situation that, in the investigator's opinion, may put the 
participant at significant risk, may confound the study results, or may interfere significantly with 
the participant's participation in the study may be withdrawn from receiving study intervention. 
Discontinuation of study intervention also requires discontinuation from the study. Please see 
previous section above regarding final assessments to be completed for discontinuation from 
study.


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The following conditions require participants to be withdrawn from study:

Women who become pregnant will be withdrawn from the study and should refrain from 
taking further study intervention. The participant should return to the clinic for ET Visit 
study procedures (Visit 4/ET Visit) if the participant has been randomized.

Participants who reply with yes to questions 4 or 5 in the suicidal ideation section 
indicating having suicidal ideation with intent (with or without plan) or yes to any 
question in the suicidal behavior section of the C-SSRS should receive appropriate 
follow-up as in routine clinical practice. The participant should return to the clinic for 
ET Visit study procedures (Visit 4/ET Visit) if the participant has been randomized.

Posttreatment ALT/AST values meeting the following criteria: 
o
ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance 
of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
or eosinophilia (> 5%)
o
ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN
o
ALT or AST ≥ 3 × ULN and INR > 1.5
o
ALT or AST ≥ 5 × ULN for more than 2 weeks
o
ALT or AST ≥ 8 × ULN
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.1.
Criteria for Study Termination
The sponsor may stop the study (and/or the study site) for any reason with appropriate 
notification. 
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request (a clear 
reason must be documented), or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is expected 
to be uncommon.

See the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.

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.


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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 or not 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 should 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 Section 10.1
(Appendix 1).


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All 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.
Participant Entry Procedures
Prospective participants as defined by the inclusion criteria in Section 5.1 and exclusion criteria 
in Section 5.2 will be considered for entry into this study. At the Screening Visit (Visit 1) and 
Randomization Visit (Visit 2), participants must meet all of the inclusion criteria and must not 
meet any of the exclusion criteria. Rescreening of participants may be considered with 
permission from the sponsor. 
The study will be discussed with the participant and a participant wishing to participate must 
give informed consent prior to any study-related procedures or change in treatment. The 
participant must also give authorization and other written documentation in accordance with 
local privacy requirements (where applicable) prior to any study-related procedures or change in 
treatment.
Each participant that provides informed consent will be assigned a participant number that will 
be used on participant documentation throughout the study.
The investigator or qualified designee will explain the PK substudy consent to the participant and 
answer all of his/her questions. If the participant would like to participate in this optional PK 
substudy, participants will sign a separate consent form before performing any procedure related 
to the substudy.
Procedures for Duplicate Participant Identification 
A central vendor will be used to verify participants' current and past research study status in 
order to mitigate safety concerns associated with duplicate enrollment and protocol deviations 
associated with multiple trial enrollment. The procedure for identifying duplicate participants is 
mandatory. Following proper informed consent and after issuing a participant number, each 
participant will be checked for duplicate participation (see the SoA; Section 1.3). Partial 
identifiers will be utilized. Participants who are identified as verified duplicates must not 
be enrolled without documented approval from the sponsor.
Visits and Associated Procedures
This study will include 4 clinic visits and 1 phone call: Screening Visit (Visit 1), a phone call 
during the screening period, a Randomization Visit (Visit 2), a Posttreatment Visit (Visit 3) after 


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treating the first qualifying prodrome event, and a Posttreatment/ET Visit (Visit 4) after treating 
the second qualifying prodrome event.
Screening Visit (Visit 1)
The following study procedures will be carried out at the Screening Visit (Visit 1):

Obtain informed consent and participant privacy

Obtain informed consent for optional PK substudy  (if participant wants to participate in 
the substudy)

Duplicate Participation Identification consent and verification

Register participant in IWRS

Collect demographic information

Assess inclusion/exclusion criteria

Collect medical history (including CV disease and risk factors, as outlined in the Study 
Reference Manual)

Collect migraine history and confirm diagnosis

Conduct comprehensive structured interview (see additional detail following this list)

Review prior medications (both prescription and over-the-counter), including prophylactic 
medication use (taken in the past 6 months for all medications and all past medications for 
migraine taken during the participants' lifetime) and concomitant medication. 

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, height, and weight)

Perform ECG

Perform physical examination

Collect blood and urine samples for clinical laboratory tests (chemistry, hematology, 
urinalysis, and coagulation)

Perform urine pregnancy test (for WOCBP only)

Collect urine sample for drug screen

Assess C-SSRS on eTablet (the Screening/baseline assessment of the C-SSRS will be 
completed)

Conduct eDiary training and dispense eDiary to participant

Review and assess AEs (from time of informed consent)


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At the Screening Visit (Visit 1), the investigator or medically qualified subinvestigator, familiar 
with diagnosing migraine, will collect a detailed medical history, including migraine diagnosis
and migraine history. As part of this assessment, a comprehensive structured interview with the 
participant must be conducted to examine all aspects of the participant's migraine, including the
prodrome phase and headache phase, treatments, and to record the following:

Specific prodrome symptom(s) that the participant experiences

Usual timeframe from onset of prodrome symptom(s) to onset of headache 

Establish that the participant routinely experiences prodrome symptom(s) that are reliably 
followed by headache pain of any intensity within 1 to 6 hours after experiencing the 
prodrome symptoms (at least 3 of 4 times, or 75% of the time). The investigator must 
document confirmation.
A worksheet will be provided to investigational sites to guide the interview and document 
confirmation.
Participants who meet initial eligibility requirements at the Screening Visit (Visit 1) will be 
trained on the use of the eDiary and instructed on recording their qualifying prodrome events and 
their headache (if it occurs), nonheadache symptoms as well as all the assessments to complete 
on the device. In addition, the site will review the timing of the reminders and assessments as 
well as qualifications for a prodrome event that requires recording on the eDiary. Refer to 
Section 6.3.1 for the definition of a qualifying prodrome event to be recorded in the eDiary.
Participants can use rescue medication during the screening period as outlined in Section 6.5.3. 
Once site staff are confident that the participant understands their responsibility, a 
patient-specific eDiary with the participant's own prodrome symptoms preprogrammed can be 
dispensed to the participant. The site will instruct the participant to return with the eDiary to each 
future visit as the same device will be used for the duration of study participation.
During Screening Period (between Visit 1 and Visit 2)
During the screening period (between Visit 1 and Visit 2), participants will have 60 days to 
demonstrate the reliability of developing a headache after experiencing a qualifying prodrome 
event. Participants will be instructed to record their qualifying prodrome events and headaches in 
the eDiary. Participants who record less than 3 qualifying prodrome events in the screening 
period (60 days) (ie, 1 or 2 events) will be screen failed (for failure to meet inclusion criterion 
2.06). 
Phone Call
A phone call will be made 30 days (± 7 days) after Visit 1 to check in with the participants 
to ensure there are no issues with their eDiary and recording of the participants' responses. 
Review the data collected in the eDiary including compliance in answering all questions. A 
review of concomitant medications and review and assessment of AEs will also be conducted.
Randomization Visit (Visit 2)
Review eDiary data collected during the screening period (between Visit 1 and Visit 2) to 
confirm that inclusion criteria 2.06 and 2.07 (Section 5.1) are met.


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Confirm that the participant has met the following criteria to be randomized:

3 to 16 qualifying prodrome events have been recorded during the screening period
o
For participants who record only 3 qualifying prodrome events, all events (100%) 
must be followed by a headache within 1 to 6 hours. 
o
For participants who record 4 to 16 qualifying prodrome events, at least 75% of 
events must be followed by a headache within 1 to 6 hours. 
If eligible to continue, the remaining study procedures will be carried out at the Randomization 
Visit (Visit 2):

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight)

Perform urine pregnancy test (for WOCBP only) 

Assess C-SSRS on eTablet (the Since the Last Visit assessment of the C-SSRS will be 
completed) 

Perform ECG

Review concomitant medication

Collect migraine treatment history (eg, prior migraine preventative medication response 
and  historical triptan response), as outlined in the Study Reference Manual

Review and assess AEs 

Collect blood and urine samples for clinical laboratory tests (chemistry, hematology, 
urinalysis)

Participant completes ASC-12 (allodynia questionnaire)

Register the participant's visit in IWRS and obtain the kit number for study intervention. If 
the participant does not qualify for the study, then the study site must enter the participant 
into the IWRS as a screen failure.

Review dosing with the participant, including the qualifying prodrome events that need to 
occur before taking double-blind study intervention, prohibited medications, and rescue 
medication use (see Section 6.3.1, Section 6.5.1, and Section 6.5.3). Remind participants
of the importance of completing all the assessments in the eDiary. To improve 
compliance, remind participants to treat qualifying prodrome events that occur in the 
morning or early afternoon so that assessments can be collected in the eDiary during 
waking hours. If participant understands their responsibilities and has successfully 
completed their eDiary training, dispense double-blind study intervention to treat 
1 qualifying prodrome event.

Provide the participant the side effects diary to list the date and time of any side effects the 
participant experiences after taking double-blind study intervention.


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
For participants who have consented and are participating in the optional PK substudy:
o
Train participants on the collection of DBS samples
o
A DBS sample will be collected at this visit by the participant to ensure 
participant comprehension of the process. The sample can then be destroyed.
o
If DBS sample collection is unsuccessful during the training, the participant may 
not participate in the optional PK substudy.
o
Review collection timing, handling, and storage of DBS samples that will be 
collected at home, as well as recording the information in the eDiary, before 
providing the participant with the supplies for PK sample collection.
Treatment of First and Second Qualifying Prodrome Events (between Visit 2 and Visit 4)
During the double-blind treatment period (between Visit 2 and Visit 4), participants will have up 
to 60 days from the Randomization Visit (Visit 2) to treat 2 qualifying prodrome events at home 
with double-blind study intervention at the earliest time the participant is confident that a 
headache will inevitably follow within 1 to 6 hours of each qualifying prodrome event. The 
treatment of these 2 qualifying prodrome events will be separated by Visit 3 to ensure a 
minimum 7-day washout period. 
The participant will report information in the eDiary at the time of each qualifying prodrome 
event:

Confirmation that the participant is experiencing a qualifying prodrome event 

Identification and intensity of individually specific prodrome symptom(s)

Headache pain and intensity (if it occurs) 

Nonheadache symptoms (photophobia, phonophobia, nausea, dizziness) including 
intensity (mild, moderate, severe)

Presence or absence of aura

Health Outcomes assessments
Participants will be asked to complete their eDiary at prespecified timepoints (1, 2, 3, 4, 6, 8, 24, 
and 48 hours). In addition, the date and time of when the dose of double-blind study intervention
is taken will be captured, as well as rescue medication use. After recording a qualifying 
prodrome event, it is very important that the participant captures the development of a headache 
(if it happens) and completes all questions at every timepoint. To ensure maximum compliance, 
the participant can be contacted to be reminded to complete all assessments. 
A side-effects diary (paper diary, not eDiary) will be kept by the participant to record any 
side effects experienced within 48 hours of taking double-blind study intervention.
Posttreatment Visit (Visit 3) After Treatment of First Qualifying Prodrome Event
This visit will occur 4 days (-2/+4 days) after double-blind study intervention is taken for the 
first qualifying prodrome event. It can occur as early as 2 days after taking double-blind study 
intervention (after the 48 hour assessment has been completed) and as late as 8 days after taking 


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double-blind study intervention; however, participants should be encouraged to come in for this 
visit as soon as possible after completing their 48 hour assessments.
The following study procedures will be carried out at the Posttreatment Visit (Visit 3):

Register the participant's visit in the IWRS

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight) 

Review concomitant medication

Review and assess AEs

Assess C-SSRS on eTablet (the Since the Last Visit assessment of the C-SSRS will be 
completed)

Perform urine pregnancy test (for WOCBP only)

Review eDiary entries and ensure all questions and assessments were completed. Ensure 
the eDiary is functioning appropriately, sending data as programmed, and the participant 
continues to understand how to use the eDiary. Complete retraining if needed. Redispense 
the eDiary back to the participant.

Collect side effects diary. Review the side effects listed on the diary and enter identified 
AEs in EDC. Provide participant with new side effects diary.

Collect study intervention blister package; review compliance against the information 
collected in the eDiary. 

Obtain the kit number for study intervention in IWRS and dispense a blister card with the 
study intervention for the second qualifying prodrome event. Review dosing instructions 
with the participant again if needed.
For those participants participating in the optional PK substudy:

Collect the DBS samples that the participant collected at home and ensure that the 
collection dates and times are recorded in the eDiary

Review collection timing, handling, and storage of DBS samples that will be collected at 
home after the second qualifying prodrome event. Provide the participant with the 
supplies for PK sample collection.
The first and second qualifying prodrome events must be 2 separate and distinct events that are at 
least 7 days apart.
Posttreatment Visit (Visit 4) After Treatment of Second Qualifying Prodrome Event/ 
ET Visit 
This visit will occur 4 days (-2/+4 days) after double-blind study intervention is taken for the 
second qualifying prodrome event. It can occur as early as 2 days after taking double-blind study 
intervention (after the 48 hour assessment has been completed) and as late as 8 days after taking 
double-blind study intervention; however, participants should be encouraged to come in for this 
visit as soon as possible after completing their 48 hour assessments.


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If none or 1 qualifying prodrome event has been treated during the double-blind treatment period 
and the 60-day time period has ended, the site will call the participant to schedule an ET Visit.
Randomized participants who exit the study early for any reason, whether or not they have taken 
study intervention, should also receive these evaluations. The following study procedures will be 
carried out at the Posttreatment/ET Visit (Visit 4):

Register the participant's visit in the IWRS

Collect vital sign measurements (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, and weight) 

Review concomitant medication

Review and assess AEs

Assess C-SSRS on eTablet (the Since the Last Visit assessment of the C-SSRS will be 
completed)

Perform ECG

Perform physical examination

Collect blood and urine samples for clinical laboratory tests (chemistry, hematology, and 
urinalysis) 

Perform urine pregnancy test (for WOCBP only)

Collect eDiary and ensure all recorded data has been sent

Review eDiary entries and ensure all questions and assessments were completed

Collect side effects diary. Review the side effects listed on the diary and enter identified 
AEs in EDC. 

Collect study intervention blister package; review compliance against the information 
collected in the eDiary
For those participants participating in the optional PK substudy:

Collect the DBS samples that the participant collected at home and ensure that the 
collection dates and times are recorded in the eDiary
Unscheduled Visits
Additional examinations, laboratory assessments, and pregnancy tests may be performed as 
necessary to ensure the safety and well-being of the participants during the study. Unscheduled 
visit eCRFs should be completed for each unscheduled visit. 
Instructions for Participants
Section 5.3.1, Section 5.3.2, and Section 5.3.3 list dietary restrictions and activity instructions for 
participants enrolled in the study. 
Participants will be provided with instructions on the use of the eDiary to complete when they 
experience qualifying prodrome events and they will be made aware of timepoints as to when 


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they are expected to enter data in the eDiary. A practice session with a hypothetical scenario 
should be administered to ensure the participants' comprehension of the questions and the 
information to be entered. In addition, criteria for qualifying prodrome events to be treated as 
well as prohibited medications should be reviewed with the participants. Participants should 
receive instructions on how to take the study intervention, the criteria for a qualifying prodrome 
event, and when participants are allowed to take rescue medication. Participants will be 
instructed to bring their eDiary at the next study visit and return their study intervention (used 
and unused). 
For participants participating in the optional PK substudy, DBS sample collection training will 
be provided at Visit 2. For participants who have successfully completed the collection training, 
participants will be provided with the PK collection supplies and provided instructions on when 
the DBS samples must be collected and the dates and times recorded in the eDiary. Participants 
will collect 3 DBS samples at home after treating each qualifying prodrome event and record the 
date and time in their eDiary. Collection times are outlined in Section 8.5.
8.1.
Efficacy Assessments
Efficacy measurement assessments are based on information recorded by the participant in 
an eDiary.
Absence/Presence of and Rating of Intensity of Prodrome Symptom(s) 
After experiencing each qualifying prodrome event, the absence or presence of each identified 
prodrome symptom(s) will be followed (up to 48 hours) and the intensity subjectively rated 
(mild, moderate, or severe) for those that are present. 
Absence/Presence of Headache and Rating of Headache Intensity
After the prodrome symptoms have started, the participant will be alerted to record the presence 
of a headache when it occurs or record the absence/presence at various timepoints (up to 
48 hours) following the dose of double-blind study intervention (during the double-blind 
treatment period). If a headache is reported as present, the intensity will be subjectively rated 
(mild, moderate, or severe). 
Absence/Presence of and Rating of Intensity of Nonheadache Symptoms 
The participant will record whether nonheadache symptoms (photophobia, phonophobia, nausea, 
and/or dizziness) were absent or present as well as the intensity (mild, moderate, or severe) of the 
present nonheadache symptom (up to 48 hours).
Absence/Presence of Aura
The participant will record whether aura was present or absent (up to 48 hours).
Health outcomes assessments are described in Section 8.10.
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3).


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8.2.1.
Physical Examinations
A complete physical examination will be performed at the visits outlined in SoA (Section 1.3). 

A professionally trained physician or healthcare professional licensed to perform physical 
examinations will examine the participant for any detectable abnormalities of the 
following body systems: general appearance; neck (including thyroid); head, eyes, ears, 
nose, and throat; lungs; heart/cardiovascular; abdomen; neurologic; extremities; back; 
musculoskeletal; lymphatic; skin; and other. 

The neurologic examination should be conducted to detect the presence of any significant 
sensory/motor abnormalities.
8.2.2.
Vital Signs
Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, 
respiratory rate, temperature, body weight, and height (at Visit 1 only), will be performed at 
every visit. 
Sitting and standing BP and pulse rate will be determined as follows: BP and pulse 
measurements will be performed after the participant sits quietly for 5 minutes, followed by a 
second set of measurements taken after the participant stands for 3 minutes (but no longer than 
10 minutes).
8.2.3.
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in the SoA (Section 1.3). Only one ECG 
is required for each assessment at each specified visit. All ECGs should be performed after the 
participant has been supine for at least 5 minutes. A copy of the ECG will be saved as a source 
document. ECGs will be transmitted electronically to the central ECG laboratory for analysis 
according to the instructions provided by the laboratory to be read by a cardiologist. If multiple 
ECGs are completed, all ECGs (readable and unreadable) must be transmitted to the central ECG 
vendor. The overall interpretation of the clinical significance of the ECGs will be determined by 
the investigator and recorded in the source notes.
8.2.4.
Clinical Safety Laboratory Assessments

See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. Hematology, chemistry, urinalysis, and urine 
pregnancy tests will be conducted at the Screening Visit (Visit 1), Randomization Visit 
(Visit 2), and Posttreatment/ET Visit (Visit 4). Coagulation, and the urine drug screen will 
be conducted at the Screening Visit (Visit 1) only. 

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 screen failed or withdrawn from 
the study.


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
Positive results on the urine drug screen (unless explained by previously reported 
concomitant medication use, such as opioids prescribed for migraine pain) will be 
excluded from the study.

A positive pregnancy test at Visit 1 or Visit 2 will exclude the participant from 
participation in the study. Participants who are confirmed to be pregnant during the study 
will be withdrawn.

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 or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by 
the investigator.
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 Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3) or 
laboratory manual.
o
If laboratory values from nonprotocol specified laboratory assessments performed 
at the institution's local laboratory require a change in participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded as an SAE or AE in the eCRF.
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring
Ubrogepant is considered to be CNS active and participants being treated should be monitored 
appropriately and observed closely for suicidal ideation and behavior. 
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and 
behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific 
active suicidal thoughts), 3 (active suicidal ideation with any methods [no plan] without intent to 
act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active 
suicidal ideation with specific plan and intent). The C-SSRS also captures information about the 
intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons 
for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no 
suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), 
and 4 (actual attempt). More than 1 classification can be selected provided they represent 
separate episodes. For actual attempts only, the actual or potential lethality is classified for the 
initial, most lethal, and most recent attempts. 


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The C-SSRS will be completed at all study visits. At the Screening Visit (Visit 1) the C-SSRS 
will be completed for the participant's lifetime history and 6 months of suicidal ideation and 
suicidal behavior to assess eligibility. Based on this assessment and investigator judgment, if 
there is significant risk of self harm or harm to others, the participant must be excluded from the 
study. At all other visits, the C-SSRS will be completed for ideation and behavior since the 
previous visit. 
The C-SSRS will be completed on the eTablet by the investigator or designee with current and 
valid training in administering the assessment. A participant should not be released from the 
study center until the results of C-SSRS are reviewed and it is confirmed that the participant is 
not considered to be at risk. 
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs and AEs from the signing of the ICF until 30 days after the last dose of study 
intervention will be collected at the timepoints specified in the SoA (see Section 1.3), and as 
observed or reported spontaneously by study participants.
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded in the AE section of the eCRF and will be considered pretreatment AEs.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
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.
8.3.2.
Method of Detecting AEs and SAEs
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.
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.


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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 10.3)
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). Further information on follow-up procedures is 
provided in Appendix 3.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the
investigator will provide the sponsor or designee with a copy of any postmortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a 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, IRB/IEC, 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 and will notify the IRB/IEC, if 
appropriate according to local requirements.

