Clinical trial NCT04574362
Conditions: Acute Migraine
Keywords: Migraine
Sponsor: Pfizer
Start date: 2020-10-22; Completion date: 2021-12-16
Enrollment: 1648 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is to determine whether BHV3000 (rimegepant) 75mg is safe and effictive as a treatment for acute migraine in Chinese and Korean patients

Detailed description:
Biohaven Pharmaceuticals, Inc. is the agent for BioShin Limited, the sponsor of the studies in China and Korea.

Arms: arm 1: One 75mg oral disintegration tablet arm 2: Matching placebo
Interventions: intervention 1: Rimegepant intervention 2: Placebo
Intervention descriptions: intervention 1: One 75mg orally disintegrating tablet intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 































































































































































SAP_001.pdf: 
BioShin Limited 
Statistical Analysis Plan 
BHV3000-310 
Version: 1.0 
 
1 
 
 
 
BioShin Limited 
 
 
BHV3000-310: Phase 3: Double-Blind, Randomized, Placebo Controlled, 
Safety and Efficacy Trial of BHV-3000 (rimegepant) 75 mg for the Acute 
Treatment of Migraine 
 
 
BHV3000-310 
 
Statistical Analysis Plan 
 
 
 
 
 
Version: 1.0 
Date˖28Jan2022 
 
 


BioShin Limited
Statistical Analysis Plan
BHV3000-310
Version: 1.0
2
Sponsor Approval Page  
BHV3000-310: Phase 3: Double-Blind, Randomized, Placebo Controlled, Safety and 
Efficacy Trial of BHV-3000 (rimegepant) 75 mg for the Acute Treatment of Migraine
BHV3000-310
Statistical Analysis Plan
Version: 1.0
Project Statistician:
Company Name:
Signature:
Review Statistician:
Company Name:
Signature:
Date:
Approved by Sponsor:
Company Name:
BioShin Limited
Signature:
Date
Approved by Sponsor
Statistician:
Company Name:
BioShin Limited
Signature:
Date:
Date:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


BioShin Limited 
Statistical Analysis Plan 
BHV3000-310 
Version: 1.0 
 
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Modification History 
Version 
Version Date 
Author 
Description 
1.0 
2022/1/28 
 
FINAL VERSION 
 
PPD


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Table of Contents 
ABBREVIATIONS .............................................................................................................................................. 6 
1 
INTRODUCTION .................................................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................................................ 8 
2.1 
PRIMARY OBJECTIVE .............................................................................................................................. 8 
2.2 
SECONDARY OBJECTIVES ....................................................................................................................... 8 
2.2.1 
Key Secondary Objectives ............................................................................................................ 8 
2.2.2 
Other Secondary Objectives ......................................................................................................... 8 
2.3 
EXPLORATORY OBJECTIVES ................................................................................................................... 9 
3 
STUDY DESIGN ...................................................................................................................................... 9 
4 
ENDPOINTS ........................................................................................................................................... 11 
4.1 
PRIMARY ENDPOINTS ........................................................................................................................... 11 
4.2 
SECONDARY ENDPOINTS ...................................................................................................................... 12 
4.2.1 
Key Secondary Endpoints ........................................................................................................... 12 
4.2.2 
Other Secondary Endpoints........................................................................................................ 12 
4.3 
SAFETY ENDPOINTS .............................................................................................................................. 12 
4.4 
EXPLORATORY ENDPOINTS .................................................................................................................. 13 
5 
SAMPLE SIZE ....................................................................................................................................... 14 
6 
ANALYSIS SETS ................................................................................................................................... 14 
7 
STATISTICAL METHODS .................................................................................................................. 15 
7.1 
GENERAL STATISTICAL CONSIDERATIONS ............................................................................................ 15 
7.2 
ADJUSTING OF COVARIATES ................................................................................................................. 15 
7.3 
MULTIPLE COMPARISONS ..................................................................................................................... 15 
7.4 
DATA HANDLING CONVENTIONS .......................................................................................................... 16 
7.4.1 
Premature Withdrawal and Missing Data ................................................................................. 16 
7.4.2 
Derived and Transformed Data ................................................................................................. 17 
7.5 
STUDY SUBJECTS .................................................................................................................................. 17 
7.5.1 
Disposition of Subjects ............................................................................................................... 17 
7.5.2 
Protocol Deviations.................................................................................................................... 18 
7.5.3 
Demographic and Baseline Characteristics ............................................................................... 18 
7.5.4 
Medical History .......................................................................................................................... 18 
7.5.5 
Prior and Concomitant Therapies .............................................................................................. 18 
7.5.6 
Compliance ................................................................................................................................ 19 
7.6 
EFFICACY ANALYSES ........................................................................................................................... 19 
7.6.1 
Primary Efficacy Analyses ......................................................................................................... 19 
7.6.2 
Key Secondary Efficacy Analyses ............................................................................................... 21 
7.6.3 
Other Secondary Efficacy Analyses............................................................................................ 23 
7.6.4 
Exploratory Efficacy Analyses ................................................................................................... 23 
7.7 
SAFETY ANALYSES ............................................................................................................................... 27 
7.7.1 
Extent of Exposure ..................................................................................................................... 27 
7.7.2 
Adverse Events ........................................................................................................................... 28 
7.7.3 
Clinical Laboratory Evaluations ................................................................................................ 29 
7.7.4 
12-Lead ECG ............................................................................................................................. 31 
7.7.5 
Vital Signs .................................................................................................................................. 32 
7.7.6 
Physical Examination ................................................................................................................. 32 
7.8 
PHARMACOKINETIC ANALYSES ............................................................................................................ 32 
7.9 
OTHER ANALYSES ................................................................................................................................ 32 
7.9.1 
Subgroup Analyses ..................................................................................................................... 32 


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7.9.2 
COVID-19 Impact Analysis ........................................................................................................ 33 
7.10 
CHANGES FOR PLANNED ANALYSES IN PROTOCOL .......................................................................... 33 
8 
REFERENCES ....................................................................................................................................... 33 
9 
TABLES, FIGURES AND LISTING SHELLS ................................................................................... 33 


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Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DAIDS 
Division of AIDS 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
eGFR 
Estimated Glomerular Filtration Rate 
FDS 
Functional Disability Scale 
IP=F 
Taking IP prior to reporting the MBS, or failure to report an MBS 
=Failure 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MBS 
Most Bothersome Symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
NC=F 
Non-Completers=Failure 
NC1=F 
Non-Completer with more than 1 missing data point = Failure 
NRS 
Numeric Rating Scale 
NSAID 
Non- Steroidal Anti-inflammatory 
ODT 
Orally Disintegrating Tablet 
PPS 
Per Protocol Set 
PT 
Preferred Term 
QTc 
QT Interval Corrected for Heart Rate 
RM=F 
Rescue Medication=Failure 
SAE 
Serious Adverse Event 


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Abbreviation 
Description 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Events 
ULN 
Upper Limit of Normal 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 


