Clinical trial NCT03873116
Conditions: Hereditary Angioedema, HAE
Keywords: BCX7353
Sponsor: BioCryst Pharmaceuticals
Start date: 2018-12-27; Completion date: 2021-07-08
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE who live in Japan.

Detailed description:

Arms: arm 1: BCX7353 capsules administered orally once daily arm 2: BCX7353 capsules administered orally once daily arm 3: Matching placebo oral capsules administered orally once daily
Interventions: intervention 1: BCX7353 capsules intervention 2: BCX7353 capsules intervention 3: Placebo oral capsule
Intervention descriptions: intervention 1: BCX7353 capsules administered orally once daily intervention 2: BCX7353 capsules administered orally once daily intervention 3: Matching placebo capsules administered orally once daily

Protocol documents:
Prot_000.pdf: 
Protocol 
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1.
TITLE PAGE
BIOCRYST 
PHARMACEUTICALS, INC. 
Protocol No. BCX7353-301 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF TWO DOSE 
LEVELS OF BCX7353 AS AN ORAL TREATMENT FOR THE 
PREVENTION OF ATTACKS IN SUBJECTS WITH 
HEREDITARY ANGIOEDEMA  
Version 6.0: 07 August 2020 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703 
Phone: (919) 859-1302 
Fax: (919) 851-1416 
The information in this document contains proprietary and confidential information belonging to 
BioCryst Pharmaceuticals, Inc. As a result, no part of this document should be copied, referred 
to, released, published or otherwise disclosed in any manner or media without prior written 
approval from BioCryst Pharmaceuticals, Inc. 
CONFIDENTIAL 


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Substitution of Text after the Approval of BCX7353 
Once BCX7353 (berotralstat) receives marketing authorization in Japan, this study will continue 
as a post-marketing study until such time as BCX7353 is commercially available at each site. 
The sponsor of the study will be changed from BioCryst Pharmaceuticals, Inc. (BioCryst) to the 
marketing authorization holder in Japan, OrphanPacific, Inc. However, the clinical conduct of 
the study will continue to be overseen by BioCryst. The study will be conducted in compliance 
with Japan post-marketing regulations; only approved formulations and dosing regimens of 
BCX7353 will be provided in the study. The text used in this protocol will be substituted as 
follows: 
Items 
Substitution 
Before Marketing Authorization 
After Marketing Authorization 
All text in the 
protocol 
Text describing investigational 
clinical study 
Text describing post-marketing 
clinical study 
 


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Protocol Number: 
BCX7353-301 (APeX-J) 
Study Title: 
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of two dose levels of BCX7353 as 
an oral treatment for the prevention of attacks in subjects with hereditary 
angioedema  
Investigational Product: 
BCX7353 
Indication Studied: 
Hereditary angioedema 
Sponsor: 
Prior to BCX7353 marketing authorization in Japan: 
BioCryst Pharmaceuticals, Inc. (BioCryst) 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703, USA 
After BCX7353 marketing authorization in Japan: 
OrphanPacific, Inc. 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
BioCryst will continue to oversee the clinical conduct of the 
post-marketing study. 
Japan Medical Monitor: 
BioCryst Medical Monitoring team 
Phone: +81-3-6811-2332 
Email: mmj@biocryst.com 
BioCryst Medical 
Monitor: 
Sylvia Dobo, MD 
Phone (24 hours): +1 919-859-7905 
Email: mmj@biocryst.com 
BioCryst Clinical Study 
Manager: 
Lacy Reese 
Office: + 1 919-226-5877 
Email: lreese@biocryst.com 
Compliance Statement: 
This study will be conducted in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki and clinical research 
guidelines established by the Code of Federal Regulations (Title 21, CFR 
Parts 50, 56, and 312), International Council for Harmonisation guidelines, 
and all locally applicable regulations. Essential study documents are 
currently archived in accordance with applicable regulations.  
Final Protocol Date(s): 
Version 1.0: 19 July 2018 
Version 2.0: 26 September 2018 
Version 3.0: 11 October 2018 (matches Pharmaceuticals and Medical 
Devices Agency [PMDA]-accepted Version 1.1 dated 01 October 2018) 
Version 4.0: 15 October 2018 
Version 5.0: 29 August 2019 
Version 6.0: 07 Aug 2020 




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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No: 
BCX7353-301 (APeX-J) 
Protocol Title: 
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study 
to evaluate the efficacy and safety of two dose levels of BCX7353 as an oral 
treatment for the prevention of attacks in subjects with hereditary angioedema  
 
Date: 
 
Version 6.0: 07 August 2020 
 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, International Council for Harmonisation guidelines for Good Clinical 
Practice, and all applicable regulatory requirements. 
 
 
_____________________________________________________________________ 
Investigator’s Signature                                                                      Date 
 
 
_________________________________ 
Name (Print) 
 


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2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. (BioCryst) 
After BCX7353 marketing authorization in Japan: 
OrphanPacific, Inc. 
BioCryst will continue to oversee the clinical conduct of the post-marketing study. 
Name of Investigational Product: 
BCX7353 (berotralstat) 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-
fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 
Title of Study: 
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of two dose levels of BCX7353 as an oral treatment for the prevention of attacks 
in subjects with hereditary angioedema (Study BCX7353-301) 
Study centers: Approximately 15 centers in Japan  
Enrollment period: Approximately 3 months 
Phase of development: 3 
Part 1 Primary Objective: 
• 
To determine the efficacy of BCX7353 110 and 150 mg administered once daily (QD) for 
24 weeks compared to placebo in the prevention of angioedema events in subjects with 
hereditary angioedema (HAE) 
Part 1 Secondary Objectives: 
• 
To assess the safety and tolerability of BCX7353 110 and 150 mg QD administered for 
24 weeks 
• 
To assess the effects of BCX7353 on HAE disease activity and angioedema event 
characteristics 
• 
To evaluate the effects of BCX7353 on quality of life (QoL) 
• 
To characterize the pharmacodynamic (PD) effects of BCX7353 
Part 1 Primary Efficacy Endpoint: 
• 
The rate of expert-confirmed angioedema events during dosing in the entire 24-week 
treatment period (Days 1 to 168).  
Part 1 Secondary Efficacy Endpoints: 
• 
Change from baseline in Angioedema Quality of Life questionnaire (AE-QoL) at 
Week 24 (total score) 
• 
Number and proportion of days with angioedema symptoms through 24 weeks 


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• 
Rate of expert-confirmed angioedema events during dosing in the effective treatment 
period (beginning on Day 8 through 24 weeks) 
Part 1 Exploratory Efficacy Endpoints: 
• 
Number and proportion of subjects with no angioedema events over 24 weeks 
• 
Use of medications to treat angioedema events over 24 weeks 
• 
The proportion of responders to study drug, separately defined as at least a 50%, 70%, or 
90% relative reduction in the rate of expert-confirmed angioedema events during 
treatment compared with the baseline expert-confirmed angioedema event rate 
Part 1 Safety Endpoints: 
• 
Number and proportion of subjects with a treatment-emergent adverse event (TEAE) 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent serious adverse 
event (TESAE)  
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 
laboratory abnormality 
Part 1 Health Outcome Endpoints: 
• 
EuroQoL 5-dimensional, 5-level questionnaire (EQ-5D-5L) scores 
• 
Treatment Satisfaction Questionnaire for Medication (TSQM) scores 
• 
Work Productivity and Activity Impairment Questionnaire (WPAI) scores 
Part 2 Primary Objective: 
• 
To evaluate the long-term safety and tolerability of BCX7353 110 and 150 mg in subjects 
with HAE 
Part 2 Secondary Objectives: 
• 
To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 over 
a 24- to 52-week administration period 
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 52-week 
administration period 
• 
To evaluate subject satisfaction with BCX7353 over a 24- to 52-week administration 
period 
Part 2 Primary Endpoints: 
• 
Number and proportion of subjects with a TEAE 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a TESAE 


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• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 
laboratory abnormality 
• 
The proportion of subjects with a treatment-emergent, treatment-related adverse event 
(AE) consistent with a drug rash  
Part 2 Secondary Endpoints: 
• 
Number and rate of angioedema events 
• 
Durability of response (angioedema event rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of medications to treat angioedema events 
• 
Discontinuations due to lack of efficacy 
• 
Durability in AE-QoL questionnaire scores 
• 
Durability in EQ-5D-5L scores 
• 
Durability in TSQM scores 
• 
Durability in WPAI scores 
Part 3 Primary Objective: 
• 
To evaluate the long-term safety and tolerability of BCX7353 administered QD over a 
52- to up to 104-week administration period in subjects with HAE 
Part 3 Secondary Objectives: 
• 
To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 
over a 52- to up to 104-week administration period 
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 52- to up to 104-week 
administration period 
• 
To evaluate subject satisfaction with BCX7353 over a 52- to up to 104-week 
administration period 
Part 3 Primary Endpoints: 
• 
Number and proportion of subjects with a TEAE 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a TESAE 
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 
laboratory abnormality 
• 
The proportion of subjects with a treatment-emergent, treatment related AE consistent 
with a drug rash 


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Part 3 Secondary Endpoints:  
• 
Number and rate of angioedema events 
• 
Durability of response (angioedema event rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of medications to treat angioedema events 
• 
Durability in AE-QoL questionnaire scores 
• 
Durability in EQ-5D-5L scores 
• 
Durability in TSQM scores 
• 
Durability in WPAI scores 
Methodology:  
This is a randomized, placebo-controlled, double-blind, parallel-group, 3-part study. Part 1 is 
designed to test the hypothesis that the angioedema event rate during 24 weeks of prophylactic 
BCX7353 treatment at 2 dosage levels will be less than that observed during 24 weeks of placebo. 
An angioedema event is defined as an attack, symptoms, or swelling due to a subject’s underlying 
hereditary angioedema disease. The primary efficacy endpoint will be assessed after the last subject 
completes Part 1 (through Week 24). Part 2 is designed to primarily evaluate the long-term safety of 
BCX7353 at 2 dosage levels. Part 3 is open-label and designed to primarily evaluate the long-term 
safety of BCX7353. Parts 1, 2, and 3 will be conducted in sequence. All subjects will receive 
BCX7353 in Parts 2 and 3, including those randomized to receive placebo in Part 1.  
Part 1 (24-week evaluation of blinded efficacy and safety) 
Subjects with HAE Type 1 or 2 will be eligible for the study following assessment of data obtained 
from screening procedures, including demonstration of a minimum number of angioedema events 
documented during a prospective run-in period of 8 weeks from the date of the screening visit.  
Treatment-eligible subjects will receive study drug (BCX7353 or placebo) in Part 1 of the study 
based on randomization in a 1:1:1 (active:active:placebo) ratio into 1 of 3 treatment groups: 
Group 1: BCX7353 110 mg QD administered orally for 24 weeks 
Group 2: BCX7353 150 mg QD administered orally for 24 weeks 
Group 3: Placebo QD administered orally for 24 weeks 
Enrollment into treatment groups will be stratified by the baseline angioedema event rate 
(≥ 2 angioedema events per month vs. < 2 angioedema events per month).  
Details of all angioedema events (attack, symptoms, or swelling due to HAE) and compliance with 
study drug will be recorded in an electronic diary (e-diary). Angioedema events will be treated in 
accordance with the subject’s normal standard of care. Treatment medications for angioedema events 
will not be provided by the sponsor. 
Within approximately 2 business days of the end of each angioedema event that occurs beginning at 
the screening visit through the Week 24 visit, subjects will be contacted by the investigator 
(or appropriately-trained designee) to discuss the clinical characteristics of the angioedema event, 
any questions the investigator has on the entered data, or to gain additional details on the event that 
are not included in the e-diary that the investigator deems important to clinically evaluate the event, 
as applicable.  


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The investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each event recorded in the e-diary as a confirmed angioedema 
event. All expert-confirmed angioedema events must include symptoms of swelling; prodromal 
symptoms in the absence of swelling are not considered angioedema events, regardless of treatment. 
The expert will consider that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal swelling. 
Under no circumstances should the run-in angioedema event requirement for eligibility be disclosed 
to study subjects. 
The study will include adolescent and adult subjects (≥ 12 years of age).  
Safety and tolerability will be evaluated through assessments of AEs, laboratory analyses (clinical 
chemistry, hematology, and urinalysis), vital signs, electrocardiograms (ECGs), and physical 
examinations. 
Study visits in Part 1 will occur at screening, baseline, and Weeks 2, 4, 8, 12, 18, and 24. The 
primary efficacy analysis will occur after the last subject completes the Week 24 visit and will 
include all data through Week 24. Subject treatment will remain blinded to the subject, site, and 
sponsor staff interacting with sites during Part 1.  
Part 2 (evaluation of safety of blinded BCX7353) 
Part 2 of the study will start with the administration of study drug dispensed at the Week 24 visit. 
Subjects in Groups 1 and 2 will continue to receive the same BCX7353 dose to which they were 
randomized in Part 1 of the study in a blinded manner. Subjects randomized to Group 3 will undergo 
a second randomization in a 1:1 ratio to receive either a 110 or 150 mg QD dose of BCX7353 in a 
blinded manner beginning at the Week 24 visit (see figure below for visual depiction of treatments in 
all study parts). The active dose a subject receives in Part 2 will be blinded for all subjects; subjects 
will be informed that they will receive an active dose of BCX7353 in Part 2. 
Study visits during Part 2 will occur during Weeks 26, 28, 32, 36, 48, and 52, with telephone contact 
at Weeks 40 and 44. Subjects will continue to document all angioedema events (attack, symptoms, or 
swelling due to HAE) that occur while on study drug, as well as compliance with the study drug, in 
their e-diary and will have regular visits to assess safety and tolerability; investigator confirmation of 
angioedema events will continue to be required for Part 2. Interim safety analyses will be conducted 
while Parts 2 and 3 are ongoing to support regulatory filings. 
Part 3 (up to 52-week evaluation of the safety of open-label BCX7353) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 52 visit. 
Based on the safety profile and efficacy of the 150 mg dose in Part 1 of the similarly designed 
Study BCX7353-302, all subjects in the current study receiving 110 mg QD will be transitioned to 
open-label 150 mg QD at the Week 52 visit. 
Study visits during Part 3 will occur during Week 60 and approximately every 12 weeks thereafter, 
for a total study duration of up to 104 weeks, until another mechanism is available to provide drug to 
the subject (eg, market access), or until the sponsor discontinues development of the product for the 
prevention of angioedema events, whichever comes first. Telephone contacts will occur at Weeks 56, 
64, 68, 76, 80, 88, 92, and 100. 
Subjects will continue to document all angioedema events (attack, symptoms, or swelling due to 
HAE) that occur while on study drug in their e-diary in Part 3. However, subjects will not be required 
to document compliance with the study drug. In addition, investigator confirmation of angioedema 
events will not be required in Part 3. All angioedema events recorded by the subjects will be 
reviewed and confirmed or rejected according to a set of pre-defined rules prior to inclusion in the 
effectiveness analyses. These rules will be outlined in the Statistical Analysis Plan. 


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Post-Marketing Study 
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to BCX7353 
through Week 104 or until such time as BCX7353 is commercially available at his or her site, 
whichever occurs first, unless the subject discontinues his or her participation in the study. During 
this period, BCX7353 will be administered at the dose regimen that is approved in Japan. In the 
event that BCX7353 is not commercially available when the first and each subsequent subject at each 
site reaches Week 104, then the treatment period will be extended with additional telephone contacts 
conducted at 4-week intervals (Weeks 108, 112, etc.) and clinic visits completed at 12-week intervals 
(Week 116, etc.) to allow each subject to continue treatment with BCX7353 until commercially 
available, unless the subject discontinues his or her participation in the study. Once BCX7353 is 
commercially available at each site, an end-of-study (EOS) visit will be scheduled for each subject to 
complete his or her participation in the study and transition to commercial drug product. Subjects 
will not have to wait for their next scheduled clinic visit to complete the EOS visit. Subjects may not 
continue on study for more than 3 months after National Health Insurance price listing in Japan. 
Subjects who choose not to continue their participation in the study at any time will be asked to 
complete an early termination visit within 3 weeks (+ 1 week) after their last dose of BCX7353. 
The study is summarized in the following schema: 
 
Abbreviations: e-diary = electronic diary; QD = once daily. 
* In the event that BCX7353 is not commercially available when the first and each subsequent subject at each 
site reaches Week 104, then the treatment period may be extended to allow the subject to continue treatment 
with BCX7353 until commercially available, unless the subject discontinues his or her participation in the 
study. After marketing authorization, BCX7353 will be administered at the dose regimen that is approved in 
Japan. 
Number of subjects (planned):  
Approximately 24 subjects with Type 1 or 2 HAE are planned to be enrolled (n = approximately 8 
per group in Part 1 [110 mg BCX7353, 150 mg BCX7353, and placebo]). 
Main criteria for inclusion:  
1. Males and non-pregnant, non-lactating females ≥ 12 years of age.  


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2. Able to provide written, informed consent. Subjects aged 12 to 17 years must be able to read, 
understand, and be willing to sign an assent form in addition to a caregiver providing 
informed consent.  
3. A clinical diagnosis of HAE Type 1 or Type 2, defined as having a C1-esterase 
inhibitor (C1-INH) functional level < 50% and a complement 4 (C4) level below the lower 
limit of the normal (LLN) reference range, as assessed during the screening period.  
In the absence of a low C4 value drawn during the intercritical period (ie, subject is not 
having an angioedema event), 1 of the following is acceptable to confirm the diagnosis of 
HAE: 1) a SERPING-1 gene mutation known or likely to be associated with HAE Type 1 or 
2 assessed during the screening period; 2) a confirmed family history of C1-INH deficiency; 
3) a C4 redrawn and retested during an angioedema event in the screening period with the 
results below the LLN reference range.  
For a C1-INH that is between 50% and the LLN (74%), a SERPING-1 gene mutation known 
or likely to be associated with HAE Type 1 or 2 HAE is acceptable to confirm the diagnosis 
of HAE.  
SERPING-1 gene analysis results indicating a “possibly pathogenic” mutation will be 
considered on a case-by-case basis by the medical monitor and may require additional testing 
for eligibility. 
4. Access to and ability to use an acute treatment for angioedema events approved by the Japan 
Ministry of Health, Labor, and Welfare (plasma-derived C1-INH or icatibant).  
5. Subjects must be medically appropriate for on-demand treatment as the sole medicinal 
management for their HAE during the study, that is, subjects must be medically appropriate 
to be managed without prophylactic treatments for HAE.  
6. The subject must have at least 2 angioedema events as assessed by an independent expert that 
meet all requirements below during the run-in period of 56 days beginning at the screening 
visit: 
• 
The angioedema events are unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• 
The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject not being able to perform daily 
activities without restriction (ie, subject records that he/she is at least slightly 
restricted in daily activities during the angioedema event). 
• 
The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• 
The angioedema events are otherwise confirmed by an independent expert to be 
angioedema events.    
Under no circumstances should the run-in angioedema event requirement for eligibility be 
disclosed to study subjects. 
7. Female subjects must agree to the contraception requirements and must meet the inclusion 
criteria regarding contraception, as outlined in Section 8.2.1. 
8. In the opinion of the investigator, the subject is expected to adequately comply with all 
required study procedures for the duration of the study. The subject must demonstrate 


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adequate compliance with all study procedures required from the screening visit through 
randomization, including e-diary recording of angioedema events beginning at the screening 
visit. 
Main criteria for exclusion: 
1. Any clinically significant medical or psychiatric condition or medical history that, in the 
opinion of the investigator or sponsor, would interfere with the subject’s ability to participate in 
the study or increases the risk to the subject by participating in the study.  
2. Dementia, altered mental status, or any psychiatric condition or stay in an institution further to 
an official or court order that would prohibit the understanding or rendering of informed 
consent or participation in the study. 
3. Anticipated use of short-term prophylaxis of angioedema events for a preplanned procedure 
during the screening or study periods.  
4. Concurrent diagnosis of any other type of recurrent angioedema. 
5. Clinically significant abnormal ECG at the screening visit. This includes, but is not limited to, a 
corrected QT interval using Fridericia’s method (QTcF) > 470 msec for women, a QTcF 
> 450 msec for men, or ventricular and/or atrial premature contractions that are more frequent 
than occasional, and/or as couplets or higher in grouping. 
6. Any clinically significant history of angina, myocardial infarction, syncope, cardiac 
arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other clinically significant 
cardiovascular abnormality such as poorly controlled hypertension. 
7. Known family history of sudden cardiac death. Family history of sudden death from HAE is not 
exclusionary. 
8. History of or current implanted defibrillator or pacemaker. 
9. Any abnormal laboratory or urinalysis parameter at screening that, in the opinion of the 
investigator, is clinically significant and relevant for this study. A calculated creatinine 
clearance of ≤ 30 mL/min or aspartate aminotransferase or alanine aminotransferase value 
≥ 3 × the upper limit of the normal reference range value obtained during screening is 
exclusionary.  
10. Prior enrollment in a BCX7353 study. 
11. Suspected C1-INH resistance in the opinion of the investigator or sponsor. 
12.  History of alcohol or drug abuse within the previous year prior to the screening visit, or current 
evidence of substance dependence or abuse (self-reported alcohol intake > 3 drinks/day). 
13. Positive serology for human immunodeficiency virus or current infection with hepatitis B virus 
or hepatitis C virus. 
14. Pregnant or planning to become pregnant during the study. 
15. Currently breastfeeding. Women who want to enter the study must agree to suspend 
breastfeeding at the screening visit. Women must wait at least 3 weeks after the last dose of 
BCX7353 to commence breastfeeding.  


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16. Positive drugs of abuse screen (unless drug is used as medical treatment with a prescription). 
17. History of severe hypersensitivity to multiple medicinal products or severe 
hypersensitivity/anaphylaxis with unclear etiology. 
18. Use of androgens or tranexamic acid for prophylaxis of angioedema events within the 28 days 
prior to the screening visit or initiation during the study.  
19. Use of C1-INH for prophylaxis of angioedema events within the 14 days prior to the screening 
visit or initiation during the study. Use of a C1-INH therapy for treatment of angioedema events 
is not excluded at any time, nor is C1-INH for preprocedural prophylaxis for an 
unplanned/unforeseen procedure. 
20. Use of concomitant medications that are metabolized by cytochrome P450 (CYP) 2D6, 
CYP2C9, CYP2C19, and/or CYP3A4 and have a narrow therapeutic range, within 7 days of the 
baseline visit or planned initiation during the study.  
21. Use of a medication that is clinically known to prolong the QT interval and is metabolized by 
CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to the baseline visit or planned 
initiation during the study. 
22. Use of a medication that is transported by P-glycoprotein and has a narrow therapeutic range, 
within 7 days of the baseline visit or planned initiation during the study. 
23. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study.  
24. Initiation of an estrogen-containing hormonal contraceptive within 56 days of the screening 
visit or planned initiation during the study.  
25. Current participation in any other investigational drug study or received another investigational 
drug within 30 days of the screening visit. 
26. An immediate family relationship to either sponsor employees, the investigator, or employees 
of the study site named on the delegation log. 
27. Held in an institution by a government or judicial order.  
Investigational product, dosage, and mode of administration:  
BCX7353 capsules, to be administered orally.  
Parts 1 and 2 
BCX7353 capsules contain 55 and 75 mg of the active ingredient (free base equivalents). 
Subjects will take the following orally once daily at approximately the same time each day, with 
whichever meal is typically the largest of the day: 
Treatment Group 1 (110 mg QD) Parts 1 and 2: two 55-mg capsules of BCX7353 
Treatment Group 2 (150 mg QD) Parts 1 and 2: two 75-mg capsules of BCX7353 
Subjects randomized to Treatment Group 1 or 2 will receive the same dose of study drug in both 
Parts 1 and 2.  
Subjects randomized to Treatment Group 3 (placebo) in Part 1 will be automatically randomized to 
receive active study drug from the Week 24 visit (Part 2): 
Treatment Group 3a (110 mg QD) Part 2: two 55-mg capsules of BCX7353 
Treatment Group 3b (150 mg QD) Part 2: two 75-mg capsules of BCX7353 


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Part 3 
BCX7353 capsules contain 150 mg of the active ingredient (free base equivalent). Subjects will take 
a single capsule orally once daily at approximately the same time each day, with whichever meal is 
typically the largest of the day. 
Subjects randomized to Treatment Groups 1 and 2 will receive a total of up to 104 weeks of active 
BCX7353 treatment. Subjects randomized to Treatment Group 3 will receive a total of up to 
80 weeks of active BCX7353 treatment. 
Reference therapy, dosage, and mode of administration:  
Placebo-to-match BCX7353 capsules. Subjects randomized to Treatment Group 3 will take 
2 capsules of placebo orally QD for 24 weeks during Part 1 with their largest meal of the day.  
Duration of treatment:  
Subjects will take capsules of BCX7353 or placebo orally for 24 weeks in Part 1 and capsules of 
BCX7353 orally for up to 80 weeks (28 weeks in Part 2 and up to 52 weeks in Part 3), for a total 
duration of study drug treatment of up to 104 weeks. 
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to BCX7353 
until such time as BCX7353 is commercially available at his or her site unless the subject 
discontinues his or her participation in the study. During this period, BCX7353 will be administered 
at the dose regimen that is approved in Japan. 
Criteria for evaluation: 
Efficacy: 
Number of angioedema events and related details (timing, duration of symptoms, anatomical 
location, treatment used, emergency room visits, hospitalizations), number of days with HAE 
symptoms, number of subjects who are angioedema event-free, assessment of angioedema event 
severity, and discontinuations due to lack of efficacy. 
Safety: 
AEs, laboratory analyses (clinical chemistry, hematology, coagulation, urinalysis, creatine 
kinase-MB, troponin I and T, neutrophil gelatinase-associated lipocalin), vital signs, ECGs, and 
physical examinations. An independent Data Monitoring Committee (DMC) will periodically review 
safety data in accordance with a DMC Charter. Relationships between safety assessment findings and 
human leukocyte antigen typing results may be examined on a meta-study basis.  
Health Outcomes: 
AE-QoL, EQ-5D-5L, TSQM, and WPAI questionnaire scores. 
Pharmacodynamics: 
Kallikrein inhibition. Additional exploratory assays to elucidate PD properties of BCX7353 may also 
be conducted on plasma samples drawn for PD analyses.  
Pharmacokinetics: 
Blood samples for BCX7353 concentrations will be drawn. Population pharmacokinetic parameters 
of BCX7353 will be evaluated on a meta-study basis.  
Statistical methods: The primary study hypothesis is that the rate of angioedema events during 
24 weeks of prophylactic BCX7353 will be less than the corresponding rate on placebo. The primary 
efficacy endpoint in Study BCX7353-301 is the monthly expert-confirmed angioedema event rate in 
the entire treatment period (Day 1 [post-dose] to Day 168) in the intent-to-treat (ITT) population, 
which includes all randomized subjects. The primary analysis will be conducted on the BCX7353-
301 study population. It should be noted that the sample size considered feasible for enrollment in 


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Japan has limited statistical power. A supplemental analysis will combine data from this study with 
data from Study BCX7353-302. The primary efficacy endpoint in Study BCX7353-302 is the 
monthly investigator-confirmed angioedema event rate in the entire treatment period (Day 1 
[post dose] to Day 168) in the ITT population. The angioedema event rate and the treatment 
comparisons between each BCX7353 dose and placebo in the rate of investigator- or 
expert-confirmed HAE angioedema events during the entire dosing period will be analyzed using a 
negative binomial regression model. The number of investigator- or expert-confirmed angioedema 
events will be included as the dependent variable, the treatment will be included as a fixed effect, the 
stratification variable (baseline angioedema event rate) will be included as a covariate, and the 
logarithm of duration on treatment will be included as an offset variable. The estimated rate of 
angioedema event for each treatment group, the treatment differences expressed as the angioedema 
event rate ratio (BCX7353 over placebo rate ratio), and their associated 95% confidence intervals 
will be provided from the negative binomial regression model. Monthly will be defined as 4 weeks.  
Descriptive summaries, figures, and listings will be produced for efficacy endpoints of interest. 
Safety data analyses will be conducted using data from the current study alone. 
The safety analyses will be analyzed separately for Part 1 alone; a later data analysis will evaluate 
long-term safety data for the current study. 
Safety endpoints that will be summarized include, at a minimum, the number and proportion of 
subjects 1) with a TEAE; 2) who discontinue BCX7353 due to a TEAE 3) who experience a TESAE; 
4) who experience a Grade 3 or 4 TEAE; and 5) who experience a treatment-emergent Grade 3 or 4 
laboratory abnormality. In addition, the proportion of subjects with treatment-emergent, 
treatment-related AEs consistent with a drug rash will also be summarized. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
Substitution of Text after the Approval of BCX7353 ......................................................................2 
1.1. 
Protocol Approval Signature Page ................................................................................4 
1.2. 
Clinical Study Protocol Agreement ..............................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................23 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................24 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
Background .................................................................................................................27 
5.2. 
Nonclinical Findings for BCX7353 ............................................................................27 
5.3. 
Clinical Findings for BCX7353 ..................................................................................28 
5.3.1. 
Summary of Study BCX7353-302 ..............................................................................29 
5.3.2. 
Summary of Study BCX7353-203 ..............................................................................30 
5.3.3. 
Data Monitoring Committee Review of Ongoing Studies BCX7353-302 and 
BCX7353-204 .............................................................................................................31 
5.4. 
Rationale for Study .....................................................................................................31 
5.4.1. 
Rationale for Study Design .........................................................................................31 
5.4.2. 
Rationale for BCX7353 Doses and Regimen .............................................................32 
5.4.3. 
Rationale for Study Population ...................................................................................33 
5.4.4. 
Rationale for Control Group and Prohibition of Current Prophylactic 
Medications .................................................................................................................33 
5.4.5. 
BCX7353 Benefit-Risk Analysis ................................................................................34 
5.4.6. 
Benefits of Trial Participation ....................................................................................35 
5.4.7. 
Overall Benefit-Risk Assessment ...............................................................................35 
6. 
TRIAL OBJECTIVES ................................................................................................35 
6.1. 
Objectives ...................................................................................................................35 
6.1.1. 
Part 1 Primary Objective ............................................................................................35 
6.1.2. 
Part 1 Secondary Objectives .......................................................................................35 
6.1.3. 
Part 2 Primary Objective ............................................................................................35 


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6.1.4. 
Part 2 Secondary Objectives .......................................................................................35 
6.1.5. 
Part 3 Primary Objectives ...........................................................................................36 
6.1.6. 
Part 3 Secondary Objectives .......................................................................................36 
7. 
OVERALL STUDY DESIGN AND PLAN ...............................................................36 
7.1. 
Endpoints ....................................................................................................................40 
7.1.1. 
Part 1 Primary Efficacy Endpoint ...............................................................................40 
7.1.2. 
Part 1 Secondary Efficacy Endpoints .........................................................................40 
7.1.3. 
Part 1 Exploratory Efficacy Endpoints .......................................................................40 
7.1.4. 
Part 1 Safety Endpoints ..............................................................................................40 
7.1.5. 
Part 1 Health Outcome Endpoints ..............................................................................40 
7.1.6. 
Part 2 Primary Endpoints ............................................................................................41 
7.1.7. 
Part 2 Secondary Endpoints ........................................................................................41 
7.1.8. 
Part 3 Primary Endpoints ............................................................................................41 
7.1.9. 
Part 3 Secondary Endpoints ........................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
8.1. 
Number of Subjects ....................................................................................................42 
8.2. 
Subject Selection ........................................................................................................42 
8.2.1. 
Inclusion Criteria ........................................................................................................42 
8.2.2. 
Exclusion Criteria .......................................................................................................44 
8.3. 
Subject Withdrawal from the Study and from Study Drug ........................................46 
8.3.1. 
Subject Withdrawal from the Study ...........................................................................46 
8.3.2. 
Subject Discontinuation from Study Drug .................................................................46 
8.4. 
End of Study Definition ..............................................................................................47 
9. 
TREATMENT OF SUBJECTS ..................................................................................48 
9.1. 
Description of Study Drug and Study Drug Product ..................................................48 
9.2. 
Description of Study Drug Packaging, Labeling, and Storage ...................................48 
9.3. 
Randomization and Study Drug Blinding...................................................................48 
9.3.1. 
Blinding ......................................................................................................................48 
9.3.2. 
Randomization ............................................................................................................49 
9.3.2.1. 
Part 1 Randomization .................................................................................................49 
9.3.2.2. 
Part 2 Randomization .................................................................................................50 
9.4. 
Study Drug Administration and Treatment Compliance ............................................51 
9.5. 
Study Drug Dose Modification ...................................................................................52 


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9.6. 
Study Drug (Investigational Medicinal Product) Accountability ...............................52 
9.7. 
Concomitant Medications ...........................................................................................52 
9.7.1. 
Prohibited Medications ...............................................................................................53 
10. 
STUDY CONDUCT ...................................................................................................53 
10.1. 
Overview .....................................................................................................................53 
10.2. 
Schedule of Assessments ............................................................................................54 
10.3. 
Study Visits .................................................................................................................63 
10.3.1. 
Screening Visit ............................................................................................................63 
10.3.2. 
Period Between Screening and Baseline ....................................................................64 
10.3.3. 
Part 1 ...........................................................................................................................66 
10.3.3.1. 
Baseline Visit (Day 1) ................................................................................................66 
10.3.3.2. 
Week 2 Visit ...............................................................................................................67 
10.3.3.3. 
Week 4, 8, 12, and 18 Visits .......................................................................................67 
10.3.3.4. 
Week 24 Visit .............................................................................................................68 
10.3.4. 
Part 2 ...........................................................................................................................69 
10.3.4.1. 
Week 26 Visit .............................................................................................................69 
10.3.4.2. 
Week 28, 32, 36, 48, and 52 Visits .............................................................................69 
10.3.4.3. 
Week 40 and 44 Phone Calls ......................................................................................70 
10.3.5. 
Part 3 ...........................................................................................................................70 
10.3.5.1. 
Week 60, 72, 84, 96, and 104 Visits ...........................................................................70 
10.3.5.2. 
Week 56, 64, 68, 76, 80, 88, 92, and 100 Phone Calls ...............................................71 
10.3.5.3. 
End-of-Study/Early Termination Visit .......................................................................71 
11. 
ASSESSMENTS.........................................................................................................72 
11.1. 
Chronology of Assessments .......................................................................................72 
11.2. 
Investigator-Completed Assessments .........................................................................72 
11.2.1. 
HAE Medical and Medication History .......................................................................73 
11.2.2. 
Physical Examination .................................................................................................73 
11.2.3. 
Weight/Body Mass Index ...........................................................................................73 
11.2.4. 
12-lead Electrocardiograms ........................................................................................73 
11.2.5. 
Vital Signs ..................................................................................................................74 
11.2.6. 
Clinical Laboratory Evaluations .................................................................................74 
11.2.7. 
Screening for Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C 
Serology ......................................................................................................................76 


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11.2.8. 
HLA Typing ................................................................................................................76 
11.2.9. 
Pregnancy Testing ......................................................................................................76 
11.2.10. 
HAE Diagnostic Confirmation ...................................................................................76 
11.2.11. 
Other Laboratory Assessments ...................................................................................77 
11.2.12. 
Pharmacokinetics and Pharmacodynamics .................................................................77 
11.2.13. 
Pharmacogenomic Testing ..........................................................................................77 
11.2.14. 
Rash Assessment ........................................................................................................78 
11.2.15. 
Adverse Events ...........................................................................................................79 
11.3. 
Patient-Reported Outcomes ........................................................................................79 
11.4. 
Angioedema Events and Dosing e-Diary, Investigator Event Follow-up and 
Confirmation ...............................................................................................................80 
11.4.1. 
Screening and Parts 1 and 2 ........................................................................................81 
11.4.1.1. 
Investigator Follow-up of Angioedema Events and Expert Confirmation of 
Angioedema Events ....................................................................................................81 
11.4.1.2. 
Scheduled Telephone Contact ....................................................................................82 
11.4.2. 
Part 3 ...........................................................................................................................82 
11.4.2.1. 
Confirmation of Angioedema Events .........................................................................82 
11.4.2.2. 
Scheduled Telephone Contact ....................................................................................83 
12. 
ADVERSE EVENT MANAGEMENT AND REPORTING .....................................83 
12.1. 
Adverse Events ...........................................................................................................83 
12.1.1. 
Definitions ..................................................................................................................83 
12.1.1.1. 
Adverse Event .............................................................................................................83 
12.1.1.2. 
Serious Adverse Event ................................................................................................84 
12.1.1.3. 
Adverse Events of Special Interest .............................................................................85 
12.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events .............................................................................85 
12.1.3. 
Definition of Severity .................................................................................................86 
12.1.4. 
Definition of Relationship to Study Drug ...................................................................86 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................87 
12.1.5.1. 
Reporting Adverse Events of Special Interest ............................................................88 
12.1.6. 
Pregnancy ...................................................................................................................89 
12.1.7. 
Serious Breaches of Good Clinical Practice ...............................................................89 
12.1.8. 
Treatment Interruptions ..............................................................................................89 