Investigator safety reports must be prepared for SUSAR 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 completion of the 
study.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.7.


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
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.
Adverse Events of Special Interest
AESIs that warrant ongoing monitoring and rapid communication by the investigator to the 
sponsor are outlined in Section 10.3.
8.4.
Treatment of Overdose
As the participant will only be provided with 1 dose of ubrogepant, the maximum amount of 
available ubrogepant for each participant will be at most 100 mg, an approved dose for the acute 
treatment of migraine.
8.5.
Pharmacokinetics
PK samples will be collected using the DBS method from participants who specifically 
consented to provide PK samples for the purpose of obtaining ubrogepant PK data in individuals 
with prodrome symptoms. The PK component of the study is optional. 
During the Randomization Visit (Visit 2), DBS sample collection training will be provided to the 
participants who consented to provide PK samples, and 1 DBS sample will be collected by the 
participant during the visit to ensure participant comprehension of DBS sample collection. This 
sample will be discarded.
Participants participating in the optional PK substudy will be instructed to collect a total of 
6 DBS samples at home and record the date and time of DBS sample collection in their eDiary.
After treating the first qualifying prodrome event, the participant will collect:

A DBS sample 15 minutes after taking double-blind study intervention 

A DBS sample 1 hour after taking double-blind study intervention

A DBS sample anytime between 4 and 12 hours after taking double-blind study 
intervention
After treating the second qualifying prodrome event, the participant will collect:

A DBS sample 30 minutes after taking double-blind study intervention

A DBS sample 2 hours after taking double-blind study intervention

A DBS sample anytime between 4 and 12 hours after taking double-blind study 
intervention
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.


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8.8.
Biomarkers and Other Assessments
Biomarkers are not evaluated in this study.
12-item Allodynia Symptom Checklist (ASC-12)
The ASC-12 is a patient-reported measure of how often pain or an unpleasant sensation in the 
skin during the most severe headache is experienced in the following scenarios: combing your 
hair, pulling your hair back (eg, ponytail), shaving your face, wearing eyeglasses, wearing 
contact lenses, wearing earrings, wearing a necklace, wearing tight clothing, taking a shower 
(when shower water hits your face), resting your face or head on a pillow, exposure to heat 
(eg, cooking, washing your face with hot water), and exposure to cold (eg, using an ice pack, 
washing your face with cold water). For each item, there are 5 response options ranging from 
does not apply to me to half the time or more, resulting in a total score that ranges from 0 (all 
items do not apply to me) to 24 (all items occur half the time or more). The total score can then 
be used to categorize each participant as having no cutaneous allodynia (0 to 2), mild (3 to 5), 
moderate (6 to 8), or severe (≥ 9). This measure will be conducted at Visit 2 in the eTablet.
8.9.
Immunogenicity Assessments
Immunogenicity is not assessed in this study.
8.10.
Health Economics Outcomes Assessments
Functional Disability Scale
The FDS is a single item used to measure the participant's level of functional disability 
(Cady 2015, Tepper 2015). Participants will be asked to rate the performance of daily activities 
using 4 response options ranging from 0 (no disability, able to function normally) to 3 (severely 
impaired, cannot do all or most things, bed rest may be necessary). The measure will be assessed 
at predose (baseline) and 1, 2, 3, 4, 6, 8, 24, and 48 hours after double-blind study intervention 
for treating the first and second qualifying prodrome events.
Satisfaction with Study Medication
Overall satisfaction with study medication for migraine will be assessed using a single item and 
7-point rating scale ranging from extremely satisfied (0) to extremely dissatisfied (6). The 
question will be answered by the participants in their eDiary at 8 hours and 24 hours after taking 
double-blind study intervention for treating the first and second qualifying prodrome events.
Activity Limitation
A single-item measure assessing activity limitation based on a 24-hour recall will be 
administered as an additional health outcome measure. The measure will be used to evaluate 
activity limitation with a 5-level response ranging from "Not at all limited – I could do 
everything" to "Extremely limited." The measure will be administered at 24 hours after taking 
double-blind study intervention.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
Primary null hypothesis: Ubrogepant 100 mg is the same as placebo in the acute treatment of 
migraine when administered during the prodrome, as measured by the proportion of participants 
who do not develop headache of moderate/severe intensity within 24 hours after taking double-
blind study intervention during the prodrome.
Primary alternative hypothesis: Ubrogepant 100 mg is superior to placebo in the acute treatment 
of migraine when administered during the prodrome, as measured by the proportion of 
participants who do not develop headache of moderate/severe intensity within 24 hours after 
taking double-blind study intervention during the prodrome.
Secondary null hypothesis 1: Ubrogepant 100 mg is the same as placebo in the acute treatment of 
migraine when administered during the prodrome, as measured by the proportion of participants 
who do not develop headache of moderate/severe intensity within 48 hours after taking the 
double-blind study intervention during the prodrome.
Secondary alternative hypothesis 1: Ubrogepant 100 mg is superior to placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the proportion of 
participants who do not develop headache of moderate/severe intensity within 48 hours after 
taking the double-blind study intervention during the prodrome.
Secondary null hypothesis 2: Ubrogepant 100 mg is the same as placebo in the acute treatment of 
migraine when administered during the prodrome, as measured by the proportion of participants 
who are able to function normally over 24 hours after taking the double-blind study intervention 
during the prodrome.
Secondary alternative hypothesis 2: Ubrogepant 100 mg is superior to placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the proportion of 
participants who are able to function normally over 24 hours after taking the double-blind study 
intervention during the prodrome.
Secondary null hypothesis 3: Ubrogepant 100 mg is the same as placebo in the acute treatment of 
migraine when administered during the prodrome, as measured by the proportion of participants 
who do not develop headache of any intensity within 24 hours after taking the double-blind study 
intervention during the prodrome.
Secondary alternative hypothesis 3: Ubrogepant 100 mg is superior to placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the proportion of 
participants who do not develop headache of any intensity within 24 hours after taking the 
double-blind study intervention during the prodrome.
9.2.
Sample Size Determination
The primary efficacy parameter is the absence of a headache of moderate/severe intensity within 
24 hours after taking double-blind study intervention during the prodrome. Based on the 
assumption of a response rate of 64% for the placebo group and 80% for the ubrogepant 100 mg 
group, 240 participants in each study intervention will provide at least 95% power to detect the 


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above intervention difference at the 2-sided 5% significance level. The nQuery Advisor 7.0 was 
used for the power calculation.
A blinded sample size re-estimation has been performed as planned. Given that 7% of 
participants had no determinable primary endpoint as observed based on the data cut of 
July 5, 2021, approximately 516 participants will be randomized to maintain the effect sample 
size of 480 participants.
The actual power will be higher with the crossover design as some participants will contribute
2 qualifying prodrome events during the double-blind treatment period.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
ITT
All randomized participants. Participants will be summarized according 
to the randomized study/sequence intervention
Safety
All treated participants who take ≥ 1 administration of study intervention. 
Participants will be summarized according to the study intervention they 
actually received.
mITT
All randomized participants with ≥ 1 assessment of headache occurrence 
within 24 hours after taking double-blind study intervention for at least 
1 qualifying prodrome event during the double-blind treatment period. 
Participants will be summarized according to the randomized study 
intervention.
PK
All participants who have evaluable PK parameters
9.4.
Statistical Analyses
9.4.1.
Efficacy Analyses
The efficacy analyses will be based on the mITT population. All statistical tests will be 2-sided 
hypothesis tests performed at the 5% level of significance for main effects. All CIs will be 
2-sided 95% CIs, unless stated otherwise.
9.4.1.1.
Analysis Endpoints
The primary and secondary efficacy endpoints are listed below and analyses will be defined in 
the following sections. All analyses for other efficacy endpoints listed below will be defined in 
the SAP.
Primary efficacy endpoint:

Absence of a headache of moderate/severe intensity within 24 hours after taking 
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Secondary efficacy endpoints:

Absence of a headache of moderate or severe intensity within 48 hours after taking 
double-blind study intervention during the prodrome

Ability to function normally over 24 hours after taking double-blind study intervention 
during the prodrome

Absence of a headache of any intensity within 24 hours after taking double-blind study 
intervention during the prodrome
Additional endpoints:

Absence of headache of any intensity by timepoint (excluding the endpoints that are 
already captured as primary and secondary endpoints)

Absence of moderate/severe headache by timepoint (excluding the endpoints that are 
already captured as primary and secondary endpoints)

Absence of severe headache by timepoint

Time to development of headache of any intensity within 48 hours after taking 
double-blind study intervention during the prodrome (Kaplan-Meier analysis)

Time to development of headache of moderate/severe intensity within 48 hours after 
taking double-blind study intervention during the prodrome (Kaplan-Meier analysis)

Time to development of headache of severe intensity within 48 hours after taking 
double-blind study intervention during the prodrome (Kaplan-Meier analysis)

For each of the 5 most common individual prodrome symptoms:
o
Absence of any intensity at each timepoint
o
Absence of moderate/severe intensity at each timepoint
o
Absence of severe intensity at each timepoint
o
Time to absence of any intensity

After a headache of any intensity is reported:
o
Absence of nonheadache migraine symptoms (photophobia, phonophobia, nausea, 
dizziness) at each timepoint
o
Absence of nonheadache migraine symptoms (photophobia, phonophobia, nausea, 
dizziness) of moderate/severe intensity at each timepoint
o
Absence of nonheadache migraine symptoms (photophobia, phonophobia, nausea, 
dizziness) of severe at each timepoint

Absence of aura at each timepoint

Rescue medication use within 24 and 48 hours after taking double-blind study 
intervention


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
Time to rescue medication use within 48 hours after taking double-blind study 
intervention (Kaplan-Meier analysis)

Satisfaction with study medication at 8 and 24 hours after taking double-blind study 
intervention during the prodrome

Activity Limitation within 24 hours after taking double-blind study intervention during the 
prodrome
9.4.1.2.
Primary Analyses
The primary efficacy endpoint for the absence of a headache of moderate/severe intensity within 
24 hours after taking double-blind study intervention during the prodrome will be analyzed using 
a GLMM based on determinable data on the primary efficacy endpoint. Specifically, the status of 
absence of a headache of moderate/severe intensity within 24 hours should be decided based on 
all observed data including headache reported at a series of scheduled timepoints, reported 
event-driven, 24-hour recall headache, and whether a participant took rescue medication. If a 
participant did not report moderate/severe headache and has a missing 24-hour recall assessment, 
that participant will be counted as indeterminable. This GLMM model assumes a binary 
distribution for the response and uses a logit link. The analysis model will include period, and 
treatment as categorical fixed effects. An unstructured covariance matrix will be used for the 
covariance matrix of the residual effect for the repeated measurements (corresponding to the 
2 qualifying prodrome events) within a participant. The treatment difference in terms of odds 
ratio between ubrogepant 100 mg and placebo will be estimated from the GLMM model.
The carryover effect will be tested although no or very minimum carryover effect is expected as 
the minimum 7-day washout period is much longer than the 5 times of half-life. A similar 
GLMM model will be fitted. The model includes period and treatment as categorical fixed 
effects, and period-by-treatment interaction. The carryover effect will be tested using the 
confounded period-by-treatment interaction. If the carryover effect is significant, the analysis 
should use first period only data. For sensitivity analysis purpose, first period only data analysis 
will be performed regardless of the significance level of the carryover effect.
A sensitivity analysis will use multiple imputation approach to impute the missing headache 
occurrence or indeterminable status within 24 hours for each qualifying prodrome event. 
Specifically, for a participant who has not experienced headache of moderate/severity by time tj
(< 24 hours) after taking double-blind study intervention and has missing headache severity 
assessment at the next timepoint tj+1, whether the participant will experience headache of 
moderate/severe intensity at tj+1 will be imputed based on other participants on the same 
treatment who have not experienced headache of moderate/severe intensity by time tj but have 
observed headache severity assessment at tj+1 . So firstly, the missing headache severity 
assessment at time t1 will be imputed. The missing headache at the following timepoints (2, 3, 4, 
6, 8, 24, and 48 hours) will be imputed step by step similarly. The treatment difference between 
ubrogepant 100 mg and placebo will be estimated from the GLMM model for each imputed data 
set and combined across imputations to obtain the multiple imputation estimate using standard 
multiple imputation techniques.
Additional sensitivity analysis will impute participants with missing headache occurrence status 
within 24 hours as nonresponders for the qualifying prodrome event. For participants who go 


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through the 60-day double-blind treatment period with only 1 qualifying prodrome event due to 
lack of qualifying event or having an event but with no headache assessment, the missing data 
for the missing qualifying prodrome event will be considered as missing at random. For 
participants who discontinued the double-blind treatment period with only 1 qualifying prodrome 
event for other reasons, the missing data for the second qualifying prodrome event will be 
imputed based on the observed data for the second qualifying prodrome event from participants 
who use placebo to treat the second qualifying prodrome event. The treatment difference 
between ubrogepant 100 mg and placebo will be estimated from the GLMM model for each 
imputed data set and combined across imputations to obtain the multiple imputation estimate 
using standard multiple imputation techniques.
9.4.1.3.
Secondary Analyses
The first and third secondary endpoints (ie, the absence of a headache of moderate or severe 
intensity within 48 hours after taking double-blind study intervention during the prodrome and
absence of a headache of any intensity within 24 hours), will be analyzed using a GLMM model
based on observed data similar to the one used for the analysis of the primary endpoint.
A sensitivity analysis will use multiple imputation approach described for the primary endpoint 
to impute the missing headache occurrence status within 24 hours/48 hours for the participant for 
each qualifying prodrome event with an unknown status of headache occurrence within 
24 hours/48 hours after taking double-blind study intervention.
A sensitivity analysis will impute participants with missing headache occurrence or 
indeterminable status within 24 hours/48 hours as nonresponders. For participants who go 
through the 60-day double-blind treatment period with only 1 qualifying prodrome event due to 
lack of qualifying event or having an event but with no headache assessment, the missing data 
for the missing qualifying prodrome event will be considered as missing at random. For 
participants who discontinued the double-blind treatment period with only 1 qualifying prodrome 
event for other reasons, the missing data for the second qualifying prodrome event will be 
imputed based on the observed data for the second qualifying prodrome event from participants 
who use placebo to treat the second qualifying prodrome event. Analyses using only the first 
period data will also be performed as a sensitivity analysis.
The second secondary endpoint, ie, ability to function normally over 24 hours after taking
double-blind study intervention during the prodrome, includes the repeated measures of 
dichotomized FDS response at each postdose timepoint over 24 hours. The dichotomized 
response takes value 1 if the participant records no disability, able to function normally on the 
FDS, and takes value 0 otherwise. The repeated binary responses will be analyzed using a GEE 
model with a logit link. The GEE model will include period, treatment, time, treatment-by-time 
interaction as categorical fixed effects, predose baseline FDS score for the period, and predose 
baseline-by-time interaction as covariates. An unstructured working correlation matrix will be 
used for the repeated measures within each participant. The treatment effect will be expressed in 
terms of the geometric mean of the odds ratios of ubrogepant 100 mg relative to placebo 
estimated at the scheduled timepoints within 24 hours after taking double-blind study 
intervention.
A serial gatekeeping procedure will be used to control the overall type I error rate at the 
0.05 level for multiple comparisons across the primary and 3 secondary efficacy endpoints. The 


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primary endpoint will serve as the gatekeeper for the first secondary endpoint. The first 
secondary endpoint will serve as the gatekeeper for the second secondary endpoint, which, in 
turn, serves as the gatekeeper for the third secondary endpoint.
9.4.1.4.
Other Efficacy Analyses
The absence of a headache of any intensity by each timepoint after taking double-blind study 
intervention will be analyzed using the same GLMM model as primary endpoint. Similar 
analyses will be performed for the absence of a headache of moderate/severe intensity and 
absence of severe headache by timepoint. Kaplan-Meier curves for time to development of any 
intensity headache (or rescue medication taken), time to development of moderate/severe 
headache, time to development of severe headache within 48 hours will be produced by 
treatment and compared between treatment using the log-rank test. Additional Kaplan-Meier 
curves will be generated treating rescue medication as an event for the time to development of 
moderate/severe intensity headache and time to development of severe headache.
For each of the 5 most common individual prodrome symptoms, the absence of any intensity, 
absence of moderate/severe intensity, absence of severe intensity at each timepoint will be 
analyzed using the same GLMM model as primary endpoint. Similar analyses will be performed 
for the absence of any intensity nonheadache migraine symptom, absence of moderate/severe 
nonheadache migraine symptom, absence of severe nonheadache migraine symptom at each 
timepoint, and absence of aura at each timepoint. Kaplan-Meier curves for time to absence of 
prodrome symptoms will be produced by treatment and compared between treatment using the 
log-rank test. Kaplan-Meier curves will also be generated censoring data collected after rescue 
medication.
The observed proportions of participants who used rescue medication within 24 and 48 hours 
after taking double-blind study intervention will be summarized and analyzed using the same 
GLMM model as primary endpoint. The treatment comparisons will be conducted using the 
primary model. Kaplan-Meier curves for time to rescue medication use within 48 hours after 
taking double-blind study intervention will also be produced by treatment and compared by 
log-rank test.
Analysis methods for the endpoints of satisfaction with study medication and Activity Limitation 
will be specified in the SAP.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, clinical laboratory tests, ECGs, vital signs, and the 
C-SSRS. For each of the clinical laboratory tests, vital signs, and ECG parameters, the last 
nonmissing safety assessment before the first dose of double-blind study intervention will be 
used as the baseline for all analyses of that safety parameter.
9.4.2.1.
Adverse Events
An AE will be assigned to a study intervention if it occurred on or after the first dose of the study 
intervention and before the first dose of the next study intervention. An AE will be assigned to 


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the last study intervention of the treatment sequence if it occurred on or after the first dose of the 
last study intervention.
AEs will primarily be assessed through the analysis of AEs reported in the 48 hours following 
the administration of study intervention. A supportive analysis will include AEs reported within 
30 days after the last dose of the study intervention (and before the first dose of the next 
intervention if any).
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 Period 1 study intervention and before the date of 
the Period 2 study intervention and an AE that occurs more than 30 days after the Period 2 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.
The number and percentage of participants with TEAEs in each study intervention will be 
tabulated by system organ class and preferred term and by system organ class, preferred term, 
and severity.
The number and percentage of participants with treatment-related TEAEs in each study 
intervention 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 on the same study 
treatment, 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. Listings of all AEs, SAEs, and AEs leading to discontinuation by 
participant will be presented.
The definitions of an AE and SAE can be found in Section 10.3 (Appendix 3).
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline and changes from 
baseline at postdose assessment will be presented by study intervention for each clinical 
laboratory assessment.
The criteria for potentially clinically significant laboratory values will be detailed in the SAP. 
The number and percentage of participants who have potentially clinically significant 
postbaseline clinical laboratory values will be tabulated by study intervention. The assessment 
will be presented in the last study intervention the participant received. The percentages will be 
calculated relative to the number of participants who have available nonpotentially clinically 
significant baseline values and at least 1 postbaseline assessment. The numerator will be the total 
number of participants with at least 1 potentially clinically significant postbaseline value. A 
supportive listing of participants with potentially clinically significant postbaseline values will be 
provided for the safety population.