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1 
Introduction 
This document presents the statistical analysis plan (SAP) for BioShin Limited, Protocol 
BHV3000-310: Double-Blind, Randomized, Placebo Controlled, Safety and Efficacy Trial of 
BHV-3000 (rimegepant) 75 mg for the Acute Treatment of Migraine. 
This SAP is based on the BHV3000-310, V2.3, protocol dated 25-May-2021. It contains the 
analysis details and methodology to answer the study objectives, including planned summary 
tables, by-subject listings, and figures, which will provide the basis for the results section of the 
clinical study report (CSR). Operational aspects related to collection and timing of planned 
clinical assessments are not repeated in this SAP unless relevant to the planned analyses. 
2 
Study Objectives 
2.1 
Primary Objective 
x 
To evaluate the efficacy of rimegepant compared with placebo in the acute treatment of 
migraine as measured by the co-primary endpoints of pain freedom and freedom from the 
most bothersome symptom (MBS), associated with migraine, at two hours post dose.   
2.2 
Secondary Objectives 
2.2.1 Key Secondary Objectives 
1. To compare rimegepant to placebo on pain relief at 2 hours post-dose 
2. To compare rimegepant to placebo on the ability to function normally at 2 hours post-
dose as reported on the Functional Disability scale (FDS) 
3. To compare rimegepant to placebo on the Use of Rescue Medications through 24 hours 
post-dose 
4. To compare rimegepant to placebo on sustained pain freedom from 2 to 24 hours post-
dose 
5. To compare rimegepant to placebo on sustained pain freedom from 2 to 48 hours post-
dose 
2.2.2 Other Secondary Objectives 
1. To compare rimegepant to placebo on pain freedom at 15, 30, 45, 60 and 90 minutes 
post-dose 
2. To compare rimegepant to placebo on freedom from MBS at 15, 30, 45, 60 and 90 
minutes post-dose 
3. To compare rimegepant to placebo for the incidence of pain relapse from 2 to 48 hours 
post-dose 


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2.3 
Exploratory Objectives 
1. To compare rimegepant to placebo on pain relief at all post-dose timepoints.  
2. To compare rimegepant to placebo on pain freedom at all post-dose timepoints.  
3. To compare rimegepant to placebo on freedom from MBS at all post-dose timepoints.  
4. To compare rimegepant to placebo on freedom from functional disability at all post-dose 
timepoints.  
5. To compare rimegepant to placebo on freedom from phonophobia at all post-dose time 
points 
6. To compare rimegepant to placebo on freedom from photophobia at all post-dose time 
points 
7. To compare rimegepant to placebo on freedom from nausea at all post-dose time points 
8. To compare rimegepant to placebo on sustained pain relief from 2 to 24 hours post-dose 
9. To compare rimegepant to placebo on sustained pain relief from 2 to 48 hours post-dose 
10. To compare rimegepant to placebo on freedom from MBS from 2 to 24 hours post-dose 
11. To compare rimegepant to placebo on freedom from MBS from 2 to 48 hours post-dose 
12. To compare rimegepant to placebo on the ability to function normally from 2 to 24 hours 
post-dose as reported on the FDS 
13. To compare rimegepant to placebo on the ability to function normally from 2 to 48 hours 
post-dose as reported on the FDS 
3 
Study Design 
This is a double-blind, randomized, regional, multicenter, outpatient evaluation of the safety and 
efficacy of rimegepant as compared to placebo in the acute treatment of moderate or severe 
migraine. The study drug will be rimegepant presented in a 75 mg Orally Disintegrating Tablet 
(ODT) or matching placebo.  
The study will randomize approximately 1,430 subjects. The subjects will be randomized in a 1:1 
ratio to the rimegepant or placebo treatment groups. The randomization will be stratified by the 
use of prophylactic migraine medications (yes or no) and country (Korea or China). 
A subject whose usual migraine attack results in headache pain of moderate or severe intensity 
and who is otherwise found acceptable for entry into this trial based on inclusion and exclusion 


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criteria will first participate in the screening phase (3 – 28 day period). Subjects on prophylactic 
migraine medication are permitted to remain on therapy provided they have been on a stable 
dose for at least 3 months prior to study entry.  
After randomization, the subject will be dispensed a single dose of the double-blind study 
medication that will be taken at the time a migraine attack reaches moderate or severe pain 
intensity (described below) on the numeric rating scale (NRS) as indicated in the electronic diary 
(eDiary). The subject will be instructed to take their study medication, as an outpatient, when (if) 
they have a migraine headache which reaches moderate or severe pain intensity and only after 
they have identified their most bothersome migraine-associated symptom (phonophobia, 
photophobia or nausea) in the eDiary. The subject will complete an eDiary for forty-eight hours 
after taking study medication. The subject will telephone the study center immediately if a severe 
or serious adverse event occurs. 
Subjects will record efficacy data in their eDiary. This includes the following: onset time of 
headache, intensity of the headache prior to and at time of taking study medication. Subject 
should not dose with study medication until headache reaches moderate to severe intensity.  
Headache severity will be recorded using a four-point numeric rating scale (no pain, mild pain, 
moderate pain, severe pain) at the onset of the migraine and after dosing at time points of 15, 30, 
45, 60, and 90 minutes and 2, 3, 4, 6, 8, 24 and 48 hours. The presence or absence of associated 
symptoms (nausea, photophobia, phonophobia) and ratings of functional disability (four-point 
scale: normal, mildly impaired, severely impaired, requires bedrest) will be recorded at the same 
time points as the headache severity ratings. Subjects who experience reduction of headache pain 
to a mild intensity or pain free intensity level will be considered to have achieved pain relief. The 
subject who does not experience relief of their migraine headache at the end of two hours after 
dosing with study medication (and after the two hour assessments have been completed on the 
eDiary) will be permitted to use the following rescue medications: aspirin, ibuprofen, 
acetaminophen up to 1000mg/day (this includes Excedrin Migraine), naprosyn (or any other type 
of non- steroidal anti-inflammatory (NSAID)), antiemetics (e.g., metoclopramide or 
promethazine), or baclofen. These are the only medications allowed for rescue treatment after 2 
hours post dose of study medication. If at the end of 48-hours after dosing with study medication 
(but before the End of Treatment Visit) subjects are in need of migraine relief, they may take 
their prescribed standard of care medications, including triptans if not contraindicated, provided 
all of the assessments have been completed on the eDiary. Exclusionary rescue medication such 
as opioids, ergotamines, butalbital compounds, and muscle relaxants (except baclofen as a rescue 
medication, see above) are not allowed on this study. Similarly, if the migraine is relieved by 
study medication at 2 hours after dosing but then recurs to a moderate or severe intensity level 
between two and forty-eight hours, the subject will be permitted to take the same rescue therapy 
as outlined above. In all circumstances, the subject will always continue to complete his or her 
eDiary for up to forty-eight hours after consuming the study medication. During the 45 days the 
subject is participating in the study, if the subject has a nonqualifying migraine (mild migraine) 
or a migraine that they do not treat with study medication, the subject is permitted to use only the 
following medications: aspirin, ibuprofen, naprosyn (or any other type of non- steroidal anti-
inflammatory (NSAID)), antiemetics (e.g., metoclopramide or promethazine), or baclofen. 
Subjects will return to the study site within 7 days (+2) of study treatment for review of the 
eDiary, assessment of medication compliance, and monitoring of tolerability and safety 


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(including vital signs, laboratory tests, and electrocardiography).  If a subject has NOT 
experienced a migraine headache of sufficient severity within 45 days after randomization, they 
still are required to complete all EOT visit procedures.  All subjects must return unused study 
medication and eDiary to the study center.   
Study Schematic 
 
4 
Endpoints 
4.1 
Primary Endpoints 
The co-primary endpoints are the following: 
Pain freedom at 2 hours will be assessed using the number of evaluable subjects that report no 
pain at two hours post-dose. Pain will be measured on a 4-point Likert scale (0=none, 1=mild, 
2=moderate, 3=severe).  
Freedom from the MBS at 2 hours will be assessed using the number of evaluable subjects that 
report the absence of their MBS at 2 hours post-dose.  The MBS (nausea, phonophobia or 
photophobia) will be measured using a binary scale (0=absent, 1=present). 