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12.1.9. 
Emergency Procedures ...............................................................................................89 
12.2. 
Adverse Event Management .......................................................................................90 
12.2.1. 
Rash ............................................................................................................................90 
12.2.1.1. 
Study Drug Administration for Grade 1 or 2 Rashes Considered Related to 
Study Drug ..................................................................................................................90 
12.2.2. 
Aminotransferase (ALT or AST) Elevation ...............................................................90 
12.2.3. 
Overdose .....................................................................................................................91 
12.3. 
Data Monitoring Committee .......................................................................................92 
13. 
STATISTICS ..............................................................................................................92 
13.1. 
Hypotheses ..................................................................................................................92 
13.1.1. 
Primary Hypotheses ....................................................................................................92 
13.1.2. 
Secondary Hypotheses ................................................................................................93 
13.1.3. 
Controlling for Multiplicity ........................................................................................93 
13.2. 
Sample Size Considerations .......................................................................................94 
13.2.1. 
Sample Size for Study BCX7353-301 Alone .............................................................95 
13.2.2. 
Sample Size for the Combined Analysis of Studies BCX7353-301 and 
BCX7353-302 .............................................................................................................95 
13.3. 
Stratification ...............................................................................................................95 
13.4. 
Statistical Methods ......................................................................................................95 
13.4.1. 
Analysis Populations ..................................................................................................96 
13.4.1.1. 
Screen Failures ............................................................................................................96 
13.4.1.2. 
Intent-to-Treat Population ..........................................................................................96 
13.4.1.3. 
Safety Population ........................................................................................................96 
13.4.1.4. 
Per Protocol Population ..............................................................................................96 
13.4.1.5. 
Completers Population ................................................................................................96 
13.4.1.6. 
Pharmacodynamic Population ....................................................................................96 
13.4.1.7. 
PK Concentration/PD Population ...............................................................................96 
13.4.2. 
General Considerations for Data Analysis .................................................................97 
13.4.3. 
Subject Demographic and Disposition Data ...............................................................97 
13.4.4. 
Analysis of Efficacy Variables ...................................................................................97 
13.4.4.1. 
Primary Efficacy Analysis ..........................................................................................98 
13.4.4.2. 
Secondary and Exploratory Efficacy Analyses ..........................................................98 
13.4.5. 
Planned Analyses ........................................................................................................99 


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13.4.6. 
Analysis of Safety Variables ......................................................................................99 
13.4.7. 
Health Outcome Analyses ........................................................................................100 
13.4.8. 
Pharmacokinetic Analyses ........................................................................................101 
13.4.9. 
Pharmacodynamic Analyses .....................................................................................101 
13.4.10. 
PK Concentration /Pharmacodynamic Analyses ......................................................101 
14. 
STUDY ADMINISTRATION .................................................................................101 
14.1. 
Regulatory and Ethical Considerations ....................................................................101 
14.1.1. 
Regulatory Authority Approvals ..............................................................................101 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals .................................102 
14.1.3. 
Subject Informed Consent: Adults ............................................................................102 
14.1.4. 
Subject Informed Consent: Adolescents ...................................................................103 
14.1.5. 
Investigator Reporting Requirements .......................................................................103 
14.2. 
Study Monitoring ......................................................................................................103 
14.3. 
Quality Assurance .....................................................................................................104 
14.4. 
Study Termination and Site Closure .........................................................................104 
14.5. 
Records Retention .....................................................................................................105 
14.6. 
Confidentiality of Information and Data ..................................................................105 
14.7. 
Study Publication ......................................................................................................105 
15. 
REFERENCES .........................................................................................................106 
16. 
APPENDICES ..........................................................................................................108 
16.1. 
DMID Adult Adverse Event Table (DRAFT, Publish Date: November 2007) .......108 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................24 
Table 2: 
Schedule of Assessments: Part 1 of Study BCX7353-301 .........................................55 
Table 3: 
Schedule of Assessments: Part 2 of Study BCX7353-301 .........................................59 
Table 4:  
Schedule of Assessments: Part 3 of Study BCX7353-301 .........................................61 
Table 5: 
Clinical Laboratory Evaluations .................................................................................75 
Table 6: 
Power Calculations to Support Sample Size ..............................................................95 
 


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LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................38 
Figure 2: 
Study Randomization ..................................................................................................50 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation  
Explanation 
ABW 
absolute body weight 
AE 
adverse event 
AE-QoL 
Angioedema Quality of Life Questionnaire 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BCX7353 
berotralstat 
BK 
bradykinin 
BMI 
body mass index 
BMP 
di-docosahexaenoyl (22:6)-bis(mono)acylglycerol phosphate 
C1-INH 
C1 esterase inhibitor 
C3 
complement 3 
C4 
complement 4 
CI 
confidence interval 
CK-MB 
creatine kinase MB isoenzyme 
CLCR 
creatinine clearance 
Cmax 
maximum plasma concentration of the drug 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CSR 
clinical study report 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases, US National Institutes of Allergy and 
Infectious Diseases 
EC50 
concentration that elicits a 50% response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e-diary 
electronic diary 
EOS 
end-of-study 
EOSI 
event of special interest 
EQ-5D-5L 
EuroQoL 5-dimensional, 5-level questionnaire 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GI 
gastrointestinal 
HAE 
hereditary angioedema 
HBV 
hepatitis B virus 


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Abbreviation  
Explanation 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HK 
high-molecular weight kininogen 
HLA 
human leukocyte antigen 
IB 
investigator’s brochure 
ICxx 
xx% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product (study drug) 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IXRS 
interactive (web or voice) response system 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
NGAL 
neutrophil gelatinase-associated lipocalin 
NHI 
National Health Insurance 
NHP 
non-human primates 
NOAEL 
no observed adverse effect level 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein efflux pump 
PK 
pharmacokinetic 
PKK 
prekallikrein 
PLD 
phospholipidosis  
PMDA 
Japan Pharmaceuticals and Medical Devices Agency 
PP 
per protocol 
PR 
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex, representing time for atrial and ventricular depolarization, respectively 
QD 
once daily 
QoL 
quality of life 
QRS 
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave, representing the time for ventricular depolarization 
QT 
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur 


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Abbreviation  
Explanation 
QTcF 
QT interval corrected by Fridericia's formula 
RR 
interval between successive heart beats using the R-wave peaks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SN 
salt nomenclature 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
US 
United States 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 


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5. 
INTRODUCTION 
5.1. 
Background 
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency is an autosomal 
dominant disorder characterized by recurrent episodes of swelling of the skin, pharynx, larynx, 
gastrointestinal tract (GI), genitals, and extremities (Longhurst and Cicardi 2012). The frequency 
of attacks varies, from rarely in some patients to every few days in others. Angioedema attacks 
may or may not be precipitated by a stimulus (such as stress, trauma, or estrogen) and are 
typically rapid in onset, with symptoms subsiding gradually over the following 3 to 5 days 
(Zuraw and Christiansen 2011). Oropharyngeal swelling can be life-threatening (Bork, Hardt et 
al. 2012), while attacks in other sites, including limbs, genitalia, face, and intestines, can be 
painful, disabling, and disfiguring and have a significant impact on functionality and quality of 
life (QoL) (Lumry, Castaldo et al. 2010). Although mortality risk from asphyxiation is much 
higher in undiagnosed patients with HAE, deaths still occur in diagnosed patients with access to 
care at centers of excellence (Bork, Hardt et al. 2012). 
Extensive evidence from animal models and clinical studies supports the role of bradykinin (BK) 
as the principal mediator of the signs and symptoms that characterize attacks of HAE (Han, 
MacFarlane et al. 2002, Kaplan 2010, Zuraw and Christiansen 2011). Plasma kallikrein is a 
serine protease integral to the contact activation pathway (Saxena, Thompson et al. 2011). 
Kallikrein circulates in plasma as a zymogen, prekallikrein (PKK), bound to one of its main 
substrates, high-molecular-weight kininogen (HK). During contact activation, PKK is cleaved by 
activated factor XII, forming the active protease kallikrein. Kallikrein in turn cleaves HK, 
producing BK (Kaplan and Ghebrehiwet 2010). The activation of the BK B2 receptor by BK 
ultimately results in vasodilatation, increased vascular permeability, and contraction of smooth 
muscle, all of which lead to the tissue swelling that characterizes HAE (Kaplan 2010).  
BCX7353 (berotralstat) is a potent, synthetic small molecule inhibitor of plasma kallikrein. In 
contrast to parenterally administered options commercially available for prophylaxis against 
HAE attacks, inhibition of kallikrein with an orally bioavailable small molecule such as 
BCX7353 offers the advantage of oral administration. 
5.2. 
Nonclinical Findings for BCX7353 
The principal results of nonclinical pharmacology, pharmacokinetics (PK), and toxicology 
studies of BCX7353 are found in the investigator’s brochure (IB). 
Safety pharmacology studies of BCX7353 indicated multiple cardiac ion channel effects, 
including the human ether-à-go-go-related gene (hERG) K+ channel and the Na+ and Ca2+ 
channels. However, studies in non-human primates (NHP) showed quantitatively small 
drug-related prolongation of the QT interval. There were no concerns for phototoxicity or 
genotoxicity.  
Embryo-fetal developmental toxicity studies in the rat and rabbit showed no evidence of direct 
fetal toxicity of BCX7353, and no effects were seen in male and female rats in fertility studies. 
Chronic-dosing toxicology studies were conducted in the NHP (39 weeks) and rat (26 weeks). 
BCX7353 was well tolerated in both rats and monkeys at doses up to 30 and 20 mg/kg/day, 
respectively, and these dose levels were the no observed adverse effect levels (NOAELs). In the 


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NHP, at the NOAEL dose of 30 mg/kg/day, mean maximum plasma concentration (Cmax) and 
AUC from time 0 to 24 hours (AUC0-24) values on Day 270 (sexes combined) were 277 ng/mL 
and 3950 ng.h/mL, respectively. In the rat, at the NOAEL dose level of 20 mg/kg/day, Cmax was 
686 ng/mL and AUC0-24 was 9710 ng.h/mL on Day 182. 
In the chronic toxicology study in rats, the target organ was the liver. Minimal to mild bile duct 
hyperplasia and foamy/pigmented macrophages were observed at 20 mg/kg/day. Vacuolated 
epithelium of hepatic bile ducts was noted with minimal severity. A pathology peer-review of 
liver findings in the 26-week study concluded that the microscopic changes, including bile duct 
hyperplasia, were non-adverse.  
In monkeys, the primary target organs were the liver and kidney. In one study that evaluated 
doses up to 20 mg/kg/day, the only effect noted was a mild increase in alanine aminotransferase 
(ALT), which partially resolved during the study despite continued dosing. In another study that 
evaluated doses of 30, 55, and 80 mg/kg/day, adverse findings in the liver and kidney were noted 
at 55 and 80 mg/kg/day. Increased liver weights and panlobular hepatocellular hypertrophy were 
observed together with increased ALT and aspartate aminotransferase (AST); increased kidney 
weights, renal tubular epithelial cell degeneration, and renal tubular hyperplasia were also 
observed. Each of these effects was reversible during a 13-week drug-free recovery period.  
In monkeys, pigmented and foamy macrophages were present in all regions of the small 
intestine, in mesenteric lymph nodes, and in liver Kupffer cells at doses ≥ 30 mg/kg/day in 
females, and at doses ≥ 55 mg/kg/day in males. Dose-dependent increases in the urinary 
concentrations of the experimental biomarker for phospholipidosis (PLD), di-docosahexaenoyl 
(22:6)-bis(mono) acylglycerol phosphate (BMP), were observed in both rats and monkeys. 
Electron microscopy evaluation of liver from rats in the 13-week toxicity studies demonstrated 
myelinosomes within the cytoplasm of Kupffer cells. These effects are consistent with PLD, a 
phenomenon noted in nonclinical toxicity studies with several approved drugs. PLD is 
considered an adaptive response to the presence of a drug, rather than a toxic manifestation.  
In monkeys, spleen and thymus weights were increased at 55 and 80 mg/kg/day. The increased 
spleen weight correlated with lymphoid hyperplasia; there was no microscopic correlate for the 
increased thymus weights. 
5.3. 
Clinical Findings for BCX7353 
A clinical program, including 5 Phase 1 studies (BCX7353-101 and BCX7353-102 
[clinical study reports (CSRs) available], BCX7353-103, BCX7353-105, and BCX7353-112 
[preliminary data available]) and 1 Phase 2 clinical study [BCX7353-203 (results reported and 
summarized herein)] relevant to the current study have been conducted. One Phase 3 study 
(BCX7353-302, summarized herein) has been conducted with results reported for the primary 
analysis (Part 1). Study BCX7353-302 and a Phase 2, parallel-group, long-term safety study 
(BCX7353-204) remain ongoing globally.  
The principal results of clinical pharmacology, PK, and clinical safety and efficacy studies of 
BCX7353 are described in the BCX7353 IB.  


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5.3.1. 
Summary of Study BCX7353-302 
Study BCX7353-302 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
3-part study in subjects with Type 1 or 2 HAE. The primary objective of the study was to 
determine the efficacy of prophylactic BCX7353 110 and 150 mg administered orally once daily 
(QD) for 24 weeks (Part 1) compared to placebo in subjects with HAE.  
In Part 2, all subjects receive active treatment with BCX7353 from Weeks 25 through 48, and 
Part 3 of the study extends treatment with BCX7353 through 96 weeks. Results for Part 1 are 
summarized herein; Parts 2 and 3 of the study are ongoing. 
Overall, a total of 160 subjects were screened, 121 subjects were randomized (stratified by 
baseline attack rate, < 2 vs. ≥ 2 per 28 days), and 120 randomized subjects (99%) were treated. 
Of these, 108 subjects completed 24 weeks of study drug dosing in Part 1: 37 of 40 BCX7353 
150 mg subjects (93%), 37 of 41 BCX7353 110 mg subjects (90%), and 34 of 39 placebo 
subjects (85%). 
The mean baseline rate was 2.98 attacks per month. The majority of subjects (70%) had 
≥ 2 attacks per month at baseline, and the attack frequency was generally well distributed across 
the 3 treatment groups. 
The primary efficacy endpoint was the rate of investigator-confirmed HAE attacks during dosing 
in the entire 24-week treatment period. This study achieved its primary endpoint for both dose 
levels, with the 150 and 110 mg doses reducing HAE attacks by 44% (p < 0.001) and 30% 
(p = 0.024), respectively, vs. placebo. The attack rate per 28 days over the 24-week Part 1 dosing 
period was 1.31 for BCX7353 150 mg subjects, 1.65 for BCX7353 110 mg subjects, and 2.35 for 
placebo subjects. These results were supported by sensitivity analyses and were generally 
consistent in subgroup analyses. Effects of BCX7353 in reducing attack rate were evident in the 
first 4 weeks and stable over the entire 24-week duration of Part 1. 
Secondary endpoints (change from baseline in the angioedema quality of life questionnaire 
[AE QoL], number and proportion of days with angioedema symptoms, and rate of 
investigator-confirmed HAE attacks during the effective dosing period [beginning on Day 8 
through Week 24]) were analyzed using hierarchical testing. Results for the first secondary 
endpoint, AE QoL, were not statistically significant vs. placebo for either treatment group; 
therefore, inferential statistical testing was not performed on the descending secondary efficacy 
endpoints. 
BCX7353 significantly reduced the use of rescue medication per 28 days vs. placebo by 53.6% 
(p < 0.001) for 150 mg and 46.3% (p < 0.001) for 110 mg. In responder analyses, 58%, 50%, and 
23% of subjects receiving 150 mg BCX7353 had a ≥ 50%, ≥ 70%, or ≥ 90% reduction in their 
HAE attack rates compared to baseline vs. 25%, 15%, and 8% of placebo subjects, p = 0.005, 
p = 0.002, and p = 0.073 respectively.  
Administration of BCX7353 at doses of 150 and 110 mg QD for 24 weeks was generally safe 
and well tolerated. 
Overall, 81.7% of subjects experienced a treatment-emergent adverse event (TEAE) on study: 
85.0% of 150 mg subjects, 82.9% of 110 mg subjects, and 76.9% of placebo subjects; 39.5% of 
BCX7353 treated subjects and 33.3% of placebo subjects experienced a drug-related TEAE. 
Five subjects discontinued study drug due to TEAEs: 1 (2.5%) on 150 mg, 3 (7.3%) on 110 mg, 


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and 1 (2.6%) on placebo. No subjects on 150 mg, 1 subject on 110 mg (2.4%), and 3 subjects on 
placebo (7.7%) experienced serious adverse events (SAEs) on study; none of these events were 
drug related. All drug-related TEAEs were mild to moderate on placebo and in the 150 mg 
group, and the majority of TEAEs in the 110 mg group were mild to moderate; 3/41 (7.3%) 
110 mg subjects experienced Grade 3 drug-related TEAEs. Few subjects had treatment-emergent 
Grade 3 or 4 laboratory abnormalities. One subject on 150 mg BCX7353 who had previously 
been exposed to androgens had Grade 4 ALT elevation and Grade 3 AST elevation without 
symptoms, which resolved after discontinuing study drug. 
The most common TEAEs across all arms were nasopharyngitis, nausea, and vomiting. Overall, 
50.0% and 41.5% of BCX7353 150 and 110 mg subjects, respectively, had GI 
abdominal-associated TEAEs vs. 35.9% of placebo subjects. There were no drug-related events 
of special interest (EOSI; defined as BCX7353-related rash per protocol). 
Orally administered BCX7353 was a generally safe, well-tolerated, and effective treatment for 
the prevention of HAE attacks in Part 1 of this study, with better efficacy at the 150 mg dose 
compared to the 110 mg dose, and no increase in safety risk. 
5.3.2. 
Summary of Study BCX7353-203 
The results of the Phase 2 trial, Study BCX7353-203, were published in the New England 
Journal of Medicine (Aygoren-Pursun, Bygum et al. 2018). In summary, this Phase 2 sequential 
dose de-escalating, randomized, placebo-controlled study evaluated 4 dose levels of BCX7353 
administered QD for 28 days: 350, 250, 125, and 62.5 mg (salt nomenclature [SN]). As reported 
in the publication: 
“The APeX-1 trial showed that BCX7353 at doses of 125 mg or more administered orally 
once daily resulted in markedly lower rates of angioedema attacks than placebo. 
An apparent U-shaped dose response was observed in the primary endpoint, with the 
highest treatment effect observed at the 125-mg dose: the attack rate was 73.8% lower 
than with placebo, and 43% of patients were attack-free. 
The data suggest that the efficacy of the BCX7353 doses of 250 mg and 350 mg was 
probably masked by GI adverse events [AEs] that may have been misattributed as early 
symptoms of abdominal angioedema attacks. Only the 125-mg dose group had a lower 
rate of abdominal attacks than the placebo group, whereas all groups that received 
BCX7353 at doses of 125 mg or more had lower rates of peripheral attacks than the 
placebo group (difference, 68% to 82%). GI AEs were more common at the doses of 
250 mg and 350 mg than at lower doses, and a small number of liver abnormalities were 
observed at the highest doses in patients with extensive previous use of androgens. 
The side-effect profile in this trial was consistent with a trial involving healthy 
volunteers, in which GI AEs were more commonly reported in higher BCX7353 dose 
groups (Cornpropst, Dobo et al. 2016). 
The effectiveness of BCX7353 was further supported by secondary efficacy endpoints 
involving a post hoc hierarchical analysis, with substantial improvements observed in 
patients’ QoL at the 125-mg dose level, although post hoc p-values should be interpreted 
with some caution. The mean improvement (change from baseline) in the AE-QoL total 


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score was > 4 times the minimal clinically important difference [MCID] of 6 points 
(Weller, Magerl et al. 2016).” 
5.3.3. 
Data Monitoring Committee Review of Ongoing Studies BCX7353-302 and 
BCX7353-204 
Data from Studies BCX7353-302, BCX7353-204, and the current study, BCX7353-301, are 
reviewed by the BCX7353 Data Monitoring Committee (DMC) at protocol-specified intervals.  
The latest data review as of the time of the protocol amendment was completed on 
16 April 2020. The review included data from 120 dosed subjects on Study BCX7353-302, 
323 dosed subjects on Study BCX7353-204, and 19 dosed subjects on Study BCX7353-301, 
with 259 subjects receiving study treatment for > 336 days (> 48 weeks). The DMC 
recommended that all three studies continue per protocol. 
5.4. 
Rationale for Study 
The genetic and clinical features of HAE in Japan mirror Western patients (Yamamoto, Horiuchi 
et al. 2012). Currently, the only treatment approved for prevention of angioedema attacks in 
Japan is Berinert, a C1-INH concentrate, which is approved for the treatment of acute episodes 
and pre-procedure prevention (short-term prophylaxis) of acute episodes of HAE. Therefore, 
androgens and medications with limited, if any, effectiveness such as tranexamic acid and 
antihistamines are often used as prophylaxis in Japan (Ohsawa, Honda et al. 2015). Berinert must 
be administered by a healthcare professional. Icatibant (BK B2 receptor antagonist) and Berinert 
have been approved for HAE treatment in Japan. 
A survey of Japanese physicians who treat patients with HAE revealed that time to diagnosis is 
long and licensed treatment options for HAE are underused (Ohsawa, Honda et al. 2015). 
Ten percent of patients had attacks that required airway management (emergency intubation or 
tracheotomy), 3% of patients underwent abdominal surgery with an uncertain diagnosis, 21% of 
patients required hospitalization, 8% of patients had at least 20 HAE attacks per year, and 12% 
of patients reported the death of a relative due to HAE (Ohsawa, Honda et al. 2015). In Japan, 
there remains a significant medical need to provide additional HAE treatment options that are 
efficacious, convenient, and well tolerated, especially given the lack of effective treatments for 
the prevention of attacks in Japan (Ohsawa, Honda et al. 2015). 
BCX7353 is an oral kallikrein inhibitor in development for prevention of angioedema attacks in 
patients with HAE Type 1 and 2. BCX7353 has activity against plasma kallikrein at low 
nanomolar concentrations (Section 5.2) that are attainable and sustained in humans following 
oral administration. In both the randomized, double-blind, placebo-controlled, Phase 3 study 
(BCX7353-302) and the proof-of-concept, 28-day, placebo-controlled, Phase 2 study 
(BCX7353-203), the rate of angioedema attacks in subjects randomized to BCX7353 was 
statistically significantly lower than in placebo subjects and BCX7353 was generally safe and 
well tolerated. These data support further clinical development of BCX7353 as a potential future 
option for the prevention of HAE attacks in patients around the world.  
5.4.1. 
Rationale for Study Design  
This study is designed to evaluate the efficacy of 2 doses of BCX7353 compared to placebo in 
preventing angioedema events in Japanese subjects with Type 1 and 2 HAE, as measured by the 


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rate of expert-confirmed angioedema events during dosing in the entire 24-week treatment period 
in Part 1. The current study expands upon the scope of APeX-1 by evaluating the safety and 
efficacy of BCX7353 over a longer duration (24 weeks in Part 1 and 28 weeks in Part 2). 
Moreover, in the current study, the efficacy of BCX7353 will be evaluated in an HAE population 
potentially characterized by a wider range of angioedema event frequency (a minimum of 
2 angioedema events in 8 weeks are required for entry). The current study will be conducted as a 
parallel cohort assessment of active doses vs. placebo. The current study was designed similarly 
to Study BCX7353-302, following consultation with and guidance from the Pharmaceuticals and 
Medical Device Agency (PMDA).  
Subjects randomized to Treatment Groups 1 and 2 in Part 1 will continue to be administered their 
same dose of BCX7353 in Part 2. Subjects randomized to placebo in Part 1 will be randomized 
to receive an active dose in Part 2. Conduct of Part 2, the blinded extension on active drug, in 
part satisfies regulatory authorities’ requirement to obtain safety data at each dose over an 
extended treatment duration to support the intended indication as a chronic therapy. The doses of 
BCX7353 will remain blinded during Part 2 because subjects will reach the Week 24 visit based 
on enrollment date, precluding unblinding until the Part 1 analysis is complete, at the earliest. 
Conduct of Part 3, an unblinded extension on active drug at the 150 mg QD dose, based on better 
efficacy and no increase in safety risk in Study BCX7353-302. This will provide additional 
safety and effectiveness data at the 150 mg QD dose over an extended treatment period. The 
extension also offers subjects access to BCX7353 treatment for up to 104 weeks, until another 
mechanism is available to provide drug to the subject (eg, market access), or until the sponsor 
discontinues development of the product for the prevention of angioedema attacks, whichever 
comes first. 
Efficacy and safety data from the randomized, double-blind, placebo-controlled, Phase 3 study 
(BCX7353-302) and accumulating safety data on subjects enrolled in the Phase 2, long-term 
safety study (BCX7353-204) support long-term treatment with BCX7353 (Section 5.3.3). 
5.4.2. 
Rationale for BCX7353 Doses and Regimen 
The BCX7353 dosage regimens selected for evaluation in this study are 110 and 150 mg QD 
BCX7353 (equivalent to 125-mg and 175-mg QD [SN]). Exposure to BCX7353 was similar in 
Japanese and Western subjects in Study BCX7353-101 (Investigator Brochure); therefore, 
dosing will be the same in Parts 1 and 2 as in the ongoing Phase 3 Study BCX7353-302. The 
dose levels assessed in this study have been agreed upon with the PMDA. 
In Study BCX7353-203, the HAE attack rate was significantly lower vs. placebo in subjects who 
received daily doses of 125, 250, or 350 mg BCX7353 (SN) and the drug was generally safe and 
well tolerated. The plasma drug levels achieved at each dose were generally predictable and had 
an acceptable level of inter-subject variability. 
Two doses (110 mg QD and 150 mg QD) were studied in the pivotal Phase 3 clinical trial 
(BCX7353-302) and the Phase 2 long-term safety study (BCX7353-204). In the 24-week 
Phase 3 study (BCX7353-302), the rate of angioedema attacks in subjects randomized to 
BCX7353 was statistically significantly lower than in placebo subjects, with the 150 mg and 
110 mg doses reducing HAE attacks by 44% (p < 0.001) and 30% (p = 0.024), respectively, 
vs. placebo. Orally administered BCX7353 was a generally safe, well-tolerated, and effective 


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treatment for the prevention of HAE attacks in Part 1 of the BCX7353-302 study, with better 
efficacy at the 150 mg dose compared to the 110 mg dose, and no increase in safety risk.  
As a result of these safety and efficacy findings in Study BCX7353-302 indicating a more 
favorable benefit: risk profile for 150 mg QD, all subjects in Studies BCX7353-302 and 
BCX7353-204 are being transitioned to a 150 mg QD dose after a year of either 110 or 150 mg 
QD (ie, completion of Parts 1 and 2). Because the steady-state exposure of BCX7353 in Western 
subjects is similar to Japanese subjects (Investigator Brochure), the DMC has identified no safety 
issues in this ongoing study, and the current study is not sufficiently powered on its own to detect 
a treatment difference between placebo and BCX7353, subjects in Study BCX7353-301 will be 
similarly transitioned to 150 mg QD after 1 year of treatment (ie, completion of Parts 1 and 2), 
when they enter Part 3 of the study. 
5.4.3. 
Rationale for Study Population  
The current study is limited to adults and adolescents (≥ 12 years of age) of both sexes with HAE 
Type 1 and 2. Children < 12 years of age are excluded from participation in BCX7353 clinical 
trials until the benefit-risk profile in adults and adolescents has been better characterized. It is 
anticipated that exposure in adolescent subjects will not exceed safe and tolerable exposures in 
adults. 
Based on past and ongoing studies conducted in subjects with HAE, it is anticipated that female 
subjects will comprise at least 50% of the subject population. HAE affects both males and 
females, although the disease has a greater burden on females, with an increased frequency and 
severity of HAE attacks in women (Bork, Meng et al. 2006, Lumry, Castaldo et al. 2010). 
Estrogen appears to worsen the disease, as evidenced by an increased number of attacks reported 
following onset of puberty and when estrogen-containing therapy is initiated (Bouillet, 
Longhurst et al. 2008, Caballero, Farkas et al. 2012). Due to the gender distribution of HAE and 
the influence of hormones on the frequency of attacks, it is considered important to include both 
male and female subjects in this clinical study to gain an assessment of potential safety and 
population PK differences.  
Although there is no evidence of embryofetal developmental toxicity with BCX7353 in 
reproductive toxicology studies (Section 5.2), appropriate precautions are still warranted with 
respect to administration of BCX7353 to women of reproductive age, in accordance with 
International Council for Harmonisation (ICH) guidelines. Women of childbearing potential may 
be enrolled in this trial provided they meet the contraceptive requirements and have a negative 
pregnancy test (Section 8.2.1).  
Pregnant women will be excluded from participation in the current study. Additionally, any 
female subject who becomes pregnant on study will be required to immediately discontinue 
study drug and will be followed through the end of the pregnancy (see Section 12.1.6). 
Breastfeeding women will also be excluded from this study.  
5.4.4. 
Rationale for Control Group and Prohibition of Current Prophylactic 
Medications 
In the current study, all participants must have access to an effective, approved treatment for 
attacks or episodes of angioedema as part of their routine medical care. Each subject will 
continue to use his or her prescribed acute medication to treat attacks, under the medical 


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management plan advised by his or her physician, throughout the study. This is consistent with 
guidance documents that strongly support the position that all subjects with C1-INH deficiency 
should have access to medications for treating attacks (Cicardi, Bork et al. 2012, Zuraw, Banerji 
et al. 2013).  
While in some countries (not including Japan) there are approved therapies for prophylaxis 
against HAE attacks, such as C1-INH, consensus recommendations do not exist for either 
prophylactic treatment as a standard of care or a definition of indications for prophylaxis. 
The International World Allergy Organization/European Academy of Allergy and Clinical 
Immunology guidelines for the management of HAE recommends prophylaxis be considered for 
patients who “face events in life that are associated with increased disease activity,” specifically 
C1-INH for first-line, long-term prophylaxis (Maurer, Magerl et al. 2018). Given the lack of 
wide availability of such a treatment in Japan and the limitations of intravenous (IV) therapy, a 
study of an orally available product such as BCX7353 is appropriate.  
A subject randomized to placebo in the current study who has access to effective attack 
medications is therefore considered to be treated in line with current guidelines. 
Unapproved prophylactic therapies may be used by some HAE patients in Japan. To guard 
against enrolling subjects who need prophylaxis, subjects must meet an inclusion criterion 
assessing whether they are medically appropriate for on-demand treatment as the sole medicinal 
management for their HAE during the study. The informed consent and assent for this study will 
inform subjects on available prophylactic therapies and will note that they cannot discontinue 
prophylaxis for the sole purpose of screening for the trial; there must be medical and personal 
choice reasons to do so. If a subject has voluntarily discontinued prophylactic therapy outside of 
the specified window (see below) in advance of the Screening visit for medical or personal 
choice reasons, then they may be screened for study eligibility. 
Use of androgens or tranexamic acid for prophylaxis of HAE attacks is not allowed within 
28 days of the screening visit; C1-INH prophylaxis is not permitted within 14 days of the 
screening visit. Initiation of any of these prophylactic medications is not allowed during the 
study.  
The stipulated timeframe in advance of screening is intended to allow stabilization of the 
angioedema event rate after discontinuing prophylactic therapies before prospective collection of 
angioedema events required for eligibility and for the baseline angioedema event rate, which 
begins at screening. However, it should be noted that subjects may receive approved C1-INH 
therapies for acute treatment of angioedema attacks, if available, at any time.  
5.4.5. 
BCX7353 Benefit-Risk Analysis 
Given that BCX7353 is a small molecule kallikrein inhibitor with safety data available from 
completed and ongoing Phase 1, 2, and 3 studies, there is an acceptably low risk of severe or 
serious adverse reactions. Potential risks and findings from nonclinical and clinical studies of 
BCX7353 are discussed in Section 6 of the IB (Summary of Data and Guidance for the 
Investigators).  


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5.4.6. 
Benefits of Trial Participation 
Study subjects will receive regular medical care for the duration of the study. Subjects may 
experience a reduction in the number of angioedema events if they are randomized to a 
BCX7353 treatment. The development of BCX7353 is expected to be of benefit to the wider 
community/patients with HAE.  
5.4.7. 
Overall Benefit-Risk Assessment 
The risks from daily oral administration of BCX7353 seen to date in both nonclinical and clinical 
studies were primarily mild, monitorable, and reversible. Based on the utility of other kallikrein 
inhibitors, such as C1-INH, the pharmacology of BCX7353, and Phase 3 data from 
Study BCX7353-302, there is an expectation of benefit to the individual subject. The information 
obtained from this study will support the development of BCX7353 for HAE, a serious, 
debilitating, and potentially life-threatening disease. The overall benefit-risk balance is therefore 
considered to be acceptable. 
6. 
TRIAL OBJECTIVES 
6.1. 
Objectives 
6.1.1. 
Part 1 Primary Objective 
• To determine the efficacy of BCX7353 110 and 150 mg QD administered for 
24 weeks compared to placebo in the prevention of angioedema events in subjects 
with HAE  
6.1.2. 
Part 1 Secondary Objectives 
• To assess the safety and tolerability of BCX7353 110 and 150 mg QD administered 
for 24 weeks 
• To assess the effects of BCX7353 on HAE disease activity and angioedema event 
characteristics 
• To evaluate the effects of BCX7353 on QoL 
• To characterize the PD effects of BCX7353 
6.1.3. 
Part 2 Primary Objective 
• To evaluate the long-term safety and tolerability of BCX7353 110 and 150 mg in 
subjects with HAE 
6.1.4. 
Part 2 Secondary Objectives 
• To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 
over a 24- to 52-week administration period 
• To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 52-week 
administration period 


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• To evaluate subject satisfaction with BCX7353 over a 24- to 52-week administration 
period 
6.1.5. 
Part 3 Primary Objectives 
• To evaluate the long-term safety and tolerability of BCX7353 administered QD over 
a 52- to up to 104-week administration period in subjects with HAE 
6.1.6. 
Part 3 Secondary Objectives 
• To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 
over a 52- to up to 104-week administration period 
• To evaluate QoL and HAE disease activity of BCX7353 over a 52- to up to 104-week 
administration period 
• To evaluate subject satisfaction with BCX7353 over a 52- to up to 104-week 
administration period 
7. 
OVERALL STUDY DESIGN AND PLAN 
This is a randomized, placebo-controlled, double-blind, parallel-group, 3-part study. Part 1 is 
designed to test the hypothesis that the angioedema event rate during 24 weeks of prophylactic 
BCX7353 treatment at 2 dosage levels will be less than that observed during 24 weeks of 
placebo. An angioedema event is defined as an attack, symptoms, or swelling due to a subject’s 
underlying hereditary angioedema disease. The primary efficacy endpoint will be assessed after 
the last subject completes Part 1 (through Week 24). Part 2 is designed to primarily evaluate the 
long-term safety of BCX7353. Part 3 is open-label and designed to primarily evaluate the 
long-term safety of BCX7353. Parts 1, 2, and 3 will be conducted in sequence. All subjects will 
receive BCX7353 in Parts 2 and 3, including those randomized to receive placebo in Part 1.  
In addition, efficacy data in Part 1, where appropriate, will be statistically analyzed by 
combining data from this study with data from Study BCX7353-302 to ensure adequate 
statistical power.  
Part 1 (24-week evaluation of blinded efficacy and safety) 
Subjects with HAE Type 1 or 2 will be eligible for the study following assessment of data 
obtained from screening procedures, including demonstration of a minimum number of 
qualifying angioedema events documented during a prospective run-in period of 8 weeks from 
the date of the screening visit.  
Approximately 24 treatment-eligible subjects ≥ 12 years of age will receive study drug 
(BCX7353 or placebo) in Part 1 of the study based on randomization in a 1:1:1 ratio into one of 
3 treatment groups: 
• Group 1 (N=8): BCX7353 110 mg QD administered orally for 24 weeks 
• Group 2 (N=8): BCX7353 150 mg QD administered orally for 24 weeks 
• Group 3 (N=8): Placebo administered orally QD for 24 weeks 


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Enrollment into treatment groups will be stratified by the baseline angioedema event rate at 
baseline (≥ 2 angioedema events per month from the date of screening vs. < 2 angioedema events 
per month from the date of screening).  
Qualifying angioedema events that are counted in the baseline angioedema event rate for 
stratification and those that are used to qualify a subject during the run-in period must be 
characterized as follows: 
• The angioedema events must be unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
have been documented to cause functional impairment, based on the subject’s entry in 
the electronic diary (e-diary). Functional impairment is defined as the subject not 
being able to perform his or her daily activities without restriction (ie, subject records 
that he/she is at least slightly restricted in daily activities during an angioedema 
event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events are otherwise confirmed by an independent expert to be 
angioedema events.  
A study schematic can be found in Figure 1. 
Throughout the entire study, details of all angioedema events (attacks, symptoms, or swelling 
due to HAE) and compliance with study drug will be recorded in an e-diary. Angioedema events 
will be treated in accordance with the subject’s normal standard of care. Within approximately 
2 business days of the end of each angioedema event that occurs from the screening visit through 
the Week 52 visit in Part 2, subjects will be contacted by the investigator (or appropriately 
trained designee) to discuss the clinical characteristics of the angioedema event, any questions on 
the entered data, or to gain additional details on the event that are not included in the e-diary that 
the investigator deems important to clinically evaluate the event, as applicable. The 
investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each angioedema event recorded in the e-diary as a 
confirmed angioedema event. All expert-confirmed angioedema events must include symptoms 
of swelling; prodromal symptoms in the absence of swelling are not considered angioedema 
events, regardless of treatment. The expert will consider that symptoms of swelling, in addition 
to visible swelling, may also include symptoms in the oropharyngeal or abdominal regions that 
are indicative of internal swelling. Under no circumstances should the run-in angioedema event 
requirement for eligibility be disclosed to study subjects. 
Study visits in Part 1 will occur at screening, baseline, and Weeks 2, 4, 8, 12, 18, and 24. 
The primary efficacy analysis will occur after the last subject completes the Week 24 visit and 
will include all data through Week 24. 
 