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9.4.2.3.
Vital Signs
Descriptive statistics for vital signs (sitting and standing systolic and diastolic BP, sitting and 
standing pulse rate, respiration rate, temperature, weight, and body mass index) at baseline and 
changes from baseline at postdose assessment will be presented by study intervention.
Vital signs values will be considered to be potentially clinically significant 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 potentially clinically significant 
postbaseline vital sign values will be tabulated by study intervention. The assessment will be 
presented in the last study intervention the participant received. The percentages will be 
calculated relative to the number of participants who have available nonpotentially clinically 
significant baseline values and at least 1 postbaseline assessment. The numerator will be the total 
number of participants with at least 1 potentially clinically significant postbaseline value. A 
supportive listing of participants with potentially clinically significant postbaseline values will be 
provided for the safety population.
9.4.2.4.
Electrocardiograms
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS interval, RR interval, QT 
interval, QTcB, and QTcF) at baseline and changes from baseline values at postdose assessment 
will be presented by study intervention.
The criteria for potentially clinically significant ECG values will be detailed in the SAP. The 
number and percentage of participants who have potentially clinically significant postbaseline 
ECG values will be tabulated by study intervention. The assessment will be presented in the last 
study intervention the participant received. The percentages will be calculated relative to the 
number of participants who have available nonpotentially clinically significant baseline values 
and at least 1 postbaseline assessment. The numerator will be the total number of participants 
with at least 1 potentially clinically significant postbaseline value. A supportive listing of 
participants with potentially clinically significant postbaseline values will be provided for the 
safety population.
9.4.2.5.
Suicidality Assessment
For the C-SSRS, the number of participants with suicidal ideation and suicidal behavior in 
lifetime history and after taking double-blind study intervention will be summarized by study 
intervention for the safety population. The assessment will be presented in the last study 
intervention the participant received. A supportive listing of participants with suicidal ideation or 
suicidal behavior will be provided for the safety population.
9.4.2.6.
Potential Hy's Law
Potential Hy's Law criteria within a 24-hour window is defined by elevated ALT or AST 
laboratory value that is ≥ 3 × ULN and an elevated total bilirubin laboratory value that is 
≥2 × ULN and, at the same time, an alkaline phosphatase laboratory value that is < 2 × ULN, all 
based on blood draws collected within a 24-hour period.
Potential Hy's Law criteria without time window (evaluation of drug-induced serious 
hepatotoxicity) is defined by maximum of postbaseline elevation of ALT or AST laboratory 


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value that is ≥ 3 × ULN, along with maximum of postbaseline total bilirubin laboratory value 
that is ≥ 2 × ULN.
Participants who meet the potential Hy's Law criteria after taking study intervention and to the 
end of study participation will be summarized. If participants have unscheduled laboratory 
results after Visit 4 that meet potential Hy's Law criteria, the participants will be included in 
analysis. Supportive tabular displays will also be provided.
Participants who meet the potential Hy's Law criteria will be summarized by study treatment. 
The assessment will be present in the last study treatment the participant received.
9.4.3.
PK Analyses
9.4.3.1.
PK Parameters
Tmax, Cmax, and AUC0-last of ubrogepant will be calculated for all participants in the optional PK 
substudy. In addition, estimates of T1/2 and AUC0-inf will be calculated, if a sufficient portion of 
the terminal elimination phase has been captured until the last PK sample collection.
9.4.3.2.
Statistical Analyses of PK Data
Details of the statistical analyses of PK data (both PK concentrations and PK parameters) will be 
described in a separate PK analysis plan, that will be finalized before database lock. Descriptive 
statistics will be provided for PK concentrations and PK parameters by participant for all 
participants in the PK population.
9.4.4.
Other Analyses
Health outcomes exploratory analyses will be described in a SAP finalized before database lock.
9.4.4.1.
Subgroup Analyses
Subgroup analyses of the primary efficacy endpoint will be performed by current exposure 
(yes/no) to a migraine preventative medication with proven efficacy, and by allodynia status at 
randomization (absence/presence).
9.5.
Interim Analyses
No unblinded interim analysis is planned for the study.


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10.
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/ISO GCP Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations
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, privacy and data protection requirements, 
and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented 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 by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; any identifiable 
participant information will only be transferred in accordance with the signed Informed 
Consent provisions.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local privacy and data protection laws. The level of 
disclosure must also be explained to the participant who will be required to give consent 
for their personal data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Committees Structure
Not applicable.
10.1.6.
Dissemination of Clinical Study Data

Study data and information may be published in nonpromotional, peer-reviewed 
publications either by or on behalf of the sponsor. 

Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required.

Company-sponsored study information and tabular study results will be posted on the US 
National Institutes of Health's website www.ClinicalTrials.gov and other publicly 
accessible sites.


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10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the monitoring plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

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.
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator's site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records should be available.

Definition of what constitutes source data can be found in the Study Reference Manual.


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10.1.9.
Study and Site Start and Closure
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. If a premature termination or 
suspension occurs, the sponsor shall remain responsible for providing resources to fulfill the 
protocol obligations and existing agreements for follow-up of participants enrolled in the study, 
and each investigator or authorized designee shall promptly inform enrolled participants, if 
applicable.
10.1.10.
Publication Policy

The sponsor has proprietary interest in this study. Authorship and manuscript composition 
will reflect joint cooperation between multiple investigators and sites and sponsor 
personnel. Authorship will be established prior to the writing of the manuscript. As this 
study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with the sponsor.

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. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.1.11.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB/IEC according to the IRB/IEC's reporting requirements.


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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.

Investigators must document their review of each laboratory safety report.
Table 10-1
Protocol-required Clinical Laboratory Tests
Category
Parameter
Chemistry
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine,
total bilirubin, alkaline phosphatase, AST, ALT, lactate dehydrogenase, creatine 
kinase, total protein, albumin, calcium, phosphorus, uric acid, total cholesterol, 
high density lipoprotein, low density lipoprotein, total triglycerides. The estimated 
glomerular filtration rate will be calculated by the central laboratory.
Hematology
Hemoglobin; hematocrit; red blood cell count; red blood cell indices (mean
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin
concentration); white blood cell count, including differential (neutrophils,
lymphocytes, monocytes, eosinophils, and basophils); platelet count
Urinalysis
Urine dipstick for specific gravity, pH, protein, glucose, ketones, bilirubin, and
blood; microscopic exam including red blood cells/high-power field, white blood
cells/high-power field, and casts/low-power field.
Coagulation
At Visit 1 only: INR
Urine Drug Screen
Screening for drugs of abuse (eg, marijuana, cocaine, phencyclidine, 
amphetamines, benzodiazepines, barbiturates, opiates) will be conducted using a 
urine drug screen at Visit 1. Urine drug screens positive for recreational (including 
marijuana regardless of legality) or illicit drugs or nondisclosed concomitant 
medications are allowed to be repeated. Further urine drug screens may be repeated 
with permission from the sponsor; a negative result or an explanation of a positive 
result due to concomitant medication use (eg, opioids prescribed for migraine pain) 
will be required for randomization.
Refer to Section 10.3 for information regarding clinical laboratory tests for AESIs. 
















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10.4.
Appendix 4: Abbreviations
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ASC-12
12-item Allodynia Symptom Checklist
AST
aspartate aminotransferase
AUC0-inf
area under the blood concentration versus time curve from time 0 to infinity
AUC0-last
area under the blood concentration versus time curve from time 0 to time t, where t is 
the last quantifiable/collected timepoint 
BCRP
breast cancer resistance protein
BMI
body mass index
BP
blood pressure
CBD
cannabidiol
CDISC
Clinical Data Interchange Standards Consortium
CFR
Code of Federal Regulations
CGRP
calcitonin gene-related peptide
CGRP-RA
calcitonin gene-related peptide receptor antagonist
Cmax
maximum blood concentrations
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
cardiovascular
CYP3A4
cytochrome P450 3A4
DBS
dry blood spot
ECG
electrocardiogram
EC90
90% maximal effective concentration
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic diary
EOS
end of study
ET
early termination
eTablet
electronic tablet
FDA
Food and Drug Administration
FDS
Functional Disability Scale
FSH
follicle-stimulating hormone
GBD
Global Burden of Disease
GCP
Good Clinical Practice
GEE
generalized estimating equations
GLMM
generalized linear mixed model
HEOR
Health Economics Outcomes Research
HIV
Human immunodeficiency virus


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Abbreviation
Definition
HRT
hormone replacement therapy
ICF
informed consent form
ICH
International Council for Harmonisation
ICHD-3
International Classification of Headache Disorders criteria, 3rd Edition
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
ISO
International Organization for Standardization
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
mITT
modified intent-to-treat
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
PK
pharmacokinetic
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)1/2)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)1/3)
SAE
serious adverse event
SAP
statistical analysis plan
SNRI
serotonin norepinephrine reuptake inhibitor
SoA
schedule of activities
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
T1/2
terminal elimination half life
TEAE
treatment-emergent adverse event
TENS
transcutaneous electrical nerve stimulation
TESAE
treatment-emergent serious adverse event
Tmax
time to achieve maximum concentrations
ULN
upper limit of normal
WOCBP
women 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)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Failure to meet randomization criteria
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI)
Progressive disease
A disease process that is increasing in extent or severity (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Recovery
A healing process and/or an outcome implying relative health. The 
term is typically used in the context of direct and indirect effects of 
sickness or injury. (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)


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CDISC Submission Value
CDISC Definition
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by parent/guardian
An indication that a study participant has been removed from the 
study by the parent or legal guardian
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)


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10.6.
Appendix 6: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).
Parameter Group
Parameter
Value
Trial information
Trial Title
A Phase 3, Multicenter, Randomized, Double-
blind, Placebo-controlled, Crossover Study to 
Evaluate the Efficacy, Safety, and Tolerability 
of Oral Ubrogepant in the Acute Treatment of 
Migraine When Administered During the 
Prodrome
Clinical Study Sponsor
AbbVie Inc
Trial Phase Classification
Phase 3
Trial Indication
Migraine
Trial Indication Type
Treatment
Trial Type
Efficacy
Safety
Trial Length
Approximately 4 months
Planned Country of Investigational Sites
United States
Planned Number of Subjects
Approximately 516 participants
FDA-regulated Device Study
No
FDA-regulated Drug Study
Yes
Pediatric Study
No
Subject 
information
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18 years
Planned Maximum Age of Subjects
75 years
Sex of Participants
Both
Stable Disease Minimum Duration
1 year
Treatments
Investigational Therapy or Treatment
Ubrogepant
Intervention Type
Drug
Dose per Administration
100 mg
Dose Units
50 mg
Dosing Frequency
One dose (100 mg) to treat a qualifying 
prodrome event. Placebo would be taken to 
treat second qualifying prodrome event.
Route of Administration
Oral
Trial design
Study Type
Interventional
Intervention Model
Crossover
Planned Number of Arms
2 sequences
Trial Is Randomized
Yes
Trial Blinding Schema
Double blind
Adaptive Design
No


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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with one of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation can come from the site personnel's: review of the participant's medical 
records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, 
in the absence of 12 months of amenorrhea, confirmation with more than 1 FSH 
measurement is required.

Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following for the duration of the study:

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent


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
Agree to use a male condom with spermicide plus partner use of a contraceptive method 
with a failure rate of < 1% per year as described in Table 10-2 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 for the 
duration of the study.
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 for the duration of the study.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective and acceptable method of contraception consistently and correctly as described 
in Table 10-2.
Table 10-2
Highly Effective and Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.


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Acceptable Methods Acceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
Pregnancy Testing:

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test at the screening and randomization visits.

Additional pregnancy testing will be performed at Visit 3 during the study intervention 
period and at Visit 4 after the last dose of study intervention.

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

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of learning 
of a participant's pregnancy.


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
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: International Classification of Headache Disorders, 3rd 
Edition, 2018
1.
Migraine
1.1
Migraine without aura
1.2
Migraine with aura
1.2.1
Migraine with typical aura
1.2.1.1
Typical aura with headache
1.2.1.2
Typical aura without headache
1.2.2
Migraine with brainstem aura
1.2.3
Hemiplegic migraine
1.2.3.1
Familial hemiplegic migraine (FHM)
1.2.3.1.1
Familial hemiplegic migraine type 1 (FHM1)
1.2.3.1.2
Familial hemiplegic migraine type 2 (FHM2)
1.2.3.1.3
Familial hemiplegic migraine type 3 (FHM3)
1.2.3.1.4
Familial hemiplegic migraine, other loci
1.2.3.2
Sporadic hemiplegic migraine (SHM)
1.2.4
Retinal migraine
1.3
Chronic migraine
1.4
Complications of migraine
1.4.1
Status migrainosus
1.4.2
Persistent aura without infarction
1.4.3
Migrainous infarction
1.4.4
Migraine aura-triggered seizure
1.5
Probable migraine
1.5.1
Probable migraine without aura
1.5.2
Probable migraine with aura
1.6
Episodic syndromes that may be associated with migraine
1.6.1
Recurrent gastrointestinal disturbance
1.6.1.1
Cyclical vomiting syndrome
1.6.1.2
Abdominal migraine
1.6.2
Benign paroxysmal vertigo
1.6.3
Benign paroxysmal torticollis
Coded elsewhere:
Migraine-like headache secondary to another disorder (symptomatic migraine) is coded as a secondary headache 
attributed to that disorder.
General comment
Primary or secondary headache or both? Three rules apply to migraine-like headache, according to circumstances.
1. When a new headache with the characteristics of migraine occurs for the ﬁrst time in close temporal relation to 
another disorder known to cause headache, or fulﬁls other criteria for causation by that disorder, the new headache 
is coded as a secondary headache attributed to the causative disorder.
2. When pre-existing migraine becomes chronic in close temporal relation to such a causative disorder, both the initial 
migraine diagnosis and the secondary diagnosis should be given. 8.2 Medication-overuse headache is a particularly 
important example of this: both the migraine diagnosis (episodic or chronic) and the diagnosis 8.2 Medication-overuse
headacheshouldbe given when medication overuse is present.
3. When pre-existing migraine is made signiﬁcantly worse (usually meaning a twofold or greaterincrease in frequency and/or 
severity) in close temporal relation to such a causative disorder, both the initial migraine diagnosis and the secondary 
headache diagnosis should be given, provided that there is good evidence that the disorder can cause headache.
Introduction
Migraine is a common disabling primary headache disorder. Many epidemiological studies have documented its high prevalence 
and socio-economic and personal impacts. In the Global Burden of Disease Study 2010 (GBD2010), it was ranked as the third 
most prevalent disorder in the world. In GBD2015, it was ranked the third-highest cause of disability worldwide in both males 
and females under the age of 50 years.


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Migraine has two major types: 1.1 Migraine without aura is a clinical syndrome characterized by headache with speciﬁc features 
and associated symptoms; 1.2 Migraine with aura is primarily characterized by the transient focal neurological symptoms that 
usually precede or sometimes accompany the headache. Some patients also experience a prodromal phase, occurring hours or days
before the headache, and/or a postdromal phase following headache resolution. Prodromal and postdromal symptoms include 
hyperactivity, hypoactivity, depression, cravings for particular foods, repetitive yawning, fatigue and neck stiffness and/or pain.
When a patient fulﬁls criteria for more than one type, subtype or subform of migraine, all should be diagnosed and coded. 
For example, a patient who has frequent attacks with aura but also some attacks without aura should be coded as 1.2 Migraine 
with aura and 1.1 Migraine without aura. However, since the diagnostic criteria for 1.3 Chronic migraine subsumeattacks of 
all types, subtypes or subforms, additional coding is unnecessary for episodic subtypes of migraine.
1.1
Migraine without aura
Previously used terms: Common migraine; hemicrania simplex
Description: Recurrent headache disorder manifesting in attacks lasting 4–72 hours Typical characteristics of the headache 
are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and 
association with nausea and/or photophobia and phonophobia.
Diagnostic criteria:
A.
At least ﬁve attacks1 fulﬁlling criteria B–D
B.
Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated)2,3
C.
Headache has at least two of the following four characteristics:
1.
unilateral location
2.
pulsating quality
3.
moderate or severe pain intensity
4.
aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs)
D.
During headache at least one of the following:
1.
nausea and/or vomiting
2.
photophobia and phonophobia
E.
Not better accounted for by another ICHD-3 diagnosis.
Notes:
1. One or a few migraine attacks may be difficult to distinguish from symptomatic migraine-like attacks. Furthermore, 
the nature of a single or a few attacks may be difficult to understand. Therefore, at least ﬁve attacks are required. 
Individuals who otherwise meet criteria for 1.1 Migraine without aura but have had fewer than ﬁve attacks should 
be coded 1.5.1 Probable migraine without aura.
2. When the patient falls asleep during a migraine attack and wakes up without it, duration of the attack is reckoned
until the time of awakening.
3. In children and adolescents (aged under 18 years), attacks may last 2–72 hours (the evidence for untreated durations 
of less than two hours in children has not been substantiated).
Comments: Migraine headache in children andadolescents (aged under 18 years) is more often bilateral than is the case in
adults; unilateral pain usually emerges in late adolescence orearly adult life. Migraine headache is usually frontotemporal. 
Occipital headache in children is rare and calls for diagnostic caution. A subset of otherwise typical patients have facial 
location of pain, which is called 'facial migraine' in the literature; there is no evidence that these patients form a separate 
subgroup of migraine patients. Prodromal symptoms may begin hours or a day or two before the other symptoms of a migraine 
attack without aura. They include various combinations of fatigue, difficulty in concentrating, neck stiffness, sensitivity to 
light and/or sound, nausea, blurred vision, yawning and pallor. Postdromal symptoms, most commonly feeling tired or weary, 
difficulty with concentration and neck stiffness, may follow resolution of the headache, persisting for up to 48 hours; these 
are less well studied.
Migraine attacks can be associated with cranial autonomic symptoms and symptoms of cutaneous allodynia.
In young children, photophobia and phonophobia may be inferred from their behaviour.
A minority (<10%) of women have attacks of migraine in association with the majority of their menstrual cycles; most of 
such attacks are without aura. Attacks during menstruation tend to be longer and accompanied by more severe nausea than 
attacks outside the menstrual cycle. ICHD-3 offers criteria for A1.1.1 Pure menstrual migraine without aura, A1.1.2 
Menstrually related migraine without aura and A1.1.3 Non-menstrual migraine without aura, but in the Appendix because 
of uncertainty over whether they should be regarded as separate entities. Criteria are also offered for A1.2.0.1 Pure menstrual 


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migraine with aura, A1.2.0.2 Menstrually related migraine with aura and A1.2.0.3 Non-menstrual migraine with aura to 
encourage better characterization of these uncommon subforms if they are separate entities.
Very frequent migraine attacks are distinguished as 1.3 Chronic migraine. When there is associatedmedication overuse,
both of the diagnoses 1.3 Chronic migraine and 8.2 Medication-overuse headache should be applied. 1.1 Migraine without
aura is the disease most prone to accelerate with frequent use of symptomatic medication. Regional cerebral blood ﬂow
imaging shows no changes suggestive of cortical spreading depression (CSD) during attacks of 1.1 Migraine without
aura, although blood ﬂow changes in the brainstem may occur, as may cortical changes secondary topain activation. This
contrasts with the pathognomonic spreading oligaemia of1.2 Migrainewithaura. Whilethebulk ofthe literature suggests 
that CSD does not occur in 1.1 Migraine without aura, some recent studies disagree. Furthermore, it has been suggested
that glial waves or other cortical phenomena may be involved in 1.1 Migraine without aura. The messenger molecules
nitric oxide (NO), serotonin (5-hydroxytryptamine;5-HT) and calcitonin gene-related peptide (CGRP) are involved. While 
the disease was previously regarded as primarily vascular, the importance of sensitization of pain pathways, and the
possibility that attacks may originate in the central nervous system, have gainedincreasing attention over the last decades.
At the same time, the circuitry of migraine pain, the trigeminovascular system, and several aspects of its 
neurotransmission peripherally and in the trigeminal nucleus caudalis, central mesencephalic grey and thalamus, have
been recognized. Highly receptor- speciﬁc acute medications including 5-HT1B/D receptor agonists (triptans), 5-HT1F
receptor agonists and CGRP receptor antagonists have demonstrated efficacy in the acute treatment of migraine 
attacks. Because of their high receptor-speciﬁcity, their mechanisms ofaction provide new insight into migraine 
mechanisms. It is now clear that 1.1 Migraine without aura is a neurobiological disorder, while clinical as well as basic
neuroscience studies continue to advance our knowledge of migraine mechanisms.
1.2
Migraine with aura
Previously used terms: Classic or classical migraine; ophthalmic, hemiparaesthetic, hemiplegic or aphasic migraine;
migraine accompagnee; complicated migraine.
Description: Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system 
symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms.
Diagnostic criteria:
A.
At least two attacks fulﬁlling criteria B and C
B.
One or more of the following fully reversible aura symptoms:
1.
visual
2.
sensory
3.
speech and/or language
4.
motor
5.
brainstem
6.
retinal
C.
At least three of the following six characteristics:
1.
at least one aura symptom spreads gradually over ≥5 minutes
2.
two or more aura symptoms occur in succession
3.
each individual aura symptom lasts 5–60 minutes1
4.
at least one aura symptom is unilateral2
5.
at least one aura symptom is positive3
6.
the aura is accompanied, or followed within 60 minutes, by headache
D.
Not better accounted for by another ICHD-3 diagnosis.
Notes:
1. When, for example, three symptoms occur during an aura, the acceptable maximal duration is 3 x 60 minutes. Motor
symptoms may last up to 72 hours.
2. Aphasia is always regarded as a unilateral symptom; dysarthria may or may notbe.
3. Scintillations and pins and needles are positive symptoms of aura.
Comments: Many patients who have migraine attacks with aura also have attacks without aura; they should be coded as 
both 1.2 Migraine with aura and 1.1 Migraine without aura.