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4.2 
Secondary Endpoints 
4.2.1 Key Secondary Endpoints 
1. Pain Relief at 2 hours post-dose, will be assessed using the number of subjects that report 
a pain level of moderate or severe at baseline and then report a pain level of none or mild 
at two hours post-dose. 
2. The proportion of subjects able to function normally, at 2 hours post-dose, will be 
assessed using the number of subjects that self-report as “normal” on the FDS in the 
subset of subjects that report any level of disability just prior to taking study medication. 
3. The use of rescue medication will be assessed using the number of subjects that take 
rescue medication within 24 hours after administration of study medication (rimegepant 
or placebo). 
4. Sustained pain freedom, from 2 to 24 hours, will be assessed using the number of subjects 
that do not experience any headache pain through the time period of interest.  
5. Sustained pain freedom, from 2 to 48 hours, will be assessed using the number of subjects 
that do not experience any headache pain through the time period of interest.  
4.2.2 Other Secondary Endpoints 
1. Pain freedom at 15, 30, 45, 60 and 90 minutes will be assessed using the number of 
subjects that report a pain level of moderate or severe just before taking study medication 
and then report a pain level of none at the timepoint of interest. 
2. Freedom from the MBS at 15, 30, 45, 60 and 90 minutes will be assessed using the 
number of subjects that report the absence of their MBS at the time point of interest. 
3. Pain relapse will be assessed using the number of subjects that are pain free at 2 hours 
post-dose and then have a migraine of any pain severity (response of:  2 or 3 on the 4-
point scale) within 48 hours after administration of study medication. 
4.3 
Safety Endpoints 
The safety endpoints are the following: 
x 
Adverse events and serious adverse events; 
x 
Laboratory tests (hematology, blood chemistry/electrolyte, lipid panel, estimated glomerular 
filtration rate (eGFR), urinalysis, urine drug screen); 
x 
12-lead ECG; 
x 
Physical examination; 
x 
Vital signs. 


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4.4 
Exploratory Endpoints 
1. Pain Relief at 15, 30, 45, 60, and 90 minutes, 3, 4, 6, 8, 24, and 48 hours post-dose will 
be assessed using the number of subjects that report a pain level of moderate or severe at 
baseline and then report a pain level of none or mild at the timepoint of interest. 
2. Pain freedom at 3, 4, 6, 8, 24, and 48 hours post-dose will be assessed using the number 
of evaluable subjects that report no pain at the timepoint of interest. 
3. Freedom from MBS at 3, 4, 6, 8, 24, and 48 hours post-dose will be assessed using the 
number of evaluable subjects that report the absence of their MBS at the timepoint of 
interest. 
4. The proportion of subjects able to function normally, at all post-dose timepoints except 2 
hours, will be assessed using the number of subjects that self-report as “normal” on the 
FDS in the subset of subjects that report any level of disability just prior to taking study 
medication. 
5. Freedom from phonophobia at all post-dose time points will be assessed using the 
number of evaluable subjects that report the absence of their phonophobia at the 
timepoint of interest. 
6. Freedom from photophobia at all post-dose time points will be assessed using the number 
of evaluable subjects that report the absence of their photophobia at the timepoint of 
interest. 
7. Freedom from nausea at all post-dose time points will be assessed using the number of 
evaluable subjects that report the absence of their nausea at the timepoint of interest.  
8. Sustained pain relief from 2 to 24 hours, will be assessed using the number of subjects 
that report a pain level of none or mild through the time period of interest. 
9. Sustained pain relief from 2 to 48 hours, will be assessed using the number of subjects 
that report a pain level of none or mild through the time period of interest. 
10. Freedom from MBS from 2 to 24 hours post-dose will be assessed using the number of 
evaluable subjects that report the absence of their MBS through the time period of 
interest. 
11. Freedom from MBS from 2 to 48 hours post-dose will be assessed using the number of 
evaluable subjects that report the absence of their MBS through the time period of 
interest. 
12. The proportion of subjects able to function normally from 2 to 24 hours post-dose, will be 
assessed using the number of subjects that self-report as “normal” on the FDS through the 
time period of interest. 


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13. The proportion of subjects able to function normally from 2 to 48 hours post-dose, will be 
assessed using the number of subjects that self-report as “normal” on the FDS through the 
time period of interest. 
14. Time to rescue medication use up to 24 hours pose-dose 
15. Time to first report of pain freedom up to 8 hours pose-dose 
16. Time to first report of freedom from MBS up to 8 hours pose-dose 
17. Time to first report of pain relief up to 8 hours pose-dose 
18. Time to first report of absence of nausea up to 8 hours pose-dose 
19. Time to first report of absence of photophobia up to 8 hours pose-dose 
20. Time to first report of absence of phonophobia up to 8 hours pose-dose 
21. Time to first report of return to normal functioning up to 8 hours post dose 
5 
Sample Size 
If roughly 85% of the 715 subjects randomized to each treatment arm have a migraine in the 
allotted time period, there will be approximately 600 treated subjects per group.  
Based on data from studies BHV3000-301 and BHV3000-302, 600 treated subjects provides 
95% power to detect a difference between rimegepant and placebo on the subject’s self-reported 
most bothersome symptom. Also, 600 subjects provides 95% power to detect a difference in 
freedom from pain at 2 hours. Having at 95% power on each co-primary endpoint provides 
roughly 90% power to detect a difference on both endpoints jointly.  
6 
Analysis Sets 
The following analysis sets will be evaluated and used for presentation and analysis of 
the data: 
• 
Enrolled subjects: Subjects who sign an informed consent form and are assigned a subject 
identification number.  
 
• 
Randomized subjects: Enrolled subjects who receive a randomization treatment assignment 
from the IWRS (rimegepant or placebo). 
 
• 
Treated subjects: Enrolled subjects who take study therapy (rimegepant or placebo). 
 
• 
Modified Intent to Treat (mITT) subjects: randomized subjects that take study therapy, have 
a migraine of moderate or severe intensity at the time of treatment, and provide at least one 
post-treatment efficacy data point.  


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No separate per protocol analysis set is defined for this study.  There will not be any per protocol 
analysis conducted for this study. 
7 
Statistical Methods 
7.1 
General Statistical Considerations 
All relevant data from all subjects entered into the database will be included in subject data 
listings. Unless specified otherwise, by-subject listings will be sorted by site, subject ID, and 
additional variables such as time points, as applicable. Listings will display site-subject ID and as 
randomized treatment group (as-treated treatment group for safety). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and other 
parameters by as-randomized treatment group (BHV3000, Placebo) and overall, unless specified 
otherwise.  For safety analyses, tabulations will be produced by as-treated treatment group 
(BHV3000, Placebo) and overall, unless specified otherwise. For categorical variables, summary 
tabulations of the number and percentage of subjects within each category will be presented. If 
applicable, a category for missing data will also be presented. For continuous variables, 
descriptive statistics (e.g., n, mean, median, standard deviation (SD), minimum, and maximum) 
will be presented. The minimum and maximum will be presented with the same precision as the 
data. The mean and median will be presented with the precision of the data + 1 decimal place. 
The SD will be presented with the precision of the data + 2 decimal places. In general, the 
maximum number of decimal places reported should be 4 for any summary statistics. 
Formal statistical hypothesis testing and summary statistics will be presented, as well as 
confidence intervals (CIs) on selected endpoints, as described in the sections below. 
Unscheduled or repeat assessments will not be included in summary tables unless specified 
otherwise, but will be included in listings.  
For efficacy analyses, baseline is considered as the assessment at the onset of the treated 
migraine. Otherwise, baseline is the last non-missing assessment before or on the randomization 
date.  
All statistical computations and construction of tables, listing and figures will be performed 
using SAS® Version 9.4 or later.  
7.2 
Adjusting of Covariates 
The randomization is stratified by the use of prophylactic migraine medication (yes 
or no) and country (China and Korea). Hence, most analyses are stratified by the use or 
prophylactic medication and country.   
7.3 
Multiple Comparisons 
Each co-primary endpoint will be tested for superiority to placebo at a two-sided alpha level of 
0.05 without further adjustment for multiplicity. If the primary endpoint tests are both 