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Figure 1: 
Study Schema 
 
Abbreviations: e-diary = electronic diary; QD = once daily. 
* In the event that BCX7353 is not commercially available when the first and each subsequent subject at each site reaches Week 104, then the treatment period 
will be extended with additional telephone contacts conducted at 4-week intervals (Weeks 108, 112, etc.) and clinic visits completed at 12-week intervals 
(Week 116, etc.) to allow the subject to continue treatment with BCX7353 until commercially available, unless the subject discontinues his or her participation 
in the study. After marketing authorization, BCX7353 will be administered at the dose regimen that is approved in Japan. 
 


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Part 2 (evaluation of safety of blinded BCX7353) 
Part 2 of the study will start upon administration of study drug dispensed at the Week 24 visit. 
Subjects in Groups 1 and 2 will continue to receive the same BCX7353 dose to which they were 
randomized in Part 1 of the study in a blinded manner. Subjects randomized to Group 3 will 
undergo a second randomization in a 1:1 ratio to receive either a 110 or 150 mg QD dose of 
BCX7353 in a blinded manner beginning at the Week 24 visit (see Figure 1). The active dose a 
subject receives in Part 2 will be blinded for all subjects; subjects will be informed that they will 
receive an active dose of BCX7353 in Part 2. Once Part 1 results are available, all subjects in 
Part 2 may be moved to a single dose of BCX7353, based on the data from Part 1.  
Study visits in Part 2 will occur during Weeks 26, 28, 32, 36, 48, and 52, with telephone contact 
at Weeks 40 and 44. Subjects will continue to document all angioedema events that occur while 
on study drug, as well as compliance with the study drug, in their e-diary and will have regular 
visits to assess safety and tolerability; investigator confirmation of angioedema events will 
continue to be required for Part 2. Interim safety analyses will be conducted while Parts 2 and 3 
are ongoing to support regulatory filings. 
Part 3 (up to a 52-week evaluation of the safety of open-label BCX7353 150 mg QD) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 52 
visit. Based on the safety profile and efficacy of the 150 mg dose in Part 1 of the similarly 
designed Study BCX7353-302, all subjects in the current study receiving 110 mg QD will be 
transitioned to open-label 150 mg QD at the Week 52 visit. 
Study visits in Part 3 will occur during Week 60 and approximately every 12 weeks thereafter, 
for a study duration of up to 104 weeks, until another mechanism is available to provide drug to 
the subject (eg, market access), or until the sponsor discontinues development of the product for 
the prevention of angioedema attacks, whichever comes first. Telephone contact will occur at 
Weeks 56, 64, 68, 76, 80, 88, 92, and 100. 
Subjects will continue to document all angioedema events that occur in their diary throughout 
Part 3 and will have regular visits to assess safety and tolerability. However, subjects will not be 
required to document compliance with the study drug. In addition, investigator and expert 
confirmation of angioedema events will not be required in Part 3. All angioedema events 
recorded by the subjects will be reviewed and confirmed or rejected according to a set of 
pre-defined rules prior to inclusion in effectiveness analyses. These rules will be outlined in the 
Statistical Analysis Plan (SAP). 
Post-Marketing Study 
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to 
BCX7353 through Week 104 or until such time as BCX7353 is commercially available at his or 
her site, whichever occurs first, unless the subject discontinues his or her participation in the 
study. During this period, BCX7353 will be administered at the dose regimen that is approved in 
Japan. In the event that BCX7353 is not commercially available when the first and each 
subsequent subject at each site reaches Week 104, then the treatment period will be extended 
with additional telephone contacts conducted at 4-week intervals (Weeks 108, 112, etc.) and 
clinic visits completed at 12-week intervals (Week 116, etc.) to allow each subject to continue 


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treatment with BCX7353 until commercially available, unless the subject discontinues his or her 
participation in the study. Once BCX7353 is commercially available at each site, an end-of-study 
(EOS) visit will be scheduled for each subject to complete his or her participation in the study 
and transition to commercial drug product. Subjects will not have to wait for their next scheduled 
clinic visit to complete the EOS visit. Subjects may not continue on study for more than 
3 months after National Health Insurance (NHI) price listing in Japan. Subjects who choose not 
to continue their participation in the study at any time will be asked to complete an early 
termination visit within 3 weeks (+ 1 week) after their last dose of BCX7353. 
7.1. 
Endpoints 
7.1.1. 
Part 1 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is as follows: 
• The rate of expert-confirmed angioedema events during dosing in the entire 24-week 
treatment period (Days 1 to 168) 
7.1.2. 
Part 1 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows:  
• Change from baseline in AE-QoL at Week 24 (total score) 
• Number and proportion of days with angioedema symptoms through 24 weeks 
• Rate of expert-confirmed angioedema events during dosing in the effective treatment 
period (beginning on Day 8 through 24 weeks) 
7.1.3. 
Part 1 Exploratory Efficacy Endpoints 
• Number and proportion of subjects with no angioedema events over 24 weeks 
• Use of medications to treat angioedema events over 24 weeks 
• The proportion of responders to study drug, separately defined as at least a 50%, 
70%, or 90% relative reduction in the rate of expert-confirmed angioedema events 
during treatment compared with the baseline expert-confirmed angioedema event rate 
7.1.4. 
Part 1 Safety Endpoints 
• Number and proportion of subjects with a TEAE 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a TESAE  
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
7.1.5. 
Part 1 Health Outcome Endpoints 
• EuroQoL 5-dimensional, 5-level questionnaire (EQ-5D-5L) scores  


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• Treatment Satisfaction Questionnaire for Medication (TSQM) scores 
• Work Productivity and Activity Impairment Questionnaire (WPAI) scores 
7.1.6. 
Part 2 Primary Endpoints 
• Number and proportion of subjects with a TEAE 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a TESAE  
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
• The proportion of subjects with a treatment-emergent, treatment-related AE 
consistent with a drug rash 
7.1.7. 
Part 2 Secondary Endpoints 
• Number and rate of angioedema events 
• Durability of response (angioedema event rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Use of medications to treat angioedema events 
• Discontinuations due to lack of efficacy 
• Durability in AE-QoL questionnaire scores 
• Durability in EQ-5D-5L scores  
• Durability in TSQM scores 
• Durability in WPAI scores 
7.1.8. 
Part 3 Primary Endpoints 
• Number and proportion of subjects with a TEAE 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a TESAE 
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
• Proportion of subjects with a treatment-emergent, treatment-related AE consistent 
with a drug rash 
7.1.9. 
Part 3 Secondary Endpoints 
• Number and rate of angioedema events 
• Durability of response (angioedema event rate trend over time) 


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• Number and proportion of days with angioedema symptoms 
• Use of medications to treat angioedema events 
• Durability in AE-QoL questionnaire scores 
• Durability in EQ-5D-5L scores 
• Durability in TSQM scores 
• Durability in WPAI scores 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Approximately 24 subjects are planned to be enrolled in the study.  
8.2. 
Subject Selection 
8.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1.  Males and non-pregnant, non-lactating females ≥ 12 years of age.  
2. Able to provide written, informed consent. Subjects who are aged 12 to 17 years at 
screening must be able to read, understand, and be willing to sign an assent form in 
addition to a caregiver providing informed consent.  
3. A clinical diagnosis of HAE Type 1 or 2, defined as having a C1-INH functional level 
< 50% and a complement 4 (C4) level below the lower limit of the normal (LLN) 
reference range, as assessed during the screening period.  
In the absence of a low C4 value drawn during the intercritical period (ie, subject is not 
having an angioedema event), one of the following is acceptable to confirm the diagnosis 
of HAE: 1) a SERPING-1 gene mutation known or likely to be associated with HAE 
Type 1 or 2 assessed during the screening period; 2) a confirmed family history of 
C1-INH deficiency; 3) a C4 redrawn and retested during an angioedema event in the 
screening period with the results below the LLN reference range.  
For a C1-INH that is between 50% and the LLN (74%), a SERPING-1 gene mutation 
known or likely to be associated with HAE Type 1 or 2 is acceptable to confirm the 
diagnosis of HAE. 
SERPING-1 gene analysis results indicating a “possibly pathogenic” mutation will be 
considered on a case-by-case basis by the medical monitor and may require additional 
testing for eligibility. 
4. Access to and ability to use an acute treatment for angioedema events approved by the 
Japan Ministry of Health, Labor, and Welfare (plasma-derived C1-INH or icatibant).  


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5. Subjects must be medically appropriate for on-demand treatment as the sole medicinal 
management for their HAE during the study; that is, subjects must be medically 
appropriate to be managed without prophylactic treatments for HAE. 
6. The subject must have at least 2 angioedema events as assessed by an independent expert 
that meet all requirements below during the run-in period of 56 days beginning at the 
screening visit: 
• The angioedema events are unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of an angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform daily 
activities without restriction (ie, subject records that he or she is at least slightly 
restricted in his or her daily activities during the angioedema event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events are confirmed by an independent expert to be angioedema 
events.  
Under no circumstances should the run-in angioedema event requirement for eligibility 
be disclosed to study subjects. 
7. Female subjects must meet at least 1 of the following requirements: 
a. Be a woman of childbearing potential (defined as a nonmenopausal adult or 
adolescent female who has not had a hysterectomy, bilateral oophorectomy, or 
documented ovarian failure) who agrees to use at least 1 acceptable effective 
contraceptive method during the study and for a duration of 30 days after last dose of 
study drug. One or more of the following methods are acceptable:  
− Surgical sterilization (ie, bilateral tubal occlusion or vasectomy of male partner) 
− Placement of an intrauterine device (IUD) or intrauterine system (IUS; implanted 
any time prior to or during screening) 
− Combined (estrogen and progesterone containing) oral hormonal contraception 
associated with inhibition of ovulation. It must be noted that estrogen-containing 
hormonal contraception cannot be initiated within 56 days of the screening visit. 
Also, they cannot be initiated until the end of the study. 
− Male condom with or without spermicide 
− Use of male condom with or without spermicide, together with diaphragm 
Female subjects who report being postmenopausal for ≤ 2 years and have a 
follicle-stimulating hormone (FSH) ≤ 40 mIU/mL must agree to use at least an 


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acceptable effective contraceptive method (as proposed above) during study and 
for 30 days after the last dose of study drug.  
b. Be a woman of nonchildbearing potential (defined as postmenopausal for > 2 years or 
having an FSH > 40 mIU/mL if postmenopausal ≤ 2 years or have had a 
hysterectomy, bilateral oophorectomy, or documented ovarian failure). 
c. Be a woman who, as a lifestyle choice, chooses to not engage in heterosexual 
intercourse or is a woman who exclusively has female sexual partners.  
8. In the opinion of the investigator, the subject is expected to adequately comply with all 
required study procedures for the duration of the study. The subject must demonstrate 
adequate compliance with all study procedures required from the screening visit through 
randomization, including diary recording of angioedema events beginning at the 
screening visit. 
8.2.2. 
Exclusion Criteria 
Subjects must meet none of the numbered exclusion criteria below to be eligible for participation 
in this study. Medications prohibited for use during the study are addressed in Section 9.7.1. 
1. Any clinically significant medical or psychiatric condition or medical history that, in the 
opinion of the investigator or sponsor, would interfere with the subject’s ability to 
participate in the study or increases the risk to the subject by participating in the study.  
2. Dementia, altered mental status, or any psychiatric condition, or stay in an institution 
further to an official or court order that would prohibit the understanding or rendering of 
informed consent or participation in the study. 
3. Anticipated use of short-term prophylaxis of angioedema events for a pre-planned 
procedure during the screening or study periods. 
4. Concurrent diagnosis of any other type of recurrent angioedema. 
5. Clinically significant abnormal ECG at the screening visit. This includes, but is not 
limited to, a QTcF > 470 msec for women, a QTcF > 450 msec for men, or ventricular 
and/or atrial premature contractions that are more frequent than occasional, and/or as 
couplets or higher in grouping. 
6. Any clinically significant history of angina, myocardial infarction, syncope, cardiac 
arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other clinically 
significant cardiovascular abnormality such as poorly controlled hypertension. 
7. Known family history of sudden cardiac death. Family history of sudden death from HAE 
is not exclusionary. 
8. History of or current implanted defibrillator or pacemaker. 
9. Any abnormal laboratory or urinalysis parameter at screening that, in the opinion of the 
investigator, is clinically significant and relevant for this study. A calculated creatinine 
clearance (CLCR) of ≤ 30 mL/min or AST or ALT value ≥ 3 × the upper limit of the 
normal (ULN) reference range value obtained during screening is exclusionary.  
10. Prior enrollment in a BCX7353 study. 


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11. Suspected C1-INH resistance in the opinion of the investigator or sponsor. 
12. History of alcohol or drug abuse within the previous year prior to the screening visit, or 
current evidence of substance dependence or abuse (self-reported alcoholic intake 
> 3 drinks/day). 
13. Positive serology for human immunodeficiency virus (HIV) or current infection with 
hepatitis B virus (HBV) or hepatitis C virus (HCV). 
14. Pregnant or planning to become pregnant during the study.  
15. Currently breastfeeding. Women who want to enter the study must agree to suspend 
breastfeeding at the screening visit. Women must wait at least 3 weeks after the last dose 
of BCX7353 to commence breastfeeding.  
16. Positive drugs of abuse screen (unless drug is used as medical treatment with a 
prescription). 
17. History of severe hypersensitivity to multiple medicinal products or severe 
hypersensitivity/anaphylaxis with unclear etiology. 
18. Use of androgens or tranexamic acid for prophylaxis of angioedema events within the 
28 days prior to the screening visit or initiation during the study. 
Prophylaxis is defined as administration of a medication in the absence of symptoms of 
an angioedema event.  
19. Use of C1-INH for prophylaxis of angioedema events within the 14 days prior to the 
screening visit or initiation during the study. Use of a C1-INH therapy for treatment of 
angioedema events is not excluded at any time, nor is C1-INH for preprocedural 
prophylaxis for an unplanned/unforeseen procedure. 
Prophylaxis is defined as administration of a medication in the absence of symptoms of 
an angioedema event.  
20. Use of concomitant medications that are metabolized by cytochrome P450 (CYP) 2D6, 
CYP2C9, CYP2C19, and/or CYP3A4 and have a narrow therapeutic range, within 7 days 
of the baseline visit or planned initiation during the study (see Section 9.7.1). 
21. Use of a medication that is clinically known to prolong the QT interval and is 
metabolized by CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to the 
baseline visit or planned initiation during the study (see Section 9.7.1). 
22. Use of a medication that is transported by P-glycoprotein (P-gp) and has a narrow 
therapeutic range within 7 days of the baseline visit or planned initiation during the study 
(see Section 9.7.1). 
23. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study. 
24. Initiation of an estrogen-containing hormonal contraceptive within 56 days of the 
screening visit or planned initiation during the study. Established use (initiation ≥ 56 days 
prior to screening) during the study is permitted. 


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25. Current participation in any other investigational drug study or received another 
investigational drug within 30 days of the screening visit. 
26. An immediate family relationship to either sponsor employees, the investigator, or 
employees of the study site named on the delegation log. 
27. Held in an institution by a government or judicial order. 
8.3. 
Subject Withdrawal from the Study and from Study Drug 
8.3.1. 
Subject Withdrawal from the Study 
Participation in the study is strictly voluntary; a subject may withdraw consent to contribute 
additional study information at any point. A subject who withdraws consent will be requested to 
attend an early termination visit to complete all EOS evaluations. Although a subject may 
withdraw from the study at any time without specifying a reason for withdrawal, the reason for 
withdrawal, if provided by the subject, will be recorded in the subject’s medical records (source 
documents) and also in the electronic case report form (eCRF). If the reason for subject 
withdrawal is not known, the subject must be contacted to establish whether the reason was an 
AE, and if so, this must be reported in accordance with the procedures outlined in Section 12. 
If at any point in the study the clinic is unable to contact the subject after appropriate attempts 
have been made, the subject will be considered lost to follow-up.  
Once subjects have withdrawn from the study, the sponsor will no longer provide treatment 
through the study. Following withdrawal from the study, a subject will be able to receive further 
treatment as recommended by his or her treating physician and according to the accepted 
standard of care. 
8.3.2. 
Subject Discontinuation from Study Drug 
A subject will be permanently discontinued from study drug for any of the following reasons, 
which will be recorded in the source documents and eCRF.  
• Emergence of any laboratory abnormality or AE that in the judgment of the 
investigator compromises the ability of the subject to continue study-specific 
procedures or it is considered not to be in the subject’s best interest due to an altered 
benefit-risk profile. 
• Reoccurrence of treatment-emergent AST or ALT elevation > 5 × ULN (confirmed) 
if BCX7353 is restarted after meeting hold criteria as outlined in Section 12.2.2. 
• Treatment-emergent ALT or AST > 3 × ULN combined with either laboratory 
abnormalities indicative of significant hepatic toxicity (ie, meeting Hy’s law, total 
bilirubin > 2 × ULN OR with an international normalized ratio [INR] > 1.5) or with 
symptomatology of acute hepatitis (ie, severe fatigue, nausea, vomiting, right upper 
quadrant pain and tenderness, fever, rash, and/or eosinophilia [> 5%]). 
• Subsequent determination that inclusion/exclusion criteria were not met.  
• Intercurrent illness or emergence of a new illness/medical condition that would, in the 
judgment of the investigator, affect assessments of clinical status to a significant 
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• Subject noncompliance with study drug or to the protocol. 
• The subject has a QTcF > 500 msec (confirmed on repeat ECG testing). 
• The subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
from the mean QTcF value obtained from triplicate ECGs obtained at the baseline 
visit and a simultaneous absolute QTcF > 450 msec (male) or 470 msec (female).  
• Subjects with a study drug-related Grade 3 or 4 rash as described by the Division of 
Microbiology and Infectious Diseases (DMID) criteria “skin-mucocutaneous” will be 
discontinued from study drug and treated according to best medical practice. 
All subjects with a suspected drug rash should undergo specific rash evaluation as 
described in Section 12.2.1. A Grade 3 rash is defined as vesiculation or moist 
desquamation or ulceration and a Grade 4 rash is defined as exfoliative dermatitis, 
mucous membrane involvement or erythema multiforme or suspected 
Stevens-Johnson syndrome or necrosis requiring surgery. Subjects with a Grade 1 or 
2 study drug-related rash may be continued on BCX7353 if the investigator, subject, 
and sponsor deem it appropriate. The protocol for continuing BCX7353 in the 
presence of a rash is described in Section 12.2.1.  
Subjects who discontinue from study drug in Parts 1 or 2 will be requested to complete all 
regularly scheduled visits and procedures outlined in Table 2 and Table 3 through the end of the 
study part (ie, Part 1 or 2) in which they were currently being treated. Subjects who discontinue 
in Part 1 will be requested to complete all regularly scheduled visits and procedures through 
Week 24. Subjects who discontinue in Part 2 will be requested to complete all regularly 
scheduled visits and procedures through Week 52. Subjects who discontinue in Part 3 will have 
an EOS visit 3 weeks after the last dose of study drug. All subjects who discontinue from all 
parts should be treated in accordance with local clinical practice for HAE. 
If a subject who discontinues from study drug subsequently withdraws consent to continue study 
visits as previously outlined, please see Section 8.3.1.  
Subjects are not eligible for treatment in Parts 2 or 3 if they discontinue study drug in 
Parts 1 or 2, respectively due to any of the above cited reasons. 
8.4. 
End of Study Definition 
The end of study will be defined as when the last subject completes the last protocol-scheduled 
study visit.  
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to 
BCX7353 until such time as BCX7353 is commercially available at his or her site, unless the 
subject discontinues his or her participation in the study. Once the last subject is able to access 
commercial drug product or discontinues from the study, the study will be terminated. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug and Study Drug Product 
BCX7353 is an oral, small molecule inhibitor of plasma kallikrein. All subjects will receive a 
dose of BCX7353 (150 or 110 mg) or matching placebo (Part 1 only) capsules for oral 
administration once daily for up to 104 weeks (placebo capsules will be administered for 
24 weeks followed by once daily treatment with BCX7353 for up to 80 weeks). Study drug or 
investigational medicinal product (IMP) in this study consists of BCX7353 and placebo capsules. 
The investigational active pharmaceutical ingredient (API) is BCX7353, which is supplied as 
55 or 75 mg capsules in Parts 1 and 2 and as a 150 mg capsule in Part 3. The capsules are 
composed of the API (BCX7353) blended with the excipients pregelatinized starch, 
polyplasdone XL, colloidal silicon dioxide, and magnesium stearate in a gelatin capsule.  
The matching placebo will also be provided as capsules to match the BCX7353 capsules. 
The matching placebo will contain microcrystalline cellulose and magnesium stearate.  
In Parts 1 and 2, subjects will be instructed to take 2 capsules of study drug (55 or 75 mg 
capsules) together at the same time daily. In Part 3, subjects will take a single capsule of 
study drug (150 mg capsule) daily. After the study has been transitioned to a post-marketing 
study following marketing authorization of BCX7353, BCX7353 will be administered at the 
dose regimen that is approved in Japan. 
Additional details for the chemical and physical characteristics of BCX7353 may be found in 
the IB. 
9.2. 
Description of Study Drug Packaging, Labeling, and Storage 
The study drug will be packaged in bottles. Subjects will be dispensed a sufficient number of 
bottles and capsules to cover the dosing period until the next study visit.  
Each bottle of study drug will be labeled with the information required per local law and may 
include the following: sponsor name, study protocol number, description of the contents, expiry 
date, kit number, and either a statement regarding the investigational (clinical trial) or 
post-marketing clinical study use of the study drug, as applicable. 
Study drug must be stored between 15°C and 25°C (room temperature). 
Details on the study drug packaging, labeling, shipment, storage, and dispensing will be provided 
in the IMP manual. 
9.3. 
Randomization and Study Drug Blinding 
9.3.1. 
Blinding 
This is a double-blind study throughout both Parts 1 and 2. As such, study drug assignment will 
be blinded to the investigator, study staff, study subjects, and clinical research organization staff. 
Part 3 will be open-label. No blinding will be used.  
During Part 1, sponsor employee(s) will also be blinded to the treatment allocation of individual 
subjects, with the exception of sponsor staff responsible for managing clinical supplies. 


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Employees who are not blinded to drug assignment will have no access to any other subject-level 
information for the duration of the study. Sponsor employees interacting with sites will remain 
blinded for Part 2 of the study; however, unblinding of these staff may occur out of necessity 
during document preparation for regulatory filings of the study. 
The bioanalytical laboratory performing BCX7353 plasma concentration analysis may be given a 
copy of the randomization scheme.  
Information on unblinding in the event of an SAE is provided in Section 12.1.9. 
9.3.2. 
Randomization 
Subjects will be randomized via interactive (web or voice) response system (IXRS). Details on 
the processes to be followed for randomization will be provided in a separate manual. 
9.3.2.1. 
Part 1 Randomization 
Approximately 24 subjects will be randomized in a 1:1:1 (active:active:placebo) ratio to the 
following treatments in Part 1:  
• Treatment Group 1: BCX7353 110 mg administered orally QD for 24 weeks  
• Treatment Group 2: BCX7353 150 mg administered orally QD for 24 weeks 
• Treatment Group 3: placebo administered orally QD for 24 weeks 
Randomization will proceed in accordance with a computer-generated randomization schedule 
prepared by an unblinded statistician.  
Sites will randomize eligible subjects in the IXRS, preferably after all baseline assessments to 
reconfirm eligibility have been completed. If required by site procedures (ie, dispensing of 
randomized study drug must occur through a pharmacy), the subject may be randomized on the 
business day prior to the planned baseline visit.  
The sponsor may require review of screening data prior to randomizing a subject 
(eg, concomitant medications); any requirements will be provided to the site separately. 
Enrollment into treatment groups will be stratified by the qualifying angioedema event rate at 
baseline (≥ 2 angioedema events per month vs. < 2 angioedema events per month) entered into 
the IXRS at the time of randomization. The baseline angioedema event rate must be provided 
during randomization and is calculated by: 
(the number of angioedema events meeting the criteria of an angioedema event below from 
the screening visit through the time of randomization × 28) divided by the number of days 
during the timeframe from the screening visit through randomization, rounded up to 
2 decimal places 
Angioedema events to be utilized in calculation of the baseline angioedema event rate must meet 
the following criteria: 
• The angioedema events must be unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 


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• The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform his or her 
daily activities without restriction (ie, subject records that he or she is at least slightly 
restricted in daily activities during the angioedema event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events must be confirmed by an independent expert to be 
angioedema events, based upon the e-diary record and investigator-collected 
information.  
9.3.2.2. 
Part 2 Randomization 
Subjects who received active BCX7353 in Part 1 of the study (treatment Groups 1 and 2) will 
continue to receive the same dosing regimen in Part 2. Subjects who received placebo (treatment 
Group 3) during Part 1 will be randomized in a 1:1 ratio to receive a 110 or 150 mg QD dose of 
BCX7353 during Part 2. 
Subjects who received placebo during Part 1 will be automatically randomized for Part 2 in the 
IXRS, which will occur at the time of the Week 24 visit (Figure 2). Sites will assign drug for 
Part 2 of the study in the IXRS beginning at the Week 24 visit.  
Note: Sites will assign 150 mg kits in Part 3 of the study in the IXRS beginning at Week 52. 
Sites using a centralized pharmacy may assign drug to a subject the day prior to a study visit. 
Figure 2: 
Study Randomization 
 
Abbreviations: QD = once daily. 
* In the event that BCX7353 is not commercially available when the first and each subsequent subject at each site 
reaches Week 104, then the treatment period will be extended with additional telephone contacts conducted at 
4-week intervals (Weeks 108, 112, etc.) and clinic visits completed at 12-week intervals (Week 116, etc.) to allow 
the subject to continue treatment with BCX7353 until commercially available, unless the subject discontinues his 
or her participation in the study. After marketing authorization, BCX7353 will be administered at the dose regimen 
that is approved in Japan. 


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9.4. 
Study Drug Administration and Treatment Compliance 
Subjects will be instructed to take BCX7353 capsules together orally QD at approximately the 
same time each day for up to 104 weeks as follows: 
• Treatment Group 1 (110 mg QD) 
o Parts 1 and 2: two 55-mg capsules of BCX7353 QD × 52 weeks  
o Part 3: one 150-mg capsule of BCX7353 QD × 52 weeks 
• Treatment Group 2 (150 mg QD) 
o Parts 1 and 2: two 75-mg capsules of BCX7353 QD × 52 weeks 
o Part 3: one 150-mg capsule of BCX7353 QD × 52 weeks 
• Treatment Group 3 
o Parts 1 and 2 (placebo in Part 1, 110 mg or 150 mg in Part 2): two capsules 
of placebo QD × 24 weeks (Days 1 to 168) followed by two 55-mg or 
75-mg capsules of BCX7353 QD × 28 weeks (Days 169 to 365) 
o Part 3: one 150-mg capsule of BCX7353 QD × 52 weeks 
• Post-marketing authorization: Once BCX7353 receives marketing authorization in 
Japan, this study will be transitioned to a post-marketing study. BCX7353 will be 
administered at the dose regimen that is approved in Japan. Subject treatment will 
continue until Week 104 or until such time as BCX7353 is commercially available at 
his or her site, unless the subject discontinues his or her participation in the study. In 
the event that BCX7353 is not commercially available when the first and each 
subsequent subject at each site reaches Week 104, then the treatment period will be 
extended to allow each subject to continue treatment with BCX7353 until 
commercially available, unless the subject discontinues his or her participation in the 
study. 
Subjects will be instructed to take study drug at approximately the same time each day, with 
whichever meal is typically the largest meal of the day, or up to 30 minutes after consuming that 
meal. It is recommended that the study drug be administered with food to help minimize GI 
effects. If GI-related symptoms are noted as an AE, the site should query the subject and record 
whether the drug is being taken as instructed (ie, with a meal). 
Day 1 for purposes of analysis in Part 1 is defined as the day that subjects take their first dose of 
study drug. If the study drug administration is different than the day of the baseline visit, 
subsequent visits will be calculated from the day of first dose (Day 1), rather than the day of the 
baseline visit. Clinic administration of study drug during study visits is not required. Subjects 
will take study drug in Part 1 beginning on Day 1 and will complete Part 1 dosing on 
Study Day 168 (the day before the Week 24 visit). Subjects will take Part 2 active study drug no 
sooner than the conclusion of the Week 24 visit on Study Day 169, after all other study 
procedures have been completed. Subjects will take Part 3 unblinded study drug no sooner than 
the conclusion of the Week 52 visit. 
Subjects will be instructed to maintain approximately the same daily dosing interval between 
study drug doses. If a subject forgets to take the study drug at the correct time, the dose may be 
taken later in the day; however, no more than 1 dose of BCX7353 should be taken on any 


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calendar day. The subject should resume regular dosing schedule on the next day. Dosing may 
not be split across a day. 
Subjects will be instructed to record in the e-diary the time of day study drug was taken and the 
number of capsules of study drug taken (Parts 1 and 2 only).  
Drug dispensation will occur in-clinic but may be delivered to subjects by other means 
(eg, traceable courier) if warranted due to extenuating circumstances (eg, coronavirus disease 
2019 [COVID-19] restrictions), which will be determined individually for each site and/or 
subject. 
With the exceptions of the Week 2 and Week 26 visits, subjects will be instructed to bring all 
drug kits (including both unused and used bottles) and diaries with them for each study visit. 
Accountability and adherence will be reviewed at these visits. 
9.5. 
Study Drug Dose Modification 
Dose reductions are not permitted. Study drug interruptions are discussed in Section 12.1.8. 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability 
Accountability of study drug dispensed and returned (as applicable) will be performed at Day 1 
and at each study visit with the exceptions of the Week 2 and 26 visits. Returned study drug 
bottles and/or kits must be retained and reviewed during monitoring visits by the clinical 
research associate (CRA) (Section 14.2). 
The investigator/pharmacist must maintain accurate records of the disposition of all study drugs 
received from the sponsor, issued to the subject (including date), and any drug accidentally 
destroyed. At the end of the study, information describing study drug supplies (eg, kit numbers) 
and disposition of supplies for each subject must be provided, signed by the investigator or 
designee, and collected by the CRA. If any errors or irregularities in any shipment of study 
medication to the site are discovered at any time, the sponsor (and or designee) must be 
contacted immediately. 
At the end of the study or at other times as agreed by all involved parties, all study drug not 
dispensed or administered will either be collected under the supervision of the CRA and returned 
to the sponsor or destroyed on site as dictated by the appropriate Standard Operating Procedure 
at the participating institution. 
9.7. 
Concomitant Medications 
All subjects in the study must refrain from taking prohibited concomitant medications as outlined 
in Section 9.7.1. 
Details of all prior medications (taken within 30 days of screening; prior contraceptive 
medications taken within 56 days of screening) and all current concomitant medication use 
(including herbal supplements) through the follow-up/early termination visit, including all 
medications administered for the treatment of AEs, will be recorded in the source 
documentation/eCRF.  


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9.7.1. 
Prohibited Medications 
C1-INH for prophylaxis of angioedema events is prohibited within 14 days prior to the Screening 
visit or initiation during the study. However, use of C1-INH therapy for treatment of angioedema 
events is not excluded at any time, nor is the use of C1-INH for unplanned/unanticipated 
preprocedure prophylaxis.  
The following medications are excluded during the study (Section 8.2.2):  
• Angiotensin-converting enzyme inhibitors within 7 days of the baseline visit or 
planned initiation during the study (potential for exacerbation of HAE).  
• Another investigational drug within 30 days of the screening visit or initiation during 
the study. 
• Initiation of an estrogen-containing hormonal contraceptive within 56 days of the 
screening visit or planned initiation during the study (potential for increasing 
angioedema event rate).   
• Use of a medication that is transported by P-gp and has a narrow therapeutic range, 
within 7 days of the baseline visit or planned initiation during the study. For the 
purposes of this protocol, these are: aliskiren, digoxin, posaconazole, and talinolol. 
• Use of a concomitant medication that is metabolized by CYP2D6, CYP2C9, 
CYP2C19, and/or CYP3A4 and has a narrow therapeutic range, within 7 days of the 
baseline visit or planned initiation during the study. For the purposes of this protocol, 
these are: warfarin, phenytoin, s-mephenytoin, thioridazine, alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and 
tacrolimus. Note: Topical or ophthalmic tacrolimus or sirolimus and use of 
testosterone replacement therapy is allowed. 
• Use of a medication that is clinically known to prolong the QT interval and is 
metabolized by CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to the 
baseline visit or planned initiation during the study. For the purposes of this protocol, 
these are: donepezil, haloperidol, methadone, procainamide, and amitriptyline. 
• Androgens or tranexamic acid for prophylaxis of angioedema events within the 
28 days prior to the screening visit or initiation during the study. Androgens must not 
be used at all during the study.  
10. 
STUDY CONDUCT 
10.1. 
Overview 
This is a randomized, double-blind, placebo-controlled study. A subject’s participation in this 
study is expected to be at least 107 weeks, with an additional 56 to 70 days for the screening 
period and a dosing period of up to 104 weeks, or until another mechanism is available to 
provide BCX7353 to the subject (eg, market access). Once BCX7353 receives marketing 
authorization in Japan, this study will be transitioned to a post-marketing study. Each subject 
remaining on study may continue to receive access to BCX7353 until such time as BCX7353 is 


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commercially available at his or her site, unless the subject discontinues his or her participation 
in the study. 
Each eligible subject who consents to participate in the study will receive either 24 weeks 
(168 days) of BCX7353 (110 or 150 mg) or placebo in Part 1 and 28 weeks of blinded BCX7353 
(110 or 150 mg) in Part 2. All subjects will receive BCX7353 150 mg in Part 3. All subjects will 
undergo a screening period (including a prospective angioedema event run-in period of 56 days) 
of up to 10 weeks. During the up to 104-week dosing period, all subjects will be required to 
attend at least 18 visits: Day 1 (baseline), Week 2 (Day 15; liver enzymes only), Week 4 
(Day 29), Week 8 (Day 57), Week 12 (Day 85), Week 18 (Day 127), Week 24 (Day 169), 
Week 26 (Day 183), Week 28 (Day 197), Week 32 (Day 225), Week 36 (Day 253), Week 48 
(Day 337), Week 52 (Day 365), Week 60 (Day 421), and approximately every 12 weeks 
thereafter. 
Once BCX7353 is commercially available at each site, an EOS visit will be scheduled for each 
subject to complete his or her participation in the study and transition to commercial drug 
product. Subjects will not have to wait for their next scheduled clinic visit to complete the EOS 
visit. Subjects may not continue on study for more than 3 months after NHI price listing in 
Japan. Subjects who choose not to continue their participation in the study at any time will be 
asked to complete an early termination visit 3 weeks (+ 1 week) after their last dose of BCX7353 
(eg, subjects who do not extend their treatment at Week 104 should complete the early 
termination visit at Week 107 [+ 1 week]). 
10.2. 
Schedule of Assessments 
The schedule of assessments for this study is presented in Table 2, Table 3, and Table 4 (for 
Parts 1, 2, and 3, respectively) and procedures are described in Section 11. 
 