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Field testing has compared the diagnostic criteria for 1.2 Migraine with aura in the main body of ICHD-3 beta with those 
for A1.2 Migraine with aura in the Appendix. The latter performed better in distinguishing migraine with aura from 
transient ischaemic attacks. These are now adopted in ICHD-3, which no longer has Appendix criteria for this disorder.
The aura is the complex of neurological symptoms that occurs usually before the headache of 1.2 Migraine with aura, but 
it may begin after the headache phase has commenced or continue into the headache phase.
Visual aura is the most common type of aura, occurring in over 90% of patients with 1.2 Migraine with aura, at least in 
some attacks. It often presents as a fortiﬁcation spectrum: a zigzag ﬁgure near the point of ﬁxation that may gradually 
spread right or left and assume a laterally convex shape with an angulated scintillating edge, leaving absolute or variable 
degrees of relative scotoma in its wake. In other cases, scotoma without positive phenomena may occur; this is often 
perceived as being of acute onset but, on scrutiny, usually enlarges gradually. In children and adolescents,less typical 
bilateral visual symptoms occur that may represent an aura. A visual aura rating scale with high speciﬁcity and sensitivity 
has been developed and validated.
Next in frequency are sensory disturbances, in the form of pins and needles moving slowly from the point of origin and 
affecting a greater or smaller part of one side of the body, face and/or tongue. Numbness may occur in its wake, but 
numbness may also be the only symptom.
Less frequent are speech disturbances, usually aphasic but often hard to categorize.
Systematic studies have demonstrated that many patients with visual aura occasionally have symptoms in the extremities 
and/or speech symptoms. Conversely, patients with symptoms in the extremities and/or speech or language symptoms 
almost always also experience visual aura symptoms at least during some attacks. A distinction between migraine with 
visual aura, migraine with hemiparaesthetic aura and migraine with speech and/or language aura is probably artiﬁcial, and 
therefore not recognized in this classiﬁcation: they are all coded as 1.2.1 Migraine with typical aura.
When aura symptoms are multiple, they usually follow one another in succession, beginning with visual, then sensory, 
then aphasic; but the reverse and other orders have been noted. The accepted duration for most aura symptoms is one 
hour, but motor symptoms are often longer lasting.
Patients with aura symptoms arising from the brainstem are coded as 1.2.2Migraine with brainstem aura, but they almost always 
have additional typical aura symptoms. When the aura includes motor weakness, the disorder should be coded as 1.2.3 
Hemiplegic migraine or one of its subforms. 1.2.3 Hemiplegic migraine is classiﬁed as a separate subtype because of genetic 
and pathophysiological differences from 1.2.1 Migraine with typical aura. Patients with 1.2.3 Hemiplegic migraine often have 
brainstem symptoms in addition.
Patients often ﬁnd it hard to describe their aura symptoms, in which case they should be instructed to time and record them 
prospectively. The clinical picture then becomes clearer. Common mistakes are incorrect reports of lateralization, of sudden 
rather than gradual onset and of monocular rather than homonymous visual disturbances, as well as of duration of aura and 
mistaking sensory loss for weakness. After an initial consultation, use of an aura diary may clarify the diagnosis.
Migraine aura is sometimes associated with a headache that does not fulﬁll criteria for 1.1 Migraine without aura, but this 
is still regarded as a migraine headache because of its relation to the aura. In other cases, migraine aura may occur without
headache.
Before or simultaneously with the onset of aura symptoms, regional cerebral blood ﬂow is decreased in the cortex 
corresponding to the clinically affected area and often over a wider area. Blood ﬂow reduction usually starts posteriorly and
spreads anteriorly, and is usually above the ischaemic threshold. After one to several hours, gradual transition into 
hyperaemia occurs in the same region. Cortical spreading depression of Leao is the likely underlying mechanism.
The previously deﬁned syndromes, migraine with prolonged aura and migraine with acute-onset aura, have been 
abandoned. It is not rare for aura to last more than one hour but, in most such cases, patients have at least two of the other 
characteristics of criterion C. Even when most of a patient's attacks do not fulﬁl criterion C, it is usual that other attacks 
fulﬁl criteria for one of the recognized subtypes or subforms of 1.2 Migraine with aura, and this should be the diagnosis. 
The few other cases should be coded to 1.5.2 Probable migraine with aura, specifying the atypical feature (prolonged aura or acute-
onset aura) in parenthesis. The diagnosis is usually evident after a careful history alone, although there are rare secondary mimics 
including carotid dissection, arteriovenous malformation and seizure.
Prodromal symptoms maybegin hours or a day or two before the other symptoms of a migraine attack with aura. They include 
various combinations of fatigue, difﬁculty in concentrating, neck stiﬀness, sensitivity to light and/or sound, nausea, blurred 
vision, yawning and pallor. The term 'prodrome', which has replaced 'premonitory phase' or 'premonitory symptoms', does 
not include aura. Postdromal symptoms, most commonly feeling tired or weary, difficulty with concentration and neck 
stiffness, may follow resolution of the headache, persisting for up to 48 hours; these are less well studied.


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1.2.1 Migraine with typical aura
Description: Migraine with aura, in which aura consists of visual and/or sensory and/or speech/language symptoms, but 
no motor weakness, and is characterized by gradual development, duration of each symptom no longer than one hour, a 
mix of positive and negative features and complete reversibility
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with aura and criterion B below
B.
Aura with both of the following:
1.
fully reversible visual, sensory and/or speech/ language symptoms
2.
no motor, brainstem or retinal symptoms.
1.2.1.1 Typical aura with headache
Description: Migraine with typical aura in which aura is accompanied or followed within 60 minutes by headache with 
or without migraine characteristics.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine with typical aura and criterion B below
B.
Headache, with or without migraine characteristics, accompanies or follows the aura within 60 minutes.
1.2.1.2 Typical aura without headache
Description: Migraine with typical aura in which aura is neither accompanied nor followed by headache of any sort.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.1 Migraine with typical aura and criterion B below
B.
No headache accompanies or follows the aura within 60 minutes.
Comments: In some patients, a typical aura is always followed by migraine headache, but many patients have, in 
addition, attacks with aura followed by a less distinct headache or even without headache. A number of patients have, 
exclusively, 1.2.1.2 Typical aura without headache.
In the absence of headache fulﬁlling criteria for 1.1 Migraine without aura, the precise diagnosis of aura and its 
distinction from mimics that may signal serious disease (e.g., transient ischaemic attack) becomes more difﬁcult and 
often requires investigation. When aura occurs for the ﬁrst time after age 40, when symptoms are exclusively negative 
(e.g., hemianopia) or when aura is prolonged or very short, other causes, particularly transient ischaemic attacks,
should be ruled out.
1.2.2 Migraine with brainstem aura
Previously used terms: Basilar artery migraine; basilar migraine; basilar-type migraine.
Description: Migraine with aura symptoms clearly originating from the brainstem, but no motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with aura and criterion B below
B.
Aura with both of the following:
1.
at least two of the following fully reversible brainstem symptoms:
a.
dysarthria1
b.
vertigo2
c.
tinnitus
d.
hypacusis3
e.
diplopia4
f.
ataxia not attributable to sensory deﬁcit
g.
decreased level of consciousness (GCS ≤13)5
2.
no motor6 or retinal symptoms.


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Notes:
1. Dysarthria should be distinguished from aphasia.
2. Vertigo does not embrace and should be distinguished from dizziness.
3. This criterion is not fulﬁlled by sensations of ear fullness.
4. Diplopia does not embrace (or exclude) blurred vision.
5. The Glasgow Coma Scale (GCS) score may have been assessed during admission; alternatively, deficits clearly 
described by the patient allow GCS estimation.
6. When motor symptoms are present, code as 1.2.3 Hemiplegic migraine.
Comments: Originally the terms basilar artery migraine or basilar migraine were used but, since involvement of the basilar 
artery is unlikely, the term migraine with brainstem aura is preferred.
There are typical aura symptoms in addition to the brainstem symptoms during most attacks. Many patients who have 
attacks with brainstem aura also report other attacks with typical aura and should be coded for both 1.2.1 Migraine
with typical aura and 1.2.2 Migraine with brainstem aura.
Many of the symptoms listed under criterion B1 may occur with anxiety and hyperventilation, and are therefore subject 
to misinterpretation.
1.2.3 Hemiplegic1 migraine
Description: Migraine with aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with aura and criterion B below
B.
Aura consisting of both of the following:
1.
fully reversible motor weakness2
2.
fully reversible visual, sensory and/or speech/ language symptoms.
Notes:
1. The term plegic means paralysis in most languages, but most attacks are characterized by motor weakness.
2. Motor symptoms generally last less than 72 hours but, in some patients, motor weakness may persist for weeks.
Comment: It may be difficult to distinguish weakness from sensory loss.
1.2.3.1 Familial hemiplegic migraine (FHM)
Description: Migraine with aura including motor weakness, and at least one ﬁrst- or second-degree relative has 
migraine aura including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 Hemiplegic migraine
B.
At least one ﬁrst- or second-degree relative has had attacks fulﬁlling criteria for 1.2.3 Hemiplegic migraine.
Comments: New genetic data have allowed a more precise deﬁnition of 1.2.3.1 Familial hemiplegic migraine than was 
previously possible. Speciﬁc genetic subforms have been identiﬁed: in FHM1 there are mutations in the CACNA1A gene 
(coding for a calcium channel) on chromosome 19; in FHM2 there are mutations in the ATP1A2 gene (coding for a K/Na-
ATPase) on chromosome 1; and in FHM3 there are mutations in the SCN1A gene (coding for a sodium channel) on 
chromosome 2. There may be other loci not yet identiﬁed. When genetic testingis done, the geneticsubform (ifdiscovered)
should be speciﬁed at the ﬁfth digit.
It has been shown that 1.2.3.1 Familial hemiplegic migraine very often presents with brainstem symptoms in addition to 
the typical aura symptoms, and that headache almost always occurs. Rarely, during FHM attacks, disturbances of 
consciousness (sometimes including coma), confusion, fever and cerebrospinal ﬂuid (CSF) pleocytosis can occur.
1.2.3.1 Familialhemiplegic migrainemaybe mistaken for epilepsy and treated (unsuccessfully) as such. FHM attacks can be 
triggered by (mild) head trauma. In approximately 50% of FHM families, chronic progressive cerebellar ataxia occurs 
independently of the migraine attacks.


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1.2.3.1.1 Familial hemiplegic migraine type 1 (FHM1)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial hemiplegic migraine
B.
A mutation on the CACNA1A gene has been demonstrated.
1.2.3.1.2 Familial hemiplegic migraine type 2 (FHM2)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial hemiplegic migraine
B.
A mutation on the ATP1A2 gene has been demonstrated.
1.2.3.1.3 Familial hemiplegic migraine type 3 (FHM3)
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial hemiplegic migraine
B.
A mutation on the SCN1A gene has been demonstrated.
1.2.3.1.4 Familial hemiplegic migraine, other loci
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3.1 Familial hemiplegic migraine
B.
Genetic testing has demonstrated no mutationon the CACNA1A, ATP1A2 or SCN1A genes.
1.2.3.2 Sporadic hemiplegic migraine (SHM)
Description: Migraine with aura including motor weakness, and no ﬁrst- or second-degree relative has migraine aura 
including motor weakness.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2.3 Hemiplegic migraine
B.
No ﬁrst- or second-degree relative fulﬁls criteria for 1.2.3 Hemiplegic migraine.
Comments: Epidemiological studies have shown that sporadic cases occur with approximately the same prevalence as 
familial cases.
The attacks in 1.2.3.2 Sporadic hemiplegic migraine have the same clinical characteristics as those in 1.2.3.1 Familial
hemiplegic migraine. Some apparentlysporadic cases have known FHM mutations and, in some, a ﬁrst- or second-degree 
relative later develops hemiplegic migraine, thus completing fulﬁlment of the criteria for 1.2.3.1 Familial hemiplegic 
migraine and requiring a change of diagnosis.
Sporadic cases usually require neuroimaging and other tests to rule out other causes. A lumbar puncture may be necessary 
to rule out 7.3.5 Syndrome of transient headache and neurological deﬁcits with cerebrospinal ﬂuid lymphocytosis
(HaNDL).
1.2.4 Retinal migraine
Description: Repeated attacks of monocular visual disturbance, including scintillations, scotomata or blindness, 
associated with migraine headache.
Diagnostic criteria:
A.
Attacks fulﬁlling criteria for 1.2 Migraine with aura and criterion B below
B.
Aura characterized by both of the following:
1.
fully reversible, monocular, positive and/or negative visual phenomena (e.g., scintillations, scotomata or 
blindness) conﬁrmed during an attack by either or both of the following:
a.
clinical visual ﬁeld examination


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b.
the patient's drawing of a monocular ﬁeld defect (made after clear instruction)
2.
at least two of the following:
a. spreading gradually over ≥5 minutes
b.
symptoms last 5–60 minutes
c.
accompanied, or followed within 60 minutes, by headache
C.
Not better accounted for by another ICHD-3 diagnosis, and other causes of amaurosis fugax have been excluded.
Comments: Some patients who complain of monocular visual disturbance in fact have hemianopia. Some cases without 
headache have been reported, but migraine as the underlying aetiology cannot be ascertained.
1.2.4 Retinal migraine is an extremely rare cause of transient monocular visual loss. Cases of permanent monocular visual 
loss associated with migraine have been described. Appropriate investigations are required to exclude other causes of 
transient monocular blindness.
1.3
Chronic migraine
Description: Headache occurring on 15 or more days/ month for more than three months, which, on at least eight
days/month,hasthefeaturesofmigraineheadache.
Diagnostic criteria:
A.
Headache (migraine-like or tension-type-like1) on ≥15 days/month for >3 months, and fulﬁlling criteria B and C
B.
Occurring in a patient who has had at least ﬁve attacks fulﬁlling criteria B–D for 1.1 Migraine without aura and/or 
criteria B and C for 1.2 Migraine with aura
C.
On ≥8 days/month for >3 months, fulﬁlling any of the following2:
1.
criteria C and D for 1.1 Migraine without aura
2.
criteria B and C for 1.2 Migraine with aura
3.
believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
D.
Not better accounted for by another ICHD-3 diagnosis.3–5
Notes:
1. The reason for singling out 1.3 Chronic migraine from types of episodic migraine is that it is impossible to distinguish 
the individual episodes of headache in patients with such frequent or continuous headaches. In fact, the characteristics 
of the headache may change not only from day to day but even within the same day. Such patients are extremely diﬃcult 
to keep medication-free in order to observe the natural history of the headache. In this situation, attacks with and those 
without aura are both counted, as are both migraine-like and tension-type-like headaches (but not secondary headaches).
2. Characterization of frequently recurring headache generally requires a headache diary to record information on 
pain and associated symptoms day by day for at least one month.
3. Because tension-type-like headache is within the diagnostic criteria for 1.3 Chronic migraine, this diagnosis excludes 
the diagnosis of 2. Tension-type headache or its types.
4. 4.10 Newdailypersistent headachemayhave features suggestiveof1.3Chronicmigraine.Thelatterdisorder evolvesover
timefrom 1.1Migrainewithoutauraand/ or 1.2 Migraine with aura; therefore, when these criteria A–C are fulﬁlled by 
headache that, unambiguously, is daily and unremitting from <24 hours after its ﬁrst onset, code as 4.10 New daily
persistent headache. When the manner of onset is not remembered or is otherwise uncertain, code as 1.3 Chronic
migraine.
5. The most common cause of symptoms suggestive of chronic migraine is medication overuse, as deﬁned under 8.2
Medication-overuse headache. Around 50% of patients apparently with 1.3 Chronic migraine revert to an episodic 
migraine type after drug withdrawal; such patients are in a sense wrongly diagnosed as 1.3 Chronic migraine. Equally, 
many patients apparently overusing medication do not improve after drug withdrawal; the diagnosis of 8.2 
Medication-overuse headache may be inappropriate for these (assuming that chronicity induced by drug overuse is 
always reversible). For these reasons, and because of the general rule to apply all relevantdiagnoses, patients meeting 
criteria for 1.3 Chronic migraine and for 8.2 Medication-overuse headache should be coded for both. After drug 
withdrawal, migraine will either revert to an episodic type or remain chronic and should be re-diagnosed accordingly; 
in the latter case, the diagnosis of 8.2 Medication-overuse headache may be rescinded.
1.4
Complications of migraine
Comment: Code separately for both the migraine type, subtype or subform and for the complication.


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1.4.1 Status migrainosus
Description: A debilitating migraine attack lasting for more than 72 hours.
Diagnostic criteria:
A.
A headache attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.1 Migraine without aura and/or 1.2 Migraine with aura, and typical of previous
attacks except for its duration and severity
C.
Both of the following characteristics:
1.
unremitting for >72 hours1
2.
pain and/or associated symptoms are debilitating2
D.
Not better accounted for by another ICHD-3 diagnosis.
Notes:
1. Remissions of up to 12 hours due to medication or sleep are accepted.
2. Milder cases, not meeting criterion C2, are coded 1.5.1 Probable migraine without aura.
Comment: Headache with the features of 1.4.1 Status migrainosus may often be caused by medication overuse. When 
headache in these circumstances meets the criteria for 8.2 Medication-overuse headache, code for this disorder and the relevant 
type or subtype of migraine but not for 1.4.1 Status migrainosus. When overuse of medication is of shorter duration than three 
months, code for the appropriate migraine type or subtype(s) only.
1.4.2 Persistent aura without infarction
Description: Aura symptoms persisting for one week or more without evidence of infarction on neuroimaging.
Diagnostic criteria:
A.
Aura fulﬁlling criterion B
B.
Occurring in a patient with 1.2 Migraine with aura and typical of previous auras except that one or more aura 
symptoms persists for ≥1 week
C.
Neuroimaging shows no evidence of infarction
D.
Not better accounted for by another ICHD-3 diagnosis.
Comments: Persistent aura symptoms are rare but well documented. They are often bilateral and may last for months or 
years. The one-week minimum in criterion B is based on the opinion of experts and should be formally studied.
Diagnostic work-up must distinguish 1.4.2 Persistent aura without infarction from 1.4.3 Migrainous infarction and 
exclude symptomatic aura due to cerebral infarction of other causes. Attacks with prolonged aura lasting less than one 
week and not fulﬁlling criteria for 1.2.1 Migraine with typical aura are coded 1.5.2 Probable migraine with aura.
1.4.3 Migrainous infarction
Description: One or more migraine aura symptoms occurring in association with an ischaemic brain lesion in the 
appropriate territory demonstrated by neuroimaging, with onset during the course of a typical migraine with aura 
attack.
Diagnostic criteria:
A.
A migraine attack fulﬁlling criteria B and C
B.
Occurring in a patient with 1.2 Migraine with aura and typical of previous attacks except that one or more aura 
symptoms persists for >60 minutes1
C.
Neuroimaging demonstrates ischaemic infarction in a relevant area
D.
Not better accounted for by another ICHD-3 diagnosis.


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Note:
1. There may be additional symptoms attributable to the infarction.
Comments: Ischaemic stroke in a migraine sufferer may be categorized as cerebral infarction of other cause coexisting 
with 1. Migraine, cerebral infarction of other cause presenting with symptoms resembling 1.2 Migraine with aura, or 
cerebral infarction occurring during the course of a typical attack of 1.2 Migraine with aura. Only the last fulﬁls criteria 
for 1.4.3 Migrainous infarction.
1.4.3 Migrainous infarction mostly occurs in theposterior circulation and in younger women. A twofold increased risk 
of ischaemic stroke in patients with 1.2 Migraine with aura has been demonstrated in several population-based studies. 
However, it should be noted that these infarctions are not migrainous infarctions. The mechanisms of the increased risk 
of ischaemic stroke in migraine sufferers remain unclear; likewise, the relationship between increased risk and frequency 
of aura and the nature of aura symptoms denoting the increase in risk are unknown. Most studies have shown a lack of 
association between 1.1 Migraine without aura and ischaemic stroke.
1.4.4 Migraine aura-triggered seizure
Description: A seizure triggered by an attack of migraine with aura.
Diagnostic criteria:
A.
A seizure fulﬁlling diagnostic criteria for one type of epileptic attack, and criterion B below
B.
Occurring in a patient with 1.2 Migraine with aura, and during or within one hour after an attack of migraine with
aura
C.
Not better accounted for by another ICHD-3 diagnosis.
Comment: Migraine and epilepsy are prototypical examples of paroxysmal brain disorders. While migraine-like headaches 
are quite frequently seen in the epileptic post-ictal period, sometimes a seizure occurs during or following a migraine 
attack. This phenomenon, sometimes referred to as migralepsy, is a rare event, originally described in patients with 1.2 
Migraine with aura. Evidence of an association with 1.1 Migraine without aura is lacking.
1.5
Probable migraine
Previously used term: Migrainous disorder.
Coded elsewhere: Migraine-like headache secondary to another disorder (symptomatic migraine) is coded according to 
that disorder.
Description: Migraine-like attacks missing one of the features required to fulﬁl all criteria for a type or subtype of migraine 
coded above, and not fulﬁlling criteria for another headache disorder.
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A-D for 1.1 Migraine without aura, or all but one of criteria A–C for 1.2 
Migraine with aura
B.
Not fulﬁlling ICHD-3 criteria for any other headache disorder
C.
Not better accounted for by another ICHD-3 diagnosis.
Comment: In making a headache diagnosis, attacks that fulﬁl criteria for both 2. Tension-type headache and 1.5 Probable 
migraine are coded as the former in accordance with the general rule that a deﬁnite diagnosis always trumps a probable 
diagnosis. However, in patients who already have a migraine diagnosis, and where the issue is to count the number of 
attacks they are having (e.g., as an outcome measure in a drug trial), attacks fulﬁlling criteria for 1.5 Probable migraine 
should be counted as migraine. The reason for this is that mild migraine attacks, or attacks treated early, often do not 
achieve all characteristics necessary for a migraine attack diagnosis but nevertheless respond to speciﬁc migraine
treatments.
1.5.1 Probable migraine without aura Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A-D for 1.1 Migraine without aura
B.
Not fulﬁlling ICHD-3 criteria for any other headache disorder


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C.
Not better accounted for by another ICHD-3 diagnosis.
1.5.2 Probable migraine with aura
Diagnostic criteria:
A.
Attacks fulﬁlling all but one of criteria A–C for 1.2 Migraine with aura or any of its subtypes
B.
Not fulﬁlling ICHD-3 criteria for any other headache disorder
C.
Not better accounted for by another ICHD-3 diagnosis.
1.6
Episodic syndromes that may be associated with migraine
Previously used terms: Childhood periodic syndromes; periodic syndromes of childhood.
Comments: This group of disorders occurs in patients who also have 1.1 Migraine without aura or 1.2 Migraine with 
aura, or who have an increased likelihood to develop either of these disorders. Although historically noted to occur in 
childhood, they may also occur in adults.
Additional conditions that may also occur in these patients include episodes of motion sickness and periodic sleep 
disorders including sleep walking, sleep talking, night terrors and bruxism.
1.6.1 Recurrent gastrointestinal disturbance
Previously used terms: Chronic abdominal pain; functional abdominal pain; functional dyspepsia; irritable bowel 
syndrome; functional abdominal pain syndrome.
Description: Recurrent episodic attacks of abdominal pain and/or discomfort, nausea and/or vomiting, occurring 
infrequently, chronically or at predictable intervals, that may be associated with migraine.
Diagnostic criteria:
A.
At least ﬁve attacks with distinct episodes of abdominal pain and/or discomfort and/or nausea and/or vomiting
B.
Normal gastrointestinal examination and evaluation
C.
Not attributed to another disorder.
1.6.1.1 Cyclic vomiting syndrome
Description: Recurrent episodic attacks of intense nausea and vomiting, usually stereotypical in the individual and with 
predictable timing of episodes. Attacks may be associated with pallor and lethargy. There is complete resolution of 
symptoms betweenattacks.
Diagnostic criteria:
A.
At least ﬁve attacks of intense nausea and vomiting, fulﬁlling criteria B and C
B.
Stereotypical in the individual patient and recurring with predictable periodicity
C.
All of the following:
1.
nausea and vomiting occur at least four times per hour
2.
attacks last for ≥1 hour, up to 10 days
3.
attacks occur ≥1 week apart
D.
Complete freedom from symptoms between attacks
E.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination do not show signs of gastrointestinal disease.
Comments:1.6.1.1 Cyclic vomiting syndrome is typically a self-limiting episodic condition occurring in childhood, 
with periods of complete normality between episodes. The cyclic nature is the hallmark, and attacks are predictable.
This disorder was ﬁrst included as a childhood periodic syndrome in ICHD-II. The clinical features of this syndrome 
resemble those found in association with migraine headaches, and multiple threads of research over the last years have 
suggested that 1.6.1.1 Cyclic vomiting syndrome is a condition related to migraine.