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significant, then the key secondary endpoints are evaluated using the procedure, conducted at 
alpha=0.05.    
The Hochberg Procedure works as follows: 
Step 1: Conduct all of your statistical tests and find the p-value for each test. 
Step 2: Arrange the p-values in order from smallest to largest, assigning a rank to each one – the 
smallest p-value has a rank of 1, the next smallest has a rank of 2, etc. 
Step 3: Calculate the Hochberg critical value for each p-value, using the formula (i/m)*Q, where: 
i = rank of p-value 
m = total number of tests 
Q = your chosen false discovery rate 
Suppose a 10% false discovery rate, with 5 tests, to calculate the Hochberg critical value 
for each p-value, we can use the following formula: (i/5)*0.1 where i = rank of p-value. 
Step 4: Find the largest p-value that is less than the critical value. Designate every p-value that is 
smaller than this p-value to be significant. 
7.4 
Data Handling Conventions 
7.4.1 Premature Withdrawal and Missing Data 
For efficacy analyses, partial or missing dates will not be imputed. The relative study days, 
where determined, will be calculated for full dates only. 
For rescue medication, if the time of rescue medication is missing, then all endpoints on or after 
the date of rescue medication will be imputed as failures. 
For missing start date of AE or prior/concomitant medication, the following rules will be 
applied:  
o 
If the start date is completely missing, the start date will be equal to the first dose date of 
study drug. However, if the stop date is not missing and is before the first dose date of study 
drug, then the stop date will be used instead.  
o 
If the start day and month are missing and year is present, then the first day of the first 
month (January) will be used. However, if the year is the same as the year of first dose date, 
then the start date will be equal to the first dose date.  
o 
If the start day is missing and year and month are present, the first day of that month will be 
used. However, if the year and month are the same as the year and month of first dose date, 
then the start date will be equal to the first dose date.  
For missing stop date of AE or prior/concomitant medication, the following rules will be applied:  


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o 
If the stop date is completely missing and the medication is not ongoing, the stop date will 
be equal to the date of completion/withdrawal, whichever is the latest. Otherwise, if the stop 
date is completely missing, it will not be imputed.  
o 
If the stop day and month are missing and year is present, then the last day of the last month 
(December) will be used. However, if the year is the same as the year of date of 
completion/withdrawal, then the stop date will be equal to the date of 
completion/withdrawal.  
o 
If the stop day is missing and year and month are present, the last day of that month will be 
used. However, if the year and month are the same as the year and month of date of 
completion/withdrawal, then the stop date will be equal to the date of 
completion/withdrawal.  
These imputed dates will used to determine whether the AEs or medications are on-treatment.  
7.4.2 Derived and Transformed Data 
Calculation of Study Day 
Study day describes the day of assessment/event date relative to the randomization date. It will 
be defined as: 
x Date of assessment/event – randomization date + 1, if date of assessment/event is at or after 
randomization 
x Date of assessment/event – randomization date, if date of assessment/event is prior to 
randomization  
7.5 
Study Subjects 
7.5.1 Disposition of Subjects 
A summary of subject disposition will be tabulated for all enrolled subjects by treatment group 
and overall. The disposition table will support the creation of a consort diagram. The categories 
in the table will include: 
• 
Number of subjects screened 
• 
Number of screen failed subjects and reason for screen failure  
• 
Number of subjects randomized  
• 
Number of subjects not treated, and the reasons for not being treated 
• 
Number of subjects treated 
• 
Completed Study 
• 
Discontinued, and reasons for discontinuation 
• 
Number of subjects in each analysis population 
 
A by-subject listing of subject disposition information, including the reason for discontinuation, 
if applicable, will be presented.  
 


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7.5.2 Protocol Deviations 
The major protocol deviations will be tabulated by category based on randomized subjects. All 
major protocol deviations will be listed by subject based on medical review. 
7.5.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by as-randomized treatment group 
and overall for the mITT population including: age, gender, childbearing potential for females, 
country, weight, height, body mass index (BMI), history of allergies (yes vs. no). A similar table 
will be made for the treated population by as-treated treatment group and overall to support safety. 
A separate set of tabulation of demographic information will be made for subjects enrolled but not 
randomized (overall only) and subjects randomized but not treated (by as-randomized treatment 
group and overall).  
The migraine history will be summarized by as-randomized treatment group and overall for the 
mITT population including but not limited to: age at migraine onset, experience migraines for at 
least one year prior to screening (yes vs. no), migraine history in years, duration of migraine attacks, 
number of moderate or severe migraines per month within last 3 months, use of prophylactic 
migraine medications (yes vs. no), primary migraine type. A similar table will be made for the 
treated population by as-treated treatment group and overall to support safety. 
Demographic and baseline characteristics, and migraine history will be listed for all randomized 
subjects.  
 
7.5.4 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 or later. 
Based on the mITT population with as-randomized treatment group, the medical history data will 
be summarized with frequencies and percentages of subjects with at least one medical history, and 
subject frequencies and percentages on the System Organ Class (SOC) and Preferred Term (PT) 
levels. The table will be sorted by overall descending frequency of SOC and then, within a SOC, 
by overall descending frequency of PT.  A similar table will be made for the treated population by 
as-treated treatment group and overall to support safety. 
Medical history will be listed by subject. 
7.5.5 Prior and Concomitant Therapies 
Non-study medications will be coded into Anatomical Therapeutic Chemical (ATC) 
classification codes and preferred drug names using the World Health Organization (WHO) Drug 
<DDE (Enhanced) B3 Format, March 2020 or later>. For each subject, multiple records of the 
same medication will be counted only once within each ATC Level 2 and/or PT term. 
The following non-study medications will be tabulated: 