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Table 2: 
Schedule of Assessments: Part 1 of Study BCX7353-301  
Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
Screening Visita,b 
(up to Week -10) 
Run-in 
Perioda 
Day 1a 
Week 2c 
Day 15 
± 2 days  
Week 4 
Day 29 
± 2 days 
Week 8 
Day 57 
± 2 days 
Week 12 
Day 85 
± 2 days 
Week 18 
Day 127 
± 2 days 
Week 24 
Day 169d 
Informed consentb 
X 
 
 
 
 
 
 
 
 
In-clinic evaluation 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
Telephone contacte 
 
 
Inclusion-exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Medical historyf 
X 
 
X 
 
 
 
 
 
 
HAE medical and medication 
historyf 
X 
 
 
 
 
 
 
 
 
Weight/height/BMIg 
X 
 
X 
 
X 
X 
X 
X 
X 
Drugs of abuse screenh 
X 
 
 
 
 
 
 
 
 
Physical examinationi 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy testj 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signsk 
X 
 
X 
 
X 
X 
X 
X 
X 
FSHl 
X 
 
 
 
 
 
 
 
 
HIV, HCV, HBV serology 
X 
 
 
 
 
 
 
 
 
Diagnosis of HAE 
establishedm 
X 
 
 
 
 
 
 
 
Angioedema events 
eligibility determinationn 
 
X 
 
 
 
 
 
 
 
Safety laboratory 
evaluationsh 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
Troponin I & troponin T 
 
 
X 
 
X 
X 
X 
X 
X 
C1-INH antigenic level 
X 
 
 
 
 
 
 
 
 
C3  
 
 
X 
 
 
 
 
 
 
HLA typingo 
 
 
X 
 
 
 
 
 
 
Optional sample for possible 
exploratory 
pharmacogenomic testingp 
 
 
X 
 
 
 
 
 
 
NGAL 
 
 
X 
 
X 
X 
X 
X 
X 
CK-MB 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysish 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
12-lead ECGq 
X 
 
X 
 
X 
X 
X 
X 
X 


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Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
Screening Visita,b 
(up to Week -10) 
Run-in 
Perioda 
Day 1a 
Week 2c 
Day 15 
± 2 days  
Week 4 
Day 29 
± 2 days 
Week 8 
Day 57 
± 2 days 
Week 12 
Day 85 
± 2 days 
Week 18 
Day 127 
± 2 days 
Week 24 
Day 169d 
EQ-5D-5Lr,s 
 
 
X 
 
X 
X 
X 
X 
X 
AE-QoL, TSQM, and WPAIs 
 
 
X 
 
X 
X 
X 
X 
X 
Concomitant medications 
 
AEs 
 
Randomizationt 
 
 
X 
 
 
 
 
 
X 
e-diary instruction/review/ 
set-upu 
X 
X 
X 
 
X 
X 
X 
X 
X 
e-diary completionv 
 
Study drug dosingw 
 
 
 
Investigator review of 
angioedema eventsx 
 
Study drug accountability/ 
dispensing 
 
 
X 
 
X 
X 
X 
X 
X 
Plasma for PK and PD 
analysisy 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; 
AST = aspartate aminotransferase; BMI = body mass index; C1-INH = C1 esterase inhibitor; C3 = complement 3; CK-MB = creatine kinase MB isoenzyme; 
ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; FSH = follicle 
stimulating hormone; GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HLA = human leukocyte antigen; IXRS = interactive (voice/Web) response system; NGAL = neutrophil gelatinase-associated 
lipocalin; PD = pharmacodynamics; PK = pharmacokinetics; QTcF = QT interval corrected by Fridericia’s formula; TSQM = Treatment Satisfaction 
Questionnaire for Medication; WPAI = Work Productivity and Activity Impairment Questionnaire. 
a 
The baseline visit must be held within 10 weeks (70 days) of the screening visit, accommodating a run-in period of 56 days. The investigator must gain 
sponsor approval to enroll subjects who are not randomized within 10 weeks of the screening visit; this may require screening laboratory tests to be redrawn. 
Subjects will not be permitted to rescreen if they did not meet the angioedema event requirements during the run-in period. 
b 
Signing of informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures, including 
e-diary dispensing, are performed. 
c 
The Week 2 visit will consist of monitoring liver function tests only (ALT, AST, GGT, total and direct bilirubin, ALP); urine and additional tubes of blood 
will be required to accommodate possible reflex testing for abnormal GGT, AST, or ALT.  
d 
The last visit in Part 1 (Week 24) must occur the day following 24 weeks of study drug dosing in Part 1. 
e 
The investigator (or designee) must call and talk to the subject at least weekly in between the Screening and Baseline visits and on-treatment through 
Week 24; alternative forms of interactive communication such as returned email and cellular text correspondence are acceptable. During all calls, the 
investigator (or designee) will assess the subject’s overall wellbeing, discuss compliance (if applicable), proper recording of angioedema event details 


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(if applicable), or any usability issues with the e-diary. A weekly phone call may be omitted if the subject records an angioedema event as the investigator 
must call and confirm or reject the angioedema event (see Footnote ‘x’). 
f 
An HAE medical history form will be completed by the subject at screening. Medical and medication history will be taken at screening and updated at 
baseline.  
g 
BMI calculation and height at screening; weight is to be recorded at each scheduled in-clinic visit during Part 1 except at Week 2. 
h 
Table 5 lists parameters to be assessed.  
i 
Full physical examinations will be performed at screening, baseline, and Week 24; abbreviated physical examinations targeted to signs and symptoms will 
be performed at all other post-baseline visits except for Week 2. 
j 
For all women of childbearing potential (including adolescents), a serum pregnancy test will be administered at screening. Urine pregnancy tests will be 
assessed at all subsequent visits as indicated in the table. Demonstration of a negative urine pregnancy test will be required prior to the subject taking study 
drug on Day 1.  
k 
To include blood pressure and pulse rate. Temperature and respiratory rate will be captured at screening, baseline, and Week 24 only. Prior to obtaining vital 
signs, subjects should rest in a supine position for at least 5 minutes.  
l 
For women who declare that they have been post-menopausal ≤ 2 years.  
m  
A clinical diagnosis of HAE Type 1 or 2 must be demonstrated during screening for this study as outlined in Inclusion Criterion 3 (Section 8.2.1). 
n  
The subject will be determined as eligible for the study based upon screening evaluations and the prospective recording of angioedema events during the 
run-in period of 56 days. The subject must have at least 2 angioedema events during the run-in period as assessed by an independent expert which meet all of 
the following requirements:1) the angioedema events are unique, which is defined as an angioedema event that does not begin within 48 hours of the end of 
a previous angioedema event; 2) the angioedema events must have either been treated, required medical attention, or be documented to cause functional 
impairment based on subject entry in the e-diary; 3) the angioedema events must include symptoms of swelling. The expert will consider that symptoms of 
swelling, in addition to visible swelling, may also include symptoms in the oropharyngeal or abdominal regions that are indicative of internal swelling and; 
4) the angioedema events are otherwise confirmed by an independent expert to be angioedema events (see Footnote ‘x’). 
o 
A blood sample for HLA typing will be drawn at the baseline/Day 1 visit; if a blood sample is not obtained at baseline, the sample may be drawn at any time 
during the study.  
p 
A blood sample for possible exploratory pharmacogenomic testing will be drawn at the Baseline/Day 1 visit only if consent/assent is obtained for this 
optional testing; if a blood sample is not obtained at Baseline, the sample may be drawn at any time during the study following consent obtained from the 
subject.  
q 
Bedside 12-lead ECGs will be conducted in triplicate (ie, 3 separate readings) at 1- to 5-minute intervals predose on Day 1 and Week 24, with values for 
these visits calculated from an average of the 3 readings. All other ECGs during the study will be single assessments. Prior to obtaining an ECG, subjects 
should rest quietly in a supine position for at least 10 minutes. ECGs should be obtained prior to any blood sampling. An ECG should be repeated for a 
change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
r 
The EQ-5D-5L will be administered once at baseline and 1 to 2 × at Weeks 4, 8, 12, 18, and 24 visits. The subject will fill out the first EQ-5D-5L at baseline 
and on-study to describe his or her current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a 
recollection of his or her health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema 
event since the last study visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L. 
s 
Where possible, quality of life and health outcome questionnaires should be collected as the first assessments at a visit. 
t 
Sites will randomize eligible subjects in the IXRS at the Day 1 visit, preferably after all baseline assessments have been completed. Sites using a centralized 
pharmacy may randomize the subject the day prior to the baseline visit. The baseline event rate generated from the date of screening through the time of 
randomization must be calculated at this time (Section 9.3.2.1). 


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u 
The investigator (or designee) will set up the e-diary at the screening visit and as needed during the study; any issues (including mediocre or poor 
compliance) warranting e-diary re-education should occur on an as-needed basis. 
v 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details and 
dosing information (as applicable) at least once per day. 
w 
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits. Subjects will take study drug in Part 1 beginning on Day 1 and will complete Part 1 dosing on Study Day 168 (day before 
Week 24 visit). Subjects will take Part 2 active study drug no sooner than the conclusion of the Week 24 visit on Study Day 169, after all other study 
procedures have been completed. 
x 
An independent expert will review the e-diary record in conjunction with investigator-collected details of all angioedema events that occur from screening 
through follow-up and either confirm or reject each event as an angioedema event. At least 2 angioedema events that occur during the run-in period must 
meet the requirements outlined in Footnote ‘n’ in order to qualify the subject to randomize in the study. For all angioedema events that are recorded, subjects 
will be contacted within approximately 2 business days of the end of the angioedema event to discuss the clinical characteristics of the angioedema event, 
any questions the investigator has on the entered data, or to gain additional details on each event not included in the e-diary that the investigator deems 
important to clinically evaluate the event, as applicable. The investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each event recorded in the diary as a confirmed angioedema event. The investigator e-diary data review and subject 
contact summaries will be documented in the source records and made available to an independent expert for their verification (confirmation or rejection) of 
the event.  
y 
Concentration and PD blood samples will be drawn on all subjects at the scheduled visits. For at least one of these time points, a PK and PD sample should 
be drawn approximately 3 to 6 hours after the last dose of study drug. The remaining time points can be drawn with no particular relationship to the timing 
of study drug dosing. The investigator (or designee) must ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary 
(this may also be captured in the eCRF). 
 


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Table 3: 
Schedule of Assessments: Part 2 of Study BCX7353-301  
Assessment 
Part 2 
Double-Blind, Active Study Drug Administrationa 
 
Week 26b 
Day 183 
± 2 days 
Week 28 
Day 197 
± 2 days 
Week 32 
Day 225 
± 2 days 
Week 36 
Day 253 
± 2 days 
Week 40 
Week 44 
Week 48 
Day 337 
± 7 days 
Week 52 
(Day 365) 
± 2 days 
In-clinic evaluation 
X 
X 
X 
X 
 
 
X 
X 
Telephone contactc 
 
 
 
 
X 
X 
 
 
Subject weight 
 
X 
X 
X 
 
 
X 
X 
Physical examinationd 
 
X 
X 
X 
 
 
X 
X 
Urine pregnancy test 
 
X 
X 
X 
 
 
X 
X 
Vital signse 
 
X 
X 
X 
 
 
X 
X 
Safety laboratory evaluationsf 
Xb 
X 
X 
X 
 
 
X 
X 
Troponin I & troponin T 
 
X 
X 
X 
 
 
X 
X 
NGAL 
 
X 
X 
X 
 
 
X 
X 
CK-MB 
 
X 
X 
X 
 
 
X 
X 
Urinalysisf 
Xb 
X 
X 
X 
 
 
X 
X 
12-lead ECGg 
 
X 
X 
X 
 
 
X 
X 
EQ-5D-5Lh,i 
 
X 
X 
X 
 
 
X 
X 
AE-QoL, TSQM, and WPAIi 
 
X 
X 
X 
 
 
X 
X 
Concomitant medications 
 
AEs 
 
e-diary instruction/reviewj 
 
X 
X 
X 
X 
X 
X 
X 
e-diary daily completionk 
 
Study drug dosingl 
 
Investigator review of angioedema 
eventsm 
 
Study drug accountability/ dispensing 
 
X 
X 
X 
 
 
X 
X 
Plasma for BCX7353 concentration and 
PD analysisn 
 
X 
X 
X 
 
 
X 
X 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; AST aspartate 
aminotransferase; CK-MB = creatine kinase MB isoenzyme; ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; 
EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; NGAL = neutrophil 
gelatinase-associated lipocalin; PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; QTcF = QT interval corrected by Fridericia’s formula; 
TSQM = Treatment Satisfaction Questionnaire for Medication; WPAI = Work Productivity and Activity Impairment Questionnaire. 
a 
Period 2 study drug is to be initiated upon administration of study drug, dispensed at the Week 24 visit. 


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b 
The Week 26 visit will consist of monitoring liver function tests only (ALT, AST, GGT, total and direct bilirubin, ALP); urine and additional tubes of blood 
will be required to accommodate possible reflex testing for abnormal GGT, AST, or ALT (see Table 5). If preferred by the subject and clinical site, 
laboratory values may be drawn and resulted locally, with results entered into the eCRF. 
c 
The investigator (or designee) must call and talk to the subject during Weeks 40 and 44; alternative forms of interactive communication such as returned 
email and cellular text correspondence are acceptable. During all calls, the investigator (or designee) will assess the subject’s overall wellbeing, discuss 
compliance (if applicable), proper recording of angioedema event details (if applicable), or any usability issues with the e-diary. The phone call may be 
omitted if the subject records an angioedema event as the investigator must call and discuss details of the event (see Footnote ‘m’). 
d 
Abbreviated physical examinations targeted to signs and symptoms will be performed at post-baseline visits. 
e 
To include blood pressure and pulse rate. Prior to obtaining vital signs, subjects should rest in a supine position for at least 5 minutes.  
f 
Table 5 lists parameters to be assessed. 
g 
ECGs may be single assessments. Prior to obtaining an ECG, subjects should rest quietly in a supine position for at least 10 minutes. ECGs should be 
obtained prior to any blood sampling. An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
h  
The EQ-5D-5L will be administered 1 to 2 × at Weeks 28, 32, 36, 48, and 52. The subject will fill out the first EQ-5D-5L at baseline and on-study to 
describe his or her current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a recollection of his 
or her health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema event since the last 
study visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L.  
i 
Where possible, QoL and health outcome questionnaires should be collected as the first assessments at a visit. Additional information about long-term 
experience on study may be collected at Week 52. 
j 
Any issues (including mediocre or poor compliance) warranting e-diary re-education should occur on an as-needed basis. 
k 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details and 
dosing information (as applicable) at least once per day. 
l 
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits.  
m 
An independent expert will review the e-diary record in conjunction with investigator-collected details of all angioedema events that occur from screening 
through follow-up during Parts 1 and 2 and either confirm or reject each event as an angioedema event. For all angioedema events that are recorded, subjects 
will be contacted within approximately 2 business days of the end of the angioedema event to discuss the clinical characteristics of the angioedema event, 
any questions the investigator has on the entered data, or to gain additional details on the event that are not included in the e-diary that the investigator deems 
important to clinically evaluate the event, as applicable. The investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each event recorded in the e-diary as a confirmed angioedema event. The investigator e-diary data review and subject 
contact summaries will be documented in the source records and made available to an independent expert for their verification (confirmation or rejection) of 
the event. 
n 
PK and PD blood samples will be drawn on all subjects with no particular relationship to the timing of study drug dosing. The investigator (or designee) 
must ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary (this may also be captured in the eCRF). 
 


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Table 4:  
Schedule of Assessments: Part 3 of Study BCX7353-301 
Assessment 
Part 3 
Open-Label, Active Study Drug Administrationa 
 
Early 
Termination 
Visit/Follow-
Up/EOSc 
Week
 56 
Week 60 
Day 421 
± 6 days 
Weeks 
64 and 
68 
Week 72 
Day 505 
± 6 days 
Weeks 
76 and 
80 
Week 84 
Day 589 
± 6 days 
Weeks 
88 and 
92 
Week 96 
Day 673 
± 6 days 
Week 
100 
Week 104 
(Day 729 
± 7 days) 
+each 
4 wksb 
+each 
12 wksb 
In-clinic evaluation 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Telephone contactd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Subject weight/heighte 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examinationf 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine pregnancy test 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signsg 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Safety laboratory evaluationsh 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Troponin I & troponin T 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NGAL 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CK-MB 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysish 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECGi 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
EQ-5D-5Lj,k 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
AE-QoL, TSQM, and WPAIk 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Concomitant medications 
 
 
AEs 
 
 
Diary instruction/reviewl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary daily completionm 
 
 
Study drug dosingn 
 
 
 
Study drug accountability/ 
dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xo 
Plasma for BCX7353 
concentration and PD analysisp 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; AST aspartate 
aminotransferase; CK-MB = creatine kinase MB isoenzyme; ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; EOS = end of 
study; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; NGAL = neutrophil 
gelatinase-associated lipocalin; NHI = National Health Insurance; PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; QTcF = QT interval 
corrected by Fridericia’s formula; TSQM = Treatment Satisfaction Questionnaire for Medication; WPAI = Work Productivity and Activity Impairment 
Questionnaire. 
a 
Period 3 study drug is to be initiated upon administration of study drug, dispensed at the Week 52 visit. 


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b 
In the event that BCX7353 is not commercially available when the first and each subsequent subject at each site reaches Week 104, then the treatment period 
will be extended with additional telephone contacts conducted at 4-week intervals (Weeks 108, 112, etc.) and clinic visits completed at 12-week intervals 
(Week 116, etc.) to allow each subject to continue treatment with BCX7353 until commercially available, unless the subject discontinues his or her 
participation in the study. 
c Once BCX7353 is commercially available at each site, an EOS visit will be scheduled for each subject to complete his or her participation in the study and 
transition to commercial drug product. Subjects will not have to wait for their next scheduled clinic visit to complete the EOS visit. Subjects may not 
continue on study for more than 3 months after NHI price listing in Japan Subjects who choose not to continue their participation in the study at any time 
will be asked to complete an early termination visit and/or a follow-up visit 3 weeks (+ 1 week) after their last dose of BCX7353 (eg, subjects who do not 
extend their treatment at Week 104 should complete the follow-up visit at Week 107 (+ 1 week). Subjects who transition to commercial BCX7353 will not 
need to return 3 weeks after their last dose of study drug.  
d 
The investigator (or designee) must call and talk to the subject during Weeks 56, 64, 68, 76, 80, 88, 92, and 100; alternative forms of interactive 
communication such as returned email and cellular text correspondence are acceptable. During all calls, the investigator (or designee) will assess the 
subject’s overall wellbeing, discuss compliance (if applicable), proper recording of angioedema event details (if applicable), or any usability issues with the 
e-diary. If needed, additional telephone contacts will be conducted at 4-week intervals post-Week 104 to allow the subjects to continue treatment with 
BCX7353 until commercially available. 
e 
Adolescent subjects will have height measured at Weeks 48 and 96.  
f 
Abbreviated physical examinations targeted to signs and symptoms will be performed at post-baseline visits. 
g 
To include blood pressure and pulse rate. Prior to obtaining vital signs, subjects should rest in a supine position for at least 5 minutes.  
h 
Table 5 lists parameters to be assessed. 
i 
ECGs may be single assessments. Prior to obtaining an ECG, subjects should rest quietly in a supine position for at least 10 minutes. ECGs should be 
obtained prior to any blood sampling. An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
j 
The EQ-5D-5L will be administered 1 to 2 × at Weeks 60, 72, 84, 96, and 104. The subject will fill out the first EQ-5D-5L at baseline and on-study to 
describe his or her current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a recollection of his 
or her health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema event since the last 
study visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L.  
k 
Where possible, QoL and health outcome questionnaires should be collected as the first assessments at a visit.  
l 
Any issues (including mediocre or poor compliance) warranting e-diary re-education should occur on an as-needed basis. 
m 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details (as 
applicable) at least once per day. Subjects are not required to enter dosing information in the e-diary in this part. 
n 
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits.  
o 
Early termination visit only (if occurring during dosing phase). 
p 
PK and PD blood samples will be drawn on all subjects with no particular relationship to the timing of study drug dosing through the Week 52 visit only. 
The investigator (or designee) must ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary (this may also be 
captured in the eCRF). 
q 
PK and PD blood samples will be drawn at the ET visit, only if the ET visit occurs prior to Week 52. 
 


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10.3. 
Study Visits 
10.3.1. 
Screening Visit 
Written informed consent and assent (as applicable) must be obtained from each subject before 
initiation of any screening assessments or procedures. Each subject will receive a copy of the 
signed and dated study-specific informed consent form (ICF). Prospective subjects who have 
signed an ICF who are interested in participation in the study will then undergo assessments at a 
screening visit to determine eligibility. Signing of the ICF may occur prior to the screening visit, 
which is defined as the visit where site-conducted screening procedures, including e-diary 
dispensing, are performed.  
The investigator (or designee) will conduct the following assessments at the screening visit, 
including: 
• Signing of ICF (if not done prior to the visit) and assent (as applicable) 
• Review of inclusion and exclusion criteria  
• Medical and medication history (including HAE medical, medication history and 
prohibited medications) 
• Complete physical examination 
• 12-lead ECG  
• Height/weight/BMI estimation  
• Vital signs (blood pressure, pulse rate, temperature, and respiratory rate) 
• Serum pregnancy test for all female subjects of childbearing potential (including 
adolescents) 
• Blood collection for clinical chemistry, hematology, coagulation, HBV/HIV/HCV 
serology, C-INH function level, C4 level, C1-INH antigenic level, and FSH (for 
women who declare that they have been post-menopausal ≤ 2 years). Blood may also 
be drawn for possible SERPING-1 gene analysis (see Section 11.2.10) 
• Urine collection for urinalysis, drugs of abuse screen, and possible reflex testing for 
abnormal GGT, AST, or ALT  
• Recording of AEs and concomitant medications  
• Provision and instruction of the e-diary 
All subjects will receive an e-diary at the screening visit to establish eligibility during the run-in 
period (ie, 56 days from the date of the screening visit) and also to provide a baseline 
angioedema event rate to properly stratify the subject into a Part 1 treatment group during 
randomization. The subject will record daily angioedema events in the e-diary beginning at the 
screening visit. 
In the case of limitations for conduct of the screening visit to occur on a single day, a site is 
permitted to perform screening assessments over more than one screening visit. However, an 


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e-diary to capture angioedema events should be dispensed on the first screening visit day, 
initiating the run-in period. 
Rescheduling of the screening visit should be considered if the subject reports a dose of C1-INH 
has been taken for an angioedema event within approximately 3 days of the visit as C1-INH 
functional level is more likely to come back normal or to not meet inclusion criterion 3.  
10.3.2. 
Period Between Screening and Baseline 
Procedures to be performed by the site and/or clinical trial participants between screening and 
baseline are outlined in Table 2, and described in Section 11. Subject attendance at the clinic is 
not required to complete these procedures, unless additional blood sampling to confirm HAE 
diagnosis is warranted. 
A subject’s eligibility based upon the number of angioedema events will be determined during 
the run-in period; the baseline angioedema event rate of the subject will also be calculated during 
the period from the screening visit through randomization for the purposes of properly stratifying 
the subject during randomization.  
For all angioedema events that are recorded following the screening visit, subjects will be 
contacted within approximately 2 business days of the end of the angioedema event to discuss 
the clinical characteristics of the angioedema event, any questions on the entered data, or to gain 
additional details on the event not included in the e-diary that the investigator deems important to 
clinically evaluate the event, as applicable. The investigator-collected information, in 
conjunction with the e-diary record, will be used by an independent expert to verify or reject 
each event as a confirmed angioedema event. The investigator e-diary data review and subject 
contact summary worksheets will be documented in the source records and made available to an 
independent expert for their verification (confirmation or rejection) of the event. 
For the subject to qualify for the study, the subject must have at least 2 angioedema events as 
assessed by an independent expert during the run-in period (56 days beginning at the screening 
visit) that meet all of the following requirements below: 
• The angioedema events are unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform his or her 
daily activities without restriction (ie, subject records that he or she is at least slightly 
restricted in daily activities during the angioedema events).  
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events are otherwise confirmed by an independent expert to be 
angioedema events.  


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Under no circumstances should the run-in angioedema event requirement for eligibility be 
disclosed to study subjects. 
The investigator (or designee) must call and talk to the subject at least weekly in between the 
screening and baseline visits; alternative forms of interactive communication such as returned 
email and cellular text correspondence are acceptable. During all calls, the investigator 
(or designee) will assess the subject’s overall wellbeing, discuss compliance (if applicable), 
proper recording of angioedema event details (if applicable), or any usability issues with the 
e-diary. A weekly phone call may be omitted if the subject records an angioedema event, as the 
investigator must call and confirm or reject the angioedema events. 
If a subject has a normal C4 level (as is the case in a small percentage of subjects with HAE) 
drawn at the screening visit, the site may take another C4 level during an angioedema event. 
Normal C4 drawn during an angioedema event excludes the subject from study participation. 
Alternatively, the site may also utilize SERPING-1 gene mutational analysis or a family history 
of C1-INH deficiency in the case of a normal C4. To utilize a family history of C1-INH 
deficiency to establish an HAE diagnosis for eligibility, the investigator should document this as 
a source file note based on either the investigator’s personal knowledge (ie, if a relative of the 
screening subject is also a patient of the same investigator/practice) or interaction with medical 
staff of the treatment facility where the relative receives HAE care, who confirms the diagnosis. 
No historical laboratory documentation on the relative should be collected in the source 
documents. A SERPING-1 mutation known or likely to be associated with HAE Type 1 or 2 
HAE is acceptable to confirm the diagnosis of HAE. A SERPING-1 analysis that does not 
identify a likely or pathologic mutation indicative of HAE excludes the subject from study 
participation. 
For a C1-INH that is between 50% and the LLN (74%), the site may draw another C1-INH 
functional level or, if desired, have a SERPING-1 gene mutational analysis performed. 
A C1-INH functional level < 50% or a SERPING-1 mutation known or likely to be associated 
with HAE Type 1 or 2 HAE is acceptable to confirm the diagnosis of HAE. A SERPING-1 
analysis that does not identify a likely or pathologic mutation indicative of HAE excludes the 
subject from study participation. 
SERPING-1 gene analysis results indicating a “possibly pathogenic” mutation will be considered 
on a case-by-case basis by the medical monitor and may require additional testing for eligibility. 
Blood for possible SERPING-1 gene sequencing may be drawn at the screening visit or during 
the period between screening and baseline but analyzed only if required (normal C4 at screening 
or a C1-INH level between 50% and the LLN [74%]). 
Subjects who are deemed ineligible for the study will return their e-diary to the study site. 
Rescreening of ineligible subjects, where there is a reasonable expectation that the subject will 
become eligible, will be approved or denied on a case-by-case basis by the sponsor medical 
monitor. Retesting of specific assessments within the screening period without entirely 
rescreening a subject may be permitted. Additionally, the investigator must gain sponsor 
approval to enroll subjects who are not randomized within 10 weeks of the screening visit; this 
may require screening labs to be redrawn. Subjects will not be permitted to rescreen if they did 
not meet the angioedema event requirements during the run-in period. 


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A screening failure eCRF page will be completed for those subjects who do not proceed with 
study dosing, recording the reason for screen failure. 
AEs and concomitant medications will be recorded if reported during this period. 
10.3.3. 
Part 1 
10.3.3.1. Baseline Visit (Day 1) 
Subjects who meet all study eligibility criteria, and who agree to participate will be asked to 
return for a scheduled Day 1 visit, to be held 70 days or less from the screening visit.  
Before any study drug is administered the following assessments will be completed: 
• Administration of EQ-5D-5L, AE-QoL, TSQM, and WPAI questionnaires. 
Where possible, the questionnaires should be completed by the subject prior to other 
assessments to prevent influencing subject perceptions. 
• Review of inclusion and exclusion criteria, medical and medication history, and 
prohibited medications 
• Subject weight 
• Vital signs (blood pressure, temperature, respiratory rate, and pulse rate) 
• 12-lead ECG (in triplicate) 
• Full physical examination 
• Blood collection for clinical chemistry, hematology, coagulation, C3, troponin I and 
troponin T, NGAL, human leukocyte antigen (HLA) typing, and CK-MB 
• PK concentration and PD plasma samples 
• Optional blood collection for exploratory pharmacogenomics testing (provided a 
separate informed consent/assent has been obtained; sample can be drawn at any 
visit)  
• Urine collection for urinalysis, possible reflex testing for abnormal GGT, AST, or 
ALT, and urine pregnancy test for all female subjects of childbearing potential. 
A negative urine pregnancy result must be recorded before the subject can be dosed.  
• Review of concomitant medications and AEs 
• e-diary instruction and review. Where required, the e-diary should be turned to the 
dosing phase in Part 1 at the conclusion of these assessments, prior to randomization 
and study drug dispensing.  
• Calculation of baseline angioedema event rate for stratification in IXRS 
• Randomization, study drug accountability and dispensing. It is preferred that 
randomization occur after all baseline assessments have been completed.  
After completion of the above bulleted items, the first dose of study drug may be administered in 
the clinic or should be administered at home on the day of the visit (see Section 9.3.2). Day 1 of 
the study is defined as the day in which subjects take the first dose of study drug.  