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1.6.1.2 Abdominal migraine
Description: An idiopathic disorder seen mainly in children as recurrent attacks of moderate to severe midline 
abdominal pain, associated with vasomotor symptoms, nausea and vomiting, lasting 2–72 hours and with normality 
between episodes. Headache does not occur during these episodes.
Diagnostic criteria:
A.
At least ﬁve attacks of abdominal pain, fulﬁlling criteria B–D
B.
Pain has at least two of the following three characteristics:
1.
midline location, periumbilical or poorly localized
2.
dull or 'just sore' quality
3.
moderate or severe intensity
C.
At least two of the following four associated symptoms or signs:
1.
anorexia
2.
nausea
3.
vomiting
4.
pallor
D.
Attacks last 2–72 hours when untreated or unsuccessfully treated
E.
Complete freedom from symptoms between attacks
F.
Not attributed to another disorder.1
Note:
1. In particular, history and physical examination do not show signs of gastrointestinal or renal disease, or such disease 
has been ruled out by appropriate investigations.
Comments: Pain of 1.6.1.2 Abdominal migraine is severe enough to interfere with normal daily activities.
In young children, the presence of headache is often overlooked. A careful history of presence or absence of headache 
must be taken and, when headache or head pain during attacks is identiﬁed, a diagnosis of 1.1 Migraine without aura 
should be considered.
Children may ﬁnd it difficult to distinguish anorexia from nausea. Pallor is often accompanied by dark shadows under 
the eyes. In a few patients, ﬂushing is the predominant vasomotor phenomenon.
Most children with abdominal migraine will develop migraine headache later in life.
1.6.2 Benign paroxysmal vertigo
Description: A disorder characterized by recurrent brief attacks of vertigo, occurring without warning and resolving 
spontaneously, in otherwise healthy children.
Diagnostic criteria:
A.
At least ﬁve attacks fulﬁlling criteria B and C
B.
Vertigo1 occurring without warning, maximal at onset and resolving spontaneously after minutes to hours without 
loss of consciousness
C.
At least one of the following ﬁve associated symptoms or signs:
1.
nystagmus
2.
ataxia
3.
vomiting
4.
pallor
5.
fearfulness
D.
Normal neurological examination and audiometric and vestibular functions between attacks
E.
Not attributed to another disorder.2
Notes:
1. Young children with vertigo may not be able to describe vertiginous symptoms. Parental observation of episodic periods 
of unsteadiness may be interpreted as vertigo in young children.


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2. In particular, posterior fossa tumours, seizures and vestibular disorders have been excluded.
Comment: The relationship between 1.6.2 Benign paroxysmal vertigo and A1.6.6 Vestibular migraine (see Appendix) 
needs to be further examined.
1.6.3 Benign paroxysmal torticollis
Description: Recurrent episodes of head tilt to one side, perhaps with slight rotation, which remit spontaneously. The 
condition occurs in infants and small children, with onset in the ﬁrst year.
Diagnostic criteria:
A.
Recurrent attacks1 in a young child, fulﬁlling criteria B and C
B.
Tilt of the head to either side, with or without slight rotation, remitting spontaneously after minutes to days
C.
At least one of the following ﬁve associated symptoms or signs:
1.
pallor
2.
irritability
3.
malaise
4.
vomiting
5.
ataxia2
D.
Normal neurological examination between attacks
E.
Not attributed to another disorder.3
Notes:
1. Attacks tend to recur monthly.
2. Ataxia is more likely in older children within the affected age group.
3. The differential diagnosis includes gastro-oesophageal reﬂux, idiopathic torsional dystonia and complex partial seizure, 
but particular attention must be paid to the posterior fossa and craniocervical junction where congenital or acquired 
lesions may produce torticollis.
Comments: The child's head can be returned to the neutral position during attacks: some resistance may be 
encountered but can be overcome.
These observations need further validation by patient diaries, structured interviews and longitudinal data collection.
1.6.3 Benign paroxysmal torticollis may evolve into
1.6.2 Benign paroxysmal vertigo or 1.2 Migraine with aura (particularly 1.2.2 Migraine with brainstem aura) or cease 
without further symptoms.
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Sances G, Guaschino E, Perucca P, et al. Migralepsy: a call for revision of the deﬁnition. Epilepsia 2009; 50: 2487–2496.
Ter Berg HW. Migraine-associated seizure: a case of reversible MRI abnormalities and persistent non- dominant 
hemisphere syndrome. Headache 2001; 41: 326–328.
Velioglu SK and Ozmenoglu M. Migraine-related seizures in an epileptic population. Cephalalgia 1999; 19: 797–801.
Verrotti A, Coppola G, Di Fonzo A, et al. Should ''migralepsy'' be considered an obsolete concept? A multicenter 
retrospective clinical/EEG study and review of the literature. Epilepsy Behav 2011; 21: 52–59.
1.5 Probable migraine
Granella F, Alessandro RD, Manzoni GC, et al. International Headache Society classiﬁcation: inter- observer reliability in 
the diagnosis of primary headaches. Cephalalgia 1994; 14: 16–20.
Rains JC, Penzien DB, Lipchik GL, et al. Diagnosis of migraine: empirical analysis of a large clinical sample of atypical 
migraine (IHS 1.7) patients and proposed revision of the IHS criteria. Cephalalgia 2001, 21: 584–595.
Rasmussen BK, Jensen R and Olesen J. A population- based analysis of the diagnostic criteria of the International
Headache Society. Cephalalgia 1991; 11: 129–134.
Russell MB and Olesen J. Migrainous disorder and its relation to migraine without aura and migraine with aura. A genetic 
epidemiological study. Cephalalgia 1996; 16: 431–435.


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1.6.1 Recurrent gastrointestinal disturbance
Abu-Arafeh I and Russel G. Prevalence and clinical features of abdominal migraine compared with those of migraine 
headache. Arch Dis Child 1995; 72: 413–417.
Al-Twaijri WA and Shevell MI. Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 
2002; 26: 365–368.
Dignan F, Abu-Arafeh I and Russell G. The prognosis of childhood abdominal migraine. Arch Dis Child 2001; 84: 415-418.
Drossman DA and Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver 
Dis 2006; 15: 237–241.
Farquar HA. Abdominal migraine in children. BMJ 1956; i: 1082–1085.
Fleisher DR. Cyclic vomiting syndrome and migraine. J Pediatr 1999; 134: 533–535.
Haan J, Kors EE and Ferrari MD. Familial cyclic vomiting syndrome. Cephalalgia 2002; 22: 552-554.
Li BU. Cyclic vomiting syndrome: age-old syndrome and new insights. Semin Pediatr Neurol 2001; 8: 13-21.
Li BUK, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and 
Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol 
Nutr 2008; 47: 379–393.
Rashed H, Abell TL, Familoni BO, et al. Autonomic function in cyclic vomiting syndrome and classic migraine. Dig Dis 
Sci 1999; 44(Suppl 8): 74S-78S.
Russell G, Abu-Arafeh I and Symon DN. Abdominal migraine: evidence for existence and treatment options. Paediatr Drugs 
2002; 4: 1-8.Thiessen PN. Recurrent abdominal pain. Pediatr Rev 2002; 23: 39-46.
Welch KM. Scientiﬁc basis of migraine: speculation on the relationship to cyclic vomiting. Dig Dis Sci 1999; 44(Suppl 8):
26S–30S.
1.6.2 Benign paroxysmal vertigo
Drigo P, Carli G and Laverda AM. Benign paroxysmal vertigo of childhood. Brain Dev 2001; 23: 38–41.
Dunn DW and Snyder CH. Benign paroxysmal vertigo of childhood. Am J Dis Child 1976; 130: 1099–1100.
Fenichel GM. Migraine as a cause of benign paroxysmal vertigo of childhood. J Pediatr 1967; 71:114–115.
1.6.3 Benign paroxysmal torticollis
Drigo P, Carli G and Laverda AM. Benign paroxysmal torticollis of infancy. Brain Dev 2000; 22: 169–172. 
Giffin NJ, Benton S and Goadsby PJ. Benign paroxysmal torticollis of infancy: four new cases and linkage to 
CACNA1A mutation. Dev Med Child Neurol 2002; 44: 490–493.
Rosman NP, Douglass LM, Sharif UM, et al. The neurology of benign paroxysmal torticollis of infancy: report of 10 new 
cases and review of the literature. J Child Neurol 2009; 24: 155-160.


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10.9.
Appendix 9: Examples of Prohibited Medications and Allowed 
Medications (with Restrictions)
Prohibited Medications: The following classes of medications below are not allowed to be 
taken during the double-blind treatment period, between Visit 2 and Visit 4/ET. Participants
taking these medications at the Screening Visit (Visit 1) will need to discontinue them prior to 
randomization at Visit 2. Participants who cannot or should not be taken off these medications 
should not be enrolled. If a participant requires concomitant treatment with these medications at 
any time during the study, the participant must be discontinued.
Strong/Moderate CYP3A4 Inducers
Strong/Moderate CYP3A4 Inhibitors
Antidepressant/ 
Antianxiety
Barbiturates

Amobarbital (Amytal®)

Aprobarbital (Alurate®)

Butalbital (Fiorinal®, Fioricet®)

Butabarbital (Busodium®,
Butisol®)

Mephobarbital (Mebaral®)

Pentobarbital (Nembutal®)

Phenobarbital (Luminal®,
Solfoton®)

Secobarbital (Seconal®)
Nefazodone (Serzone®)
Antiseizure
Carbamazepine (Atretol®, Carbatrol®,
Epitol®, Equetro®, Tegretol®)
Oxcarbazepine (Trileptal®)
Phenytoin (Dilantin®, Phenytek®)
Primidone (Myidone®, Mysoline®)
Diabetes
Pioglitazone (Actos®)
Troglitazone (Rezulin®, Resulin®)
Antiemetic
Aprepitant (Emend®)
Antihypertension
Diltiazem (Cardizem®)
Verapamil (Calan®, Calan SR®)
Glucocorticoid 
(systemic 
[oral/intravenous])
Betamethasone (Celestone®)
Dexamethasone (Baycadron®, DexPak®)
Hydrocortisone (Cortef®)
Methylprednisolone (Medrol®)
Prednisolone (Prelone®)
Prednisone (Deltasone®)
Triamcinolone (Kenalog®)
Antibiotics
Rifabutin (Mycobutin®)
Rifampicin/Rifampin (Rifadin®, Rifater®, 
Rimactane®)
Erythromycin (Benzamycin®, EryTab®)
Clarithromycin (Biaxin®)
Telithromycin (Ketek®)


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Strong/Moderate CYP3A4 Inducers
Strong/Moderate CYP3A4 Inhibitors
Antifungal 
(systemic 
[oral/intravenous])
Fluconazole (Diflucan®, Trican®)
Itraconazole (Sporanox®)
Ketoconazole (Nizoral®)
HIV protease 
inhibitors
Efavirenz (Stocrin®, Sustiva®)
Nevirapine (Viramune®)
Indinavir (Crixivan®)
Nelfinavir (Viracept®)
Ritonavir (Norvir®)
Saquinavir (Fortovase®, Invirase®)
Immunosuppressant
Cyclosporine - oral/IV only (Neoral®,
Sandimmune®)
Other
St John's Wort
Enzalutamide (Xtandi®)
Modafinil (Provigil®)
Buprenorphine (Cizol®, Subutex®,
Suboxone®), Quinine, armodafinil
(NuvigilTM)
Cimetidine (Tagamet®)
Inhibitors of the BCRP (breast cancer resistance protein) transporter (eg, rifampicin)
Medications prohibited for the duration of the study (Visit 1-4)

Oral gepants (ie, Ubrelvy™, Nurtec™)

All injectable migraine prophylactic medications: botulinum toxin (Botox) and injectable monoclonal 
antibodies blocking the CGRP pathway (eg, Aimovig™, Emgality™, Ajovy®)

Cannabinoids  (ie, marijuana), CBD oil (systemic use)


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The following medications are examples of allowed medications during the study; however, they 
are prohibited within 48 hours prior to taking study intervention:
Triptan or Ditan
Almotriptan (Axert®)
Eletriptan (Relpax®)
Frovatriptan (Frova®)
Naratriptan (Amerge®)
Rizatriptan (Maxalt®)
Sumatriptan (Imitrex®)
Zolmitriptan (Zomig®)
Lasmitidan (Reyvow®)
Ergot Derivative
Dihydroergotamine (DHE 45®, Migranal®)
Ergotamine (Cafergot®, Ergomar®, Wigraine®)
Opioid
Tramadol (eg, Ultracet®, Ultram®)
Butorphanol (Stadol®)
Codeine-containing analgesics (eg, Tylenol with Codeine #3®)
Hydrocodone (Zohydro ER™ )/Hydrocodone-containing analgesics
(eg, Vicodin®)
Oxycodone (Oxycontin®, Roxicodone®)/Oxycodone-containing
analgesics (eg, Percocet®)
Morphine (MS Contin®)
NSAID
Aspirin
Combination medicines with NSAIDs (eg, Excedrin®)
Diclofenac (Arthrotec®, Cataflam®, Voltaren®)
Ibuprofen (eg, Advil®, Excedrin IB®, Motrin®)
Ketoprofen (eg, Orudis®)
Naproxen (eg, Aleve®, Naprosyn®)
Analgesic
Acetaminophen (eg, Tylenol® or any combination drug with acetaminophen, Excedrin®)
Antiemetic agent
Chlorpromazine (Thorazine®)
Hydroxyzine (Vistaril®)
Metoclopramide (Reglan®)
Ondansetron (Zofran®)
Prochlorperazine (Compazine®)
Promethazine (Phenergan®, Mepergan®)


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11.
References
Aurora SK, Barrodale PM, McDonald SA, Jakubowski M, Burstein R. Revisiting the efficacy of 
sumatriptan therapy during the aura phase of migraine. Headache. 2009;49:1001-1004.
Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, et al. for the Sumatriptan Aura 
Study Group. Subcutaneous sumatriptan during the migraine aura. Neurology. 
1994;44:1587-1592.
Cady RK, McAllister PJ, Spierings ELH, Messina J, Carothers J, Djupesland PG, Mahmoud RA. 
A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of 
sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study). 
Headache. 2015;55:88–100. 
Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, Szegedi A. Ubrogepant for 
the treatment of migraine. N Engl J Med. 2019;381:2230-2241.
Dodick DW, Goadsby PJ, Lakkis H, Lu K, Jakate A, Finnegan M, et al. Ubrogepant Achieves 
Onset of Pain Relief at 1 Hour for the Acute Treatment of Migraine. Poster presented at the 
American Headache Society, Philadelphia, PA, July 11-14, 2019.
Dowson A. Can oral 311C90, a novel (5-HT1D) agonist, prevent migraine headache when taken 
during an aura? Eur Neurol. 1996;36:28-31.
Dowson A, Mathew NT, Pascual J. Review of clinical trials using early acute intervention with 
oral triptans for migraine management. Int J Clin Pract. 2006;60:698-706.
FDA Guidance for Industry (2018): Migraine: Developing Drugs for Acute Treatment.
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 
195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 
Lancet. 2017;390(10100):1211-1259.
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffman J, Schankin C, Akerman S. 
Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553-622.
Headache Classification Committee of the International Headache Society (IHS). The 
international classification of headache disorders, 3rd edition (ICHD-3). Cephalalgia. 
2018;38:1-211.
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United 
States: disability and economic costs. Arch Intern Med. 1999;159:813–818.
Karsan N, Goadsby PJ. Biological insights from the premonitory symptoms of migraine. 
Nat Rev Neurol. 2018;14:699-710.
Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic 
migraine and chronic migraine. Curr Pain Headache Rep. 2012;16:86-92.
Laurell K, Artto V, Bendtsen L, Hagen K, Häggström J, Linde M, et al. Premonitory symptoms 
in migraine: a cross-sectional study in 2714 persons. Cephalalgia. 2016;36:951-959.


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Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Szegedi A, Trugman JM. Effect of 
ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute 
treatment of migraine: The ACHIEVE II randomized clinical trial. JAMA. 2019;322:1887-1898.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, on behalf of the AMPP 
advisory group. Migraine prevalence, disease burden, and the need for preventive therapy. 
Neurology. 2007;68:343–349.
Luciani R, Carter D, Mannix L, Hemphill M, Diamond M, Cady R. Prevention of migraine 
during prodrome with naratriptan. Cephalalgia. 2000;20:122-126.
Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: The 
American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 
2015;55:3-20.
Messlinger K. The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular 
system. J Headache Pain. 2018;19:1-7.
Olesen J, Bousser M-G, Diener H-C, Dodick D, First M, et al. New appendix criteria open for a 
broader concept of chronic migraine. Cephalalgia. 2006;26:742-746.
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight Project. 
J Headache Pain. 2010;11:289-299.
Tepper SJ, Cady RK, Silberstein S, Messina J, Mahmoud RA, Djupesland PG, et al. AVP-825 
breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral 
sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative 
randomized clinical trial across multiple attacks. Headache. 2015;55:621-635.
Ubrelvy™package insert. Madison, NJ: Allergan, USA, Inc.; 2019.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196.


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12.
Protocol Amendment 2 Summary
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Crossover Study 
to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of 
Migraine When Administered During the Prodrome
Protocol 3110-304-002
Amendment Summary
This amendment includes changes made to Protocol 3110-304-002 Amendment 1, dated 
01 Dec 2021. This protocol was amended to re-order the secondary endpoints.
The table below provides details on the content changes that were made in the protocol, and a 
brief rationale with these changes. Minor editorial and document formatting revisions have not 
been summarized.
Section 
Revision
Rationale
As applicable
Changed sponsor name.
Changed sponsor from 
Allergan Sales, LLC to 
AbbVie Inc.
1.1 Synopsis
In the table presented in this section, 
objectives and endpoints are re-
ordered.
The re-ordered first 
secondary is now better 
related, and in temporal 
continuation, to the 
primary endpoint 
assessment. The 
re-ordered second 
secondary endpoint now 
better reflects a 
meaningful clinical 
outcome.
3.0 Objectives and 
Endpoints
In the table presented in this section, 
objectives and endpoints are re-
ordered.
Updated in line with 
re-ordering of secondary 
endpoints
9.1 Statistical 
Hypotheses
Updated the numbering of secondary 
null and alternative hypotheses.
Updated in line with re-
ordering of secondary 
endpoints
9.1 Statistical 
Hypotheses
This sample size will provide 
approximately 75% power for the first 
secondary endpoint assuming a 
response rate of 36% for the placebo 
group and 48% for the ubrogepant 100 
mg group. 
Sentence no longer 
applicable as it described 
assumption based on 
previous first secondary 
endpoint.