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Prior medications are defined as those taken before study drug, i.e., imputed start or stop date < 
study drug start date. These include the following two subtypes: 
• 
Prior medications, defined as those taken before informed consent, i.e., those with an  
imputed start or stop date < informed consent date. 
• 
Current medications, defined as those taken on or after informed consent and before study 
drug, i.e., those with (1) informed consent datedimputed start or imputed stop date d study 
drug start date – 1, or (2) imputed start date d informed consent date dstudy drug start date 
–1 d imputed stop date. 
• 
Concomitant medications, defined as those taken on or after study drug, i.e., study drug 
start date d imputed start or stop date.  
• 
Prior prophylactic medications  
• 
Current prophylactic medications  
• 
Concomitant prophylactic medications  
All prior, current and concomitant medications will be included in a listing. Additionally, non-
drug therapies will be provided in a listing only. 
7.5.6 Compliance 
Considering the study drug will be administrated once for each subject, the treatment compliance 
will be not calculated and summarized.  
The eDiary compliance at 2, 4, 6, 8, 24, and 48 hours post-dose by counting the number of 
subjects with missing data will be summarized using the mITT population. 
7.6 
Efficacy Analyses  
Unless otherwise noted, all efficacy analyses will be conducted using the mITT population as 
outlined below. Efficacy tabulations will present results by as-randomized treatment group only 
(excluding overall), unless specified otherwise. All efficacy data will be included in listings by 
subject, treatment group, and time point (as applicable). 
7.6.1  Primary Efficacy Analyses 
The co-primary efficacy endpoints are pain freedom at 2 hours post-dose and freedom from MBS 
at 2 hours post-dose. 
7.6.1.1 Pain Freedom at 2 Hours Post-Dose 
Pain freedom is assessed using the number of mITT subjects that report pain levels of “none” at 
2 hours post-dose on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). The 
information from the 4-point scale is directly summarized as follows: 
A table showing descriptive statistics for the observed data, which includes the number and 
percentage of subjects reporting each of the 4 pain levels at baseline and each post-dose 
timepoint, and the percentage of subjects with missing data, for each treatment group. The 
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The difference in percentage of pain freedom at 2 hours post dose between treatment groups is 
evaluated by computing the common risk difference, using Cochran-Mantel-Haenszel (CMH) 
weights (sample size weights), stratified by the use of prophylactic migraine medication (yes or 
no) and country (China or Korea). The risk difference is tested at a two-sided alpha level of 0.05. 
Missing data at 2 hours post-dose will be imputed as failures (i.e., non-Completers = Failure; 
NC=F). Subjects that use rescue medication prior to reporting pain freedom at 2 hours will be 
classified as failures (i.e., Rescue Medication = Failure; RM=F). If a stratum (prophylactic 
medication use: yes or no) has sparse data (less than 5 subjects), then the strata will be pooled. 
A forest plot of the risk differences within each stratum, and common risk difference 
(similar to the risk difference plot produced by SAS Proc Freq) will be provided. 
Sensitivity analyses will be conducted as follows: 
1. The primary analysis is repeated, using the mITT population, with missing data at 2 hours 
post-dose imputed using Last Observation Carried Forward (LOCF). Baseline Observation 
Carried Forward (BOCF) is permitted. 
2. The primary analysis is repeated using only data from complete cases (data present at 
baseline and 2 hours). 
 
A sample SAS code for exact (Clopper-Pearson) 95% CIs is the following: 
proc freq data=pain; 
    by treatment pain_level; 
table response /  binomial (level="1" CL=(EXACT)); 
weight count; 
run; 
 
A sample SAS code for common risk difference from Mantel Haenszel method is the following: 
proc freq data=pain_2h; 
table prophylactic_migraine_medication*country*treatment*response /riskdiff (common 
CL=(WALD)) CMH ; 
weight count; 
run; 
 
7.6.1.2 Freedom from MBS at 2 Hours Post-Dose 
Freedom from each subject’s MBS is assessed using the number of mITT subjects who report 
that their MBS (reported at migraine onset) is absent at 2 hours post-dose. The symptoms that 
can be nominated as the MBS (phonophobia, photophobia or nausea) are measured using a 
binary scale (0=absent, 1=present). The information of MBS is directly summarized as follows: 
A table showing descriptive statistics for the observed data, which includes the number and 
percentage of subjects reporting MBS present, MBS absent, MBS not reported and each of 
the migraine associated symptoms (phonophobia, photophobia or nausea) at baseline and 


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each post-dose timepoint by treatment group and overall. The table will include exact 
(Clopper-Pearson) 95% CIs for each percentage of MBS present/absent/not reported.  
The difference in percentage of MBS free subjects (“risk difference”) between 
treatment groups, is evaluated by computing the common risk difference, using CMH weights 
(sample size weights), stratified by the use of prophylactic migraine medication (yes or no) and 
country (China or Korea). The risk difference will be tested at a two-sided alpha level of 0.05. 
Missing data at 2 hours post-dose will be imputed as failure (NC=F). Also, the use of rescue 
medication prior to providing data at the 2 hour assessment, taking IP prior to reporting the 
MBS, or failure to report a MBS are events that are imputed as treatment failures. If a stratum 
(prophylactic medication use: yes or no) has sparse data (less than 5 subjects) then the strata will 
be pooled. 
 
Sensitivity analyses will be conducted as follows: 
1. The primary analysis is repeated, using the mITT population, with missing data at 2 hours 
post-dose imputed using LOCF. BOCF is permitted. 
2. The primary analysis is repeated, using only data from complete cases (data present at 
baseline and 2 hours). 
 
7.6.2 Key Secondary Efficacy Analyses  
If the co-primary endpoint tests are both significant, then the key secondary endpoints are 
evaluated using the Hochberg Procedure. See Section 7.3 for details on the procedure. 
 
7.6.2.1 Pain Relief at 2 Hours Post-Dose 
Pain relief at 2 hours post-dose is assessed by tabulating the number of mITT subjects that report 
a pain level of none or mild (responses of 0 or 1 on the 4-point Likert scale) at 2 hours post-dose, 
by treatment group using the same methodology described in section 7.6.1.1. 
Subjects with missing data at 2 hours post-dose will be imputed as failures (NC=F). Subjects that 
use rescue medication prior to reporting pain relief at 2 hours will be classified as failures 
(RM=F).  
 
7.6.2.2 Function Normally at 2 Hours Post-Dose 
Subjects rate the level of disability they perceive as a result of their migraine in performing 
normal actions using a 4-point scale: Normal Function, Mild Impairment, Severe Impairment, or 
Required Bedrest. The proportion of mITT subjects who report “abnormal” at baseline and have 
a response of “normal” at the 2 hours post-dose will be evaluated using the same methodology 
described in section 7.6.1.1. 


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Subjects with missing data at 2 hours post-dose will be imputed as failures (NC=F). Subjects that 
use rescue medication prior to reporting function normality at 2 hours will be classified as 
failures (RM=F).  
The information from the 4-point scale will be directly summarized as follows: 
A table showing descriptive statistics for the 4-point scale, which includes the number and 
percentage of subjects reporting each of the 4 disability levels at the specified timepoint 
post-dose, and the percentage of subjects with missing data, for each treatment group, using 
the observed data. The table will include exact (Clopper-Pearson) 95% CIs for each 
percentage. 
7.6.2.3 Use of Rescue Medication within 24 Hours 
Whether or not a subject took rescue medication within 24 hours after the initial dose of study 
medication is tabulated by treatment group using mITT subjects, and the percentages are 
compared between treatment groups using the same methodology described in section 7.6.1.1. 
Information regarding the rescue medication, including the type, date and time taken, dose, 
route, and frequency, is presented in a listing by subject and treatment group.  
7.6.2.4  Sustained Pain Freedom from 2 to 24 Hours 
Sustained pain freedom is assessed using the number of mITT subjects that experienced no 
headache pain (response of 0 on Likert scale) at all time points from 2 through 24 hours post-
dose. Subjects with missing pain scores at 1 or fewer time points, given that they have responses 
of no pain (response of 0 on 4-point Likert scale) at all other time points including the 2 and 24 
hour post-dose time points, will be considered as successes. Subjects with responses missing at 
greater than 1 post-dose time point, missing data at the 2 or 24 hour time point (i.e. Non-
Completers with more than 1 missing data point = Failure; NC1=F), or with any pain score 
greater than 0; or with any rescue medication within 24 hours (RM=F) will be considered as 
failures.   
The proportion of mITT subjects who have a response of sustained pain freedom from 2 to 24 
hours will be evaluated using the same methodology described in section 7.6.1.1. 
7.6.2.5 Sustained Pain Freedom from 2 to 48 Hours 
Sustained pain freedom is assessed using the number of mITT subjects that experienced no 
headache pain (response of 0 on Likert scale) at all time points from 2 through 48 hours post-
dose. Subjects with missing pain scores at no more than 1 time point, given that they have 
responses of no pain (response of 0 on Likert scale) at the 2, 24, and 48 hour time points will be 
considered as successes. Subjects with responses missing at greater than 1 time point; missing 
data at the 2, 24, or 48 hour time point (NC1=F); or with any pain score greater than 0; or with 
any rescue medication within 48 hours (RM=F) will be considered as failures.  
The proportion of mITT subjects who have a response of sustained pain freedom from 2 to 48 
hours will be evaluated using the same methodology described in section 7.6.1.1. 