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During the Part 1 dosing period, investigators will contact subjects to discuss details of all 
angioedema events recorded in the e-diary within approximately 2 business days of the end of 
the angioedema event. Moreover, any noncompliance will warrant contact with the subject. 
The investigator (or designee) must call and talk to the subject at least weekly; alternative forms 
of interactive communication such as returned email and cellular text correspondence are 
acceptable. During all calls, the investigator (or designee) will assess the subject’s overall 
wellbeing, discuss compliance (if applicable), proper recording of angioedema event details 
(if applicable), or any usability issues with the e-diary. A weekly phone call may be omitted if 
the subject records an angioedema event, as the investigator must call and confirm or reject the 
angioedema event. 
10.3.3.2. Week 2 Visit 
The Week 2 visit will consist of monitoring liver function tests only (ALT, AST, GGT, total and 
direct bilirubin, ALP); urine and additional tubes of blood may be required to accommodate 
reflex testing for abnormal GGT, AST, or ALT (see Table 5). If preferred by the subject and 
clinical site, laboratory values may be drawn and resulted locally, with results entered into the 
eCRF. 
During Part 1, investigators will contact subjects to discuss details of all angioedema events 
recorded in the e-diary within approximately 2 business days of the end of the angioedema event. 
Moreover, any noncompliance will warrant contact with the subject. 
10.3.3.3. Week 4, 8, 12, and 18 Visits 
Subjects will return to the clinic during Week 4 (Day 29 ± 2 days), Week 8 (Day 57 ± 2 days), 
Week 12 (Day 85 ± 2 days), and Week 18 (Day 127 ± 2 days).  
Subjects do not need to withhold any doses on clinic days or take a dose in the clinic, unless the 
clinic visit falls during the subject’s normal time of dosing.  
The following assessments will be performed: 
• Administration of EQ-5D-5L (1 or 2 questionnaires), AE-QoL, TSQM, and WPAI 
questionnaires. Where possible, the questionnaires should be completed by the 
subject prior to other assessments to prevent influencing subject perceptions.  
• Subject weight 
• Vital signs (blood pressure and pulse rate) 
• 12-lead ECG (single assessments) 
• Abbreviated physical examination (targeted to new signs and symptoms) 
• Blood collection for clinical chemistry, hematology, and coagulation, troponin I and 
troponin T, NGAL, and CK-MB 
• PK concentration and PD plasma samples  
• Urine collection for urinalysis, possible reflex testing for abnormal GGT, AST, or 
ALT, and urine pregnancy test for all female subjects of childbearing potential 


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• Review of concomitant medications and AEs 
• Review of angioedema event and dosing e-diary completion and study drug 
compliance 
• Study drug accountability and dispensing  
During the Part 1 dosing period, investigators will contact subjects to discuss details of all 
angioedema events recorded in the e-diary within approximately 2 business days of the end of 
the angioedema event. Moreover, any noncompliance will warrant contact with the subject. 
The investigator (or designee) must call and talk to the subject at least weekly; alternative forms 
of interactive communication such as returned email and cellular text correspondence are 
acceptable. During all calls, the investigator (or designee) will assess the subject’s overall 
wellbeing, discuss compliance (if applicable), proper recording of angioedema event details 
(if applicable), or any usability issues with the e-diary. A weekly phone call may be omitted if 
the subject records an angioedema event, as the investigator must call and confirm or reject the 
angioedema event. 
At the Week 18 visit and during phone calls prior to Week 24, subjects will be instructed to take 
their last dose of study drug in Part 1 on Day 168, the day prior to the Week 24 visit.  
10.3.3.4. Week 24 Visit 
The Week 24 visit will be conducted on Day 169, the day after the last dose of study drug in 
Part 1. Before any study drug for Part 2 is administered, the following assessments will be 
completed: 
• Administration of EQ-5D-5L (1-2 questionnaires), AE-QoL, TSQM, and WPAI 
questionnaires. Where possible, the questionnaires should be completed by the 
subject prior to other assessments to prevent influencing subject perceptions. 
• Subject weight 
• Vital signs (blood pressure, temperature, respiratory rate, and pulse rate) 
• 12-lead ECG (in triplicate) 
• Complete physical examination 
• Blood collection for clinical chemistry, hematology, and coagulation, troponin I and 
troponin T, NGAL, and CK-MB 
• PK concentration and PD plasma samples  
• Urine collection for urinalysis, possible reflex testing for abnormal GGT, AST, or 
ALT, and urine pregnancy test for all female subjects of childbearing potential. 
A negative urine pregnancy result must be recorded in order for the subject to be 
dosed.  
• Review of concomitant medications and AEs 
• Part 1 study drug collection/accountability  


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• e-diary instruction and review and set up. The e-diary should be turned to Part 2 at the 
conclusion of these assessments, prior to randomization and study drug dispensing for 
Part 2. 
After completion of the above bulleted items at the conclusion of the visit, Part 2 study drug may 
be dispensed from the IXRS and accountability performed. The first dose of study drug in Part 2 
may be administered (if timing coincides with typical dosing time, see Section 9.3.2). Study drug 
in Part 2, if not given at the visit, should be taken the day of the visit.  
During the Part 2 dosing period, investigators will contact subjects to discuss details of all 
angioedema events recorded in the e-diary within approximately 2 business days of the end of 
the angioedema event. Moreover, any noncompliance will warrant contact with the subject. 
10.3.4. 
Part 2 
10.3.4.1. Week 26 Visit  
The Week 26 visit (Day 183 ± 2 days) will consist of monitoring liver function tests only (ALT, 
AST, GGT, total and direct bilirubin, ALP); urine and additional tubes of blood may be required 
to accommodate reflex testing for abnormal GGT, AST, or ALT (see Table 5). If preferred by 
the subject and clinical site, laboratory values may be drawn and resulted locally, with results 
entered into the eCRF. 
During the Part 2 dosing period, investigators will contact subjects to discuss details of all 
angioedema events recorded in the e-diary within approximately 2 business days of the end of 
the angioedema event. Moreover, any noncompliance will warrant contact with the subject. 
10.3.4.2. Week 28, 32, 36, 48, and 52 Visits 
Subjects will return to the clinic during Week 28 (Day 197 ± 2 days), Week 32 
(Day 225 ± 2 days), Week 36 (Day 253 ± 2 days), Week 48 (Day 337 ± 7 days), and Week 52 
(Day 365 ± 2 days).  
Subjects do not need to withhold any doses on clinic days or take a dose in the clinic, unless the 
clinic visit falls during the subject’s normal time of dosing.  
The following assessments will be performed: 
• Administration of EQ-5D-5L (1-2 questionnaires), AE-QoL, TSQM, and WPAI 
questionnaires. Where possible, the questionnaires should be completed by the 
subject prior to other assessments to prevent influencing subject perceptions.  
• Subject weight 
• Vital signs (blood pressure and pulse rate) 
• 12-lead ECG (single assessments) 
• Abbreviated physical examination (targeted to new signs and symptoms) 
• Blood collection for clinical chemistry, hematology, and coagulation, troponin I and 
troponin T, NGAL, and CK-MB 
• PK concentration and PD plasma samples  


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• Urine collection for urinalysis, possible reflex testing for abnormal GGT, AST, or 
ALT, and urine pregnancy test for all female subjects of childbearing potential 
• Review of concomitant medications and AEs 
• Review of angioedema events and dosing e-diary completion and study drug 
compliance. The e-diary should be turned to Follow-up at the conclusion of the 
Week 52 visit. 
• Study drug accountability and dispensing.  
During the Part 2 dosing period, investigators will contact subjects to discuss details of all 
angioedema events recorded in the e-diary within approximately 2 business days of the end of 
the angioedema event. Moreover, any noncompliance will warrant contact with the subject. 
10.3.4.3. Week 40 and 44 Phone Calls 
The investigator (or designee) must call and talk to the subject once during Weeks 40 and 44; 
alternative forms of interactive communication such as returned email and cellular text 
correspondence are acceptable. During all calls, the investigator (or designee) will assess the 
subject’s overall wellbeing, discuss compliance (if applicable), proper recording of angioedema 
event details (if applicable), or any usability issues with the e-diary. The phone call may be 
omitted if the subject records an angioedema event as the investigator must call and confirm or 
reject the angioedema event.  
10.3.5. 
Part 3 
10.3.5.1. Week 60, 72, 84, 96, and 104 Visits 
Subjects will return to the clinic during Week 60 (Day 421 ±6 days), Week 72 
(Day 505 ± 6 days), Week 84 (Day 589 ± 6 days), Week 96 (Day 673 ± 6 days), and Week 104 
(Day 729 ± 7 days). 
Subjects do not need to withhold any doses on clinic days or take a dose in the clinic, unless the 
clinic visit occurs during the subject’s normal time of dosing. 
The following assessments will be performed: 
• Administration of EQ-5D-5L (1 or 2 questionnaires), AE-QoL, TSQM, and WPAI 
questionnaires. Where possible, the questionnaires should be completed by the 
subject prior to other assessments to prevent influencing subject perceptions.  
• Subject weight (adolescent subjects will also have height measured at Weeks 48 and 
96) 
• Vital signs (blood pressure and pulse rate) 
• 12-lead ECG (single assessments) 
• Abbreviated physical examination (targeted to new signs and symptoms) 
• Blood collection for clinical chemistry, hematology, and coagulation, troponin I and 
troponin T, NGAL, and CK-MB 


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• Urine collection for urinalysis, possible reflex testing for abnormal GGT, AST, or 
ALT, and urine pregnancy test for all female subjects of childbearing potential 
• Review of concomitant medications and AEs 
• Review of e-diary data, to include recording of angioedema events.  
• Study drug accountability and dispensing (collection only at Week 104)  
During the Part 3 dosing period, investigator confirmation of angioedema events recorded in the 
e-diary is not required nor is recording of daily dosing. The e-diary should be reviewed with the 
subject at all study visits. Any noncompliance will warrant contact with the subject. 
Post-Marketing Study 
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to 
BCX7353 through Week 104 or until such time as BCX7353 is commercially available at his or 
her site, whichever occurs first, unless the subject discontinues his or her participation in the 
study. In the event that BCX7353 is not commercially available when the first and each 
subsequent subject at each site reaches Week 104, then the treatment period will be extended to 
allow each subject to continue treatment with BCX7353 until commercially available, unless the 
subject discontinues his or her participation in the study. Once BCX7353 is commercially 
available at each site, an EOS visit will be scheduled for each subject to complete his or her 
participation in the study and transition to commercial drug product. Subjects may not continue 
on study for more than 3 months after NHI price listing in Japan. 
10.3.5.2. Week 56, 64, 68, 76, 80, 88, 92, and 100 Phone Calls 
The investigator (or designee) must call and talk to the subject once during Weeks 56, 64, 68, 76, 
80, 88, 92, and 100; alternative forms of interactive communication such as returned email and 
cellular text correspondence are acceptable. During all calls, the investigator (or designee) will 
assess the subject’s overall welling, discuss compliance (if applicable), proper recording of 
angioedema event details (if applicable), or any usability issues with the e-diary. 
If needed, additional telephone contacts will be conducted at 4-week intervals post-Week 104 to 
allow the subjects to continue treatment with BCX7353 until commercially available. 
10.3.5.3. Early Termination Visit/Follow-Up/End-of-Study 
The following assessments will be performed for study completers at the EOS or at the Early 
Termination/Follow-Up visit (as applicable) for those subjects who discontinue, held 
approximately 3 weeks following the last dose of study drug.  
Subjects who will transition to commercial drug product will have an EOS visit once BCX7353 
is commercially available at each site. Subjects who transition to commercial BCX7353 will not 
need to return 3 weeks after their last dose of study drug. These assessments will also be 
conducted at an Early Termination Visit for those withdrawing consent (see Section 8.3.1): 
• Subject weight 
• Targeted physical examination 


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• Vital signs (blood pressure and pulse rate) 
• 12-lead ECG 
• Blood collection for clinical chemistry, hematology, coagulation, troponin I and 
troponin T, NGAL, and CK-MB 
• Urine collection for urinalysis, possible reflex testing for abnormal GGT, and urine 
pregnancy test for all female subjects of childbearing potential 
• Review of concomitant medications and AEs 
• Review and collection of e-diary 
• Blood for plasma PD and PK concentration analysis (early termination visit before 
Week 52 only) 
If an AE is ongoing at the last follow-up visit, additional clinic visit(s) or telephone contact(s) 
may be warranted (see Section 12.1.2). 
11. 
ASSESSMENTS 
The schedule of procedures and assessments to be conducted throughout the study are outlined in 
Table 2, Table 3, and Table 4 (for Parts 1, 2, and 3, respectively), with details on the conduct of 
the procedures/assessments provided below.  
Assessments in the study are intended to be conducted in-clinic; they may be conducted remotely 
under extenuating circumstances (eg, COVID-19 restrictions), which will be determined 
individually for each site and/or subject. At a minimum, a subject must be contacted to assess 
whether he or she has experienced any changes in his or her physical health or concomitant 
medications, and to review the adequacy of his or her existing study drug supply. If drug 
dispensation in-clinic is not possible, study drug may be delivered to the subject by other means 
(eg, traceable courier) as described in Section 9.4. 
11.1. 
Chronology of Assessments 
The following chronology of events should be adhered to during the scheduled visits, as 
applicable: 
• QoL/health outcome questionnaires: obtain prior to all clinic procedures 
• ECGs: obtain prior to vital signs and blood specimen collection 
• Vital signs: obtain prior to blood specimen collection 
• Randomization and study drug dispensing/dosing: end of the visit 
11.2. 
Investigator-Completed Assessments 
Demographic information, including year of birth, sex, race, and ethnicity will be captured for 
each subject participating in the study at the screening visit. Medical and medication history will 
be captured at the screening visit and updated at baseline.  


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Contraceptive methods enabling eligibility will be captured in source documentation at the 
screening visit. Contraceptive methods and/or lifestyle should be reviewed throughout the study 
to ensure they remain appropriate for the subject.  
11.2.1. 
HAE Medical and Medication History 
An HAE medical history questionnaire provided by the sponsor will be completed at screening. 
All questions should be completed by the investigator (or designee) from historical source 
documentation when available, with subject input as necessary to complete the remaining 
questions. The completed HAE Medical History Questionnaire will be considered a source 
document and must be entered in the eCRF in full to enable randomization (see Section 9.3.2). 
11.2.2. 
Physical Examination 
A full physical examination will be conducted at screening, baseline, and at Week 24. All other 
physical examinations will be abbreviated (ie, targeted or symptom-directed) to include, at a 
minimum, evaluation of any new signs or symptoms.  
Genitourinary and breast examinations may be omitted when not required by normal site 
practice. 
11.2.3. 
Weight/Body Mass Index 
For determination of height and weight, subjects should be clothed with shoes removed.  
BMI should be calculated using the following formula: 
BMI = weight (kg)/height (m)2 
BMI and height are only to be captured at the screening visit. 
11.2.4. 
12-lead Electrocardiograms  
A standard bedside or routine 12-lead ECG machine that calculates heart rate and measures the 
PR, QRS, QT, RR, and QTc (QTcF) intervals will be utilized. Prior to obtaining an ECG, 
subjects should rest quietly in a supine position for at least 10 minutes. 
Qualified site personnel should review the ECGs and automated findings in real-time for gross 
abnormalities and interval measurements of concern (absolute readings and for postbaseline 
ECGs, a change from baseline). For all ECGs, the clinical interpretation of the ECG and 
calculated QTcF (including adjudication of any automated interval measurements or diagnoses) 
should be recorded directly on a hard copy of the ECGs. Copies of the ECGs may be requested 
by the sponsor. All subject identifiers will be masked prior to provision to the sponsor. 
Baseline (predose) and Week 24 ECGs will be obtained in triplicate (ie, 3 separate readings 
taken at 1- to 5-minute intervals), with baseline values calculated from an average of the 
3 readings. All other ECGs will be single assessments.  
An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval 
> 500 msec. 


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11.2.5. 
Vital Signs 
Blood pressure (systolic and diastolic) and pulse rate should be taken after the subject has rested 
in the supine position for at least 5 minutes. Blood pressure measurements must be obtained with 
an appropriate cuff size and with the subject’s arm supported at the level of the heart. It is 
acceptable to obtain a pulse rate from the blood pressure or ECG machine. Temperature and 
respiratory rate will be captured at screening, baseline, and Week 24 only. 
11.2.6. 
Clinical Laboratory Evaluations 
Blood and urine samples will be obtained per the schedule of events. Individual laboratory tests 
to be performed are provided in Table 5.  
All laboratory samples will be collected using kit supplies provided by the central laboratory, 
which will also analyze all samples, with the possible exception of Week 2 and Week 26 liver 
function assessments, which may be drawn and resulted locally. If results are obtained from both 
central and local laboratories for the same assessments at a single time point, only the central 
laboratory results will be used for study purposes. Additionally, urine pregnancy tests will be 
provided by the central laboratory but will be analyzed at the clinical site. A laboratory reference 
manual will be provided to the site detailing kit contents, reordering instructions, subject fasting 
requirements (if any), sample collection, handling, storage, and shipment.  
Results from the laboratory values should be reviewed as received by the investigator. Evidence 
of this review should be provided in the source records and may include printing of the 
laboratory reports with a signature attesting to a review. For out-of-range laboratory findings, the 
interpretation of clinically significant or not clinically significant should be denoted in the source 
records. Clinically significant laboratory findings in the opinion of the investigator should be 
recorded as an AE and handled as described in Section 12.1. 


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Table 5: 
Clinical Laboratory Evaluations 
Chemistry 
Coagulation 
• Albumin 
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Bilirubin (total and direct) 
• Blood glucose   
• Blood urea nitrogen (BUN) 
• Electrolytes (calcium, sodium, potassium, 
chloride, phosphorus)  
• Lipid panel (total cholesterol, triglycerides) 
• Creatine kinase 
• Creatinine and calculated CLCR 
• Gamma-glutamyltransferase (GGT) 
• Lactate dehydrogenase (LDH) 
• Total serum protein 
• Uric acid 
• Amylase 
• If amylase is > 2 × ULN, reflex to lipase 
• Prothrombin time (PT) and international normalized 
ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
Pregnancy Test 
Serum (screening) and urine (other scheduled visits) 
β-hCG for women of childbearing potential (including 
adolescents) only  
Drug screen  
• Amphetamines 
• Barbiturates 
• Benzodiazepines 
• Cocaine 
• Opiates 
• Methamphetamine 
• Ecstasy 
Urinalysis 
• Specific gravity 
• Blood  
• Bilirubin 
• Glucose  
• Leukocytes 
• Ketones 
• Nitrites 
• pH 
• Protein 
• Urobilinogen 
• Microalbumin to creatinine ratio 
• Reflex microscopy if dipstick is abnormal  
Additional Tests 
• FSH for women postmenopausal ≤ 2 years 
• Hepatitis B surface antigen, hepatitis C antibody, 
HIV antibody; if HCV antibody positive, reflex to 
HCV RNA testing 
• Troponin I 
• Troponin T 
• Neutrophil gelatinase-associated lipocalin (NGAL) 
• CK-MB 
• C3 
• HLA typing 
• Sample for possible exploratory pharmacogenomic 
analysis (optional) 
• C1-INH functional level 
• C1-INH antigenic level 
• C4 
• If GGT, AST, or ALT is ≥ 3 × ULN, reflex to 
carbohydrate deficient transferrin (CDT) 
• If GGT, AST, or ALT is ≥ 3 × ULN, reflex to urinary 
ethyl glucuronide 
Hematology 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration 
(MCHC) 
• Mean corpuscular volume (MCV) 
• White blood cell count, with differential 
(lymphocytes, monocytes, neutrophils, 
eosinophils, and basophils) 
• Platelets 
CLCR will be calculated using the Cockcroft-Gault formula and absolute body weight (ABW): 
CLCR (mL/min) = (140 – age in years) × ABW (kg) (× 0.85 for females) 
72 × serum creatinine (in mg/dL) 


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11.2.7. 
Screening for Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C 
Serology  
Blood samples will be collected at screening for serologic testing for evidence of HIV, chronic 
hepatitis B, and chronic hepatitis C infection. 
11.2.8. 
HLA Typing 
All subjects will have a blood sample drawn at baseline (or any other time point on study if not 
obtained at baseline) for HLA typing. Samples will be sent to a central laboratory for analysis. 
The results will not be communicated back to the investigator or subjects because the results are 
not intended for diagnostic or prognostic purposes and will be used in a research-related fashion 
only. Relationships between safety assessment findings and HLA typing results may be 
examined on a meta-study basis. 
11.2.9. 
Pregnancy Testing 
FSH will be measured at screening in women declaring themselves postmenopausal ≤ 2 years to 
establish childbearing status. At screening, a serum pregnancy test should also be drawn in the 
event a woman subject postmenopausal ≤ 2 years is found to be of childbearing potential. 
For all women and adolescents of childbearing potential, a serum pregnancy test will be 
administered at screening. This will be done regardless of contraceptive or lifestyle choice 
(ie, those choosing not to engage in heterosexual activity or exclusively having female partners). 
Urine pregnancy tests will be assessed at all subsequent visits. A serum pregnancy test should 
immediately be drawn and sent for analysis for any positive urine pregnancy test. 
Urine pregnancy tests will be provided by the central laboratory but will be resulted locally.  
11.2.10. 
HAE Diagnostic Confirmation 
C1-INH functional level and C4 are to be drawn at the screening visit; it is recommended that 
samples not be drawn within 3 days of C1-INH administration (as used for treatment of an 
angioedema event). Last use of C1-INH for treatment of an angioedema event prior to this 
measurement should be denoted in the eCRF. 
If a subject has a normal C4 level (as is the case in a small percentage of subjects with HAE) 
drawn at the screening visit, the site may take another C4 level during an angioedema event. 
A normal C4 level drawn during an angioedema event excludes the subject from study 
participation. 
Alternatively, the site may also utilize SERPING-1 gene mutational analysis or a family history 
of C1-INH deficiency in the case of a normal C4 level. To utilize a family history of C1-INH 
deficiency to establish an HAE diagnosis for eligibility, the investigator should document this as 
a source file note based on either the investigator’s personal knowledge (ie, if a relative of the 
screening subject is also a patient of the same investigator/practice) or interaction with medical 
staff of the treatment facility where the relative receives HAE care, who confirms the diagnosis. 
No historical laboratory documentation on the relative should be collected in the source 
documents. A SERPING-1 mutation known or likely to be associated with HAE Type 1 or 2 
HAE is acceptable to confirm the diagnosis of HAE. A SERPING-1 analysis that does not 


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identify a likely or pathologic mutation indicative of HAE excludes the subject from study 
participation. 
For a C1-INH that is between 50% and the LLN (74%), the site may draw another C1 INH 
functional level or, if desired, have a SERPING-1 gene mutational analysis performed. 
A C1-INH functional level < 50% or a SERPING-1 mutation known or likely to be associated 
with HAE Type 1 or 2 HAE is acceptable to confirm the diagnosis of HAE. A SERPING-1 
analysis that does not identify a likely or pathologic mutation indicative of HAE excludes the 
subject from study participation. 
SERPING-1 gene analysis results indicating a “possibly pathogenic” mutation will be considered 
on a case-by-case basis by the medical monitor and may require additional testing for eligibility. 
Blood for possible SERPING-1 gene sequencing may be drawn at the screening visit or during 
the period between screening and baseline, but analyzed only if required (normal C4 at screening 
or a C1-INH level between 50% and the LLN [74%]). 
11.2.11. 
Other Laboratory Assessments 
Troponin I, troponin T, NGAL, and CK-MB will be measured in this study at baseline, at 
on-treatment visits (except for Weeks 2 and 26), and at follow-up.  
C3 level will be taken at baseline and subsequently only if required for a study drug-related rash 
(see Section 11.2.14) 
A C1-INH antigenic level will be measured at screening; last use of C1-INH for treatment of an 
angioedema event prior to this measurement should be denoted in the eCRF. 
11.2.12. 
Pharmacokinetics and Pharmacodynamics  
All plasma samples for determination of BCX7353 will be analyzed using a validated liquid 
chromatography-mass spectroscopy assay. The analysis of PK concentration samples obtained 
from subjects randomized to placebo may be limited. The bioanalytical laboratory performing 
the analysis may be given the randomization scheme prior to unblinding to avoid analysis of 
subjects who received placebo. 
Blood samples for PK and kallikrein inhibition will be drawn on all subjects at baseline and 
subsequent visits through Week 52 (except Weeks 2 and 26).  
The samples ordinarily can be drawn at any time post-dose; however, during Part 1, at least 
1 sample should be drawn at the approximate Cmax of the drug, approximately 3 to 6 hours 
post-dose. Actual date and time of sample collection will be recorded in the eCRF. Sites will 
ensure that the time of the previous dose prior to the blood draw is recorded in the e-diary 
(may also be captured in the eCRF).  
Instructions for collection, processing, storage, and shipment of PK and PD samples will be 
provided to the clinical site in a separate document. 
11.2.13. 
Pharmacogenomic Testing 
All subjects who are willing to participate and sign a separate informed consent will have a blood 
sample drawn at baseline (or any other time point on study if not obtained at baseline) for 
possible exploratory pharmacogenomics testing. Testing may be undertaken in 1 or more 


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locus/loci if desired by the sponsor to examine whether allelic variations account for efficacy or 
safety findings. Samples will be sent to a central laboratory for analysis and results will not be 
returned to sites. 
Possible SERPING genetic analysis is discussed in Section 11.2.10.  
11.2.14. 
Rash Assessment 
Because of the potential for a study drug-related rash, all sites are required to have the ability to 
obtain high resolution photographs. In addition, it is preferable that sites have the ability to 
obtain or to refer to a specialist who can obtain an appropriate skin biopsy. All subjects should be 
instructed to call the site for any new skin rash. Photos may be sent by the subject to the 
investigator to help determine the need for urgent medical assessment at the site. 
Subjects should be medically evaluated within 24 to 36 hours of awareness of any diffuse 
maculopapular rash that could be drug related. Rashes that resolve within 24 to 36 hours and 
therefore cannot be medically evaluated will not result in a protocol deviation. In the event the 
site is notified of a rash by a subject on the weekend, the medical evaluation and sponsor 
notification can be performed on the next working day. The site must inform the sponsor medical 
monitor via the EOSI form of all BCX7353-related maculopapular rashes (Section 12.1.5.1). If 
the rash is assessed as not maculo-papular (eg, urticarial) or not related to BCX7353 (ie, has a 
clear alternative etiology), then the rash is reported as an AE, treated per investigator judgement, 
and no further special assessment is required. 
The following assessments must be completed for all subjects with a diffuse maculopapular rash 
assessed as related to BCX7353, as soon as logistically possible:  
• Full dermatological exam to include the scope of the rash (location), vital signs, and 
mucosal examination. The notes documenting the examination should include 
detailed description of the rash; presence or absence of desquamation; presence or 
absence of blistering and if present, its extent; presence or absence of mucosal 
involvement and if present, its extent; and any other associated abnormal physical 
findings.  
• High resolution photographs taken to provide both detail regarding the rash and 
details regarding the extent of the rash. Cameras must be able to provide clear images 
taken in close proximity to the skin. The picture should include a ruler (centimeter) 
for scale. Every attempt to protect subject anonymity should be made. 
• All detailed clinical information regarding the rash, examination, treatment, and 
interpretation of the event needs to be reported on an SAE/EOSI Report form as per 
Section 12.1.5.1. 
• Blood taken for clinical chemistry, hematology including differential, and C3 level. 
Table 5 outlines the clinical chemistry and hematology analytes to be assessed. If the 
investigator desires more rapid results, a second set of blood tubes may be sent to the 
local laboratory for faster processing. 
• Vital signs including temperature 
• Urine sent to local laboratory for urine eosinophils (if evaluation is available locally).  


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• While not mandated, subjects should be requested to undergo a standard dermatologic 
punch biopsy for hematoxylin and eosin (H&E) staining and immunofixation. The 
biopsy should be obtained from a fresh lesion for diagnostic and scientific purposes, 
after obtaining specific informed consent from the subject. This type of biopsy 
requires only antisepsis and local anesthesia, without the need for sutures. The biopsy 
results will significantly help to clarify the underlying pathophysiology of the rash 
and more fully inform the benefit-risk assessment and ultimate therapeutic course. If 
the study site cannot perform a biopsy or any of the above mandatory assessments (ie, 
photographs), then subjects should be referred to a physician who can perform the 
assessments/biopsy (ie, a dermatologist). If a nonstudy physician performs any of the 
assessments or biopsy, a full written consultation report should be obtained 
expeditiously and include clinical examination findings and clinical diagnostic 
assessment. Biopsies should be at least 3 mm minimum diameter. Instructions for 
preparation of the samples and details regarding histopathological assessment will be 
communicated to the study sites. Note: If the rash is no longer present by the time of 
medical evaluation, biopsy is not necessary. In addition, if the rash is classically 
urticarial, biopsy is not necessary.  
If a subject with drug-related treatment-emergent rash does not agree to undergo skin 
punch biopsy, study drug dosing may be continued if clinical benefit is being derived 
but the subject must undergo weekly monitoring until the rash resolves to assess for 
any worsening of symptoms, particularly mucosal involvement or systemic 
symptoms.  
Subjects will also be required to donate a blood sample for peripheral blood mononuclear cells 
(PBMCs) for analysis of possible drug-specific immune responses and possible drug-responsive 
T-cells. This sample should be obtained preferably 1 to 3 months but as late as 5 years after 
occurrence of the rash. Information on PBMC collection, processing, and shipment will be 
communicated to sites prior to sample collection. All additional detailed clinical information 
regarding the rash, examination, treatment, and interpretation of the event needs to be reported 
on the SAE/EOSI Report form as per Section 12.1.5.1. 
11.2.15. 
Adverse Events 
AEs will be assessed and recorded from the time that the ICF is signed through the last visit or 
until the AE is resolved or the subject is in a clinically stable condition with regards to the AE. 
Full details on recording and reporting AEs are provided in Section 12.1.2. 
11.3. 
Patient-Reported Outcomes 
The AE-QoL, TSQM, and WPAI will each be administered once at baseline (pre-dose) and at 
Weeks 4, 8, 12, 18, 24, 28, 32, 36, 48, 52, 60, 72, 84, 96, and 104.  
The EQ-5D-5L will be administered once at baseline (pre-dose) and at Weeks 4, 8, 12, 18, 24, 
28, 32, 36, 48, 52, 60, 72, 84, 96, and 104. Subjects will fill out this questionnaire as instructed, 
describing their current health state today. During the on-treatment visits post-baseline, subjects 
will fill out a second EQ-5D-5L questionnaire if they have had an angioedema event since the 
previous visit. The subject will be instructed to fill out this second questionnaire based on a 


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recollection of his or her health state during an average angioedema event that they experienced 
since the previous visit. 
Each questionnaire will be translated into Japanese. For all subject-completed forms, clinic staff 
should ensure the subject reads the instructions and completes the questionnaires in full prior to 
filling in the source documentation. For the baseline TSQM, separate guidance will be provided 
such that subjects complete their assessment with reference to their satisfaction with their usual 
standard of care treatment of HAE, prior to screening for the study. 
Where possible, the questionnaires should be completed by the subject prior to other assessments 
for that visit to prevent influencing subject perceptions. 
11.4. 
Angioedema Events and Dosing e-Diary, Investigator Event 
Follow-up and Confirmation 
The sponsor will supply e-diaries to sites. Study-specific manuals will be prepared for both site 
staff and subjects for use of the e-diary for this study. 
While a subject has an e-diary in his or her possession, the subject will fill out the angioedema 
event e-diary daily, recalling whether or not symptoms of an angioedema event were experienced 
in the previous 24 hours. Subjects will fill out the e-diary regardless of the presence of HAE 
symptoms. If the subject does report an angioedema event, additional details about the 
angioedema event will be entered into the e-diary including start and stop time of the 
angioedema event, angioedema event symptoms, anatomical location of swelling (if applicable), 
severity, treatment(s) administered and times of administration, and whether additional medical 
care was sought for the angioedema event. During study drug administration in Parts 1 and 2, 
subjects will also record the times of day study drug was taken in the e-diary on a daily basis.  
All subjects will fill out an HAE e-diary during the run-in period of 56 consecutive days from the 
screening visit to enable the qualifying angioedema event rate to be established. Subjects will 
continue to fill out their e-diary after the run-in period in advance of the baseline visit. Subjects 
will continue to fill out the e-diary daily during the treatment and follow-up periods. 
Site staff will set up the e-diary when a subject is initially provided an e-diary at the screening 
visit and then as needed during the study (eg, to end Part 1/begin Part 2 or to end Part 2/begin 
Part 3). Subjects should be instructed to bring their e-diary with them to each study visit, up to 
and including Week 104, except Weeks 2 and 26. Once a subject completes or discontinues the 
study, the site should ensure that e-diaries are returned.  
Given that real-time access to e-diary entries for subjects is available via website access, the 
investigator (or designee) will proactively assess compliance, beginning during the screening 
period. Further training on completing the e-diary should be provided if e-diary completion 
compliance is < 90% at any point that during the study. A phone call may be necessary if 
compliance issues are noted in between clinic visits. Scheduled phone calls during the screening 
period and through Part 1 of the study to Week 24 are required to assess the subject’s overall 
wellbeing, discuss compliance (if applicable), proper recording of angioedema event details (if 
applicable), or any usability issues with the e-diary. 
Study staff are not permitted to make any entries into the e-diary and are not permitted to change 
entries.  


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In the event that a subject’s e-diary becomes nonfunctional or is otherwise not available for data 
recording, a paper diary may be utilized for short-term angioedema event and dose recording 
until the subject receives a replacement e-diary. Other scenarios for which the use of the paper 
diary and/or the shipment of a replacement e-diary may be permitted, following consultation 
with the sponsor. During the period of paper diary use, it will be necessary for the subject to 
contact the investigator after each angioedema event that occurs. 
Subjects who discontinue study drug should continue to record the occurrence of angioedema 
events in their e-diary until the follow-up visit. 
11.4.1. 
Screening and Parts 1 and 2 
11.4.1.1. Investigator Follow-up of Angioedema Events and Expert Confirmation of 
Angioedema Events 
Sites will have real-time access to e-diary entries for their subjects, including all angioedema 
event details recorded, and will receive a notification for each angioedema event that is recorded.   
For all angioedema events that are recorded from screening through the end of Part 2, the 
investigator (or appropriately-trained designee) will review the e-diary record of the angioedema 
event details. Subjects will then be contacted within approximately 2 business days of the end of 
the angioedema event to discuss the clinical characteristics of the angioedema event and any 
questions the investigator has on the entered data, or to gain additional angioedema event details 
not included in the e-diary that the investigator deems important to clinically evaluate the event, 
as applicable. The investigator-collected information, in conjunction with the e-diary record, will 
be used by an independent expert to verify or reject each event recorded in the e-diary as a 
confirmed angioedema event.  
The investigator e-diary data review and subject contact summaries will be documented in the 
source records and made available to an independent expert for their verification (confirmation 
or rejection) of the event. 
During the run-in period of 56 days beginning at the screening visit, angioedema events used to 
establish eligibility must meet the following stipulations, in addition to expert confirmation that 
the recorded event is an angioedema event: 
• The angioedema events are unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform his or her 
daily activities without restriction (ie, subject records that he or she is at least slightly 
restricted in daily activities during the angioedema event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
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During the entire screening period (run-in period and the period after eligibility has been 
established during the run-in period but prior to randomization), angioedema events must meet 
the following stipulations to be counted in the baseline angioedema event rate calculation 
necessary for stratification, in addition to the expert confirmation: 
• The angioedema events are unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema event must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform his or her 
daily activities without restriction (ie, subject records that he or she is at least slightly 
restricted in his or her daily activities during the angioedema event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
After randomization through the end of Part 2, the expert will use their judgment to confirm or 
reject a reported event as an angioedema event; however, all angioedema events must include 
symptoms of swelling. The expert will consider that symptoms of swelling, in addition to visible 
swelling, may also include symptoms in the oropharyngeal or abdominal regions that are 
indicative of internal swelling. 
The selection of the independent expert(s) who will confirm or reject attacks will be made by the 
sponsor and may or may not be an investigator in the current study. Expert expectations for 
turn-around times of the event confirmation or rejection and how the event confirmation or 
rejection will be received by the investigator and site staff, especially in the period between 
screening and baseline, will be communicated separately. 
11.4.1.2. Scheduled Telephone Contact 
The investigator (or designee) must call and talk to the subject once weekly during Part 1 and 
during Part 2 at Weeks 40 and 44. Alternative forms of interactive communication such as 
returned email and cellular text correspondence are acceptable. During all calls, the investigator 
(or designee) will assess the subject’s overall wellbeing, discuss compliance (if applicable), 
proper recording of angioedema event details (if applicable), or any usability issues with the 
e-diary. The phone call may be omitted if the subject records an angioedema event, as the 
investigator must call and confirm or reject the angioedema event. 
11.4.2. 
Part 3 
11.4.2.1. Confirmation of Angioedema Events 
Subjects will continue to document all angioedema events that occur in their e-diary throughout 
Part 3. Investigator follow-up of angioedema events and expert confirmation of events will not 
be required for Part 3. All angioedema events recorded by the subjects will be reviewed and 
confirmed or rejected according to a set of pre-defined rules prior to inclusion in effectiveness 
analyses. These rules will be outlined in the SAP. 


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11.4.2.2. Scheduled Telephone Contact 
The investigator (or designee) must call and talk to the subject once during Weeks 56, 64, 68, 76, 
80, 88, 92, and 100. If needed, additional telephone contacts will be conducted at 4-week 
intervals post-Week 104 to allow the subjects to continue treatment with BCX7353 until 
commercially available. Alternative forms of interactive communication such as returned email 
and cellular text correspondence are acceptable. During all calls, the investigator (or designee) 
will assess the subject’s overall wellbeing and proper recording of angioedema event details 
(if applicable). 
12. 
ADVERSE EVENT MANAGEMENT AND REPORTING 
12.1. 
Adverse Events 
AEs will be assessed and recorded from the time of signing of the informed consent through the 
appropriate follow-up period.  
12.1.1. 
Definitions 
12.1.1.1. Adverse Event  
An AE is any untoward medical occurrence in a clinical study subject. No causal relationship 
with the study drug or with the clinical study itself is implied. An AE may be an unfavorable and 
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical 
study. Clinically relevant abnormal results of diagnostic procedures including abnormal 
laboratory findings (eg, requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be AEs. If the diagnostic procedure 
prompts no additional treatment, visits, or monitoring, it will not meet the definition of an 
adverse event. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period (see Section 12.1.2), including medical triggers resulting in an 
angioedema event. Emotional stress will not be considered an AE unless it results in a 
medical diagnosis or requires medical treatment.  
• Findings from protocol-mandated interventions. This can include laboratory 
assessments performed in the course of the clinical trial. AEs should be reported only 
if the abnormalities are changes from baseline and are clinically significant as 
described above. 
• Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. When recording such events on an 
AE/SAE eCRF page, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (eg, “more frequent 
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An adverse reaction is defined in Article 2(n) of Directive 2001/20/EC as follows: all untoward 
and unintended responses to a study drug/IMP related to any dose administered. The definition 
covers also medication errors and uses outside what is foreseen in the protocol, including misuse 
and abuse of the product. The definition implies a reasonable possibility of a causal relationship 
between the event and the study drug/IMP. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
For the purposes of this protocol, angioedema events and their associated symptoms will not be 
defined as AEs, even if the subject requires hospitalization. This information, as well as all HAE 
attacks and associated symptoms, are reported in the subject’s e-diary and is a reflection of the 
disease under study. The events that may trigger an angioedema event such as an infection or 
trauma are considered AEs and should be reported as such. 
Hospitalization scenarios do not require reporting as an SAE where there is no occurrence of an 
AE. These scenarios include a planned hospitalization or prolonged hospitalization to: 
• Perform a routine control screening for a preexisting illness or to diagnose a 
suspected illness. In the case of the latter, the symptomatology should be reported as 
an AE and amended if a diagnosis is confirmed. 
• Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed (eg, a joint replacement for which the subject was on a 
waiting list). 
• Undergo medical observation due to HAE (eg, admission after routine dental 
procedure in an HAE patient). 
• Undergo medical observation without the occurrence of an AE due to standard of care 
in the region or hospital. 
Surgical procedures should not be reported as AEs. The condition for which the surgery is 
required should be reported as the AE, if it occurs or is detected during the study period. Planned 
surgical measures permitted by the clinical study protocol and the conditions(s) leading to these 
measures are not AEs, if the condition(s) was (were) known before the start of study treatment. 
In the latter case the condition should be reported as medical history. 
AEs are designated as “nonserious” or “serious.” 
12.1.1.2. Serious Adverse Event 
A SAE is an adverse event/reaction that results in any of the following outcomes: 
• Death 
• Is life-threatening (subject is at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe) 
• Requires subject hospitalization (formal admission to a hospital for medical reasons) 
or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (ie, there is a substantial 
disruption of a person's ability to carry out normal life functions) 


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• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject’s health or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. For this study, examples of such events may include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in subject hospitalization.  
In addition, the sponsor considers events of abortion (spontaneous or induced), fetal demise, and 
still birth as SAEs for reporting purposes. 
Some hospitalization scenarios, as outlined in Section 12.1.1.1, do not require reporting as SAEs. 
Overdose (> 1 dose per calendar day) will be considered an SAE only if any of the seriousness 
criteria are met. Any clinical complication in association with the overdose should be reported as 
an AE or SAE (as applicable) along with the overdose (see Section 12.2.3). Details of signs or 
symptoms, clinical management, and outcome should be reported, if available. Overdose without 
associated signs or symptoms should not be recorded as AEs but should be recorded as protocol 
deviations. 
12.1.1.3. Adverse Events of Special Interest 
For this protocol, treatment-emergent maculopapular rashes that are deemed related to BCX7353 
will be considered EOSIs. This does not include other types of rashes, such as urticaria or 
eczema. All treatment-emergent skin conditions should be reported as AEs but only 
maculopapular rashes deemed related to BCX7353 should be considered EOSIs.  
An EOSI event in and of itself will not be considered serious unless it meets the seriousness 
criteria above. Events of maculopapular rash assessed as possibly, probably, or definitely related 
to BCX7353 regardless of severity must be reported to the sponsor medical monitor as described 
in Section 12.1.5.1. Management of BCX7353 drug-related rash is provided in Section 12.2.1. 
12.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events 
Reports of all AEs and SAEs, regardless of investigator attribution, are to be collected from the 
time of signing of the informed consent through to the last study visit (ie, through the 
posttreatment follow-up visit). All AEs and SAEs are to be reported in the AE eCRF.  
AEs should be documented in the eCRF as investigators become aware of them. AEs are to be 
followed until the event resolves, as follows. If an event is ongoing at the last follow-up visit, 
Grade 1 and 2 events do not need to be followed if the event is deemed unlikely to be related or 
not related to study drug (see Section 12.1.3 for AE grading). For all Grade 3 and 4 events or 
events deemed at least possibly related to use of study drug, the event should be followed until 
the AE is resolved or the subject is in a clinically stable condition with regards to the AE. 
The investigator shall report all SAEs immediately to the sponsor by communicating with the 
medical monitor (phone or email) and by entering the event into the AE eCRF and by completion 
of the SAE eCRF within 24 hours of their knowledge of the event (see Section 12.1.5). The SAE 
eCRF form is an additional form to the AE eCRF that provides important details on the SAE. 