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Section 
Revision
Rationale
9.4.1.1 Analyses 
Endpoints
Re-ordered secondary endpoints in 
bulleted list.
Updated in line with 
re-ordering of secondary 
endpoints
9.4.1.3 Secondary 
Analyses
The first and second third secondary 
endpoints (ie, the absence of a 
headache of moderate or severe 
intensity within 48 hours after taking 
double-blind study intervention during 
the prodrome and absence of a 
headache of any intensity within 
24 hours), will be analyzed using a 
GLMM model based on observed data 
similar to the one used for the analysis 
of the primary endpoint.
…
The third second secondary endpoint, 
ie, ability to function normally over 
24 hours after taking double-blind 
study intervention during the 
prodrome, includes the repeated 
measures of dichotomized FDS 
response at each postdose timepoint 
over 24 hours.
Updated in line with 
re-ordering of secondary 
endpoints
Global
Update additional efficacy endpoint to 
“Absence of aura at each timepoint”
Clarification

SAP_001.pdf: 
Ubrogepant
3110-304-002 – Statistical Analysis Plan
Version 3.0 – 10 May 2022
1
Statistical Analysis Plan for Study 3110-304-002
A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Crossover Study to Evaluate the 
Efficacy, Safety, and Tolerability of Oral Ubrogepant 
in the Acute Treatment of Migraine When 
Administered During the Prodrome
Date:  10 May 2022
Version 3.0
 
NCT04492020


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Table of Contents
1.0
Introduction...........................................................................6
2.0
Study Design and Objectives ................................................6
2.1
Objectives and Endpoints ....................................................................... 6
2.2
Study Design Overview.......................................................................... 9
2.3
Treatment Assignment and Blinding..................................................... 11
2.4
Sample Size Determination .................................................................. 11
3.0
Endpoints.............................................................................12
3.1
Primary Endpoint ................................................................................. 12
3.2
Secondary Endpoints............................................................................ 12
3.3
Other Efficacy Endpoints ..................................................................... 13
3.4
Safety Endpoints .................................................................................. 14
3.5
Additional HEOR Endpoint(s).............................................................. 14
4.0
Analysis Populations ...........................................................15
5.0
Subject Disposition..............................................................15
6.0
Study Drug Duration and Compliance ..............................16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................16
7.1
Demographics and Baseline Characteristics.......................................... 16
7.2
Medical and Migraine History.............................................................. 16
7.3
Prior and Concomitant Medications...................................................... 17
8.0
Efficacy Analyses.................................................................18
8.1
General Considerations......................................................................... 18
8.2
Handling of Missing Data..................................................................... 20
8.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 22
8.3.1
Primary Efficacy Endpoint ................................................................... 22
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint(s) ........... 22
8.3.3
Primary Efficacy Analysis.................................................................... 22
8.3.4
Sensitivity Analyses ............................................................................. 25
8.4
Secondary Efficacy Analyses ............................................................... 26
8.4.1
Secondary Efficacy Analyses ............................................................... 26
8.5
Additional Efficacy Analyses ............................................................... 31


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8.6
Efficacy Subgroup Analyses................................................................. 36
9.0
Safety Analyses....................................................................36
9.1
General Considerations......................................................................... 36
9.2
Adverse Events..................................................................................... 37
9.2.1
Treatment-Emergent Adverse Events.................................................... 37
9.2.2
Adverse Event Overview...................................................................... 37
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 37
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 38
9.2.5
Adverse Events of Special Interest........................................................ 38
9.3
Analysis of Laboratory Data................................................................. 38
9.3.1
Clinical Laboratory Parameters............................................................. 38
9.3.2
Potentially Clinically Significant Laboratory Findings.......................... 39
9.3.3
Hepatic Laboratory Abnormities........................................................... 40
9.4
Analysis of Vital Signs......................................................................... 40
9.5
Safety Subgroup Analyses.................................................................... 41
9.6
Other Safety Analyses .......................................................................... 41
9.6.1
Electrocardiogram................................................................................ 41
9.6.2
Suicidality Assessment......................................................................... 41
10.0
Other Analyses ....................................................................42
10.1
Additional Health Economics Outcomes Research (HEOR) 
Analyses............................................................................................... 42
10.2
Additional Analysis.............................................................................. 43
11.0
Interim Analyses..................................................................46
11.1
Data Monitoring Committee................................................................. 47
12.0
Overall Type-I Error Control.............................................47
13.0
SAP Version History ...........................................................47
14.0
References............................................................................50
15.0
Appendices...........................................................................51
List of Tables
Table 1.
Objectives and Endpoints ....................................................................... 6


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Table 2.
Analysis Populations ............................................................................ 15
Table 3.
Missing data handling at prodrome level and within prodrome 
level ..................................................................................................... 20
Table 4.
Summary of the Primary Estimand Attributes of the Primary 
Efficacy Endpoint................................................................................. 23
List of Figures
Figure 1.
Study Schematic................................................................................... 10
Figure 2.
Determination of absence of moderate/severe headache within 24 
hours (responder).................................................................................. 24
Figure 3.
Determination of absence of moderate/severe headache within 48 
hours (responder).................................................................................. 28
Figure 4.
Determination of absence of any intensity headache within 24 
hours (responder).................................................................................. 29
Figure 5.
Determination of absence of any intensity headache by T hours 
(1, 2, 3, 4, 6, 8, 48 hours) (responder)................................................... 32
Figure 6.
Determination of absence of moderate/severe headache by T 
hours (1, 2, 3, 4, 6, 8 hours) (responder) ............................................... 33
Figure 7.
Determination of absence of severe headache by T hours (1, 2, 3, 
4, 6, 8, 24, 48 hrs) (responder).............................................................. 34
Figure 8.
Determination of absence of moderate/severe headache within 
24 hrs in the screening period (responder) ............................................ 44
Figure 9.
Determination of absence of moderate/severe headache within 
48 hours in the screening period (responder)......................................... 45
Figure 10.
Determination of absence of moderate/severe headache by T 
hours (1, 2, 3, 4, 6, 8 hours) in the screening period (responder) ........... 46
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 51
Appendix B.
Definition of Adverse Events of Special Interest................................... 52
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 53
Appendix D.
Reporting Selected Laboratory Parameters in Conventional Unit.......... 58
Appendix E.
List of Abbreviations............................................................................ 59


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Appendix F.
Changes to Protocol-planned Analyses ................................................. 61


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1.0
Introduction
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in the protocol 
of Study 3110-304-002. Study 3110-304-002 examines the efficacy, safety, and 
tolerability of ubrogepant in the acute treatment of migraine when administered during the 
prodrome. Specifications of tables, figures and data listings are contained in a separate 
document. The pharmacokinetics (PK) analyses will be described in a separate plan.  
In general, statistical analyses will be performed using SAS version 9.4 (SAS Institute 
Inc., Cary, NC 27513) or higher. 
2.0
Study Design and Objectives
2.1
Objectives and Endpoints
The overall study objective is to evaluate the efficacy, safety, and tolerability of 
ubrogepant 100 mg compared to placebo for the acute treatment of migraine when 
administered during the prodrome.
Table 1 provides primary, secondary, additional efficacy and additional health economics 
outcomes research (HEOR) objectives, safety objective and corresponding endpoints.
Table 1.
Objectives and Endpoints
Objectives
Endpoints
Primary Efficacy
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on attenuation 
of the headache phase
Absence of a headache of moderate/severe intensity 
within 24 hours after taking double-blind study 
intervention during the prodrome
Secondary Efficacy
1: To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on prevention 
of the headache phase
Absence of a headache of moderate/severe intensity 
within 48 hours after taking double-blind study 
intervention during the prodrome 


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Objectives
Endpoints
2: To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on attenuation 
of the headache phase 
Ability to function normally over 24 hours after 
taking double-blind study intervention during the 
prodrome 
3: To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on ability to 
function normally
Absence of a headache of any intensity within 24 
hours after taking double-blind study intervention 
during the prodrome 
Additional Efficacy
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on attenuation 
of the headache phase.

Absence of a headache of any intensity by 
timepoint (excluding the endpoints that are 
already captured as primary and secondary 
endpoints) 

Absence of moderate/severe headache by 
timepoint (excluding the endpoints that are 
already captured as primary and secondary 
endpoints) 

Absence of severe headache by timepoint  

Time to development of headache of any 
intensity within 48 hours after taking 
double-blind study intervention during the 
prodrome (Kaplan-Meier analysis)

Time to development of headache of 
moderate/severe intensity within 48 hours 
after taking double-blind study 
intervention during the prodrome (Kaplan-
Meier analysis)

Time to development of headache of 
severe intensity within 48 hours after 
taking double-blind study intervention 
during the prodrome (Kaplan-Meier 
analysis)


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Objectives
Endpoints
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on prodrome 
symptoms, nonheadache migraine symptoms 
(photophobia, phonophobia, nausea, and 
dizziness), and aura
For each of the 5 most common individual 
prodrome symptoms

Absence of any intensity at each timepoint 

Absence of moderate/severe intensity at 
each timepoint

Absence of severe intensity at each 
timepoint

Time to absence of any intensity
After a headache of any intensity is reported:

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of any intensity at each 
timepoint

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of moderate/severe 
intensity at each timepoint

Absence of nonheadache migraine 
symptoms (photophobia, phonophobia, 
nausea, dizziness) of severe intensity at 
each timepoint
Other:

Absence of aura at each timepoint 
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo on use of 
rescue medication

Rescue medication use within 24 and 
48 hours after taking double-blind study 
intervention

Time to rescue medication use within 
48 hours after taking double-blind study 
intervention (Kaplan-Meier curve 
analysis)
Additional HEOR
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on satisfaction 
with study medication
Satisfaction with study medication at 8 and 
24 hours after taking double-blind study 
intervention during the prodrome
To evaluate the effect of a single dose of 
ubrogepant (100 mg) versus placebo,
administered during the prodrome, on Activity 
Limitation
Activity Limitation over 24 hours after taking 
double-blind study intervention during the 
prodrome


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Objectives
Endpoints
Safety
To evaluate the safety of ubrogepant versus 
placebo in participants with migraine
Adverse events (AEs), clinical laboratory tests, 
electrocardiograms (ECGs), vital signs, and the 
Columbia-Suicide Severity Rating Scale (C-SSRS)
2.2
Study Design Overview
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, crossover 
study to compare the efficacy, safety, and tolerability of ubrogepant 100 mg to placebo in 
the acute treatment of migraine when administered during the prodrome.
To be eligible for study participation, participants must be 18 to 75 years of age 
(inclusive) at Visit 1 (screening), have at least a 1-year history of migraine with or without 
aura consistent with a diagnosis according to the International Classification of Headache 
Disorders criteria, 3rd edition1, and experience 2 to 8 migraine attacks with moderate to 
severe headache per month by history in each of the 3 months prior to the Screening Visit 
(Visit 1).  Participants must be able to identify their prodrome symptom(s) and 
demonstrate that they reliably experience headache after experiencing prodrome 
symptom(s).  
The study includes a 60-day screening period (between Visit 1 and Visit 2) during which 
participants will demonstrate that they reliably develop headache after experiencing 
qualifying prodrome events.  After meeting eligibility criteria, participants will be 
randomized at Visit 2 and dispensed study intervention to treat their first qualifying 
prodrome event.  Four days after taking double-blind study intervention for their first 
qualifying prodrome event, participants will have Visit 3 at which time study intervention 
will be provided to treat a second qualifying prodrome event.  Visit 4 will occur 4 days 
after taking double-blind study intervention for their second qualifying prodrome event.  
In summary, participants will have up to 60 days (double-blind treatment period between 
Visit 2 and Visit 4) to treat a total of 2 qualifying prodrome events with study 
intervention. Participants unable to treat 2 qualifying prodrome events during the double-
blind treatment period will be discontinued from the study.


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This is a crossover treatment study with 2 sequences of that participants and investigators 
are blinded.
Approximately 516 eligible participants will be randomized (1:1) to treatment sequences 
A or B in this crossover study.  Participants randomized to Treatment Sequence A will 
receive placebo to treat their first qualifying prodrome event and ubrogepant 100 mg to 
treat their second qualifying prodrome event.  For those randomized to Treatment 
Sequence B, they will receive the reverse: ubrogepant 100 mg to treat their first qualifying 
prodrome event and placebo to treat their second qualifying prodrome event.
No interim analysis of unblinded data is planned for this study.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic


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2.3
Treatment Assignment and Blinding
Subjects will be randomized to the following treatment sequences in a 1:1 ratio:
First Qualifying Prodrome Event
Second Qualifying Prodrome Event
Treatment Sequence A
placebo
ubrogepant 100 mg
Treatment Sequence B
ubrogepant 100 mg
placebo
Participants randomized to Treatment Sequence A will receive placebo to treat their first 
qualifying prodrome event and ubrogepant 100 mg to treat their second qualifying 
prodrome event. For those randomized to Treatment Sequence B, they will receive the 
reverse: ubrogepant 100 mg to treat their first qualifying prodrome event and placebo to 
treat their second qualifying prodrome event.
Each blister card containing study intervention will be labeled with medication kit 
numbers. An automated Interactive Web-Response System (IWRS) will provide the site 
with the specific medication kit number(s) for each randomized participant at the time of 
randomization (Visit 2) and at Visit 3.  Sites will dispense study intervention according to 
the IWRS instructions at these 2 visits.  Sites will receive the IWRS confirmation 
notifications for each transaction.  All notifications are to be maintained with the study 
source documents.
All study interventions will be provided in identical blister cards to maintain masking of 
the study.  Tablets of ubrogepant 50 mg and placebo will be identical in appearance.
2.4
Sample Size Determination
The primary efficacy parameter is the absence of a headache of moderate/severe intensity 
within 24 hours after taking double-blind study intervention during the prodrome.  The 
original sample size of 600 participants randomized is based on the assumption of a 
response rate of 64% for the placebo group and 80% for the ubrogepant 100 mg group, 
240 participants in each study intervention will provide at least 95% power to detect the 
above intervention difference at the two-sided 5% significance level.  The nQuery 


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Advisor 7.0 was used for the power calculation.  Assuming 20% of randomized 
participants will not experience a qualified prodrome event during the double-blind 
treatment period, 300 participants will be randomized to each treatment sequence.
A blinded sample size re-estimation has been performed as planned. Given that only 7% 
of participants, rather than the 20% originally assumed, had no determinable primary 
endpoint as observed based on the data cut of July 05, 2021, it was re-estimated that 
approximately 516 participants will need to be randomized to maintain the effective
sample size of 480 participants.
The actual power will be higher with the crossover design as some participants will 
contribute 2 qualifying prodrome events during the double-blind treatment period.  
3.0
Endpoints
3.1
Primary Endpoint
The primary efficacy endpoint is the absence of a headache of moderate or severe 
(moderate/severe) intensity within 24 hours after taking double-blind study intervention 
during the prodrome.
3.2
Secondary Endpoints
Three secondary endpoints evaluate the efficacy of ubrogepant 100 mg to prevent and 
attenuate the headache phase, and to assess the ability to function normally within 
24 hours after taking double-blind study intervention during the prodrome:
●
Absence of a headache of moderate/severe intensity within 48 hours after 
taking double-blind study intervention during the prodrome.
●
Ability to function normally within 24 hours after taking double-blind study 
intervention during the prodrome.
●
Absence of a headache of any intensity within 24 hours after taking double-
blind study intervention during the prodrome.


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3.3
Other Efficacy Endpoints
Additional efficacy endpoints along with their respective clinical objectives are listed 
below in bullets in respect of the purposes.
To evaluate the effect of a single dose of ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on attenuation of the headache phase:
●
Absence of headache of any intensity by timepoint (1, 2, 3, 4, 6, 8, 48 hours 
postdose)
●
Absence of moderate/severe headache by timepoint (1, 2, 3, 4, 6, 8 hours 
postdose)
●
Absence of severe headache by timepoint (1, 2, 3, 4, 6, 8, 24, 48 hours 
postdose)
●
Time to development of headache of any intensity within 48 hours after taking 
double-blind study intervention during the prodrome (Kaplan-Meier analysis)
●
Time to development of headache of moderate/severe intensity within 48 hours 
after taking double-blind study intervention during the prodrome (Kaplan-
Meier analysis)
●
Time to development of headache of severe intensity within 48 hours after 
taking double-blind study intervention during the prodrome (Kaplan-Meier 
analysis)
To evaluate the effect of a single dose of ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on prodrome symptoms, nonheadache migraine 
symptoms (photophobia, phonophobia, nausea, and dizziness), and aura:
●
For each of the 5 most common individual prodrome symptoms:
○
Absence of any intensity at each timepoint 
○
Absence of moderate/severe intensity at each timepoint
○
Absence of severe intensity at each timepoint
○
Time to absence of any intensity
●
After a headache of any intensity is reported:


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○
Absence of nonheadache migraine symptoms (photophobia, phonophobia, 
nausea, dizziness) at each timepoint 
○
Absence of nonheadache migraine symptoms (photophobia, phonophobia, 
nausea, dizziness) of moderate/severe intensity at each timepoint
○
Absence of nonheadache migraine symptoms (photophobia, phonophobia, 
nausea, dizziness) of severe at each timepoint
●
Absence of aura at each timepoint
To evaluate the effect of a single dose of ubrogepant (100 mg) versus placebo on use of 
rescue medication:
●
Rescue medication use within 24 and 48 hours after taking double-blind study 
intervention
●
Time to rescue medication use within 48 hours after taking double-blind study 
intervention (Kaplan-Meier analysis)
3.4
Safety Endpoints
The safety parameters include AEs, clinical laboratory, ECG, vital signs, physical 
examinations, and C-SSRS. For clinical laboratory, vital signs, and ECG parameters, the 
last non-missing safety assessment before the first dose of double-blind study intervention 
will be used as the baseline for all analyses of that safety parameter.
3.5
Additional HEOR Endpoint(s)
To evaluate the effect of a single dose of ubrogepant (100 mg) versus placebo, 
administered during the prodrome, on satisfaction and Activity Limitation:
●
Satisfaction with study medication at 8 and 24 hours after taking double-blind 
study intervention during the prodrome
●
Activity Limitation within 24 hours after taking double-blind study intervention 
during the prodrome.


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4.0
Analysis Populations
The analysis populations will consist of participants as defined below:
Table 2.
Analysis Populations
Population
Definition
Study Intervention
Intent-to-treat 
(ITT) 
All randomized participants. Participants will be 
summarized according to the randomized study sequence 
intervention.
Randomized 
Safety
All treated participants who take ≥1 administration of 
study intervention. Participants will be summarized 
according to the study intervention they actually 
received.
Actual received
Modified Intent-to-
treat (mITT)
All randomized participants with ≥1 assessment of 
headache occurrence within 24 hours after taking double-
blind study intervention for at least 1 qualifying 
prodrome event during the double-blind treatment 
period. Participants will be summarized according to the 
randomized study intervention.
Randomized
For efficacy analyses, data will be analyzed according to participants' randomization 
assignments, regardless of actual study intervention received.
For safety data analyses, data will be analyzed according to participants' actual study 
intervention received (rather than as randomized).
5.0
Subject Disposition
Participant disposition encompasses the distribution of participants who enter, complete, 
and discontinue in the screening and double-blind treatment periods. Specifically, the 
number and percentage of participants with each disposition status in the screened, ITT, 
safety, and mITT populations will be summarized by treatment sequence and treatment.  
For participants who discontinue, the number and percentage of participants discontinued 
with one qualifying prodrome event, and with no qualifying prodrome event will be 
summarized.  


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6.0
Study Drug Duration and Compliance
Study treatment compliance will be provided for the safety population. A summary of 
treatment compliance to the dose of each study medication in terms of the number and 
percentage of participants who took two tablets or only one tablet will be provided by 
study intervention. 
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
7.1
Demographics and Baseline Characteristics
Demographic parameters (age; age group [<20, 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 
to 69, ≥70]; sex; race; ethnicity, weight; height; and body mass index, calculated as 
weight [kg] / (height [m])2) will be summarized descriptively by treatment sequence and 
treatment for the safety population.  In general, unless otherwise specified, continuous 
variables will be summarized by number of participants with observed values (n), mean, 
standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), minimum (min), and 
maximum (max).  Categorical variables will be summarized by number of participants 
with observed values or events (n), frequency count (N1), and percentage of participants 
with observed values or events.  
7.2
Medical and Migraine History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of participants with abnormalities in medical 
and surgical history in each system organ class (SOC) and preferred term (PT) will be 
summarized by treatment sequence and treatment for the safety population.
Migraine history (diagnosis, duration of migraines, whether migraine prescription 
medications have been taken currently or in the past, acute migraine medications that 
were taken, and whether prescription preventive migraine medications have been taken 
currently or in the past), prodrome symptom history (percentage of migraine headaches 
that are preceded by prodrome symptoms, symptoms, and time until headache onset for 


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each symptom), cardiovascular disease and risk (presence of cardiovascular disease and 
risk factors), historical triptan response (whether triptan was taken; reason if not taken; If 
taken, whether triptan relieve pain completely within 2 hours more than half the time and 
whether triptan was stopped in the past and the reasons), failed prevention therapy 
(medication currently taken and medication used in the past for migraine prophylaxis, 
whether the medication met failure definition and the primary reason, and whether the 
medication is 'not suitable' and the primary reason), and allodynia (ASC-12) questionnaire 
(allodynia score for each of the 12 questions and the severity based on ASC total score 
range: none [0-2], mild [3-5], moderate [6-8], severe [9 or more], and total score) will be 
summarized by treatment sequence and treatment in the safety population.
7.3
Prior and Concomitant Medications
The medication data will be coded using the World Health Organization (WHO) Drug 
Dictionary Enhanced Version.  Prior medication is defined as any medication taken prior 
to the start of first study intervention regardless of stop date of the medication.  
Concomitant medication by treatment is defined as any medication taken after the start of 
study intervention (and before the next intervention if any) regardless of the start date of 
the medication.  Prior and concomitant medications will be summarized using the 
Anatomical Therapeutic Chemical code (4th level, or most specific level available if 4th 
level is unavailable). 
Prior and concomitant medications will be summarized by treatment for the safety 
population.  The number and percentage of participants reporting prior or concomitant 
medications will be summarized further by ATC class and code, and preferred drug name.  
If more than one medication is coded to the same preferred drug name for the same 
participant, the participant will be counted only once for that preferred drug name. 