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7.6.3 Other Secondary Efficacy Analyses  
7.6.3.1 Pain Freedom at 15, 30, 45, 60 and 90 Minutes 
Pain freedom at 15, 30, 45, 60 and 90 minutes is assessed by tabulating the number of 
mITT subjects that report a pain level of none (responses of 0 on the 4-point Likert 
scale) at the specified post-dose time point, by treatment group. Subjects with missing data at the 
specified post-dose time point will be imputed as failures (NC=F). Subjects that use rescue 
medication prior to the specified post-dose time point will be classified as failures (RM=F).  
The proportion of mITT subjects who have a response of pain freedom at the specified post-dose 
time point will be evaluated using the same methodology described in section 7.6.1.1. 
7.6.3.2 Freedom from MBS at 15, 30, 45, 60 and 90 Minutes 
Freedom from MBS at 15, 30, 45, 60 and 90 minutes post-dose is assessed by tabulating the 
number of mITT subjects that report an absence of their MBS (reported at migraine onset) at 
specified post-dose time point, by treatment group. Subjects with missing data at the specified 
post-dose time point will be imputed as failures (NC=F). Subjects that use rescue medication 
prior to the specified post-dose time point will be classified as failures (RM=F).  Also taking IP 
prior to reporting the MBS, or failure to report a MBS are events that are imputed as treatment 
failures (IP=F). 
The proportion of mITT subjects who have a response of MBS free at the specified post-dose 
time point will be evaluated using the same methodology described in section 7.6.1.1. 
7.6.3.3 Pain Relapse from 2 to 48 Hours 
Pain relapse is assessed using the number of mITT subjects that are pain free at 2 hours post-
dose as the denominator. The numerator is the number of these subjects that then have a relapse 
of pain at any severity (response of 1, 2, or 3 on the 4-point Likert scale) within 48 hours after 
administration of study medication. Subjects with more than 1 time point with missing data or 
with missing data at the 24, or 48 hour time point are classified as relapse. 
If the subject becomes pain-free at 2 hours post dose and records the use of rescue medication, 
but no pain severity is recorded, it will be assumed that the medication is taken for relapse, and 
the subject will be counted as having experienced pain relapse. 
The proportion of mITT subjects who have a response of pain relapse from 2 to 48 hours will be 
evaluated using the same methodology described in section 7.6.1.1. 
7.6.4 Exploratory Efficacy Analyses  
7.6.4.1 Binary Exploratory Endpoints 
The binary exploratory endpoints will be evaluated using the same methodology described in 
section 7.6.1.1. The definitions of the binary exploratory endpoints are listed in the table 1 
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Table 1 Definitions of the Binary Exploratory Endpoints 
Endpoints 
 Definition of Success 
Missing Data or 
Rescue Medication 
Handling 
Pain Relief at 15, 30, 45, 60, 
and 90 minutes, 3, 4, 6, 8, 24, 
and 48 hours post-dose  
Report a pain level of none or mild 
(responses of 0 or 1 on the 4-point 
Likert scale) at specified post-dose time 
point 
NC=F; RM=F 
Pain freedom at 3, 4, 6, 8, 24, 
and 48 hours post-dose  
Report a pain level of none (responses 
of 0 on the 4-point Likert scale) at 
specified post-dose time point 
NC=F; RM=F 
Freedom from MBS at 3, 4, 
6, 8, 24, and 48 hours post-
dose  
Report an absence of their MBS 
(reported at migraine onset) at specified 
post-dose time point 
NC=F; RM=F; IP=F 
Function normally at all post-
dose timepoints except 2 
hours 
Subjects who report “abnormal” at 
baseline and have a response of 
“normal” at specified post-dose time 
point 
NC=F; RM=F 
 Freedom from phonophobia 
at all post-dose time points  
Subject who have phonophobia present 
at baseline and have absence of 
phonophobia at specified post-dose time 
point 
NC=F; RM=F 
Freedom from photophobia at 
all post-dose time points  
Subject who have photophobia present 
at baseline and have absence of 
photophobia at specified post-dose time 
point 
NC=F; RM=F 
Freedom from nausea at all 
post-dose time points  
Subjects who have nausea present at 
baseline and have absence of nausea at 
specified post-dose time point 
NC=F; RM=F 
Sustained pain relief from 2 
to 24 hours 
Subjects that experience no or mild 
headache pain (response of 0 or 1 on 
Likert scale) at all time points from 2 
through 24 hours post-dose; Subjects 
with missing pain scores at 1 or fewer 
NC1=F; RM=F 


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Endpoints 
 Definition of Success 
Missing Data or 
Rescue Medication 
Handling 
time points, given that they have 
responses of no or mild pain (response 
of 0 or 1 on 4-point Likert scale) at all 
other time points including the 2 and 24 
hour post-dose time points, will be 
considered as successes. 
Sustained pain relief from 2 
to 48 hours 
Subjects that experience no or mild 
headache pain (response of 0 or 1 on 
Likert scale) at all time points from 2 
through 48 hours post-dose; Subjects 
with missing pain scores at 1 or fewer 
time points, given that they have 
responses of no or mild pain (response 
of 0 or 1 on 4-point Likert scale) at all 
other time points including the 2, 24 and 
48 hour post-dose time points, will be 
considered as successes. 
NC1=F; RM=F 
Freedom from MBS from 2 
to 24 hours post-dose 
Subjects that experience freedom from 
their MBS at all time points from 2 
through 24 hours post-dose; Subjects 
with missing MBS data at 1 or fewer 
time points, given that they have 
responses of freedom from MBS at all 
other time points including the 2 and 24 
hour post-dose time points will be 
considered as successes. 
NC1=F; RM=F; 
IP=F 
Freedom from MBS from 2 
to 48 hours post-dose 
Subjects that experience freedom from 
their MBS at all time points from 2 
through 48 hours post-dose; Subjects 
with missing MBS data at 1 or fewer 
time points, given that they have 
responses of freedom from MBS at all 
other time points including the 2, 24, 
and 48 hour post-dose time points will 
be considered as successes. 
NC1=F; RM=F; 
IP=F 