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The investigator should follow all unresolved SAEs observed during the study until they are 
resolved, or are judged medically stable, or are otherwise medically explained. 
The investigator should attempt, if possible, to establish a diagnosis based on the presenting 
signs and symptoms. In such cases, the diagnosis should be documented as the AE and not the 
individual sign/symptom. If a clear diagnosis cannot be established, each sign and symptom must 
be recorded individually. Once a diagnosis is made during evaluation or treatment, the 
investigator will update the AE record with this diagnosis by deleting the previous symptoms and 
entering the diagnosis. The rapid reporting of SAEs ensure that the sponsor shall have the 
necessary information to continuously assess the benefit-risk profile of the study drug in a 
clinical trial. 
12.1.3. 
Definition of Severity 
All AEs will be assessed (graded) for severity and classified using the DMID criteria for grading 
AEs (Publish date November, 2007; see Appendix 16.1). Any AEs not covered by the DMID 
criteria will be assessed and classified into 1 of 4 clearly defined categories as follows: 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required. The AE does not interfere with the participant’s normal 
functioning level. It may be an annoyance. 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; no or 
minimal intervention required. The AE produces some impairment of 
functioning, but it is not hazardous to health. It is uncomfortable or an 
embarrassment. 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; medical 
intervention may be required. The AE produces significant impairment of 
functioning or incapacitation. 
Life-
threatening: 
(Grade 4): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required to prevent death, 
hospitalization; or hospice care probable. 
Severity refers to the medical perspective of an event while seriousness reflects the outcome of 
the event (ie, hospitalization). Events of mild severity can lead to hospitalization and therefore be 
serious while severe events such as a headache may not meet seriousness criteria.  
12.1.4. 
Definition of Relationship to Study Drug 
The investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug using the following guidelines: 
Not Related: 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident, and no 
temporal relationship exists between the study drug and the event. 


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Unlikely: 
The event does not follow a reasonable temporal sequence from drug 
administration and is readily explained by the subject’s clinical state or by 
other modes of therapy administered to the subject. 
Possibly 
Related: 
There is some temporal relationship between the event and the administration 
of the study drug and the event is unlikely to be explained by the subject’s 
medical condition, other therapies, or accident. 
Probably 
Related: 
The event follows a reasonable temporal sequence from drug administration, 
abates upon discontinuation of the drug, and cannot be reasonably explained 
by the known characteristics of the subject’s clinical state. 
Definitely 
Related: 
The event follows a reasonable temporal sequence from study drug 
administration, follows a known or suspected response pattern to the study 
drug, is confirmed by improvement upon stopping the study drug 
(dechallenge), and reappears upon repeated exposure (rechallenge, if 
rechallenge is medically appropriate). 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions 
Any SAE must be reported by phone or email to the sponsor medical monitor and via the AE and 
SAE eCRFs within 24 hours of the investigator’s awareness of the SAE. All additional follow-up 
evaluations of the SAE must be reported to BioCryst or its designee as soon as they are available 
by amending these eCRFs. The SAE notification should be reported to:  
Phone (24 hours): +1 919-859-7905 
Email: safety@biocryst.com and mmj@biocryst.com  
In the event the eCRF system is not functioning, the reporting of an SAE must not be delayed. 
Sites will have SAE report forms (electronic Word document) that can be completed and emailed 
to the above recipients. As soon as the eCRF system is functioning, that particular SAE must be 
entered into the AE eCRF. The SAE eCRF for that particular event does not need to be 
completed if the site communicates all follow-up on the separate SAE report form that was 
initially completed. If the site wishes to enter follow-up information on the SAE via the SAE 
eCRF, then the SAE eCRF must be completed with the initial as well as the follow-up 
information.  
Immediate reporting should allow BioCryst to take the appropriate measures to address potential 
new risks in a clinical trial. Therefore, the initial report should be submitted by the investigator 
within a very short period of time and under no circumstances should this period exceed 24 hours 
following awareness of the SAE. 
The follow-up report should allow BioCryst to determine whether the SAE requires a 
reassessment of the benefit-risk profile of the study drug in a clinical trial, if the relevant 
information was not already available and provided in the initial report. 
Japan-specific rules and requirements for safety management will be described in the Safety and 
Medical Management Plan prepared for the current protocol.  


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BioCryst or its designee will submit all suspected unexpected serious adverse reaction (SUSAR) 
reports (initial and follow-up) or other safety information (eg, revised IB) to the required 
authorities. 
BioCryst or its designee shall ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the competent authorities in all 
ICH regions, and to the institutional review boards (IRBs) or independent ethics committees 
(IECs), and in any case no later than 7 days after knowledge by BioCryst of such a case, in 
accordance with all applicable local laws. All other SUSARs shall be reported to the competent 
authorities concerned and to the IRBs/IECs concerned as soon as possible but within a maximum 
of 15 days of first knowledge by BioCryst. BioCryst or designee shall also inform all 
investigators. Investigators are responsible for retaining a copy in their files, unless otherwise 
instructed. 
12.1.5.1. Reporting Adverse Events of Special Interest 
All skin disorders or abnormal findings of the skin are adverse events and should be reported in 
the usual manner on the eCRF as per Section 12.1.2. However, events of maculopapular rash 
assessed as related to study drug/IMP, regardless of severity, are considered to be EOSIs which 
require additional reporting. Any new maculo-papular rash assessed as related to the use of study 
drug must be reported to the sponsor medical monitor via the eCRFs, specifically both the AE 
eCRF and the SAE eCRF, within 24 hours of the investigator’s assessment of the event. 
The SAE eCRF will also serve as an EOSI Report form, although the rash event itself may not 
meet seriousness criteria. High resolution photographs must also be submitted via email as 
described in Section 11.2.14. All additional follow-up evaluations of the event must be reported 
to BioCryst or its designee as soon as they are available. The notification should be sent to the 
following email addresses:  
Phone (24 hours): +1 919-859-7905 
Email: safety@biocryst.com and mmj@biocryst.com  
In the event the eCRF system is not functioning, the reporting of an EOSI must not be delayed. 
Sites will have SAE/EOSI Report forms (electronic Word document) that can be completed and 
emailed to the above recipients. As soon as the eCRF is functioning, the EOSI must be entered 
into the AE eCRF. The SAE eCRF for that particular event does not need to be completed if the 
site communicates all follow-up on the separate SAE/EOSI Report form that was initially 
completed. If the site wishes to enter follow-up information on the EOSI via the SAE eCRF, then 
the SAE eCRF must be completed with the initial as well as the follow-up information.  
This method of reporting should allow BioCryst to obtain more information including a full 
clinical description and information regarding the evaluation. Therefore, the initial report and 
photographs should be submitted by the investigator within a very short period of time and under 
no circumstances should this period exceed 24 hours following assessment of the event.  
The follow-up report should contain information about the clinical course, medical evaluation, 
additional photographs (if relevant), biopsy (if done), and laboratory results. 


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12.1.6. 
Pregnancy 
Any female subject who becomes pregnant during the study should have study drug discontinued 
immediately and must be followed through the end of the pregnancy. While pregnancy is not 
considered an AE, all cases of fetal drug exposure via the parent as a study participant (including 
partners of study participants) are to be reported immediately to BioCryst or its designee. 
Consent from a pregnant partner of a study participant will be obtained prior to reporting any 
details of the pregnancy. Information related to the pregnancy must be given on a “Pregnancy 
Confirmation and Outcome” form that will be provided by the sponsor or its designee so that the 
pregnancy may be followed and an outcome determined. Any AEs or SAEs experienced by a 
pregnant subject are to be reported as directed above in Section 12.1.2 and Section 12.1.5. 
Any complications reported in a subject’s pregnant partner should be reported on the Pregnancy 
Confirmation and Outcome form. All pregnancies must be followed to outcome which occurs 
when an infant is delivered (live or still born), there is fetal demise, or there is an abortion 
(spontaneous or induced). Abortion (spontaneous or induced), fetal demise, and still birth along 
with congenital abnormalities in the newborn, should be reported as separate SAEs. 
12.1.7. 
Serious Breaches of Good Clinical Practice 
It is the responsibility of the sponsor to notify the licensing authority of any serious breach of 
Good Clinical Practice (GCP) that is likely to effect, to a significant degree, the safety or mental 
integrity of the subjects of the study or the scientific value of the study. All serious breaches will 
be reported to the relevant competent authority within 7 days. The reporting to the sponsor will 
be performed by the party who suspects the serious breach. 
12.1.8. 
Treatment Interruptions 
Treatment interruptions as a result of investigator management of AEs potentially related to 
study drug are permissible. Resumption of study drug administration is also permissible upon 
resolution of the event, as assessed by the investigator, with a plan for stringent monitoring of the 
subject for recurrence of the AE as appropriate. In addition, other extenuating circumstances may 
lead to treatment interruptions such as vomiting during an abdominal angioedema event or 
required fasting for medical procedures; in these cases, study drug should be resumed once the 
extenuating circumstance is resolved. Treatment interruptions following suspected drug-related 
rashes are discussed in Section 12.2.1. 
The sponsor medical monitor should be notified in the event of a treatment interruption due to an 
AE. Any treatment interruption will be recorded in the eCRF and source documents, including 
the reason for the interruption. 
12.1.9. 
Emergency Procedures 
Access to study drug/IMP assignment will be available immediately through the IXRS system if 
the investigator deems it necessary to break the study blind in the interest of a subject’s medical 
safety, in case of a medical emergency, to meet regulatory reporting obligations, or if warranted 
during scheduled safety reviews. Where medically appropriate, the investigator will contact the 
sponsor medical monitor to discuss the situation that has arisen and resulted in the need for 
unblinding of the subject. The sponsor medical monitor will not be involved in the decision to 
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12.2. 
Adverse Event Management 
The investigator (or qualified designee) will grade clinically significant events and laboratory 
abnormalities according to that detailed in Section 12.1.3. Grade 3 and 4 clinically significant 
laboratory abnormalities should be confirmed by repeat testing and before any contemplated 
study drug discontinuation, unless such a delay is not consistent with good medical practice. 
In the event that a new clinically significant safety signal emerges, a meeting of the DMC may 
be convened by the sponsor to evaluate risk to subjects and recommend appropriate actions. 
Based on the data presented, a decision will be made as to whether to halt the study, to continue 
dosing, or to continue dosing with provisions introduced into the protocol via substantial 
amendment. 
12.2.1. 
Rash 
Special evaluation of maculopapular drug rash is required as per Section 11.2.14 and special 
reporting is described in Section 12.1.5.1.  
Management of rash should be based on best medical practice and address the subject’s 
presentation. If a subject experiences a Grade 3 or 4 rash suspected to be due to study drug/IMP, 
the subject should have study drug/IMP dosing stopped immediately as per Section 8.3.2. 
Grade 3 rashes would include rashes with vesiculation, moist desquamation, or ulceration, and 
Grade 4 rashes would encompass rashes with mucous membrane involvement or significant 
exfoliation, erythema multiforme, suspected Stevens-Johnson syndrome, or necrosis requiring 
surgery. 
12.2.1.1. Study Drug Administration for Grade 1 or 2 Rashes Considered Related to 
Study Drug 
Investigators and subjects may elect to continue dosing if the subject experiences a Grade 1 or 2 
rash that is deemed related to BCX7353 but the subject is considered to be deriving benefit. 
By DMID criteria, this reaction would be described as pruritus and/or erythema (Grade 1), or a 
diffuse maculo-papular rash and/or dry desquamation (Grade 2). In addition, subjects would have 
to be constitutionally well (no fever, no change in appetite, no malaise, etc), have no mucosal 
involvement, no vesicles and have no evidence of any hypersensitivity involving the liver or 
kidney. Mild or moderate eosinophilia may be present but should not prevent continuation of 
study drug if all other criteria are met. Rash treatment should primarily address symptoms (ie, 
anti-histamines, topical antipruritics and/or topical corticosteroids). Oral corticosteroids should 
be avoided, as there is no evidence that oral corticosteroids benefit patients with bland 
drug-related cutaneous reactions. 
If the subject’s rash does not improve, or worsens to include vesicles, wet desquamation, or 
ulceration (Grade 3), then BCX7353 should be immediately discontinued. Subjects who remain 
on study drug should be followed closely until the rash resolves. 
12.2.2. 
Aminotransferase (ALT or AST) Elevation  
All baseline or treatment-emergent ALT or AST elevations > 3 × ULN (ie, Grade 3 and above) 
should be confirmed within 72 hours with repeat assessment of ALT and AST as well as total 
bilirubin, ALP, prothrombin time/INR, and complete blood count for eosinophil levels. 


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If subjects are asymptomatic with no other pertinent laboratory abnormality, study drug may be 
continued under close observation with weekly assessment of transaminase levels, total bilirubin, 
and ALP. These may be done at a local laboratory as long as results are reported to the 
investigator when available and the investigative site contacts the subject to ascertain any 
symptoms. If either ALT or AST continue to increase and the subject remains asymptomatic, 
study drug must be held if: 
• Either ALT or AST is > 5 × ULN for more than 2 weeks, or 
• ALT or AST reaches > 8 × ULN. 
The subject should continue regular assessments of ALT, AST, total bilirubin, ALP, prothrombin 
time/INR, and complete blood count for eosinophil levels, as deemed appropriate by the 
investigator, until ALT and/or AST are < 3 × ULN. 
Provided specific criteria are met, the investigator and subject may elect to resume BCX7353 
dosing. All of the following criteria must be met for dosing to resume: 
• The subject is considered to have been deriving benefit from BCX7353 prior to 
holding study drug. 
• Transaminases return to ≤ 2 × ULN for subjects whose baseline transaminase levels 
were above the ULN, and ≤ ULN for those whose baseline transaminase levels were 
≤ ULN. 
• Subjects have not initiated or restarted androgens during the period BCX7353 was 
held. 
• The subject agrees to continue weekly monitoring of ALT, AST, total bilirubin, ALP, 
complete blood count (eosinophil levels), and prothrombin/INR until levels appear 
stable and transaminase levels remain < 3 × ULN for at least 1 month after restarting 
BCX7353 dosing. 
If at any time, the criteria as outlined in Section 8.3.2 are met, the study drug must be 
permanently discontinued. 
12.2.3. 
Overdose 
To date there is no experience with overdose of oral BCX7353. Single doses of up to 1000 mg, 
7 days of dosing up to 500 mg/day, and 14 days of dosing with 350 mg/day revealed no 
clinically significant safety concerns in healthy subjects. Safety data generated in 
Study BCX7353-203 with 28-day dosing of up to 350 mg/day revealed no clinically significant 
safety concerns in subjects with HAE. Subsequently, subjects enrolled in BCX7353-106 were 
exposed to BCX7353 450 mg QD for 14 days without any unexpected AEs or increased AE 
severity. 
In the event that study personnel become aware of an overdose of study drug/IMP (> 1 dose per 
calendar day) that is associated with an AE, both the overdose and the resultant event should be 
reported as AEs. Overdose without any symptoms (ie, AEs) does not need to be reported as an 
AE. If overdose occurs with or without associated AEs, subjects should undergo clinical and 
laboratory monitoring as appropriate for their clinical condition and, if indicated, should receive 


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clinically-indicated supportive therapy. Overdose without associated signs or symptoms should 
not be recorded as an AE but should be recorded as a protocol deviation. 
Additional information about overdose as an AE or SAE is discussed in Section 12.1.1.2. 
12.3. 
Data Monitoring Committee 
Data from ongoing studies BCX7353-302 (Phase 3 study), BCX7353-204 (long-term safety 
study), and the current study (BCX7353-301) are reviewed by the BCX7353 DMC at defined 
time points. At the time of this amendment, the latest data review was conducted on 
16 April 2020 and the DMC recommended that all 3 studies continue per protocol. Since 
> 200 subjects have completed through 48 weeks across the studies, the DMC members will be 
provided with data for review every 6 months until the last subject completes the study or the 
product is approved in the first country globally. Each DMC member will provide his or her 
written assessment of the safety data; a formal meeting of the DMC members will not be 
required. However, if the data review identifies any concern, the DMC members may elect to 
hold a formal DMC meeting. Where possible, scheduled DMC meetings for this study may be 
aligned with those of other studies. The DMC may also be convened if a new clinically 
significant safety signal emerges or other times as requested. 
A separate DMC charter maintained in the trial master file will describe membership, roles, 
timing of DMC review, and responsibilities of the DMC members. 
13. 
STATISTICS 
13.1. 
Hypotheses 
13.1.1. 
Primary Hypotheses 
The primary study hypothesis is that the rate of angioedema events during 24 weeks of 
prophylactic BCX7353 (at either 150 mg or 110 mg QD) will be less than the corresponding rate 
on placebo.  
As the sample size considered feasible for enrollment in Japan has limited statistical power, 
hypothesis testing will be performed on a combined analysis of the current study with 
Study BCX7353-302. The hypothesis will be tested separately for each active dose, comparing to 
placebo treatment. 
The primary null and alternative hypotheses are: 
• Ho:  RA=RP; active treatment does not have a differential effect on the rate of 
investigator- or expert-confirmed angioedema events 
• HA:  RA≠RP; active treatment does have a differential effect on the rate of 
investigator- or expert-confirmed angioedema events 
where RA is the monthly angioedema event rate for active treatment and RP is the 
monthly angioedema event rate for placebo treatment. 
The primary efficacy endpoint in Study BCX7353-301 is the monthly expert-confirmed 
angioedema event rate in the entire treatment period (Day 1 [post dose] to Day 168) in the 


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intent-to-treat (ITT) population, which includes all randomized subjects. The primary efficacy 
endpoint in Study BCX7353-302 is the monthly investigator-confirmed angioedema event rate in 
the entire treatment period (Day 1 [post dose] to Day 168) in the ITT population, which includes 
all randomized subjects. 
The primary comparisons of interest will be performed at the 5% level of significance. 
All hypothesis tests will be 2-sided.  
13.1.2. 
Secondary Hypotheses 
For each dose separately, the following secondary hypotheses will be tested in a combined 
analysis of the current study with Study BCX7353-302: 
1. Proportion of days with angioedema symptoms 
• Ho:  β=0; active treatment does not have a differential effect on the proportion of days 
with angioedema symptoms over the entire treatment period 
• HA:  β≠0; active treatment does have a differential effect on the proportion of days 
with angioedema symptoms over the entire treatment period 
where β is the parameter representing treatment effect for the dose of interest in an 
analysis of covariance (ANCOVA) model. 
2. Rate of investigator- or expert-confirmed angioedema events during the effective treatment 
period (beginning on Day 8 through 24 weeks) 
• Ho:  RA=RP; active treatment does not have a differential effect on the rate of 
expert-confirmed angioedema events during the effective treatment period 
• HA:  RA≠RP; active treatment does have a differential effect on the rate of 
expert-confirmed angioedema events during the effective treatment period 
where RA is the monthly angioedema event rate for active treatment and RP is the 
monthly angioedema event rate for placebo treatment during the effective treatment 
period. 
3. AE-QoL 
• Ho:  β=0; active treatment does not have a differential effect on the change from 
baseline AE-QoL at Week 24 
• HA:  β≠0; active treatment does have a differential effect on the change from baseline 
AE-QoL at Week 24 
where β is the parameter representing treatment effect for the dose of interest in a mixed 
effect model for repeated measurements (MMRM). 
13.1.3. 
Controlling for Multiplicity 
There are 4 endpoints being tested in the combined analysis, the primary endpoint and 
3 secondary endpoints. For each endpoint, there are 2 potential doses to be tested. The Type I 
error rate will be controlled at the study level by using a combination of hierarchical testing and 
the Hochberg procedure. The 4 endpoints will be tested in a hierarchical fashion and the 2 doses 


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will be tested using the Hochberg step-up procedure at each level of the hierarchy to which both 
doses progress through the hierarchy. 
The first endpoint to be tested is the primary endpoint, the rate of investigator or 
expert-confirmed angioedema events during dosing in the entire 24-week treatment period 
(Days 1 to 168). Using the Hochberg step-up procedure, each of the 2 doses will be tested at the 
α = 0.05 level, comparing active treatment to placebo. If the maximum of the 2 p-values is 
≤ 0.05, the null hypotheses of no difference between the rate of angioedema events for subjects 
on active and placebo treatment will be rejected for both doses and testing will proceed to the 
next endpoint in the hierarchy with α = 0.05. If the maximum of the 2 p-values is > 0.05 but the 
minimum of the 2 p-values is < 0.025, the null hypothesis for the dose with p < 0.025 will be 
rejected and testing for that dose only will proceed to the next endpoint in the hierarchy with 
α = 0.025. Otherwise, the null hypotheses for both doses will not be rejected, testing will stop, 
and the hypothesis for the next endpoint in the hierarchy will not be tested. 
The second, third, and fourth endpoints in the hierarchy are: 
• Number and proportion of days with angioedema symptoms through 24 weeks 
• Rate of investigator- or expert-confirmed angioedema events during dosing in the 
effective treatment period (beginning on Day 8 through Week 24) 
• Change from baseline in AE-QoL at Week 24 (total score) 
The process described above will be continued for each endpoint in the hierarchy until either all 
4 endpoints have been tested or testing has stopped due to non-rejection of the null hypotheses 
for both doses for endpoints earlier in the hierarchy. At each level of the hierarchy, the Hochberg 
step-up procedure is used to control Type I error rates if 2 doses are to be tested. Otherwise, if 
only 1 dose is being tested, the single test is conducted with α = 0.025. 
13.2. 
Sample Size Considerations 
The planned sample size for the current study is 8 per treatment group for each of three treatment 
groups. The primary analysis will be conducted on the BCX7353-301 study population. It should 
be noted that the sample size considered feasible for enrollment in Japan has limited statistical 
power. Therefore, all efficacy data for Part 1, where appropriate, will also be analyzed by 
combining data from this study with data from Study BCX7353-302, to ensure adequate 
statistical power. For the combined analysis with Study BCX7353-302, the sample size is 
expected to be 40 subjects per treatment group. 
The assumptions underlying the sample size calculations for this study and the combined 
analysis of results from this study and BCX7353-302 are based on the results of 
Study BCX7353-203. In Study BCX7353-203, the mean weekly angioedema event rate during 
the effective dosing period (Days 8 to 29) for placebo subjects in the full analysis set was 0.939. 
The reduction in angioedema event rate during the effective dosing period for subjects receiving 
125 mg BCX7353 was 73.8%. The model-derived standard deviation (SD) of the weekly 
angioedema event rate was 0.487. Sample size calculations have been conducted using the 
weekly angioedema event rate to be consistent with Study BCX7353-203, although the monthly 
angioedema event rate will be reported for this study. The power calculations using the monthly 
angioedema event rate would be the same. 


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Power calculations for the primary efficacy endpoint for the current study alone and those for the 
combined analyses with Study BCX7353-302 are provided in Table 6 and described in 
Sections 13.2.1 and 13.2.2. 
Table 6: 
Power Calculations to Support Sample Size 
Study  
Sample 
Size Per 
Treatment 
Group  
Attack Rate 
for Placebo 
Subjects 
(attacks/week) 
Attack Rate 
for Active 
Treatment 
(attacks/week) 
Common 
SD for 
Attack 
Rate 
Type I 
Error 
Rate 
(α) 
Power for 
Pairwise 
Comparison 
with 
Placebo 
BCX7353-
301 alone 
8 
0.9 
0.3 
0.5 
0.05 
61% 
Combined 
BCX7353-
301 and  
BCX7353-
302 
40 
0.9 
0.3 
0.5 
0.05 
>99% 
Abbreviation: SD = standard deviation. 
13.2.1. 
Sample Size for Study BCX7353-301 Alone 
Assuming a weekly angioedema event rate for placebo subject of 0.9 and a common SD of 
0.50 angioedema events per week for BCX7353 and placebo and with 8 subjects per treatment 
group in the current study alone, the power to detect a ≥ 67% angioedema event rate reduction 
(a treatment difference of 0.6 angioedema events per week) for each comparison of angioedema 
events rates between active and placebo treatment would be 61%.  
13.2.2. 
Sample Size for the Combined Analysis of Studies BCX7353-301 and 
BCX7353-302 
Assuming a weekly angioedema event rate for placebo subject of 0.9 and a common SD of 
0.50 angioedema events per week for BCX7353 and placebo, a sample size of 120 subjects 
(40 per treatment group: 8 from BCX7353-301 and 32 from BCX7353-302) will provide > 99% 
power to detect a ≥ 67% angioedema event rate reduction (a treatment difference of 
0.6 angioedema events per week) between each BCX7353 active dose and placebo, based on a 
2-sided test at significance level of 0.05. To control for familywise type I error, the Hochberg 
step-up procedure will be used to adjust for the comparison of the active doses to placebo.  
13.3. 
Stratification 
Randomization of subjects will be stratified by the baseline expert-confirmed angioedema event 
rate (≥ 2 angioedema events per month vs. < 2 angioedema events per month). 
13.4. 
Statistical Methods 
A detailed SAP will be developed to describe in detail the methods of analyses. Deviations from 
the analyses outlined in the SAP will be described in the CSR.  


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13.4.1. 
Analysis Populations 
The analysis populations are defined below. 
13.4.1.1. Screen Failures 
Subjects who give informed consent but are not dispensed study medication are considered 
screen failures. Reason for screen failure will be summarized using this population. 
13.4.1.2. Intent-to-Treat Population 
The ITT population will include all subjects who are randomized. The ITT population will be 
used as the primary population for efficacy analyses. Subjects will be analyzed based on the 
treatment to which they were randomized. 
13.4.1.3. Safety Population 
The safety population will include all subjects who received at least 1 capsule of study drug. 
This population will be used for all analyses of accountability, demographics, BCX7353 drug 
concentrations, and safety. Subjects will be analyzed based on the actual treatment received at 
first dose for all subjects for Part 1 or at first dose of Part 2 for subjects originally randomized to 
placebo. 
13.4.1.4. Per Protocol Population 
The per protocol (PP) population will include a subset of subjects in the safety population that 
complete Part 1. A decision will be made prior to database lock on which (if any) subjects are to 
be excluded from the PP population based upon major protocol deviations. In the per-protocol 
analysis, subjects will be assessed based on the actual treatment received on Study Day 1 for 
Part 1 or at first dose of Part 2 for subjects originally randomized to placebo. The PP population 
may be used as a secondary population for efficacy analyses. 
13.4.1.5. Completers Population 
The subset of subjects in the ITT population who complete Part 1 of the study will comprise the 
Completers Population. The Completers Population will be used for a sensitivity analysis of the 
primary efficacy analysis for Part 1 only. Data will be analyzed according to randomized 
treatment. 
13.4.1.6. Pharmacodynamic Population 
The PD population for plasma kallikrein inhibition will include all subjects for whom at least 
1 pre- and post-dose plasma kallikrein inhibition result can be estimated. This population will be 
used for all analyses of plasma kallikrein inhibition. 
13.4.1.7.  PK Concentration/PD Population  
The PK concentration/PD population will include all subjects for whom at least 1 pre- and 
post-dose plasma kallikrein inhibition result can be estimated with a corresponding plasma 
BCX7353 concentration (placebo samples not analyzed will be assumed to have a zero 


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concentration). This population will be used for all correlation analyses of plasma kallikrein 
inhibition and plasma BCX7353 concentrations.  
13.4.2. 
General Considerations for Data Analysis 
Descriptive summaries, figures, and listings for efficacy, safety, concentration, and PD results 
will use data from subjects enrolled in this study alone. 
In general, descriptive summaries will include n, mean, SD, median, minimum, and maximum 
for continuous variables and n and percent for categorical variables. Summaries will be presented 
by study visit. 
Selected summaries will be repeated using data from the current study and BCX7353-302.  
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA). 
13.4.3. 
Subject Demographic and Disposition Data 
Demographic and disposition data will be summarized for the current study alone and using the 
combined data. 
Demographic data and baseline characteristics including age, gender, race and ethnicity, height, 
weight, BMI, and HAE history, including medication history, will be summarized by treatment 
group. 
Subject disposition will be presented for all subjects. The number of subjects who complete the 
study and those who discontinue from the study will be provided. The reasons for early 
discontinuation also will be presented. A tabulation of the number of subjects exposed to study 
drug and duration of exposure will also be presented for each treatment group. Treatment 
adherence, dose interruptions, and reason for dose interruptions will be provided as summaries or 
listed as appropriate. 
13.4.4. 
Analysis of Efficacy Variables 
The primary efficacy endpoint will be determined from Part 1 of the current study alone, using 
the ITT population. 
A supplemental analysis will combine data from the current study and Study BCX7353-302. 
Analysis of data using the PP population will be conducted to support the combined efficacy 
analysis.  
Efficacy data will generally be summarized by treatment group and for both active doses 
combined. Angioedema events will generally be summarized over the entire dosing period. 
Selected analyses will be repeated using the steady-state or effective dosing period. 
The entire dosing period (Day 1 through Day 168, inclusive) is the date of first dose to the last 
dose on Day 168 + 24 hours, or 24 hours after the last dose of the study drug, whichever is 
earlier.  
The effective dosing period (Day 8 through first dose in Part 2) is the date of first dose + 7 days 
to the date and time of first dose in Part 2 or the date of study treatment discontinuation + 
24 hours, for subjects who discontinue treatment prior to Part 2.  


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13.4.4.1. Primary Efficacy Analysis 
The primary efficacy endpoint is the rate of expert-confirmed angioedema events during dosing 
in the entire treatment period of Part 1 of the current study.  
The sample size considered feasible for enrollment in Japan has limited statistical power. 
Therefore, a supplemental statistical analysis will be conducted using the combined monthly 
angioedema event rate (investigator-confirmed attacks in Study BCX7353-302 and 
expert-confirmed events in Study BCX7353-301) in the entire treatment period in the ITT 
population. The angioedema event rate and the treatment comparisons between each BCX7353 
dose and placebo in the rate of investigator- or expert-confirmed angioedema events during the 
entire dosing period will be analyzed using a negative binomial regression model. The number of 
investigator- or expert-confirmed angioedema events will be included as the dependent variable, 
the treatment will be included as a fixed effect, the stratification variable (baseline monthly 
angioedema event rate) will be included as a covariate, and the logarithm of duration on 
treatment will be included as an offset variable. The estimated rate of angioedema events for 
each treatment group, the treatment differences expressed as the angioedema event rate ratio 
(BCX7353 over placebo rate ratio), and their associated 95% confidence intervals (CIs) will be 
provided from the negative binomial regression model. Monthly will be defined as 4 weeks. 
The potential impact of missing data on the primary efficacy outcome will be explored. 
Sensitivity analyses will be conducted to support the primary analysis. This will include analyses 
based on subjects who completed the study and on those in the PP population.  
13.4.4.2. Secondary and Exploratory Efficacy Analyses 
Part 1 secondary efficacy endpoints include: 
• Change from baseline in AE-QoL at Week 24 (total score) 
• Number and proportion of days with angioedema symptoms through 24 weeks 
• Rate of investigator- or expert-confirmed angioedema events during dosing in the 
effective treatment period (beginning on Day 8 through Week 24) 
Part 1 exploratory efficacy endpoints include: 
• Number and proportion of subjects with no angioedema events over 24 weeks 
• Use of medications to treat angioedema events over 24 weeks 
• The proportion of responders to study drug, separately defined as at least a 50%, 
70%, or 90% relative reduction in the rate of expert-confirmed angioedema events 
during treatment compared with the baseline expert-confirmed angioedema event rate 
For the combined analysis with Study BCX7353-302, treatment comparisons in the AE-QoL 
total score change from baseline will be analyzed using an MMRM with restricted maximum 
likelihood estimation and an unstructured covariance matrix. The estimated treatment difference 
for each BCX7353 dose–placebo at each visit will be displayed together with the 95% CI and the 
associated p-value. Primary inferences will be drawn from treatment differences for the changes 
from baseline derived from the MMRM model through Week 24. The change from baseline in 
the AE-QoL domain scores (function, fatigue, nutrition, and fear/shame) will also be analyzed 
using a MMRM model. 


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Secondary and exploratory efficacy endpoints will be summarized and listed. 
The between-treatment comparisons will be performed for the combined analysis with 
Study BCX7353-302 using a similar negative binomial regression model for the investigator- or 
expert-confirmed angioedema events during the effective treatment period. 
The between-treatment comparison for the responder endpoints will be performed using 
Cochran-Mantel-Haenszel, Chi-square, or Fisher’s exact test. Multiplicity adjustments for the 
secondary endpoints are described in Section 13.1.3. 
Additional related details of angioedema events (eg, symptoms, anatomical location, 
hospitalizations, emergency room visits, and angioedema event duration) will be summarized 
and listed. Details of these analyses will be provided in the SAP. 
The efficacy endpoints for Parts 2 and 3 include: 
• Number and rate of angioedema events  
• Durability of response (angioedema event rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Use of medications to treat angioedema events 
• Discontinuations due to lack of efficacy (through Week 52 [Part 2] only) 
• Durability in AE-QoL questionnaire scores  
• Durability in EQ-5D-5L scores 
• Durability in TSQM scores 
• Durability in WPAI scores 
The analyses of efficacy for Parts 2 and 3 will be provided for the current study. For the placebo 
subjects who switched to an active BCX7353 dose, the change from placebo to the active dosing 
period will be summarized. Details of the planned efficacy analyses for the entire study will be 
provided in the SAP. 
13.4.5. 
Planned Analyses 
The primary analysis is planned after the last subject completes the 24 weeks of study (last 
subject completes Part 1).  
The investigators, study staff, and subjects will remain blinded until after the database has been 
locked and the final analysis conducted. The final analysis will occur after the last subject 
completes 52 weeks of study. Analysis of the 52-week data will be comprised of data from the 
current study alone. 
13.4.6. 
Analysis of Safety Variables 
Analysis of safety data will be conducted for the current study alone. 
The safety analyses will be analyzed separately for Part 1 alone; a later data analysis will 
evaluate long-term safety data for the current study. 