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8.0
Efficacy Analyses
8.1
General Considerations
Efficacy measurement assessments are based on information recorded by the participant 
in an eDiary.
●
Absence/Presence of and Rating of Intensity of Prodrome Symptom(s)
After experiencing each qualifying prodrome event, the absence or presence of each 
identified prodrome symptom(s) will be followed (up to 48 hours) and the intensity 
subjectively rated (mild, moderate, or severe) for those that are present.
●
Absence/Presence of Headache and Rating of Headache Intensity
After the prodrome symptoms have started, the participant will be alerted to record the 
presence of a headache when it occurs or record the absence/presence at various 
timepoints (up to 48 hours) following the dose of double-blind study intervention (during 
the double-blind treatment period). If a headache is reported as present, the intensity will 
be subjectively rated (mild, moderate, or severe).
●
Absence/Presence of and Rating of Intensity of Nonheadache Symptoms
The participant will record whether nonheadache symptoms (photophobia, phonophobia, 
nausea, and/or dizziness) were absent or present as well as the intensity (mild, moderate, 
or severe) of the present nonheadache symptom (up to 48 hours).
●
Absence/Presence of Aura
The participant will record whether aura was present or absent (up to 48 hours).
●
Health outcome assessments 


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The functional disability scale (FDS), a single item used to measure the participant's level 
of functional disability, will be used to rate the performance of daily activities using 4 
response options ranging from 0 (no disability, able to function normally) to 3 (severely 
impaired, cannot do all or most things, bed rest may be necessary).  The measure will be 
taken at predose (baseline) and 1, 2, 3, 4, 6, 8, 24, and 48 hours after double-blind study 
intervention for treating the first and second qualifying prodrome events.
Overall satisfaction with study medication for migraine will be assessed using a single-
item 7-point rating scale ranging from extremely satisfied (0) to extremely dissatisfied (6).  
The question will be answered by the participants in their eDiary at 8 hours and 24 hours 
after taking double-blind study intervention for treating the first and second qualifying 
prodrome events.
A single-item measure assessing activity limitation based on a 24-hour recall will be 
administered as an additional health outcome measure.  The measure will be used to 
evaluate activity limitation with a 5-level response ranging from "Not at all limited – I 
could do everything" to "Extremely limited."  The measure will be administered at 
24 hours after taking double-blind study intervention.
The following are general considerations for efficacy analyses:
●
Efficacy analyses will be performed based on mITT population.
●
Continuous variables will be summarized by number of participants with 
observed values (n), mean, standard deviation (SD), median, 1st and 3rd 
quartiles (Q1, Q3), minimum (min), and maximum (max).
●
Categorical variables will be summarized by number of participants with 
observed values or events and percentages based on the specified population.
●
The efficacy analyses will be performed using a GLMM in the observed binary 
response variable unless an imputation method is specified.
●
The least squares mean (LSMEAN) estimates of the treatment effects for the 
primary and secondary endpoints alongside its 95% CI will be presented.


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●
All statistical hypothesis tests will be performed at the 2-sided 5% significance 
level. 
●
Efficacy analyses will be presented by treatment or study intervention 
randomized (placebo or ubrogepant 100 mg).
8.2
Handling of Missing Data
Participants are expected to treat two qualifying prodrome events in the double-blinded 
treatment period. For each prodrome event, endpoints are derived based on all 
assessments recorded in the prodrome event. Missing data at prodrome event level and 
within prodrome event level (indeterminable endpoints within prodrome event level) will 
be handled using the following methods for the sensitivity analyses: non-responder 
imputation (NRI) for indeterminable endpoints, imputation under missing at random 
(MAR) for indeterminable endpoints, imputation under missing not at random (MNAR) 
for missing prodrome events and under MAR for indeterminable endpoints, and Period 1 
data only. 
Table 3.
Missing data handling at prodrome level and within prodrome level
Analyses
Missing prodrome event
Indeterminable endpoints 
within prodrome event level
Primary analysis 
Ignore and no imputation
Set as missing and no 
imputation
Sensitivity analysis 1: NRI for 
indeterminable endpoints
Ignore and no imputation
Set as non-responder
Sensitivity analysis 2: imputation 
under MAR for indeterminable 
endpoints
Ignore and no imputation
Sequential multiple imputation
Sensitivity analysis 3: imputation 
under MNAR for missing prodrome 
events and under MAR for 
indeterminable endpoints
MNAR
Sequential multiple imputation
Sensitivity analysis 4: Period 1 only
Ignore and no imputation
Set as missing and no 
imputation


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For sensitivity analysis 2, indeterminable endpoints will be imputed using multiple 
imputation under MAR.  The determinations of the efficacy endpoints are described in the 
corresponding endpoints sections.  Specifically for the primary endpoint, for a participant 
who has not experienced headache of moderate/severe intensity by time tj after study 
intervention and has missing headache severity assessment at the next timepoint tj+1, 
whether the participant will experience headache of moderate/severe intensity at tj+1 will 
be imputed based on other participants on the same treatment who have not experienced 
headache of moderate/severe intensity by time tj but have observed headache severity 
assessment at tj+1. Base will be used in the imputation logistic model. Base is a 
continuous variable denoting the percentage of absence of moderate/severe headache 
within time tj+1 during the screening period.  So firstly, the missing headache severity 
assessment by time t1 will be imputed. The missing headache by the following timepoints 
(2, 3, 4, 6, 8, 24, and 48 hours) will be imputed step by step similarly.  One hundred 
datasets will be imputed.
For sensitivity analysis 3, indeterminable endpoints will be imputed using multiple 
imputation under MAR, and endpoints in missing prodrome events will be imputed under 
MNAR. One hundred datasets will be imputed.
●
For participants who go through the 60-day double-blind treatment period with 
only one qualifying prodrome event due to lack of qualifying event or having 
an event but with no headache assessment, the missing data for the missing 
qualifying prodrome event will be considered as missing at random using 
multiple imputation. 
●
For participants who discontinued the double-blind treatment period with only 
one qualifying prodrome event for other reasons, the missing data for the 
qualifying prodrome event will be imputed based on the observed data for the 
second qualifying prodrome event from participants who use placebo to treat 
the second qualifying prodrome event. 


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8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the absence of a headache of moderate/severe intensity 
within 24 hours after taking double-blind study intervention during the prodrome.
8.3.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
Handling of missing data for the primary endpoint is described in Section 8.2. 
8.3.3
Primary Efficacy Analysis
The primary hypothesis is stated as follows:
Primary Null hypothesis: Ubrogepant 100 mg is the same as placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of moderate/severe intensity 
within 24 hours after taking double-blind study intervention during the prodrome.  
Primary Alternative hypothesis: Ubrogepant 100 mg is different from placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of moderate/severe intensity 
within 24 hours after taking double blind study intervention during the prodrome. 
The main attributes of the primary estimand are summarized in Table 4.


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Table 4.
Summary of the Primary Estimand Attributes of the Primary 
Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
Primary
Treatment A: 
placebo
Treatment B: 
ubrogepant 100 mg 
Placebo or 
ubrogepant 100 mg 
are assigned based 
on the 2x2 
crossover to treat 
two qualifying 
prodrome events 
(Sequence A: 
placebo/ubrogepant 
100mg, Sequence 
B: ubrogepant 
100mg/placebo). 
Absence of a 
headache of 
moderate/severe 
intensity within 
24 hours after 
taking double-
blind study 
intervention 
during the 
prodrome
mITT 
population 
(randomized 
participants 
with ≥1 
assessment 
of headache 
occurrence 
within 24 
hours after 
taking 
double-
blind study 
intervention 
for at least 1 
qualifying 
prodrome 
event during 
the double-
blind 
treatment 
period)
IE 1 at 
prodrome event 
level: data after 
the 
discontinuation 
will be handled 
by hypothetical 
strategy and 
assumed MAR. 
IE2 within 
prodrome event 
level: 
participants 
who took 
rescue 
medication 
within 24 hours 
will be counted 
as non-
responder for 
the prodrome. 
IE3 within 
prodrome event 
level: 
indeterminable 
primary 
endpoint due to 
missing data 
during the 
prodrome will 
be set as 
missing and 
assumed MAR.
Treatment 
comparison 
(odds ratio) of 
percentages of 
absence of 
moderate/severe 
headache within 
24 hours after 
taking 
ubrogepant 
100mg vs 
placebo during 
the prodrome
The status of the primary endpoint will be determined as shown in Figure 2.


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Figure 2.
Determination of absence of moderate/severe headache within 24 
hours (responder)


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The primary comparison between study intervention groups will be analyzed using a 
GLMM model with repeated measurements based on determinable data on the primary 
efficacy endpoint data.  The GLMM model assumes a binary distribution for the response 
and uses a logit link.  The analysis model will include study intervention period, and 
treatment as categorical fixed effects.  An unstructured covariance matrix will be selected 
for the covariance matrix of the residual effect for the repeated measurements 
(corresponding to the two qualifying prodrome events) within a participant.  The 
treatment difference in terms of odds ratio between ubrogepant 100 mg and placebo will 
be estimated from the GLMM model. 
The carryover effect will be tested although no or very minimum carryover effect is 
expected as the minimum 7-day washout period is much longer than the 5 times of 
half-life.  A similar GLMM model will be fitted to examine the carryover effect.  The 
model includes period and treatment as categorical fixed effects, and period by treatment 
as interaction effect.  The carryover effect will be tested using the confounded period by 
treatment interaction at 0.05 significance level.  If the carryover effect is significant, the 
analysis will use the first period only data for the primary efficacy analysis.  For 
sensitivity analysis purpose, first period only data analysis will be performed regardless of 
the significance level of the carryover effect using logistic regression model with 
treatment effect. 
8.3.4
Sensitivity Analyses
As alternative estimands for the primary study objective, the treatment condition, 
population, variable, and population-level summary will be the same as those in the 
primary estimand. However, the way to handle the discontinued participants with only 
one qualifying prodrome event and the approach to handle missing data within a 
prodrome event will be different.  For participants who discontinued the double-blind 
treatment period with only one qualifying prodrome event, the missing data for the second 
qualifying prodrome event will be handled same as the primary analysis or imputed under 
MNAR.  For indeterminable primary endpoint due to missing data within a prodrome 


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event, the primary endpoint will be set as missing, non-responder, or imputed using 
sequential multiple imputation.  Missing data handling is described in Section 8.2.
A sensitivity analysis will impute participants with indeterminable status or missing
headache occurrence within 24-hours recall as non-responders for the qualifying 
prodrome event.  Data will be analyzed using the same primary GLMM model.
An additional sensitivity analysis will use multiple imputation approaches to impute the 
missing headache occurrence status within 24 hours under MAR for each qualifying 
prodrome event with indeterminable endpoints.  Another sensitivity analysis will assume 
missing prodrome events as missing MNAR.  The treatment difference between 
ubrogepant 100 mg and placebo will be estimated from the GLMM model for each 
imputed data set and combined across imputations to obtain the multiple imputation 
estimate using standard multiple imputation techniques applied to log odds ratio.
Analyses using only first period data will also be performed as a sensitivity analysis as 
mentioned in the previous section.
8.4
Secondary Efficacy Analyses
8.4.1
Secondary Efficacy Analyses
The secondary hypotheses are stated as follows:
Secondary null hypothesis 1: Ubrogepant 100 mg is the same as placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of moderate/severe intensity 
within 48 hours after taking the double-blind study intervention during the prodrome. 
Secondary alternative hypothesis 1: Ubrogepant 100 mg is different from placebo in the 
acute treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of moderate/severe intensity 
within 48 hours after taking the double-blind study intervention during the prodrome. 


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Secondary null hypothesis 2: Ubrogepant 100 mg is the same as placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who are able to function normally over 24 hours after taking the 
double-blind study intervention during the prodrome. 
Secondary alternative hypothesis 2: Ubrogepant 100 mg is different from placebo in the 
acute treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who are able to function normally over 24 hours after taking the 
double-blind study intervention during the prodrome. 
Secondary null hypothesis 3: Ubrogepant 100 mg is the same as placebo in the acute 
treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of any intensity within 24 hours 
after taking the double-blind study intervention during the prodrome.
Secondary alternative hypothesis 3: Ubrogepant 100 mg is different from placebo in the 
acute treatment of migraine when administered during the prodrome, as measured by the 
proportion of participants who do not develop headache of any intensity within 24 hours 
after taking the double-blind study intervention during the prodrome.
Estimands for the secondary objective will be assessed using three secondary endpoints.  
The population and population-level summary, as well as the approach to handle 
intercurrent events will be the same as those for the primary endpoint except that rescue 
medication is part of the treatment condition such that it is not an intercurrent event for 
FDS. The determination of the first and third secondary endpoints are shown in Figure 3
and Figure 4.


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Figure 3.
Determination of absence of moderate/severe headache within 48 
hours (responder)


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Figure 4.
Determination of absence of any intensity headache within 24 hours 
(responder)


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The first and third secondary endpoints (i.e., the absence of a headache of 
moderate/severe intensity within 48 hours and absence of a headache of any intensity 
within 24 hours after taking double-blind study intervention during the prodrome) will be 
analyzed using a GLMM model based on observed data similar to the one used for the 
analysis of the primary endpoint.
A sensitivity analysis will impute participants with indeterminable status as non-
responders.  An additional sensitivity analysis will use the multiple imputation approach 
described for the primary endpoint to impute the missing headache occurrence status 
within 24 hours/48 hours for the participant for each qualifying prodrome event with an 
unknown status of headache occurrence within 24 hours/48 hours after taking double-
blind study intervention.
Another sensitivity analysis will assume missing prodrome events as MNAR.  Analyses 
using only first period data will also be performed as a sensitivity analysis using logistic 
regression model.
The second secondary endpoint, i.e., ability to function normally over 24 hours after 
taking double-blind study intervention during the prodrome, includes the repeated 
measures of dichotomized FDS response at each postdose timepoint over 24 hours.  The 
dichotomized response takes value 1 if the participant records no disability, able to 
function normally on the FDS, and takes value 0 otherwise.  The repeated binary 
responses will be analyzed using a GEE model with a logit link.  The GEE model will 
include period, treatment, time, treatment-by-time interaction as categorical fixed effects, 
predose baseline FDS score for the period, and predose baseline-by-time interaction as 
covariates.  An unstructured working correlation matrix will be used for the repeated 
measures within each participant.  If the unstructured correlation matrix does not 
converge, an unstructured correlation matrix or a working m-dependent (m=6) correlation 
matrix (if unstructured correlation matrix failed) will be used within each prodrome event 
and the two prodrome events will be assumed to be independent.  The treatment effect 
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relative to placebo estimated at the scheduled timepoints within 24 hours after taking 
double-blind study intervention. 
As described in Section 12.0, a serial gatekeeping procedure will be used to control the 
overall type I error rate at the 0.05 level for multiple comparisons across the primary and 
three secondary efficacy endpoints.
8.5
Additional Efficacy Analyses
The determination of absence of a headache of any intensity, moderate/severe and severe 
headache by each timepoint are shown in Figure 5, Figure 6, and Figure 7.  When a 
headache is collected in a 24-hour recall, the missing headache intensity at prespecified 
hours before the recalled headache time is assumed to be less severe than the recalled 
headache intensity. 


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Figure 5.
Determination of absence of any intensity headache by T hours 
(1, 2, 3, 4, 6, 8, 48 hours) (responder)


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Figure 6.
Determination of absence of moderate/severe headache by T hours 
(1, 2, 3, 4, 6, 8 hours) (responder)


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Figure 7.
Determination of absence of severe headache by T hours (1, 2, 3, 4, 
6, 8, 24, 48 hrs) (responder)
The absence of a headache of any intensity by each timepoint after taking double-blind 
study intervention will be analyzed using the same GLMM model as primary endpoint.  


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Similar analyses will be performed for the absence of a headache of moderate/severe 
intensity and absence of severe headache by timepoint.  Kaplan-Meier curves for time to 
development of any intensity headache (or rescue medication taken), time to development 
of moderate/severe headache, time to development of severe headache within 48 hours 
will be produced by treatment and compared between treatment using the log-rank test.  In 
addition, Kaplan-Meier curves for time to development of moderate/severe headache (or 
rescue medication taken) and time to development of severe headache within 48 hours (or 
rescue medication taken) will be produced. Hazard ratio will be estimated from cox 
proportional hazard model with treatment and period factors. 
For each of the 5 most common individual prodrome symptoms, the absence of any 
intensity, absence of moderate/severe intensity, absence of severe intensity at each 
timepoint will be analyzed using GLMM with additional predose baseline prodrome
symptom intensity category. In addition, prodrome symptoms will be summarized by 
descending frequency in ubrogepant group and by intensity at predose.  Same GLMM 
model as the primary endpoint will be performed for the absence of any intensity, absence 
of moderate/severe intensity, absence of severe intensity nonheadache migraine symptom 
at each timepoint after a headache of any intensity is reported. The absence of aura at 
timepoint will be analyzed using GLMM model with additional predose baseline aura 
status.  Kaplan-Meier curves for time to absence of each of the 5 most common individual 
prodrome symptoms will be produced by treatment and compared between treatment 
using the log-rank test.  Kaplan-Meier curves will also be generated censoring data 
collected after rescue medication for migraine associated symptoms.  Hazard ratio will be 
estimated from cox proportional hazard model with treatment and period factors. 
The observed proportions of participants who used rescue medication within 24 and 
48 hours after taking double-blind study intervention will be summarized and analyzed 
using the same GLMM model as primary endpoint.  The treatment comparisons will be 
conducted using the primary model.  Kaplan-Meier curves for time to rescue medication 
use within 48 hours after taking double-blind study intervention will also be produced by 


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treatment and compared by log rank test.  Hazard ratio will be estimated from cox 
proportional hazard model with treatment and period factor. 
8.6
Efficacy Subgroup Analyses
Subgroup analyses of the primary efficacy endpoint will be performed by current 
exposure (yes/no) to a migraine prevention medication with proven efficacy, and by 
allodynia status by history (absence/presence). 
Additional subgroup categories that may be considered are:
●
Exposure to a migraine prevention medication (current, past and none)
●
Triptan therapy historical response (triptan responders, triptan naïve, and triptan 
non-responder) 
●
Optimization of triptan therapy historical response (triptan responder, triptan 
optimized, triptan unoptimized)
●
Cardiovascular disease (presence or not)
●
Cardiovascular risk (presence or not)
●
Cardiovascular risk (none, only 1 risk factor, 2 and more risk factors)
●
Failed prevention medication (yes or no)
9.0
Safety Analyses
9.1
General Considerations
●
Safety analyses will be performed based on the safety population.  
●
Safety analysis will be presented by treatment or study intervention participants 
actually received (placebo or ubrogepant 100 mg) unless specified otherwise.
●
The baseline for safety endpoints is defined as the last non-missing assessment 
prior to the first dose of the double-blind study intervention. 


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9.2
Adverse Events
9.2.1
Treatment-Emergent Adverse Events
An AE will be considered a treatment emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date (and time, if 
known) of the study intervention. However, AEs that occurs more than 30 days after the 
Period 1 study intervention and before the date of the Period 2 study intervention and AEs
that occurs more than 30 days after Period 2 study intervention will not be counted as a 
TEAE.  A TEAE will be assigned to a study intervention if it occurred on or after the date 
of the study intervention and before the date of the next study intervention. An AE will 
be assigned to the last study intervention of the treatment sequence if it occurred on or 
after the date of the last study intervention.  An AE will be considered a treatment-
emergent serious AE (TESAE) if it is a TEAE that additionally meets any SAE criterion.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.1 or higher.
9.2.2
Adverse Event Overview
Overall summary of TEAEs will be provided on a per-participant level for TEAEs, 
treatment-related TEAEs, TESAEs, treatment-related TEAEs, deaths, and TEAEs leading 
to discontinuation.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
AEs will primarily be assessed through the analysis of AEs reported in the 48 hours 
following the administration of each study intervention. A supportive analysis will 
include AEs reported within 30 days after the study intervention (and before the next 
intervention if any). Unique participants reporting AEs will be summarized in the 
following AE categories by treatment and total for the safety population in double-blind 
treatment period.