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Endpoints 
 Definition of Success 
Missing Data or 
Rescue Medication 
Handling 
Function normally from 2 to 
24 hours post-dose  
Subjects that experience normal 
functioning on the FDS at all time 
points from 2 through 24 hours post-
dose. Subjects with missing FDS scores 
at 1 or fewer time points, given that 
they have responses of normal at all 
other time points including the 2 and 24 
hour post-dose time points will be 
considered as successes. 
NC1=F; RM=F 
Function normally from 2 to 
48 hours post-dose  
Subjects that experience normal 
functioning on the FDS at all time 
points from 2 through 24 hours post-
dose. Subjects with missing FDS scores 
at 1 or fewer time points, given that 
they have responses of normal at all 
other time points including the 2, 24 and 
48 hours post-dose time points will be 
considered as successes. 
NC1=F; RM=F 
  
7.6.4.2 Time to Event Endpoints 
Time to First Use of Rescue Medication 
Kaplan-Meier (K-M) plots will be created for the time to first use of rescue medication. The K-
M plot will cover the 24 hour period after dosing. Subjects who did not take rescue medication 
within 24 hours of dosing will be censored at 24 hours and 1 minute. Regardless of pain or MBS 
response, subjects are considered at risk until the first use of rescue medication, loss to follow-up 
(last contact date), or the end of the 24-hour period, whichever comes first.  The analysis 
population consists of mITT subjects. 
Two tables will be created to support the plot. The first table presents the median time to rescue 
medication along with 95% CIs calculated using the method of Brookmeyer and Crowley and 
the log-rank p-value. The second table presents the number of subjects at risk, with an event, 
censored, and the survival probability estimate (with 95% CI) from the K-M product limit 
method for each period (e.g., 0-<2 hours, 2-<4 hours, …, 20-<22 hours, 22-24 hours) by 
treatment group. 
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For each of the following events, two sets of K-M plots and tables will be created: 
Ь 
Time to first report of pain freedom up to 8 hours pose-dose 
Ь 
Time to first report of freedom from MBS up to 8 hours pose-dose 
Ь 
Time to first report of pain relief up to 8 hours pose-dose 
Ь 
Time to first report of absence of nausea up to 8 hours pose-dose 
Ь 
Time to first report of absence of photophobia up to 8 hours pose-dose 
Ь 
Time to first report of absence of phonophobia up to 8 hours pose-dose 
Ь 
Time to first report of return to normal functioning up to 8 hours post dose 
For both sets of analyses, the analysis population for pain freedom, pain relief and MBS is the set 
of mITT subjects. The analysis population for nausea, phonophobia, and photophobia is the 
subset of mITT subjects that reported the symptom as present at the onset of their study 
migraine. The analysis population for functional disability is the subset of mITT subjects that 
reported abnormal functioning at the onset of their study migraine. 
a) Actual Time for Event of Interest 
The first set of K-M plots and tables will be created for the above variables using actual time of 
censoring and actual time for the clinical event of interest. Subjects will be censored at the actual 
time of their first use of rescue medication or last reported data point if lost to follow-up. 
Subjects who did not have the clinical event of interest by 8 hours post dose will be censored at 
496 minutes (480 minutes + 15 minutes window + 1 minute).  
b) Nominal Time for Event of Interest 
The second set of K-M plots and tables will be created for the above variables with nominal time 
(planned time of collection, e.g., 2 hours, 3 hours, etc.) used for clinical events of interest and 
actual time used for censoring events. Subjects will be censored at the actual time of their first 
use of rescue medication or last reported data point if lost to follow-up. Subjects who did not 
have the clinical event of interest by 8 hours post dose were censored at 496 minutes (480 
minutes + 15 minutes window + 1 minute). 
7.7 
Safety Analyses 
Safety analyses will be conducted on the treated population by as-treated treatment group (i.e., 
the actual treatment received) and overall, unless otherwise specified. 
7.7.1 Extent of Exposure 
Extent of exposure is measured by subjects providing self-reported study drug exposure 
information in their eDiaries. As a check on this exposure data, study drug accountability data 
are provided by the study center on the “Study Drug Returned” CRF page. The self-reported 
study drug exposure data will be tabulated by treatment group and overall, for randomized 
subjects who had an on-study migraine, and will include: 


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The number (and percentage) of randomized subjects that either took (correctly/incorrectly) 
or did not take study medication 
 
o 
The number and percentage who took the medication prior to providing baseline study 
migraine characteristics by counting the number of subjects who answered ‘Yes’ for 
question “Did you mistakenly take your study medication already?” in eDiary data. 
 
o 
The number and percentage that took study medication after providing baseline study 
migraine characteristics by counting the number of subjects who answered ‘Yes’ for 
question “Confirm you just took your Study Medication” in eDiary data. 
 
o 
The number and percentage of randomized subjects who reported not taking study 
medication by counting the number of subjects who answered ‘No’ both for questions “Did 
you mistakenly take your study medication already?” and “Confirm you just took your 
Study Medication” in eDiary data. 
 
x 
The number and percentage of randomized subjects for whom no exposure data was 
reported 
The study drug accountability will be tabulated by treatment group and overall, for randomized 
subjects who had an on-study migraine, and will include: 
x 
The number and percentage of subjects with study drug returned and drug was not taken and 
the reason for drug not taken 
 
x 
The number and percentage of subjects with study drug not returned and drug was taken 
 