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Safety endpoints that will be summarized include, at a minimum, the number and proportion of 
subjects: 1) with a TEAE; 2) who discontinue BCX7353 due to a TEAE; 3) who experience a 
TESAE; 4) who experience a treatment-emergent Grade 3 or 4 AE; and 5) who experience a 
treatment-emergent Grade 3 or 4 laboratory abnormality. In addition, the proportion of subjects 
with a treatment-emergent, treatment-related AE consistent with a drug rash as identified by the 
investigator will also be summarized. 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ class. The occurrence of TEAEs will be summarized using 
MedDRA preferred terms, system organ classifications, and severity. Separate summaries of 
TEAEs, TESAEs, AEs considered to be related to study drug, and AEs leading to study drug 
interruption will be generated. All AEs will be listed for individual subjects showing both 
verbatim and preferred terms.  
Descriptive summaries of vital signs, weight, bedside ECG parameters, and clinical laboratory 
results will be presented. Laboratory abnormalities will be graded according to the DMID Adult 
Adverse Event Table (Publish Date: Draft, November 2007; Appendix 16.1).  
Any graded abnormality that occurs following the initiation of study drug and represents at least 
a 1-grade increase from the baseline assessment is defined as treatment emergent. The number 
and percentage of subjects experiencing treatment-emergent graded toxicities will be 
summarized. Laboratory toxicity shifts from baseline to worst postbaseline assessments will be 
summarized.  
Clinically significant abnormal morphological ECG findings will be summarized.  
The change from baseline in QTcF will be determined by routine ECGs. At each time point 
ECGs are analyzed, an individual subject’s change from baseline will be calculated as: 
∆ik= (QTcF for subject at time point k – Baseline QTcF) 
Where QTcF measurements will be the average of triplicate ECGs at baseline and single values 
at each time point.  
For routine ECGs, the number and proportion of subjects with QTcF ≤ 450, > 450 to ≤ 480, 
> 480 to ≤ 500, and > 500 msec; or changes of ≤ 30, > 30 to ≤60, or > 60 msec will be 
summarized.  
Physical examination findings will be listed.  
Concomitant medications will be coded using the World Health Organization drug dictionary 
and summarized.   
As applicable, safety data will be summarized by treatment group and total BCX7353. 
No tests of hypotheses are planned for safety data. 
13.4.7. 
Health Outcome Analyses 
Health outcome endpoints are as follows: 
• Durability in TSQM scores 
• Durability in WPAI scores 


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•
Durability in EQ-5D-5L scores
Summaries will be provided for the current study. 
The between-treatment comparisons for combined analysis with Study BCX7353-302 for 
TSQM, WPAI, and EQ-5D-5L will be performed using a mixed effect model including terms of 
treatment, visit, visit interaction, and baseline score. Details will be provided in the SAP. 
13.4.8. 
Pharmacokinetic Analyses 
Plasma samples for determination of BCX7353 concentrations are planned to be collected per 
Table 2 and Table 3. Concentration data will be listed and summarized by treatment group for 
the current study alone. 
The resulting PK data will then be pooled in a meta-analysis to facilitate population PK analyses. 
In the population PK analysis, covariates will be tested to determine the effect on PK of 
BCX7353. Region will be one of the covariates analyzed.  
Pharmacokinetic results from the meta-analysis will not be summarized in the statistical 
reporting of this study. 
13.4.9. 
Pharmacodynamic Analyses 
Plasma kallikrein inhibition data will be expressed as percentage inhibition compared to subject 
baseline activity. Ex vivo plasma kallikrein activity will be listed by subject, treatment, day, and 
time, and summarized separately by treatment, day, and time. Using data from the current study 
alone, descriptive statistics will be reported. Mean and individual plasma kallikrein inhibition 
versus time profiles will be plotted by treatment group.  
13.4.10. 
PK Concentration /Pharmacodynamic Analyses 
This analysis of PK concentration-PD relationships may be performed using data from this study 
alone or may be combined with data from Study BCX7353-302. Exposure-response analyses of 
the relationships between plasma kallikrein inhibition, efficacy endpoints, and BCX7353 plasma 
concentrations may be explored using model-based techniques as applicable. 
14.
STUDY ADMINISTRATION
14.1. 
Regulatory and Ethical Considerations
14.1.1. 
Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; GCPs, including ICH of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Guidelines (ICH E6); Japan 
PMDA regulatory requirements and other national laws as applicable; and in accordance with the 
ethical principles of the Declaration of Helsinki. In addition, the study will be conducted in 
compliance with all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
Following marketing authorization in Japan and formal transition to a post-marketing study, this 
study will be conducted in compliance with post-marketing regulations. The sponsor of the study 


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will be changed from BioCryst to the marketing authorization holder in Japan, OrphanPacific, 
Inc. However, the clinical conduct of the study will continue to be overseen by BioCryst. 
Therefore, reference to “the sponsor” in this section may encompass reference to BioCryst and/or 
OrphanPacific, Inc., as applicable. 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals 
Before initiation of the study at an investigational site, the protocol, the ICF, the subject 
information sheet (if applicable), and any other relevant study documentation will be submitted 
to the appropriate IRB/IEC. Written approval of the study must be obtained before the study 
center can be initiated or the IMP can be released to the investigator. Any necessary extensions 
or renewals of IRB/IEC approval must be obtained, in particular, for changes to the study such as 
modification of the protocol, the ICF, the written information provided to subjects, and/or other 
procedures. 
The IRB/IEC will be promptly provided any new information that may adversely affect the 
safety of the subjects or the conduct of the study. On completion of the study, the IRB/IEC will 
be provided with a report of the outcome of the study. 
Written reports of clinical study status will be submitted to the IRB/IEC annually or more 
frequently if requested by the IRB/IEC. A final study notification will also be forwarded to the 
IRB/IEC after the study is completed or in the event of premature termination of the study in 
accordance with the applicable regulations. The study will be considered completed once the last 
subject completes the last study visit. Copies of all contact with the IRB/IEC should be 
maintained in the study file. Copies of clinical study status reports (including termination) should 
be provided to the sponsor. 
14.1.3. 
Subject Informed Consent: Adults 
A signed ICF must be obtained from each subject prior to performing any study-related 
procedures. Each subject should be given both verbal and written information describing the 
nature and duration of the clinical study. The informed consent process should take place under 
conditions where the subject has adequate time to consider the risks and benefits associated with 
his/her participation in the study. Subjects will not be screened or treated until the subject has 
signed an approved ICF written in a language in which the subject is fluent.  
The ICF that is used must be approved both by the sponsor and by the reviewing IRB/IEC. The 
ICF should be in accordance with the current revision of the Declaration of Helsinki, current ICH 
and GCP guidelines, and sponsor policies. 
The investigator must explain to potential subjects the aims, methods, reasonably anticipated 
benefits, and potential hazards of the trial and any discomfort it may entail. Subjects will be 
informed that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time. They will be told that refusal to participate in the study will not prejudice 
future treatment. They will also be told that their records may be examined by competent 
authorities and authorized persons, but that personal information will be treated as strictly 
confidential and will not be publicly available. Subjects must be given the opportunity to ask 
questions. After this explanation and before entry into the trial, consent should be appropriately 
recorded by means of the subject’s dated signature. The subject should receive a signed and 
dated copy of the ICF. The original signed ICF should be retained in the study files. 


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The investigator shall maintain a log of all subjects who sign the ICF and indicate if the subject 
was enrolled into the study or reason for non-enrollment. 
14.1.4. 
Subject Informed Consent: Adolescents 
Signed informed consent must be obtained from each parent/caregiver of adolescent subjects 
aged 12 to 17 years who enroll in the study prior to performing any study-related procedures. 
Similarly, subject assent by subjects 12 to 17 years will be obtained from each adolescent prior 
to performing any study-related procedures. If the local requirements limit the age of assent, then 
assent will be obtained based on those requirements. Each parent/caregiver and subject should be 
given both verbal and written information describing the nature and duration of the clinical 
study. The informed consent process should take place under conditions where the 
parent/caregiver has adequate time to consider the risks and benefits associated with his/her 
child’s participation in the study. Subjects will not be screened or treated until the 
parent/caregiver and subject have signed an approved ICF and assent form written in a language 
in which the subject is fluent. The ICF and assent forms that are used must be approved both by 
the sponsor and by the reviewing IRB/IEC. The ICF and assent forms should be in accordance 
with the current revision of the Declaration of Helsinki, current ICH and GCP guidelines, and 
sponsor policies. 
The investigator must explain to potential subjects and their parent/caregiver the aims, methods, 
reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may 
entail. Each parent/caregiver will be informed that they are free for their child not to participate 
in the trial and that they may withdraw consent for their child to participate at any time. 
They will be told that refusal for their child to participate in the study will not prejudice future 
treatment. They will also be told that their child’s records may be examined by competent 
authorities and authorized persons, but that personal information will be treated as strictly 
confidential and will not be publicly available.  
Parents/caregivers and subjects must be given the opportunity to ask questions. After this 
explanation and before entry into the trial, consent and assent should be appropriately recorded 
by means of the parent’s/caregiver’s dated signature. The parent/caregiver should receive a 
signed and dated copy of the ICF, and the assent. The original signed informed consent and 
assent should be retained in the study files. The investigator shall maintain a log of all subjects 
for whom consent was signed and indicate if the subject was enrolled into the study or reason for 
non-enrollment. 
14.1.5. 
Investigator Reporting Requirements 
The investigator will provide timely reports regarding safety to his/her IRB/IEC as required. 
14.2. 
Study Monitoring 
During trial conduct, the sponsor or its designee will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed. The monitors will review source documents to 
confirm that the data recorded in the eCRFs are accurate. The investigator and institution will 
allow sponsor representatives, monitors, or its designees direct access to source documents to 
perform this verification. 


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It is important that the principal investigator(s) and their relevant personnel are available during 
the monitoring visits and that sufficient time is devoted to the process. 
14.3. 
Quality Assurance 
The principal investigator may be subject to visits by the IRB/IEC, and/or by a quality assurance 
group for audits performed by the sponsor or its designee, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
possible audits or inspections and that sufficient time is devoted to the process. 
14.4. 
Study Termination and Site Closure 
Overall, the sponsor may suspend enrollment into the study, suspend treatment of ongoing 
subjects, or terminate the study to ensure that subjects’ safety and welfare are protected. 
The entire study, or individual sites, may be terminated for any of the following reasons: 
• if the study drug becomes commercially available or another mechanism is available 
to provide drug to the subject 
• changes in scientific knowledge that lead to a negative impact on the benefit-risk 
profile for subjects 
• request of sponsor or competent public authorities/IRB/IEC 
• if recruitment cannot be completed in specified time frame 
• if the permit to manufacture or import IMP is revoked 
The sponsor reserves the right to discontinue the trial prior to inclusion of the intended number 
of subjects but intends only to exercise this right for valid scientific or administrative reasons. 
After such a decision, the investigator must contact all participating subjects immediately after 
notification. As directed by the sponsor, all study materials must be collected and all eCRFs 
completed to the greatest extent possible. 
An individual trial center that is determined to be unsuitable by the sponsor, competent public 
authorities, or IRB/IEC may be terminated, without affecting the other trial sites.  
Except for those situations outlined in Section 8.3, no other formal stopping rules will be defined 
for individual subjects, parts of the trial, or the entire trial. Individual subjects will be 
discontinued from the study following the emergence of any laboratory abnormality or AE that 
in the judgment of the investigator compromises the ability to continue study-specific procedures 
or is considered not to be in the subject’s best interest. 
Once BCX7353 receives marketing authorization in Japan, this study will be transitioned to a 
post-marketing study. Each subject remaining on study may continue to receive access to 
BCX7353 via this study until such time as BCX7353 is commercially available at his or her 
study center. Once the last subject is able to access commercial drug product, the study will be 
terminated. 


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14.5. 
Records Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eCRFs, and medical/hospital records), all original signed ICFs, all original signed 
assents (where applicable), all eCRFs, and detailed records of study drug accountability and 
treatment disposition. The records should be retained by the investigator according to local 
regulations or as specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to the sponsor. The investigator must obtain the sponsor’s written permission 
before disposing of any records and must notify the sponsor before transferring any records to 
another facility. 
All correspondence related to records retention, destruction or transfer of study documents 
should be sent directly to sponsor study personnel, copying the email archives@biocryst.com. 
14.6. 
Confidentiality of Information and Data 
The sponsor affirms the subject’s right to protection against invasion of privacy and secure 
maintenance of the confidential nature of their personal data. Only a subject identification 
number and subject identifiers permitted by local regulation will identify subject data retrieved 
by the sponsor. However, in compliance with federal regulations, the sponsor requires the 
investigator to permit the sponsor’s representatives and, when necessary, representatives of the 
PMDA or other regulatory authorities to review and/or copy any medical records relevant to the 
study, maintaining pseudo-anonymity. 
All parties will abide by all applicable laws and regulations regarding subject privacy and 
confidentiality. A valid authorization and consent must meet the specifications of the applicable 
laws and regulations relating to such personal data and health information. It is the responsibility 
of the investigator and institution to obtain such waiver/authorization in writing from the 
appropriate individual.  
14.7. 
Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict 
confidence along with all information furnished by BioCryst. Except as provided through prior 
written agreement with BioCryst, independent analysis and/or publication of these data by the 
investigator or any member of his/her staff is not permitted. Such consent will not be withheld 
unreasonably. BioCryst is in agreement with the principle of full disclosure of clinical trial 
results. 


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15. 
REFERENCES 
Aygoren-Pursun, E., A. Bygum, V. Grivcheva-Panovska, M. Magerl, J. Graff, U. C. Steiner, 
O. Fain, A. Huissoon, T. Kinaciyan, H. Farkas, R. Lleonart, H. J. Longhurst, W. Rae, M. 
Triggiani, W. Aberer, M. Cancian, A. Zanichelli, W. B. Smith, M. L. Baeza, A. Du-Thanh, 
M. Gompels, T. Gonzalez-Quevedo, J. Greve, M. Guilarte, C. Katelaris, S. Dobo, M. 
Cornpropst, D. Clemons, L. Fang, P. Collis, W. Sheridan, M. Maurer and M. Cicardi (2018). 
"Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema." N Engl J Med 
379(4): 352-362. 
Bork, K., J. Hardt and G. Witzke (2012). "Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency." J Allergy Clin Immunol 130(3): 692-697. 
Bork, K., G. Meng, P. Staubach and J. Hardt (2006). "Hereditary angioedema: new findings 
concerning symptoms, affected organs, and course." Am J Med 119(3): 267-274. 
Bouillet, L., H. Longhurst, I. Boccon-Gibod, K. Bork, C. Bucher, A. Bygum, T. Caballero, C. 
Drouet, H. Farkas, C. Massot, E. W. Nielsen, D. Ponard and M. Cicardi (2008). "Disease 
expression in women with hereditary angioedema." Am J Obstet Gynecol 199(5): 484.e1-4. 
Caballero, T., H. Farkas, L. Bouillet, T. Bowen, A. Gompel, C. Fagerberg, J. Bjokander, K. 
Bork, A. Bygum, M. Cicardi, C. de Carolis, M. Frank, J. H. Gooi, H. Longhurst, I. Martinez-
Saguer, E. W. Nielsen, K. Obtulowitz, R. Perricone, N. Prior and C. I. D. W. Group (2012). 
"International consensus and practical guidelines on the gynecologic and obstetric 
management of female patients with hereditary angioedema caused by C1 inhibitor 
deficiency." J Allergy Clin Immunol 129(2): 308-320. 
Cicardi, M., K. Bork, T. Caballero, T. Craig, H. H. Li, H. Longhurst, A. Reshef, B. Zuraw 
and Hawk (2012). "Evidence-based recommendations for the therapeutic management of 
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International 
Working Group." Allergy 67(2): 147-157. 
Cornpropst, M., S. Dobo, J. Collier, A. Rose, R. Wilson, Y. S. Babu, P. Collis and W. 
Sheridan (2016). "BCX7353, a Potent Inhibitor of Plasma Kallikrein, Shows Sustained 
Maximal Enzyme Inhibition When Dosed Orally Once Daily: Results from a Phase I Trial in 
Healthy Subjects." Elsevier (AAAAI, Los Angeles). 
Han, E. D., R. C. MacFarlane, A. N. Mulligan, J. Scafidi and A. E. Davis, 3rd (2002). 
"Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin 
type 2 receptor." J Clin Invest 109(8): 1057-1063. 
Kaplan, A. P. (2010). "Enzymatic pathways in the pathogenesis of hereditary angioedema: 
the role of C1 inhibitor therapy." J Allergy Clin Immunol 126(5): 918-925. 
Kaplan, A. P. and B. Ghebrehiwet (2010). "The plasma bradykinin-forming pathways and its 
interrelationships with complement." Mol Immunol 47(13): 2161-2169. 
Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-
481. 


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Lumry, W. R., A. J. Castaldo, M. K. Vernon, M. B. Blaustein, D. A. Wilson and P. T. Horn 
(2010). "The humanistic burden of hereditary angioedema: Impact on health-related quality 
of life, productivity, and depression." Allergy Asthma Proc 31(5): 407-414. 
Maurer, M., M. Magerl, I. Ansotegui, E. Aygoren-Pursun, S. Betschel, K. Bork, T. Bowen, 
H. Balle Boysen, H. Farkas, A. S. Grumach, M. Hide, C. Katelaris, R. Lockey, H. Longhurst, 
W. R. Lumry, I. Martinez-Saguer, D. Moldovan, A. Nast, R. Pawankar, P. Potter, M. Riedl, 
B. Ritchie, L. Rosenwasser, M. Sanchez-Borges, Y. Zhi, B. Zuraw and T. Craig (2018). "The 
international WAO/EAACI guideline for the management of hereditary angioedema-The 
2017 revision and update." Allergy 73(8): 1575-1596. 
Ohsawa, I., D. Honda, S. Nagamachi, A. Hisada, M. Shimamoto, H. Inoshita, S. Mano and 
Y. Tomino (2015). "Clinical manifestations, diagnosis, and treatment of hereditary 
angioedema: survey data from 94 physicians in Japan." Ann Allergy Asthma Immunol 
114(6):492-498. 
Saxena, P., P. Thompson, Y. d'Udekem and I. E. Konstantinov (2011). "Kallikrein-kinin 
system: a surgical perspective in post-aprotinin era." J Surg Res 167(1): 70-77. 
Weller, K., M. Magerl, A. Peveling-Oberhag, P. Martus, P. Staubach and M. Maurer (2016). 
"The Angioedema Quality of Life Questionnaire (AE-QoL) - assessment of sensitivity to 
change and minimal clinically important difference." Allergy 71(8): 1203-1209. 
Yamamoto, T., T. Horiuchi, H. Miyahara, S. Yoshizawa, J. Maehara, E. Shono, K. 
Takamura, H. Machida, K. Tsujioka, T. Kaneko, N. Uemura, K. Suzawa, N. Inagaki, N. 
Umegaki, Y. Kasamatsu, A. Hara, Y. Arinobu, Y. Inoue, H. Niiro, Y. Kashiwagai, S. 
Harashima, T. Tahira, H. Tsukamoto and K. Akashi (2012). "Hereditary angioedema in 
Japan: genetic analysis of 13 unrelated cases." Am J Med Sci 343(3): 210-214. 
Zuraw, B. L., A. Banerji, J. A. Bernstein, P. J. Busse, S. C. Christiansen, M. Davis-Lorton, 
M. M. Frank, H. H. Li, W. R. Lumry and M. Riedl, US Hereditary Angioedema Association 
Medical Advisory Board (2013). "US Hereditary Angioedema Association Medical Advisory 
Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 
Inhibitor Deficiency." J Allergy Clin Immunol Pract 1(5): 458-467. 
Zuraw, B. L. and S. C. Christiansen (2011). "Pathophysiology of hereditary angioedema." 
Am J Rhinol Allergy 25(6): 373-378. 
 


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16. 
APPENDICES 
16.1. 
DMID Adult Adverse Event Table (DRAFT, Publish Date: 
November 2007) 
For the purposes of this protocol, the title of the Division of Microbiology and Infectious Disease 
(DMID) table to be used grade adverse events is referred to as the ‘DMID Adult Adverse Event 
Table.’ The criteria contained in the ‘DMID Adult Adverse Event Table’ has been unaltered 
from the published DMID table under the name ‘DMID Adult Toxicity Table (DRAFT, Publish 
Date: November 2007).’ 
Copies of the DMID Adult Adverse Event Table will be available to the medical staff throughout 
the project. 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to 
moderate 
limitation 
in 
activity - some assistance may be needed; no or minimal 
medical intervention/therapy required 
GRADE 3 
Severe  
 
Marked limitation in activity, some 
assistance usually required; medical intervention/therapy 
required, hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme 
limitation 
in 
activity, 
significant 
assistance 
required; 
significant 
medical 
intervention/therapy required, hospitalization or hospice 
care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
HEMATOLOGY 
 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hemoglobin 
 
9.5 - 10.5 gm/dL 
 
8.0  - 9.4gm/dL 
 
 6.5 - 7.9 gm/dL 
 
< 6.5 gm/dL 
 
Absolute Neutrophil Count 
 
1000-1500/mm3 
 
750-999/mm3 
 
500-749/mm3 
 
<500/mm3 
 
Platelets 
 
75,000-
99,999/mm3 
 
50,000-
74,999/mm3 
 
20,000-49,999/mm3 
 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
 
 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL  
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL  
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
 
Fibrin Split Product 
 
20-40 mcg/ml 
 
41-50 mcg/ml 
 
51-60 mcg/ml 
 
> 60 mcg/ml 
 
Prothrombin  
Time (PT) 
 
1.01 - 1.25 x ULN 
 
1.26-1.5 x ULN 
 
1.51 -3.0 x ULN 
 
>3 x ULN 
 
Activated Partial 
Thromboplastin (APPT) 
 
1.01 -1.66 x ULN 
 
1.67 - 2.33 x 
ULN 
 
2.34 - 3 x ULN 
 
> 3 x ULN 
 
Methemoglobin 
 
5.0 - 9.9 % 
 
10.0 - 14.9 % 
 
15.0 - 19.9% 
 
> 20.0 % 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
CHEMISTRIES (continued) 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
 
1.0 -1.4 mg/dL  
intensive therapy  
or 
hospitalization 
required 
 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x 
ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
 
BUN 
 
1.25 - 2.5 x ULN 
 
2.6 - 5 x ULN 
 
5.1 - 10 x ULN 
 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
 
 
 
Creatinine 
 
1.1 - 1.5 x ULN  
 
1.6 - 3.0 x ULN 
 
3.1 - 6 x ULN 
 
> 6 x ULN or 
dialysis required 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ENZYMES 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Alkaline Phosphatase 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Amylase 
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
Lipase  
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
 
 
URINALYSIS 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Proteinuria 
 
1+ 
 or  
200 mg - 1 gm 
loss/day 
 
2-3+  
or  
1- 2 gm 
loss/day 
 
4+ 
 or  
2-3.5 gm loss/day 
 
nephrotic 
syndrome  
or 
> 3.5 gm loss/day 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
 
gross, with or 
without clots, OR 
red blood cell casts 
 
obstructive or 
required 
transfusion 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
SKIN 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
 
 
 
 
SYSTEMIC 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Allergic Reaction 
 
pruritus without 
rash 
 
localized 
urticaria 
 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
 
Fever: oral 
 
37.7 - 38.5 C or  
100.0 - 101.5 F 
 
38.6 - 39.5 C or 
101.6 - 102.9 F 
 
39.6 - 40.5 C or 
103 - 105 F 
 
> 40 C or 
> 105 F 
 
Fatigue 
 
normal activity 
reduced < 48 hours 
 
 normal activity 
decreased 25- 
50% > 48 hours 
 
normal activity 
decreased > 50% 
can’t work 
 
unable to care for 
self 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 1.0 
 
4 November 2019 
 
1 
 
 
CONFIDENTIAL 
 
 
BIOCRYST PHARMACEUTICALS INC. 
STATISTICAL ANALYSIS PLAN 
PHASE 3 
 
VERSION: FINAL 1.0 
DATE OF PLAN: 
04-NOV-2019 
 
BASED ON: 
Protocol Version 5.0: 29 August 2019 
CRF Version 5.0: 31 July 2019 
 
STUDY DRUG: 
BCX7353 
PROTOCOL NUMBER: 
BCX7353-301 
IND No. 135,058 
EudraCT No.  2017-003966-29 
STUDY TITLE: 
APeX-J: A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of 2 dose levels of BCX7353 as an oral treatment for the 
prevention of attacks in subjects with hereditary angioedema  
  SPONSOR: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703 
Phone: (919) 859-1302 
Fax: (919) 851-1416 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 


04-Nov-2019 | 14:08 PM EST


BioCryst Pharmaceuticals, Inc. 
BCX7353-301 
Statistical Analysis Plan Version 1.0 
4 November 2019 
3 
CONFIDENTIAL 
TECHNICAL SUMMARY REPORT (TSR) 
Name of Sponsor/Company 
BioCryst Pharmaceuticals, Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Investigational Product: 
BCX7353 
Page: 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-
(trifluoromethyl)-1H-pyrazole-5-carboxamide  
Title of Study: 
APeX-J: A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy 
and safety of 2 dose levels of BCX7353 as an oral treatment for the prevention of attacks in subjects with 
hereditary angioedema  
Study Centers: Approximately 15 centers in Japan 
Enrollment Period: Approximately 3 months 
Phase of development: 3 
Part 1 Primary Objective: 
•
To determine the efficacy of BCX7353 110 and 150 mg administered once daily (QD) for 24 weeks
compared to placebo in the prevention of angioedema events in subjects with hereditary angioedema
(HAE)
Part 1 Secondary Objectives: 
•
To assess the safety and tolerability of BCX7353 110 and 150 mg QD administered for 24 weeks
•
To assess the effects of BCX7353 on HAE disease activity and angioedema event characteristics
•
To evaluate the effects of BCX7353 on quality of life (QoL)
•
To characterize the pharmacodynamic (PD) effects of BCX7353
Part 1 Primary Efficacy Endpoint: 
•
The rate of expert-confirmed angioedema events during dosing in the entire 24-week treatment
period (Days 1 to 168).
Part 1 Secondary Efficacy Endpoints: 
•
Change from baseline in AE-QoL at Week 24 (total score)
•
Number and proportion of days with angioedema symptoms through 24 weeks
•
Rate of expert-confirmed angioedema events during dosing in the effective treatment period
(beginning on Day 8 through 24 weeks)
Part 1 Exploratory Efficacy Endpoints: 
•
Number and proportion of subjects with no angioedema events over 24 weeks
•
Use of medications to treat angioedema events over 24 weeks
•
The proportion of responders to study drug, separately defined as at least a 50%, 70%, or 90%
relative reduction in the rate of expert-confirmed angioedema events during treatment compared
with the baseline expert-confirmed angioedema event rate


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 1.0 
 
4 November 2019 
4 
CONFIDENTIAL 
Part 1 Safety Endpoints: 
• 
Number and proportion of subjects with a treatment-emergent adverse event (TEAE) 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent serious adverse event 
(TESAE)  
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory 
abnormality 
Part 1 Health Outcome Endpoints: 
• 
EuroQoL 5-dimensional, 5-level questionnaire (EQ-5D-5L) scores 
• 
Treatment Satisfaction Questionnaire for Medication (TSQM) scores 
• 
Work Productivity and Activity Impairment Questionnaire (WPAI) scores 
Part 2 Primary Objective: 
• 
To evaluate the long-term safety and tolerability of BCX7353 110 and 150 mg in subjects with 
HAE 
Part 2 Secondary Objectives: 
• 
To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 over a 24- to 
52-week administration period  
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 52-week administration 
period time 
• 
To evaluate subject satisfaction with BCX7353 over a 24- to 52-week administration period 
Part 2 Primary Endpoints: 
• 
Number and proportion of subjects with a TEAE 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a TESAE  
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory 
abnormality 
• 
The proportion of subjects with a treatment-emergent, treatment-related adverse event (AE) 
consistent with a drug rash  
 
 
 
Part 2 Secondary Endpoints: 
• 
Number and rate of angioedema events 


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BCX7353-301 
Statistical Analysis Plan Version 1.0 
 
4 November 2019 
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CONFIDENTIAL 
• 
Durability of response (angioedema event rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of medications to treat angioedema events 
• 
Discontinuations due to lack of efficacy 
• 
Durability in AE-QoL questionnaire scores 
• 
Durability in EQ-5D-5L scores 
• 
Durability in TSQM scores 
• 
Durability in WPAI scores 
Part 3 Primary Objective: 
• 
To evaluate the long-term safety and tolerability of BCX7353 administered QD over a 52- to up to 
104-week administration period in subjects with HAE 
Part 3 Secondary Objectives: 
• 
To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 over a 52- to 
up to 104-week administration period 
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 52- to up to 104-week 
administration period 
• 
To evaluate subject satisfaction with BCX7353 over a 52- to up to 104-week administration period 
Part 3 Primary Endpoints: 
• 
Number and proportion of subjects with a TEAE 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a TESAE 
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory 
abnormality 
• 
The proportion of subjects with a treatment-emergent, treatment related AE consistent with a drug 
rash 
Part 3 Secondary Endpoints:  
• 
Number and rate of angioedema events 
• 
Durability of response (angioedema event rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of medications to treat angioedema events 
• 
Durability in AE-QoL questionnaire scores 
• 
Durability in EQ-5D-5L scores 
• 
Durability in TSQM scores 


BioCryst Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan Version 1.0 
 
4 November 2019 
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CONFIDENTIAL 
• 
Durability in WPAI scores 
Methodology: 
This is a randomized, placebo-controlled, double-blind, parallel-group, 2-part study. Part 1 is designed to test the 
hypothesis that the angioedema event rate during 24 weeks of prophylactic BCX7353 treatment at 2 dosage levels 
will be less than that observed during 24 weeks of placebo. 
An angioedema event is defined as an attack, symptoms or swelling due to a subject’s underlying HAE disease. 
The primary efficacy endpoint will be assessed after the last subject completes Part 1 (through Week 24). Part 2 
is designed to primarily evaluate the long-term safety of BCX7353 at 2 dosage levels. Part 3 is open-label and 
designed to primarily evaluate the long-term safety of BCX7353. Parts 1, 2, and 3 will be conducted in sequence. 
All subjects will receive BCX7352 in Parts 2 and 3, including those randomized to receive placebo in Part 1.  
Part 1 (24-week evaluation of blinded efficacy and safety) 
Subjects with HAE Type 1 or 2 will be eligible for the study following assessment of data obtained from 
screening procedures, including demonstration of a minimum number of angioedema events documented during a 
prospective run-in period of 8 weeks from the date of the screening visit. 
Treatment-eligible subjects will receive study drug (BCX7353 or placebo) in Part 1 of the study based on 
randomization in a 1:1:1 ratio into 1 of 3 treatment groups: 
• 
Group 1: BCX7353 110 mg QD administered orally for 24 weeks 
• 
Group 2: BCX7353 150 mg QD administered orally for 24 weeks 
• 
Group 3: Placebo QD administered orally for 24 weeks 
Enrollment into treatment groups will be stratified by the baseline angioedema event rate (≥ 2 angioedema events 
per month vs. < 2 angioedema events per month). 
Details of all angioedema events (attack, symptoms, or swelling due to HAE) and compliance with study drug 
will be recorded in an electronic diary (e-diary). Angioedema events will be treated in accordance with the 
subject’s normal standard of care. Treatment medication for angioedema events will not be provided by the 
sponsor. 
Within approximately 2 business days of the end of each angioedema event that occurs beginning at the screening 
visit through the Week 24 visit, subjects will be contacted by the investigator (or appropriately-trained designee) 
to discuss the clinical characteristics of the angioedema event, any questions the investigator has on the entered 
data, or to gain additional details of the event that are not included in the e-diary that the investigator deems 
important to clinically evaluate the event, as applicable. 
The investigator-collected information, in conjunction with the e-diary record, will be used by an independent 
expert to verify or reject each event recorded in the e-diary as a confirmed angioedema event. All 
expert-confirmed angioedema events must include symptoms of swelling; prodromal symptoms in the absence of 
swelling are not considered angioedema events, regardless of treatment. 
The expert will consider that symptoms of swelling, in addition to visible swelling, may also include symptoms in 
the oropharyngeal or abdominal regions that are indicative of internal swelling. Under no circumstances should 
the run-in angioedema event requirement for eligibility be disclosed to study subjects. 
The study will include adolescent and adult subjects (≥ 12 years of age). 
Safety and tolerability will be evaluated through assessments of AEs, laboratory analyses (clinical chemistry, 
hematology, and urinalysis), vital signs, electrocardiograms (ECGs), and physical examinations. 
Study visits in Part 1 will occur at screening, baseline, and Weeks 2, 4, 8, 12, 18, and 24. The primary efficacy 
analysis will occur after the last subject completes the Week 24 visit and will include all data through Week 24.  
Subject treatment will remain blinded to the subject, site, and sponsor staff interacting with sites during Part 1. 
Part 2 (evaluation of safety of blinded BCX7353) 
Part 2 of the study will start with the administration of study drug dispensed at the Week 24 visit. 
Subjects in Groups 1 and 2 will continue to receive the same BCX7353 dose to which they were randomized in 
Part 1 of the study in a blinded manner. Subjects randomized to Group 3 will undergo a second randomization in 
a 1:1 ratio to receive either a 110 or 150 mg QD dose of BCX7353 in a blinded manner beginning at the Week 24 
visit (see figure below for visual depiction of treatments in all study parts). The active dose a subject receives in 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 1.0 
 
4 November 2019 
7 
CONFIDENTIAL 
Part 2 will be blinded for all subjects; subjects will be informed that they will receive an active dose of BCX7353 
in Part 2. 
Study visits during Part 2 will occur during Weeks 26, 28, 32, 36, 48, and 52, with telephone contact at Weeks 40 
and 44. Subjects will continue to document all angioedema events (attack, symptoms, or swelling due to HAE) 
that occur while on study drug, as well as compliance with the study drug, in their e-diary and will have regular 
visits to assess safety and tolerability. Investigator confirmation of angioedema events will continue to be 
required for Part 2. Interim safety analyses will be conducted while Parts 2 and 3 are ongoing to support 
regulatory filings.  
  
 
Abbreviations: e-diary = electronic diary; QD = once daily. 
 