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●
TEAEs by SOC and PT.
●
TEAEs by SOC, PT and severity. If more than 1 AE is coded to the same PT 
for the same participant, the participant will be counted only once for that PT 
using the maximum severity for the summarization by severity. If the severity 
of a TEAE is missing, the maximum severity will be assigned to the event for 
the summarization by severity. The value will be displayed as missing in the 
data listing.
●
Treatment-related TEAEs by SOC and PT.  If more than 1 AE is coded to the 
same PT for the same participant, the participant will be counted only once for 
that PT using the closest causal relationship to treatment for the summarization 
by causal relationship. If the relationship to the study intervention is missing 
for a TEAE, the event will be considered related to the study intervention for 
the summarization. The value will be displayed as missing in the data listing.
●
The incidence of common (≥ 2% [after rounding] of participants in either study 
intervention) TEAEs will be summarized by descending frequency in the 
ubrogepant group. 
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
TEAEs leading to discontinuation and TESAEs will be summarized by SOC and PT.  
Listings of all TEAEs, SAEs, and AEs leading to discontinuation will be provided.
9.2.5
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT recorded on case 
report form (CRF) as of special interest.
9.3
Analysis of Laboratory Data
9.3.1
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) at baseline and changes 
from baseline at each assessment time point will be presented by study intervention for 


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each clinical laboratory assessment.  An assessment will be assigned to the most recently 
administered study intervention.
●
Hematology:  Hemoglobin; hematocrit; red blood cell count; red blood cell 
indices (mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration); white blood cell count, including 
differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils);
platelet count 
●
Chemistry:  Sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine 
kinase, total protein, albumin, calcium, phosphorus, uric acid, total cholesterol, 
HDL, LDL, total triglycerides, eGFR (calculated by the central lab)
●
Urinalysis:  Specific gravity, pH.
Shift tables from baseline to end of study for these clinical laboratory parameters will be 
presented by study intervention for the following categories: low, normal, and high, which 
are categorized by the laboratory vendor based on reference ranges.
9.3.2
Potentially Clinically Significant Laboratory Findings
Clinical laboratory test values will be considered potentially clinically significant (PCS) if 
they meet either the lower-limit or higher-limit PCS criteria listed in Table C-1. 
The number and percentage of participants who have at least one PCS post-baseline 
clinical laboratory value will be tabulated by study intervention.  The percentages will be 
calculated based on the denominator of the number of participants with available non-PCS 
baseline values and at least one post-baseline value and the numerator of the number of 
participants with non-PCS baseline value and at least one PCS post-baseline value.  In 
addition, a listing of all AEs occurring in participants who have PCS clinical laboratory 
test values will be provided.


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A listing of participants with PCS postbaseline values will be provided for the safety 
population.
9.3.3
Hepatic Laboratory Abnormities
The number and percentage of participants meeting each of the criteria provided in 
Table C-2 for postbaseline hepatic laboratory abnormalities will be summarized by study 
intervention group.  The percentages will be calculated relative to the number of 
participants with at least 1 available postbaseline assessment.  The numerator will be the 
total number of participants having at least 1 postbaseline value that meets the specific 
category. 
A listing of participants with hepatic laboratory abnormalities will be provided for the 
safety population.
9.4
Analysis of Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, 
respiratory rate, and temperature) at baseline, postbaseline, and changes from baseline 
values at each postbaseline timepoint will be presented by study intervention.  An 
assessment will be assigned to the most recently administered study intervention.  Vital 
sign values will be considered PCS if they meet both the observed value criterion and the 
change from baseline value criterion, if both criteria are available, or meet either the 
observed value criterion or the change from baseline value criterion that will be detailed 
in Table C-3.
The number and percentage of participants who have PCS postbaseline vital sign values 
will be calculated relative to the number of participants who have available baseline or 
non-PCS baseline (for parameters with only the observed value criterion) values and at 
least 1 postbaseline assessment.  The numerator will be the total number of participants 
with at least 1 PCS postbaseline value during the qualifying prodrome event. 
A supportive listing of participants with PCS postbaseline values will be provided. 


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9.5
Safety Subgroup Analyses
No safety subgroup analyses are planned.
9.6
Other Safety Analyses
COVID-19 impact on participants' disposition, protocol deviation, site visits and missed 
assessments and COVID-19 vaccine will be summarized.  A summary of AEs related to 
COVID-19 will also be provided.
9.6.1
Electrocardiogram
Descriptive statistics for 12-lead ECG parameters (heart rate, PR interval, QRS interval, 
QT interval, and QTc interval) at baseline, postbaseline, and changes from baseline values 
at each postbaseline timepoint will be presented by study intervention.  An assessment 
will be assigned to the most recently administered study intervention.
ECG parameter values are considered PCS if ECG values meet either the actual value or 
change from baseline PCS high criteria listed in Table C-4. The number and percentage 
of participants with PCS postbaseline values will be tabulated by study intervention.  The 
percentages will be calculated relative to the number of participants with an available non-
PCS baseline value and at least 1 postbaseline assessment.  The numerator will be the 
total number of participants with an available non-PCS baseline value and at least 1 PCS 
postbaseline ECG value. 
A supportive listing of participants with PCS postbaseline values will be provided.  A 
listing of all AEs for participants with PCS ECG values will also be provided.
9.6.2
Suicidality Assessment
For the C-SSRS, the number and percentage of participants with suicidal ideation and 
suicidal behavior in lifetime history, 6 months prior to screening, and post the study 
intervention will be summarized by study intervention for the safety population.  An 


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assessment will be assigned to the most recently administered study intervention.  The 
assessment collected at each visit will be summarized. 
A supportive listing of participants with suicidal ideation or suicidal behavior will be 
provided for the safety population.
10.0
Other Analyses
10.1
Additional Health Economics Outcomes Research (HEOR) 
Analyses
Satisfaction with study medication responder is defined as response to the Satisfaction 
with Study Medication question of 'Satisfied' or 'Extremely Satisfied.'  The same GLMM 
model for the primary endpoint will be performed at 8 hours and 24 hours, separately.  
Descriptive statistics at 8 hours and 24 hours after taking double-blind study intervention 
will be presented by study intervention.
The ordinal activity limitation will be analyzed using Cochran-Armitage trend test.  In 
addition, responder analyses will be performed using the same GLMM model.  A 
participant will be defined as a responder if the participant records not at all limited - I 
could do everything or a little limited, and a non-responder otherwise.  Descriptive 
statistics at 24 hours taking double-blind study intervention will be presented by study 
intervention.
For FDS, by timepoint analysis will be performed using the same primary GLMM model 
with an additional covariate of predose baseline FDS score at 1, 2, 3, 4, 6, 8, and 24 hours.  
Additional endpoint will be defined as a responder if a participant records no disability, 
able to function normally at all the observed timepoints FDS (1, 2, 3, 4, 6, 8, and 24 hours 
postdose), and a non-responder otherwise.  The data will be analyzed using the same 
primary GLMM model with an additional covariate of predose baseline FDS score.


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10.2
Additional Analysis
Qualifying prodrome events and prodrome symptom data collected in the screening period 
will be analyzed for the screened population to understand the prodrome information in 
the general population. 
For each participant, number of qualifying prodrome events and positive prodrome events 
will be summarized.  The positive prodrome event rate will be calculated based on the 
denominator of the number of qualifying prodrome events and the numerator of the 
number of positive prodrome events. The positive prodrome event rate will be analyzed 
using a GLMM model with participant as a random effect.  The LSMEAN of the positive 
prodrome rate with 95% CI will be reported.
Prodrome symptoms will be analyzed in individual prodrome symptom positive rate.  The 
individual prodrome symptoms positive rate is to show how likely an individual 
qualifying prodrome event with this symptom at baseline will be positive.  The individual 
prodrome symptom positive rate will be calculated based on the denominator of the 
numbers of qualifying prodrome events with this symptom and the numerator of the 
numbers of positive qualifying prodrome events preceded with this symptom.  Individual 
prodrome symptom prevalence rate will be calculated based on the denominator of the 
numbers of qualifying prodrome events and the numerator of the numbers of qualifying 
prodrome events preceded with this symptom.  These participant-specific variables will 
then be summarized in the screened population who have entered eDiary data in the 
screening period.  The individual prodrome symptom positive rate in the screening period 
will also be analyzed in the mITT population.  In addition, Kaplan-Meier curves for time 
to onset of a headache of any intensity and time to onset of a headache of moderate/severe 
intensity using all prodrome events and using the first prodrome event will be generated. 
The derivation of the endpoints in the screening period are the same as double-blind 
period except for the absence of moderate/severe headache which are described in 
Figure 8, Figure 9, and Figure 10. 


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Figure 8.
Determination of absence of moderate/severe headache within 
24 hrs in the screening period (responder)


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Figure 9.
Determination of absence of moderate/severe headache within 
48 hours in the screening period (responder)


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Figure 10.
Determination of absence of moderate/severe headache by T hours 
(1, 2, 3, 4, 6, 8 hours) in the screening period (responder)
11.0
Interim Analyses
No interim analysis of unblinded data is planned for this study.


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11.1
Data Monitoring Committee
Data monitoring committee is not required for this study.
12.0
Overall Type-I Error Control
To control the family-wise type I error rate at 0.05 for multiplicity across the hypothesis 
tests in the primary and secondary analyses, a hierarchical gatekeeping procedure will be 
followed.
Step 1: Test the primary hypothesis.  If p-value <0.05, reject the primary hypothesis 
and go to the Step 2, otherwise stop.
Step 2: Test the first secondary hypothesis.  If the first secondary hypothesis is 
rejected, go to Step 3, otherwise stop.
Step 3: Test the second secondary hypothesis.  If 2nd secondary hypothesis is rejected, 
go to test third secondary hypothesis, otherwise stop.
Step 4: Test the third secondary hypothesis.
13.0
SAP Version History
This Statistical Analysis Plan (SAP) for Study 3110-304-002 is based on the Protocol 
Amendment 2 dated 02 May, 2020.
SAP Version History Summary
SAP 
Version
Approval Date
Change
Rationale
1
01 February 2021
Not Applicable
Original version


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SAP Version History Summary
SAP 
Version
Approval Date
Change
Rationale
2
03 May 2022
Updated the additional prodrome 
endpoints as:

Absence of 5 most common 
individual prodrome symptoms 
of any intensity at each
timepoint 

Absence of 5 most common 
individual moderate/severe 
prodrome symptoms at each
timepoint

Absence of 5 most common 
individual severe prodrome 
symptoms at each timepoint
Protocol Amendment 1. 
The 5 most common 
prodrome symptoms are 
mostly meaningful.
Updated the additional nonheadache 
migraine symptom endpoints as:

Absence of nonheadache 
migraine symptoms 
(photophobia, phonophobia, 
nausea, dizziness) of any 
intensity on or after any 
intensity headache start at each
timepoint

Absence of moderate/severe 
nonheadache migraine 
symptoms (photophobia, 
phonophobia, nausea, 
dizziness) on or after any 
intensity headache start at each
timepoint

Absence of severe nonheadache 
migraine symptoms 
(photophobia, phonophobia, 
nausea, dizziness) on or after 
any intensity headache start at 
each timepoint
Protocol Amendment 1. 
Nonheadache migraine 
symptom is collected on or 
after any intensity headache 
collected in eDiary.
Updated the additional time to prodrome 
symptom endpoint as:

Time to absence of 5 most 
common individual prodrome 
symptoms
Protocol Amendment 1. 
The 5 most common 
prodrome symptoms are 
mostly meaningful.


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SAP Version History Summary
SAP 
Version
Approval Date
Change
Rationale
Updated the sensitivity analysis 3 so that 
the missing event due to lack of 
prodrome is imputed under MAR, and 
imputed under MNAR for other reasons
Discontinuation due to all 
other reasons is considered 
as MNAR except lack of 
prodrome
Updated sample size from 600 
randomized to 516 randomized
Protocol Amendment 1. 
Sample size is reduced due 
to lower percentage of 
participants who have 
indeterminable data
Updated the secondary and additional 
headache endpoints derivation in 
Figure 4, Figure 5, Figure 6, and 
Figure 7
Updated based on the below 
assumptions:
1.
Missing headache at 
48 hours will lead to the 
endpoint within 
48 hours 
indeterminable. 
2.
When 24 hours recall 
headache is collected, 
the missing headache 
intensity at prespecified 
hours before 24 hours 
recall headache time is 
assumed less severe 
than the 24 hours recall 
headache intensity. 
Added the derivation of absence of 
moderate/severe headache in the 
screening period in Figure 9 and 
Figure 10
The derivation of absence of 
moderate/severe headache in 
the screening period is 
difference from those in the 
DB period.
Added analysis related COVID vaccine
COVID vaccine is collected 
in CRF
Re-order secondary endpoints
Protocol Amendment 2
Additional endpoint changed from 
absence of aura by timepoint to absence 
of aura at each timepoint
Protocol Amendment 2
3
10 May 2022
Clarified logistic regression model for 
period 1 data only analyses
Clarification
Added predose baseline variable in the 
Predose baseline effect 


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SAP Version History Summary
SAP 
Version
Approval Date
Change
Rationale
analysis models of absence of any 
intensity, moderate/severe intensity, 
severe intensity for the 5 most common 
individual prodrome symptom, and 
absence of aura at each timepoint
should be controlled in the 
analysis model
14.0
References
1.
Headache Classification Committee of the International Headache Society (IHS). 
The international classification of headache disorders, 3rd edition (ICHD-3). 
Cephalalgia. 2018;38:1-211.


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15.0
Appendices
Appendix A.
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, 
including importance classification. The number and percentage of participants with 
significant protocol deviations that occurred in the double-blind treatment period will be 
summarized by treatment sequence for the ITT population. 


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Appendix B.
Definition of Adverse Events of Special Interest
The following AESI(s) have been specified in the protocol and will be reported:
●
Treatment-emergent suicidal ideations with intent, with or without a plan, 
(i.e., Type 4 or 5 on the C-SSRS) or any suicidal behaviors.
●
Potential Hy's law cases: elevated ALT or AST laboratory value that is ≥ 3 × 
ULN and an elevated total bilirubin laboratory value that is ≥ 2 × ULN and, at 
the same time, an alkaline phosphatase laboratory value that is < 2 × ULN.
Responses to the C-SSRS that meet the above criterion will be captured in the eTablet and 
monitored by the sponsor.


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The potentially clinically significant criteria for clinical laboratory parameters, vital signs 
and ECG parameters are provided in the following tables. 
Clinical laboratory parameters are provided in the following tables.
Table C-1.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters
Category
Parameter
SI Unit
PCS Criteria
PCS Low
PCS High
Chemistry
Albumin
g/L
< 0.8 × LLN
> 1.2 × ULN
Alanine aminotransferase
U/L
—
≥ 3.0 × ULN
Alkaline phosphatase
U/L
—
≥ 3.0 × ULN
Aspartate aminotransferase
U/L
—
≥ 3.0 × ULN
Bicarbonate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Bilirubin, total
μmol/L
—
≥ 1.5 × ULN
Blood urea nitrogen
mmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.6 × ULN
Creatinine
μmol/L
—
> 1.5 × ULN
Creatine kinase
U/L
—
> 2.0 × ULN
Estimated glomerular filtration rate
mL/min/1.73m2
< 0.8 × LLN
—
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 2.0 × ULN
Lactate dehydrogenase (LDH)
U/L
—
> 3.0 × ULN
Phosphorus
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Triglycerides
mmol/L
—
> 2.0 × ULN
Uric acid 
μmol/L
—
> 1.2 × ULN


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Category
Parameter
SI Unit
PCS Criteria
PCS Low
PCS High
Hematology
Basophils, absolute cell count
109/L
—
> 2.0 × ULN
Eosinophils, absolute cell count
109/L
—
> 2.0 × ULN
Hematocrit
Ratio
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Lymphocytes, absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Monocytes, absolute cell count
109/L
< 0.5 × LLN
> 2.0 × ULN
Neutrophils, absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.9 × LLN
> 1.5 × ULN
Urinalysis
pH
pH
< 0.9 × LLN
> 1.1 × ULN
Glucose
mmol/L
—
Positive1
Protein 
g/L
—
Positive2
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value; ULN = upper limit of normal value; normal value provided by laboratory;
SI = Le Système International d'Unités (International System of Units)
1.
Any results other than trace or normal will be considered as positive.
2.
Any results other than trace or negative will be considered as positive.
Table C-2.
Criteria for Hepatic Laboratory Abnormalities
Laboratory Parameter
Categories
ALT
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN


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Laboratory Parameter
Categories
AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
ALT or AST
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Bilirubin Total
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Alkaline Phosphatase
≥ 1 × ULN
≥ 1.5 × ULN
≥ 2 × ULN
≥ 3 × ULN
≥ 5 × ULN
≥ 10 × ULN
≥ 20 × ULN
Concurrent Elevations1
ALT or AST ≥ 3 × ULN and Bilirubin Total ≥ 1.5 × ULN
ALT or AST ≥ 3 × ULN and Bilirubin Total ≥ 2 × ULN


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


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Table C-4.
Potentially Clinically Significant Criteria for ECG Parameters
Parameter
Unit
Actual Value
Change from Baseline
QRS interval
msec
≥ 150
—
PR interval
msec
≥ 250
—
QTcB 
msec
> 500
Increase > 60
QTcF
msec
> 500
Increase > 60
QTc = QT interval corrected for heart rate. 
QTcB = QT interval corrected for heart rate using the Bazett formula.
QTcF = QT interval corrected for heart rate using the Fridericia formula.


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Appendix D.
Reporting Selected Laboratory Parameters in Conventional Unit
All clinical laboratory parameters will be reported in the International System (SI) units as 
standard practice. In addition, descriptive statistics for values and changes from baseline 
in conventional units at all assessed visits will be reported for selected laboratory 
parameters as listed in Table D-5 below. 
Table D-5.
List of Selected Parameters to be Reported in Conventional Units
Number
Laboratory Parameter
Conventional Unit
Decimal Places
1
Alanine Aminotransferase (SGPT)
U/L
0
2
Albumin
g/dL
1
3
Alkaline Phosphatase
U/L
0
4
Aspartate Aminotransferase (SGOT)
U/L
0
5
Bilirubin, Direct (Conjugated)
mg/dL
1
6
Bilirubin, Indirect (Unconjugated)
mg/dL
1
7
Bilirubin, Total
mg/dL
1
8
Blood Urea Nitrogen
mg/dL
0
9
Calcium
mg/dL
1
10
Cholesterol, HDL
mg/dL
0
11
Cholesterol, LDL 
mg/dL
0
12
Cholesterol, LDL direct and calculated 
(combined)
(This lab parameter could be the same as #11) 
mg/dL
0
13
Cholesterol, Total
mg/dL
0
14
Creatine Kinase
U/L
0
15
Creatinine
mg/dL
1
16
Glucose
mg/dL
0
17
Insulin
uIU/mL
1
18
Triglycerides
mg/dL
0
19
Uric Acid
mg/dL
1
20
Hemoglobin
g/dL
1


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Appendix E.
List of Abbreviations
Abbreviation/Term
Definition
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASC-12
12-item Allodynia Symptom Checklist
AST
aspartate aminotransferase
CI
confidence interval
C-SSRS
Columbia–Suicide Severity Rating Scale
ECG
electrocardiogram, electrocardiographic
EOS
end of study
ET
early termination
FDS
Functional Disability Scale
GEE
generalized estimating equation
GLMM
generalized linear mixed model 
HEOR
Health Economics Outcomes Research
LLN
lower limit of normal value
LSMEAN
least squares mean
MedDRA
Medication Dictionary for Regulatory Activities
mITT
modified intent-to-treat
PCS
potentially clinically significant
PID
participant identification
PLS
population-level summary.
PT
preferred term
Q1
first quartile (25th percentile of the data)
Q3
third quartile (75th percentile of the data)
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan


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Abbreviation/Term
Definition
SD
standard deviation
SI
Le Système International d'Unités (International System of Units)
SOC
system organ class
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal value
WHO
World Health Organization


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Appendix F.
Changes to Protocol-planned Analyses
Below are the changes from the planned analyses in protocol version 1.
1.
One sensitivity analysis uses the multiple imputation approach to impute the 
missing headache for the qualifying prodrome event.  The missing headache 
severity assessment by 1 hour postdose will be imputed first.  The missing 
headache by the following timepoints (2, 3, 4, 6, 8, 24 and 48 hours) will be 
imputed step by step similarly. 
2.
In the other efficacy analyses, Kaplan-Meier curves for time to development of any 
intensity headache within 48 hours will be produced with rescue medication taken 
as an event instead of censoring data collected after the rescue medication.  
Similar Kaplan-Meier curves will also be produced for time to development of 
moderate/severe, or severe headache within 48 hours.
Predose baseline variables will be added in the analysis models of absence of any 
intensity, moderate/severe intensity, severe intensity for the 5 most common individual 
prodrome symptoms, and absence of aura at each timepoint. These are made in SAP 
version 3.0 which are changes from planned analyses in protocol versions 1, 2, and 3.