x 
The number and percentage of subjects with study drug not returned and drug was lost 
A by-subject listing will be prepared that indicates the study drug exposure and accountability 
status of all randomized subjects.  
7.7.2 Adverse Events 
All Adverse Events (AEs) will be coded using the MedDRA version 23.0 or later. AEs toxicities 
will be graded according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 5.0.   
All AEs will be summarized for the following categories: AEs with onset prior to randomization, 
AEs with onset on or after randomization but prior to study treatment, and treatment emergent 
adverse events (TEAEs) with onset on or after study treatment respectively. 
An overall summary of AEs, which includes the number and percentage of subjects reporting 
any AEs, AEs with onset prior to randomization, AEs with onset on or after randomization but 
prior to study treatment, serious AEs with onset prior to randomization, serious AEs with onset 
on or after randomization but prior to study treatment, TEAEs, drug-related TEAEs, TEAEs with 
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leading to death will be presented. The number and percentage of subjects by SOC and PT will 
also be reported.   
In the event of multiple occurrences of the same AEs being reported by the same subject, the 
maximum NCI-CTC Grade (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing > not 
applicable) will be presented in the summary tables. A subject will be counted once at the 
highest grade for which the event occurred at the SOC level and the highest grade for each 
unique PT within that SOC level. Therefore, subjects may only contribute once to each PT and 
once to each SOC level. If CTCAE grade is missing for one event and the subject had no Grade 
≥1 in the same category, “missing” row/column should be added in the summary tables with 
maximum CTCAE grade. The following summary tables will present the number and percentage 
of subjects by SOC, PT and maximum CTCAE grade.  
¡ 
TEAEs  
¡ 
Drug-related TEAEs  
The following tables summarizing the number and percentage of subjects by SOC and PT will 
present only those TEAEs that occurred in at least 5% in at least one treatment group. 
¡ 
TEAEs  
¡ 
Drug-related TEAEs  
All AEs will be included in listings. TEAEs are labelled in the listings. Listings will be provided 
for Serious Adverse Events (SAEs), AEs related to study drug, and grade >2 AEs separately. 
SAEs occurring in subjects enrolled but not treated will also be provided. AE leading to deaths 
will be listed for all enrolled subjects without regard to onset. 
7.7.3 Clinical Laboratory Evaluations 
Clinical laboratory evaluations collected in a central lab include: 
Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count (WBC) 
with differential, platelets, lymphocytes countˈneutrophils count and any other tests 
collected in the database. 
Blood chemistry/electrolyte: Sodium, potassium, chloride, bicarbonate, calcium; glucose, 
BUN (urea), serum creatinine, uric acid, ALT, AST, alkaline phosphatase, LDH, total protein, 
albumin, total bilirubin, direct bilirubin, indirect bilirubin, CK.  End of Treatment Visit -
elevations in CK (>1.5xULN) may have further CK fractionation tests performed through the 
central lab.   
Lipid panel: Cholesterol, LDL, HDL, triglycerides (Screening only). 
Estimated glomerular filtration rate: eGFR using the estimated MDRD formula will be 
calculated and reported by the central lab at each visit that clinical laboratory tests are 
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Urinalysis: pH, specific gravity, ketones, nitrites, urobilinogen, leukocyte esterase, protein, 
glucose and blood. If blood, protein or leukocytes are positive, reflex to microscopic 
examination. 
Urine Drug Screen: For drugs of abuse. 
Clinical laboratory values will be expressed using International System of Units (SI). The 
observed value and change from baseline will be summarized for select continuous laboratory 
parameters at baseline and the end of treatment visit. In addition, the shift from baseline in 
laboratory tests will be summarized as the number and percentage of subjects in each category 
(low, within reference range, high) at baseline and the end of treatment visit. For AST and ALT, 
the shift tables will use the following categories: <=ULN, >ULN to <=3x ULN, >3x ULN to <= 
5x ULN, >5x ULN to <= 10x ULN, >10x ULN to <=20x ULN and >20x ULN. 
Clinically significant laboratory abnormalities will be identified according to the numeric 
laboratory test criteria in CTCAE Version 5.0, otherwise according to Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected 
Version 2.1. For the selected laboratory tests as following, the number and percentage of subjects 
by maximum CTCAE grade (0-4) will be presented for baseline period and on-treatment period. 
The number and percentage of subjects with indicated shifts in their maximum CTCAE grade 
from baseline to post-baseline will also be presented. 
Hemoglobin, WBC, Lymphocytes Count, Neutrophils Count, platelets, ALT, AST, Total 
Bilirubin, Serum Creatinine, Sodium, Calcium, Potassium. 
All central laboratory data and local laboratory data within scheduled visit windows due to 
restrictions of COVID-19 or other exceptional circumstances are also included in the summary 
analysis. 
All laboratory data will be provided in by-subject listings that indicate which values are on study 
or on treatment. Additional listings will be presented for all abnormal laboratory values.  
The local laboratory data collected in exceptional circumstances will be provided in a separate 
listing. 
On-study laboratory values are those with collection date/time after the randomization date/time. 
On-treatment laboratory values are those with collection date/time after the first dose of study 
drug date/time. (Thus, on-treatment laboratory values are a subset of on-study values.) 
These definitions of on-study/on-treatment apply to vital signs, physical measurements, ECGs. 
7.7.3.1 Liver Toxicity Evaluation 
Potential drug induced liver injury (DILI) is those events meeting Hy’s Law, defined as: 
1. Aminotransferases (AT) ALT or AST elevation > 3 times the upper limit of normal (ULN); 


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2. Total bilirubin (TBL) > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase); and 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
included but not limited to: viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
Any on-study potential DILI, meeting the above defined criteria, will be reported as SAEs in the 
SAE summary table (see Section 7.7.2). A by-subject listing of potential DILI will be prepared 
that shows the AT and TBL values for all subjects that experience either AT > 3 times the ULN 
or TBL > 2 times the ULN at any time.  
Additionally, a table will be created that summarizes the on-study incidence (as the number and 
percentage of subjects with an elevation) of the following: 
x 
>3x, >5x, >10x, and >20x ULN elevations of AST, ALT, and either ALT or AST 
 
x 
Any elevations of bilirubin >1x ULN and >2x ULN 
 
x 
Any elevations of ALP > 1.5x ULN 
 
x 
Elevation of AST or ALT (>3x ULN) accompanied by elevated bilirubin (>1.5x ULN 
and >2x ULN) 
An evaluation of on-study Drug-Induced Serious Hepatotoxicity (eDISH) plot will be created by 
plotting the maximum ratio of total bilirubin divided by ULN against maximum ratio of ALT 
divided by ULN and presenting these data points by treatment group. The maximum values for 
each subject during the study will be identified as the maximum values that occur on study, but 
not necessarily concurrently. Maximum ratio of total bilirubin divided by ULN (presented as 
xULN) will be plotted on a log scale on the y-axis and maximum ratio of total ALT divided by 
ULN (presented as xULN) will be plotted on a log scale on the x-axis. A horizontal reference 
line will be placed at 2x ULN for maximum total bilirubin, and a vertical reference line will be 
placed at 3x ULN for maximum ALT. The lower left quadrant will be labeled “Normal Range”. 
The upper left quadrant will be labeled “Hyperbilirubinemia”. The lower right quadrant will be 
labeled “Temple’s Corollary”. The upper right quadrant will be labeled “Possible Hy’s Law 
Range”. 
7.7.4 12-Lead ECG 
Each ECG parameter (heart rate, RR interval, PR interval, QT interval, QTcF interval and QRS 
duration) at baseline and the end of treatment visit, and the corresponding change from baseline 
will be summarized by treatment group and overall with descriptive statistics.   
The shift tables with respect to normality of overall ECG assessment will be summarized.  All 
12-Lead ECG data will be listed.  


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7.7.5 Vital Signs 
Each vital sign parameter (systolic blood pressure, diastolic blood pressure, sitting pulse rate, 
respiratory rate, heart rate, temperature and weight) at baseline and the end of treatment visit, and 
the corresponding change from baseline will be summarized by treatment group and overall with 
descriptive statistics. A by-subject listing of vital sign values will also be provided. 
7.7.6 Physical Examination 
All physical examination data for subjects with at least one clinically significant abnormal 
finding will be presented in a listing.  
7.8 
Pharmacokinetic Analyses 
No pharmacokinetic data will be collected in this study. 
7.9 
Other Analyses 
7.9.1 Subgroup Analyses 
Subgroup analyses will be conducted for the co-primary endpoints and key secondary endpoints, 
unless otherwise noted. The baseline subgroup factors are defined as following. 
Table 2. Definition of Subgroup Variables 
 
Subgroup Variable 
Categories 
Intrinsic Factors 
Age Group 
< 40, ≥ 40 years  
Gender 
Male, Female 
Weight Group  
Categorized as < median, ≥ median, where 
median is calculated overall across treatment 
groups combined for mITT subjects 
Extrinsic Factors 
Country 
China, Korea 
Use of prophylactic 
migraine 
medications 
Yes, No 
Baseline aura, 
defined as the aura 
status at onset of the 
treated migraine 
Present, Absent 


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Primary migraine 
type 
Aura, Without Aura 
Number of moderate 
or severe migraines 
per month 
Categorized as < median, ≥ median, where 
median is calculated overall across treatment 
groups combined for mITT subjects 
 
7.9.2 COVID-19 Impact Analysis 
A by-subject listing of COVID-19 visit impact will be provided for randomized subjects. The 
listing includes the following information: “what is the impact?”, “how is the impact related to 
COVID-19?”, and “Subjects discontinued study due to COVID-19?”. 
7.10 Changes for Planned Analyses in Protocol 
Not applicable.  
8 
References 
 Not applicable.  
9 
Tables, Figures and Listing Shells 
Refer to attachment < BHV3000-310_TLF_MOCKS_v1.0.docx>.