Part 3 (up to 52-week evaluation of the safety of open-label BCX7353) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 52 visit. Based on 
the safety profile and efficacy of the 150 mg dose in Part 1 of the similarly-designed Study BCX7353-302 
(Study 302), all subjects in the current study receiving 110 mg QD will be transitioned to open-label 150 mg QD 
at the Week 52 visit. 
Study visits during Part 3 will occur during Week 60 and approximately every 12 weeks thereafter, for a total 
study duration of up to 104 weeks, until another mechanism is available to provide drug to the subject (eg, market 
access), or until the Sponsor discontinues development of the product for the prevention of angioedema events, 
whichever comes first. Telephone contacts will occur at Weeks 56, 64, 68, 76, 80, 88, 92, and 100. A final study 
follow-up visit (Week 107) will be scheduled approximately 3 weeks following the last administration of study 
drug. Subjects will continue to document all angioedema events (attack, symptoms or swelling due to HAE) that 
occur while on study drug in their e-diary in Part 3. However, subjects will not be required to document 
compliance with the study drug. In addition, investigator confirmation of angioedema events will not be required 
in Part 3. All angioedema events recorded by the subjects will be reviewed and confirmed or rejected according 
to a set of pre-defined rules prior to inclusion in the effectiveness analyses. These rules will be outlined in the 
Statistical Analysis Plan. 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 1.0 
 
4 November 2019 
8 
CONFIDENTIAL 
Number of Subjects (planned): 
Approximately 24 subjects with Type 1 or 2 HAE are planned to be enrolled (n = approximately 8 per group in 
Part 1 [110 mg BCX7353, 150 mg BCX7353, and placebo]).  
Main criteria for inclusion:  
1. Males and non-pregnant, non-lactating females ≥ 12 years of age.  
2. Able to provide written, informed consent. Subjects aged 12 to 17 years must be able to read, 
understand, and be willing to sign an assent form in addition to a caregiver providing informed consent.  
3. A clinical diagnosis of HAE Type 1 or Type 2, defined as having a C1 esterase inhibitor (C1-INH) 
functional level < 50% and a complement 4 (C4) level below the lower limit of the normal (LLN) 
reference range, as assessed during the screening period.  
In the absence of a low C4 value drawn during the inter-critical period (ie, subject is not having an 
angioedema event), 1 of the following is acceptable to confirm the diagnosis of HAE: 1) a SERPING-1 
gene mutation known or likely to be associated with HAE Type 1 or 2 assessed during the screening 
period; 2) a confirmed family history of C1-INH deficiency; 3) a C4 redrawn and retested during an 
angioedema event in the screening period with the results below the LLN reference range.  
For a C1-INH that is between 50% and the LLN (74%), a SERPING-1 gene mutation known or likely to 
be associated with HAE Type 1 or 2 HAE is acceptable to confirm the diagnosis of HAE.  
SERPING-1 gene analysis results indicating a “possibly pathogenic” mutation will be considered on a 
case-by-case basis by the medical monitor and may require additional testing for eligibility. 
4. Access to and ability to use an acute treatment for angioedema events approved by the Japan Ministry of 
Health, Labor, and Welfare (plasma-derived C1-INH or icatibant).  
5. Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for 
their HAE during the study; that is, subjects must be medically appropriate to be managed without 
prophylactic treatments for HAE.  
6. The subject must have at least 2 angioedema events as assessed by an independent expert that meet all 
requirements below during the run-in period of 56 days beginning at the screening visit: 
• 
The angioedema events are unique, which is defined as an angioedema event that does not 
begin within 48 hours of the end of a previous angioedema event. 
• 
The angioedema events must have either been treated, required medical attention, or be 
documented to cause functional impairment based on subject entry in the e-diary. Functional 
impairment is defined as the subject not being able to perform daily activities without 
restriction (ie, subject records that he/she is at least slightly restricted in daily activities during 
the angioedema event). 
• 
The angioedema events must include symptoms of swelling. The expert will consider that 
symptoms of swelling, in addition to visible swelling, may also include symptoms in the 
oropharyngeal or abdominal regions that are indicative of internal swelling. 
• 
The angioedema events are otherwise confirmed by an independent expert to be angioedema 
events.    
Under no circumstances should the run-in angioedema event requirement for eligibility be disclosed to 
study subjects. 
7. Female subjects must agree to the contraception requirements and must meet the inclusion criteria 
regarding contraception, as outlined in Section 8.2.1 of the protocol. 
8. In the opinion of the investigator, the subject is expected to adequately comply with all required study 
procedures for the duration of the study. The subject must demonstrate adequate compliance with all 
study procedures required from the screening visit through randomization, including e-diary recording of 
angioedema events beginning at the screening visit. 


BioCryst Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan Version 1.0 
 
4 November 2019 
9 
CONFIDENTIAL 
Main criteria for exclusion: 
1. Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the 
investigator or sponsor, would interfere with the subject’s ability to participate in the study or increases 
the risk to the subject by participating in the study.  
2. Dementia, altered mental status, or any psychiatric condition or stay in an institution further to an 
official or court order that would prohibit the understanding or rendering of informed consent or 
participation in the study. 
3. Anticipated use of short-term prophylaxis of angioedema events for a preplanned procedure during the 
screening or study periods.  
4. Concurrent diagnosis of any other type of recurrent angioedema. 
5. Clinically significant abnormal ECG at the screening visit. This includes, but is not limited to, a 
corrected QT interval using Fridericia’s method (QTcF) > 470 msec for women, a QTcF > 450 msec for 
men, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as 
couplets or higher in grouping. 
6. Any clinically significant history of angina, myocardial infarction, syncope, cardiac arrhythmias, left 
ventricular hypertrophy, cardiomyopathy, or any other clinically significant cardiovascular abnormality 
such as poorly controlled hypertension. 
7. Known family history of sudden cardiac death. Family history of sudden death from HAE is not 
exclusionary. 
8. History of or current implanted defibrillator or pacemaker. 
9. Any abnormal laboratory or urinalysis parameter at screening that, in the opinion of the investigator, is 
clinically significant and relevant for this study. A calculated creatinine clearance of ≤ 30 mL/min or 
aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the normal 
reference range value obtained during screening is exclusionary.  
10. Prior enrollment in a BCX7353 study. 
11. Suspected C1-INH resistance in the opinion of the investigator or sponsor. 
12.  History of alcohol or drug abuse within the previous year prior to the screening visit, or current 
evidence of substance dependence or abuse (self-reported alcohol intake > 3 drinks/day). 
13. Positive serology for human immunodeficiency virus or current infection with hepatitis B virus or 
hepatitis C virus. 
14. Pregnant or planning to become pregnant during the study. 
15. Currently breastfeeding. Women who want to enter the study must agree to suspend breastfeeding at the 
screening visit. Women must wait at least 3 weeks after the last dose of BCX7353 to commence 
breastfeeding.  
16. Positive drugs of abuse screen (unless drug is used as medical treatment with a prescription). 
17. History of severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis 
with unclear etiology. 
18. Use of androgens or tranexamic acid for prophylaxis of angioedema events within the 28 days prior to 
the screening visit or initiation during the study.  
19. Use of C1-INH for prophylaxis of angioedema events within the 14 days prior to the screening visit or 
initiation during the study. Use of a C1-INH therapy for treatment of angioedema events is not excluded 
at any time, nor is C1-INH for preprocedural prophylaxis for an unplanned/unforeseen procedure. 
20. Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, and CYP3A4 
and have a narrow therapeutic range, within 7 days of the baseline visit or planned initiation during the 
study.  
21. Use of a medication that is clinically known to prolong the QT interval and is metabolized by CYP2D6, 
CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to the baseline visit or planned initiation during the 
study. 
22. Use of a medication that is transported by P-glycoprotein and has a narrow therapeutic range, within 
7 days of the baseline visit or planned initiation during the study. 
23. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or planned 
initiation during the study.  
24. Initiation of an estrogen-containing hormonal contraceptive within 56 days of the screening visit or 
planned initiation during the study.  


BioCryst Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan Version 1.0 
 
4 November 2019 
10 
CONFIDENTIAL 
25. Current participation in any other investigational drug study or received another investigational drug 
within 30 days of the screening visit. 
26. An immediate family relationship to either sponsor employees, the investigator, or employees of the 
study site named on the delegation log. 
27. Held in an institution by a government or judicial order.   
 
Investigational product, dosage, and mode of administration:  
BCX7353 capsules, to be administered orally.  
Parts 1 and 2 
BCX7353 capsules contain 55 and 75 mg of the active ingredient (free base equivalents). Subjects will take the 
following orally once daily at approximately the same time each day, with whichever meal is typically the largest 
of the day: 
Treatment Group 1 (110 mg QD) Parts 1 and 2: two 55-mg capsules of BCX7353 
Treatment Group 2 (150 mg QD) Parts 1 and 2: two 75-mg capsules of BCX7353 
Subjects randomized to Treatment Group 1 or 2 will receive the same dose of study drug in both Parts 1 and 2.  
Subjects randomized to Treatment Group 3 in Part 1 will be automatically randomized to receive active study 
drug from the Week 24 visit (Part 2): 
Treatment Group 3a (110 mg QD) Part 2: two 55-mg capsules of BCX7353 
Treatment Group 3b (150 mg QD) Part 2: two 75-mg capsules of BCX7353 
Part 3 
BCX7353 capsules contain 150 mg of the active ingredient (free base equivalent). Subjects will take a single 
capsule orally once daily at approximately the same time each day, with whichever meal is typically the largest of 
the day. 
Subjects randomized to Treatment Groups 1 and 2 will receive a total of up to 104 weeks of active BCX7353 
treatment. Subjects randomized to Treatment Group 3 will receive a total of up to 80 weeks of active BCX7353 
treatment. 
Reference therapy, dosage, and mode of administration:  
Placebo-to-match BCX7353 capsules. Subjects randomized to Treatment Group 3 will take 2 capsules of placebo 
orally QD for 24 weeks during Part 1 with their largest meal of the day. 
Duration of treatment: 
Subjects will take capsules of BCX7353 or placebo orally for 24 weeks in Part 1 and capsules of BCX7353 orally 
for up to 80 weeks (28 weeks in Part 2 and up to 52 weeks in Part 3), for a total duration of study drug treatment 
of up to 104 weeks. 
Criteria for evaluation: 
Efficacy: 
Number of angioedema events and related details (timing, duration of symptoms, anatomical location, treatment 
used, emergency room visits, hospitalizations), number of days with HAE symptoms, number of subjects who are 
angioedema event-free, assessment of angioedema event severity, and discontinuations due to lack of efficacy.    
Safety: 
AEs, laboratory analyses (clinical chemistry, hematology, coagulation, urinalysis, creatine kinase-MB, troponin I 
and T, neutrophil gelatinase-associated lipocalin), vital signs, ECGs, and physical examinations. An independent 
Data Monitoring Committee (DMC) will periodically review safety data in accordance with a DMC Charter. 
Relationships between safety assessment findings and human leukocyte antigen typing results may be examined 
on a meta-study basis.  
Health Outcomes: 
AE-QoL, EQ-5D-5L, TSQM, and WPAI questionnaire scores. 


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Pharmacodynamics: 
Kallikrein inhibition. Additional exploratory assays to elucidate PD properties of BCX7353 may also be 
conducted on plasma samples drawn for PD analyses.  
Pharmacokinetics:  
Blood samples for BCX7353 concentrations will be drawn. Population pharmacokinetic parameters of BCX7353 
will be evaluated on a meta-study basis. 
Statistical methods: 
The primary study hypothesis is that the rate of angioedema events during 24 weeks of prophylactic BCX7353 
will be less than the corresponding rate on placebo. The primary efficacy endpoint in Study BCX7353-301 
(Study 301) is the monthly expert-confirmed angioedema event rate in the entire treatment period (Day 1 [post-
dose] to Day 168) in the intent-to-treat (ITT) population, which includes all randomized subjects. The primary 
analysis will be conducted on the Study 301 population. It should be noted that the sample size considered 
feasible for enrollment in Japan has limited statistical power. 
A supplemental analysis will combine data from Part 1 of this study with data from Study 302, Part 1. The 
primary efficacy endpoint in Study 302 is the monthly investigator-confirmed angioedema event rate in the entire 
treatment period (Day 1 [post-dose] to Day 168) in the ITT population.  
The angioedema event rate and the treatment comparisons between each BCX7353 dose and placebo in the rate 
of investigator- or expert-confirmed HAE angioedema events during the entire dosing period will be analyzed 
using a negative binomial regression model. The number of investigator or expert-confirmed angioedema events 
will be included as the dependent variable, the treatment will be included as a fixed effect, the stratification 
variable (baseline angioedema event rate) will be included as a covariate, and the logarithm of duration on 
treatment will be included as an offset variable. The estimated rate of angioedema event for each treatment group, 
the treatment differences expressed as the angioedema event rate ratio (BCX7353 over placebo rate ratio), and 
their associated 95% confidence intervals will be provided from the negative binomial regression model. Monthly 
will be defined as 4 weeks.  
Descriptive summaries, figures, and listings will be produced for efficacy endpoints of interest. Safety data 
analyses will be conducted using data from the current study alone. 
The safety analyses will be analyzed separately for Part 1 alone; a later data analysis will evaluate long-term 
safety data for the current study. Safety endpoints that will be summarized include, at a minimum, the number 
and proportion of subjects 
1) with a TEAE;  
2) who discontinue BCX7353 due to a TEAE  
3) who experience a TESAE; 
4) who experience a Grade 3 or 4 TEAE; and  
5) who experience a treatment-emergent Grade 3 or 4 laboratory abnormality. In addition, the proportion of 
subjects with treatment-emergent, treatment-related AEs consistent with a drug rash will also be summarized. 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .....................................................................................18 
2. 
INTRODUCTION ......................................................................................................20 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................20 
3.1. 
Study Objectives .........................................................................................................20 
3.1.1. 
Part 1 Primary Objective ............................................................................................20 
3.1.2. 
Part 1 Secondary Objectives .......................................................................................20 
3.1.3. 
Part 2 Primary Objective ............................................................................................20 
3.1.4. 
Part 2 Secondary Objectives .......................................................................................21 
3.1.5. 
Part 3 Primary Objectives ...........................................................................................21 
3.1.6. 
Part 3 Secondary Objectives .......................................................................................21 
3.2. 
Study Endpoints ..........................................................................................................21 
3.2.1. 
Part 1 Primary Efficacy Endpoint ...............................................................................21 
3.2.2. 
Part 1 Secondary Efficacy Endpoints .........................................................................21 
3.2.3. 
Part 1 Exploratory Efficacy Endpoints .......................................................................21 
3.2.4. 
Part 1 Safety Endpoints ..............................................................................................22 
3.2.5. 
Part 1 Health Outcome Endpoints ..............................................................................22 
3.2.6. 
Part 2 Primary Endpoints ............................................................................................22 
3.2.7. 
Part 2 Secondary Endpoints ........................................................................................22 
3.2.8. 
Part 3 Primary Endpoints ............................................................................................23 
3.2.9. 
Part 3 Secondary Endpoints ........................................................................................23 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Summary of Study Design ..........................................................................................23 
4.2. 
Definition of Study Drugs ..........................................................................................26 
4.3. 
Sample Size Considerations .......................................................................................26 
4.3.1. 
Sample Size for Analysis of Study 301 Alone ...........................................................26 
4.3.2. 
Sample Size for Combined Analysis of Studies 301 and 302 ....................................27 
4.4. 
Randomization ............................................................................................................27 
4.4.1. 
Part 1 Randomization .................................................................................................28 
4.4.2. 
Part 2 Randomization .................................................................................................29 
4.5. 
Clinical Assessments ..................................................................................................29 
5. 
PLANNED ANALYSES ............................................................................................38 


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5.1. 
Interim Analyses .........................................................................................................38 
5.2. 
Primary Efficacy Analysis at the End of Part 1 ..........................................................38 
5.3. 
Combined Efficacy Analysis at the End of Part 1 ......................................................38 
5.4. 
Final Analysis .............................................................................................................38 
5.5. 
Other Analyses to Support Safety Review and Regulatory Submissions ...................38 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING ...............................................................................................................39 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........39 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................42 
6.3. 
Data Management .......................................................................................................43 
6.4. 
Data Presentation Conventions ...................................................................................43 
6.5. 
Analysis Populations ..................................................................................................44 
6.5.1. 
Screen Failures ............................................................................................................44 
6.5.2. 
Intent-to-Treat Population ..........................................................................................44 
6.5.3. 
Safety Population ........................................................................................................44 
6.5.4. 
Per-Protocol Population ..............................................................................................44 
6.5.5. 
Completers Population ................................................................................................44 
6.5.6. 
Pharmacodynamic Population ....................................................................................44 
6.5.7. 
Pharmacokinetic Concentration/Pharmacodynamic Population .................................44 
6.6. 
Baseline Definition .....................................................................................................45 
6.6.1. 
Baseline Event Rate ....................................................................................................45 
6.6.2. 
Categorized Baseline Event Rate ................................................................................45 
6.6.3. 
Baseline Age ...............................................................................................................45 
6.7. 
Derived and Transformed Data ..................................................................................45 
6.7.1. 
Study Day ...................................................................................................................45 
6.7.2. 
Change from Baseline .................................................................................................45 
6.7.3. 
Visit Windows ............................................................................................................46 
6.7.4. 
Multiple Assessments .................................................................................................46 
6.7.5. 
Derived Efficacy Endpoints ........................................................................................47 
6.7.5.1. 
Event Rate ...................................................................................................................47 
6.7.5.2. 
Number and Percentage of Subjects Who Are Event Free Over Entire 
Dosing Period and Effective Dosing Period ...............................................................49 


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6.7.5.3. 
Number and Proportion of Days with Angioedema Symptoms .................................49 
6.7.5.4. 
Responder Endpoint ....................................................................................................50 
6.7.5.5. 
Event Duration ............................................................................................................50 
6.7.5.6. 
Event Onset Relative to Prior Dose of Study Drug ....................................................50 
6.7.5.7. 
Medications to Treat HAE Events ..............................................................................50 
6.7.5.8. 
Event Symptoms .........................................................................................................51 
6.7.5.9. 
Event Location ............................................................................................................51 
6.7.5.10. 
Laryngeal Events ........................................................................................................51 
6.7.5.11. 
Event Triggers ............................................................................................................51 
6.7.5.12. 
AE-QoL ......................................................................................................................52 
6.7.6. 
Derived Health Outcomes Endpoints .........................................................................53 
6.7.6.1. 
EQ-5D-5L ...................................................................................................................53 
6.7.6.2. 
Treatment Satisfaction Questionnaire for Medication ................................................55 
6.7.6.3. 
Work Productivity and Activity Impairment Questionnaire ......................................56 
6.8. 
Handling of Missing Data ...........................................................................................57 
6.8.1. 
Imputation of Missing Efficacy Endpoints Post Study Treatment 
Discontinuation ...........................................................................................................57 
6.8.2. 
Other Sensitivity Analyses for Missing Data .............................................................58 
6.8.3. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................58 
6.8.4. 
Missing Start Date, Stop Date, Severity, or Relationship for Adverse Event ............59 
6.8.5. 
Missing Time of First Dose or Time of Last Dose .....................................................59 
6.8.6. 
Incomplete Date and Time for a Subject-Reported Event ..........................................59 
7. 
STUDY POPULATION .............................................................................................60 
7.1. 
Subject Disposition .....................................................................................................60 
7.2. 
Screen Failures ............................................................................................................60 
7.3. 
Protocol Deviations and Listing of Subject Inclusion and Exclusion Criteria ...........61 
7.4. 
Demographic and Baseline Characteristics ................................................................61 
7.5. 
HAE Medical and Medication History .......................................................................62 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................62 
7.7. 
Prior and Concomitant Non-HAE and HAE Medications ..........................................62 
7.8. 
Baseline Physical Examination ...................................................................................63 
7.9. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................63 
8. 
EFFICACY .................................................................................................................63 


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8.1. 
General Considerations ...............................................................................................63 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................63 
8.3. 
Statement of the Null and Alternate Hypotheses ........................................................64 
8.4. 
Subgroup Analyses for Combined Study Analysis ....................................................64 
8.5. 
Multiple Comparisons and Multiplicity ......................................................................65 
8.6. 
Analysis of the Primary Efficacy Endpoint ................................................................66 
8.6.1. 
Primary Efficacy Analysis ..........................................................................................66 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Results ................................................67 
8.7. 
Analysis of the Secondary Efficacy Endpoints ..........................................................68 
8.7.1. 
Angioedema Quality of Life (Total and Domain Scores) ..........................................68 
8.7.2. 
Number and Proportion of Days with Angioedema Symptoms .................................68 
8.7.3. 
Rate of Expert-Confirmed HAE Events during Dosing in the Effective 
Dosing Period .............................................................................................................69 
8.7.4. 
Use of HAE Event Medications .................................................................................69 
8.7.5. 
Discontinuations due to Lack of Efficacy ..................................................................70 
8.8. 
Analysis of Additional Exploratory Efficacy Endpoints ............................................70 
8.8.1. 
Number and Proportion of Subjects with No Events ..................................................70 
8.8.2. 
Proportion of Responders to Study Drug....................................................................70 
8.8.3. 
Event Characteristics ..................................................................................................71 
8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................71 
9. 
HEALTH OUTCOMES .............................................................................................71 
9.1. 
EQ-5D-5L ...................................................................................................................71 
9.2. 
Treatment Satisfaction Questionnaire for Medication ................................................72 
9.3. 
Work Productivity and Activity Impairment ..............................................................72 
10. 
SAFETY AND TOLERABILITY ..............................................................................73 
10.1. 
Adverse Event Preferred Term and System Organ Class Summary Tables ...............73 
10.1.1. 
Summaries of Adverse Event Incidence Rates for All Subjects and Incidence 
Rates for Serious Adverse Events, Discontinuations due to Adverse Events, 
and Deaths ..................................................................................................................74 
10.1.2. 
Investigator-Identified Rash Events of Special Interest and Gastrointestinal 
Abdominal-Related Adverse Events ...........................................................................75 
10.1.3. 
Missing and Partial Adverse Event Onset Dates ........................................................76 


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10.1.4. 
Summaries of Adverse Event Incidence Rates per Person-Year of Exposure 
to Study Treatment .....................................................................................................76 
10.2. 
Exposure to Study Treatment and Treatment Compliance .........................................77 
10.3. 
Concomitant and Other Medications ..........................................................................78 
10.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........78 
10.4. 
Laboratory Data ..........................................................................................................78 
10.4.1. 
Prior Androgen Use and Liver Function Test Abnormalities .....................................79 
10.4.2. 
Complement Factors and HAE Diagnosis ..................................................................79 
10.4.3. 
Laboratory Assessments for Rash ..............................................................................80 
10.5. 
Pregnancy ...................................................................................................................80 
10.6. 
Vital Signs ..................................................................................................................80 
10.7. 
12-lead Electrocardiograms ........................................................................................80 
10.8. 
Physical Examination .................................................................................................81 
10.9. 
Study Termination Status ...........................................................................................81 
11. 
PHARMACOKINETICS ...........................................................................................81 
12. 
PHARMACODYNAMICS ........................................................................................81 
13. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................82 
14. 
PHARMACOGENETICS ..........................................................................................82 
15. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ....................................82 
16. 
REFERENCES ...........................................................................................................83 
17. 
APPENDIX .................................................................................................................84 
17.1. 
Table of Contents for Data Display Specifications ....................................................84 
17.1.1. 
Tables ..........................................................................................................................84 
17.1.1.1. 
BCX7353-301 Only ....................................................................................................84 
17.1.1.2. 
BCX7353-301 and BCX7353-302 Combined Study Output .....................................93 
17.1.2. 
Listings (BCX7353-301 Only) ...................................................................................95 
17.1.3. 
Figures ......................................................................................................................100 
17.1.3.1. 
BCX7353-301 Only ..................................................................................................100 
17.1.3.2. 
BCX7353-301 and BCX7353-302 Combined Study Output ...................................103 
17.2. 
Data Display Specifications ......................................................................................104 
17.3. 
List of Preferred Terms, High Level Terms, and High Level Group Terms 
for GI Abdominal-Related AEs ................................................................................104 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ..................................................................................................18 
Table 2: 
Power Calculations to Support Sample Size ..............................................................27 
Table 3: 
Schedule of Assessments: Part 1 of Study 301 ...........................................................30 
Table 4: 
Schedule of Assessments: Part 2 of Study 301 ...........................................................34 
Table 5:  
Schedule of Assessments: Part 3 of Study 301 ...........................................................36 
Table 6: 
Treatment Descriptors for Part 1 Only Displays ........................................................40 
Table 7: 
Treatment Descriptors for Part 2 Only Displays ........................................................40 
Table 8: 
Treatment Descriptors for Displays for Entire Study .................................................41 
Table 9: 
Adjusted Visit for Active Treatment for Subjects Originally Assigned to 
Placebo ........................................................................................................................42 
Table 10: Visit Windows (Days) ................................................................................................46 
Table 11: Determination of Event Location Using Symptoms Collected in the e-Diary ...........51 
Table 12: EQ-5D-5L Dimensions (UK English Sample Version) ..............................................54 
Table 13: List of Questions for TSQM .......................................................................................55 
Table 14: Reason for Study Treatment Discontinuation and Whether Data are 
Considered Missing at Random or Not ......................................................................58 
Table 15: Definition of Compliance Categories .........................................................................77 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................26 
Figure 2: 
Study Randomization ..................................................................................................29 
 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AE-QoL 
Angioedema Quality of Life Questionnaire 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase 
BMI 
body mass index 
C1-INH 
C1 esterase inhibitor 
C3 
complement 3 
C4 
complement 4 
CFB 
change from baseline  
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases  
EC50 
half-maximal effective concentration  
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
e-diary 
electronic diary 
EOSI 
event of special interest 
EQ-5D-5L 
EuroQoL 5-dimensional, 5-level questionnaire  
EQ VAS 
EuroQoL Visual Analogue Scale 
FDA 
Food and Drug Administration  
GI 
gastrointestinal  
HAE 
hereditary angioedema 
HLGT 
high-level group term 
ICH 
International Council for Harmonization  
ID 
identification  
ITT 
intent-to-treat 
IXRS 
interactive (web or voice) response system  


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%KKI 
percent kallikrein inhibition  
KM 
Kaplan-Meier 
LLN 
lower limit of normal 
LSM 
least squares mean 
MCID 
minimum clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MMRM 
mixed model of repeated measures 
N 
total sample size 
PD  
Pharmacodynamic 
PK 
pharmacokinetic  
PP 
per-protocol population 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTcF 
QT Interval Corrected Using Fridericia’s Method 
SD 
standard deviation 
SAP 
Statistical Analysis Plan  
SAS 
Statistical Analysis System  
SOC 
System Organ Classification  
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TSQM 
Treatment Satisfaction Questionnaire for Medication  
ULN 
upper limit of normal 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
WHODD 
World Health Organization Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment Questionnaire  
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Study BCX7353-301 (Study 301). 
Protocol Revision Chronology: 
Protocol 
19 July 2018 
Version 1 
 
26 September 2018 
Version 2 
 
11 October 2018 
Version 3 (matches the Pharmaceutical and Medical Devices 
Agency-accepted v1.1 dated 1 October 2018) 
 
15 October 2018 
Version 4 
 
29 August 2019 
Version 5 
This SAP was developed in accordance with the International Council for Harmonisation (ICH) 
E9 guideline. The purpose of this document is to provide details on the statistical methodology 
used to analyze the safety and efficacy data for Study 301. Study population definitions, 
derivations of variables, handling of missing data, and other information necessary for analysis 
of study data are provided. Planned tables, figures, and listings are specified. All decisions 
regarding interim and final analysis will be made, the SAP will be finalized, approved by the 
Sponsor, and placed on file before the database is locked for the interim analysis. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Part 1 Primary Objective 
• To determine the efficacy of BCX7353 110 and 150 mg administered once daily 
(QD) for 24 weeks compared to placebo in the prevention of angioedema events in 
subjects with hereditary angioedema (HAE). 
3.1.2. 
Part 1 Secondary Objectives 
• To assess the safety and tolerability of BCX7353 110 mg and 150 mg QD 
administered for 24 weeks  
• To assess the effects of BCX7353 on HAE disease activity and angioedema  
characteristics 
• To evaluate the effects of BCX7353 on quality of life (QoL) 
• To characterize the pharmacodynamic (PD) effects of BCX7353 
3.1.3. 
Part 2 Primary Objective 
• To evaluate the long-term safety and tolerability of BCX7353 110 and 150 mg in 
subjects with HAE 


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3.1.4. 
Part 2 Secondary Objectives 
• To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 
over a 24- to 52-week administration period 
• To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 52-week 
administration period 
• To evaluate subject satisfaction with BCX7353 over a 24- to 52-week administration 
period 
3.1.5. 
Part 3 Primary Objectives 
• To evaluate the long-term safety and tolerability of BCX7353 administered QD over 
a 52- to up to 104-week administration period in subjects with HAE 
3.1.6. 
Part 3 Secondary Objectives 
• To assess the effectiveness (ie, angioedema event frequency over time) of BCX7353 
over a 52- to up to 104-week administration period 
• To evaluate QoL and HAE disease activity of BCX7353 over a 52- to up to 104-week 
administration period 
• To evaluate subject satisfaction with BCX7353 over a 52- to up to 104-week 
administration period 
3.2. 
Study Endpoints 
3.2.1. 
Part 1 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is as follows: 
• The rate of expert-confirmed angioedema events during dosing in the entire 24-week 
treatment period (Days 1 to 168) 
3.2.2. 
Part 1 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows:  
• Change from baseline in AE-QoL at Week 24 (total score) 
• Number and proportion of days with angioedema symptoms through 24 weeks 
• Rate of expert-confirmed angioedema events during dosing in the effective treatment 
period (beginning on Day 8 through 24 weeks) 
3.2.3. 
Part 1 Exploratory Efficacy Endpoints 
• Number and proportion of subjects with no angioedema events over 24 weeks 
• Use of medications to treat angioedema events over 24 weeks 
• The proportion of responders to study drug, separately defined as at least a 50%, 
70%, or 90% relative reduction in the rate of expert-confirmed angioedema events 


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during treatment, compared with the baseline expert-confirmed angioedema event 
rate 
3.2.4. 
Part 1 Safety Endpoints 
• Number and proportion of subjects with a treatment-emergent adverse event (TEAE) 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a treatment-emergent serious 
adverse event (TESAE)  
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
3.2.5. 
Part 1 Health Outcome Endpoints 
• EuroQoL 5-Dimensional 5-Level (EQ-5D-5L) questionnaire scores 
• Treatment Satisfaction Questionnaire for Medication (TSQM) scores 
• Work Productivity and Activity Index (WPAI) questionnaire scores 
3.2.6. 
Part 2 Primary Endpoints 
• Number and proportion of subjects with a TEAE 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a TESAE  
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
• The proportion of subjects with a treatment-emergent, treatment-related adverse event 
(AE) consistent with a drug rash 
3.2.7. 
Part 2 Secondary Endpoints 
• Number and rate of angioedema events 
• Durability of response (angioedema event rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Use of medications to treat angioedema events 
• Discontinuations due to lack of efficacy 
• Durability in AE-QoL questionnaire scores 
• Durability in EQ-5D-5L scores 
• Durability in TSQM scores 


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• Durability in WPAI scores 
3.2.8. 
Part 3 Primary Endpoints 
• 
Number and proportion of subjects with a TEAE 
• 
Number and proportion of subjects who discontinue due to a TEAE 
• 
Number and proportion of subjects who experience a TESAE 
• 
Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• 
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 
laboratory abnormality 
• The proportion of subjects with a treatment-emergent, treatment related AE consistent 
with a drug rash 
3.2.9. 
Part 3 Secondary Endpoints  
• 
Number and rate of angioedema events 
• 
Durability of response (angioedema event rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of medications to treat angioedema events 
• 
Durability in AE-QoL questionnaire scores 
• 
Durability in EQ-5D-5L scores 
• 
Durability in TSQM scores 
• 
Durability in WPAI scores 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 2-part study. 
Part 1 is designed to test the hypothesis that the primary efficacy endpoint of the angioedema 
event rate during 24 weeks of prophylactic BCX7353 treatment at 2 dosage levels will be less 
than that observed during 24 weeks of placebo. This primary efficacy endpoint will be assessed 
after the last subject completes Part 1 (through Week 24). Part 2 is designed to primarily evaluate 
the long-term safety of BCX7353 at 2 dosage levels. Part 3 is open-label and designed to primarily 
evaluate the long-term safety of BCX7353. Parts 1, 2, and 3 will be conducted in sequence, with 
Parts 2 and 3 conducted as continuous roll-overs from Parts 1 and 2, respectively. All subjects will 
receive BCX7353 in Parts 2 and 3, including those randomized to receive placebo in Part 1. An 
angioedema event is defined as an attack, symptoms, or swelling due to a subject’s underlying 
HAE disease. 
In addition, all efficacy outcomes along with the pharmacokinetic (PK)/PD displays in Part 1, 
where appropriate, will be statistically analyzed by combining data from this study with data 


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from Phase 3 Study BCX7353-302 (Study 302) to ensure adequate statistical power.  Safety data 
will not be combined. 
Part 1 (24-week evaluation of blinded efficacy and safety data) 
Subjects with HAE Type 1 or 2 will be eligible for the study following assessment of data 
obtained from screening procedures, including demonstration of a minimum number of 
qualifying angioedema events documented during a prospective run-in period of 8 weeks from 
the date of the screening visit.  
Approximately 24 treatment-eligible subjects ≥ 12 years of age will receive study drug 
(BCX7353 or placebo) in Part 1 of the study based on randomization in a 1:1:1 ratio into 1 of 
3 treatment groups: 
Group 1 (N = 8): BCX7353 110 mg QD administered orally for 24 weeks 
Group 2 (N = 8): BCX7353 150 mg QD administered orally for 24 weeks 
Group 3 (N = 8): placebo administered orally QD for 24 weeks 
Enrollment into treatment groups will be stratified by the baseline angioedema event rate 
(≥ 2 angioedema events per month from the date of screening vs. < 2 angioedema events per 
month from the date of screening).  
Qualifying angioedema events that are counted in the baseline angioedema event rate for 
stratification and those that are used to qualify a subject during the run-in period must be 
characterized as follows: 
• The angioedema events must be unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
have been documented to cause functional impairment, based on the subject's entry in 
the electronic diary (e-diary). Functional impairment is defined as the subject not 
being able to perform his or her daily activities without restriction (ie, subject records 
that he/she is at least slightly restricted in daily activities during an angioedema 
event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events are otherwise confirmed by an independent expert to be 
angioedema events.  
A study schematic can be found in Figure 1. 
Throughout the entire study, details of all angioedema events (attacks, symptoms, or swelling 
due to HAE) and compliance with study drug will be recorded in an e-diary. Angioedema events 
will be treated in accordance with the subject’s normal standard of care. Within approximately 
2 business days of the end of each angioedema event that occurs from the screening visit through 
the follow-up visit after Part 2, subjects will be contacted by the investigator (or appropriately 
trained designee) to discuss the clinical characteristics of the angioedema event, any questions on 


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the entered data, or to gain additional details on the event that are not included in the e-diary that 
the investigator deems important to clinically evaluate the event, as applicable. The 
investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each angioedema event recorded in the e-diary as a 
confirmed angioedema event. All expert-confirmed angioedema events must include symptoms 
of swelling; prodromal symptoms in the absence of swelling are not considered angioedema 
events, regardless of treatment. The expert will consider that symptoms of swelling, in addition 
to visible swelling, may also include symptoms in the oropharyngeal or abdominal regions that 
are indicative of internal swelling. Under no circumstances should the run-in angioedema event 
requirement for eligibility be disclosed to study subjects. 
Study visits in Part 1 will occur at screening, baseline and Weeks 2, 4, 8, 12, 18, and 24. The 
primary efficacy analysis will occur after the last subject completes the Week 24 visit and will 
include all data through Week 24. 
Part 2 (evaluation of safety of blinded BCX7353) 
Part 2 of the study will start upon administration of study drug dispensed at the Week 24 visit. 
Subjects in Groups 1 and 2 will continue to receive the same BCX7353 dose to which they were 
randomized in Part 1 of the study in a blinded manner. Subjects randomized to Group 3 will 
undergo a second randomization in a 1:1 ratio to receive either a 110 or 150 mg QD dose of 
BCX7353 in a blinded manner beginning at the Week 24 visit (see Figure 1). The active dose a 
subject receives in Part 2 will be blinded for all subjects; subjects will be informed that they will 
receive an active dose of BCX7353 in Part 2. 
Study visits in Part 2 will occur during Weeks 26, 28, 32, 36, 48, and 52, with telephone contact 
at Weeks 40 and 44. Subjects will continue to document all angioedema events that occur while 
on study drug, as well as compliance with the study drug, in their e-diary and will have regular 
visits to assess safety and tolerability; investigator confirmation of angioedema events will 
continue to be required for Part 2. Interim safety analyses will be conducted while Parts 2 and 3 
are ongoing to support regulatory filings. 
Part 3 (up to a 52-week evaluation of the safety of open-label BCX7353 150 mg QD) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 52 
visit. Based on the safety profile and efficacy of the 150 mg dose in Part 1 of the 
similarly-designed Study 302, all subjects in the current study receiving 110 mg QD will be 
transitioned to open label 150 mg QD at the Week 52 visit. 
Study visits in Part 3 will occur during Week 60 and approximately every 12 weeks thereafter, 
for a study duration of up to 104 weeks, until another mechanism is available to provide drug to 
the subject (eg, market access), or until the Sponsor discontinues development of the product for 
the prevention of angioedema attacks, whichever comes first. Telephone contact will occur at 
Weeks 56, 64, 68, 76, 80, 88, 92, and 100. 
Subjects will continue to document all angioedema events that occur in their diary throughout 
Part 3 and will have regular visits to assess safety and tolerability. However, subjects will not be 
required to document compliance with the study drug. In addition, investigator and expert 
confirmation of angioedema events will not be required in Part 3. All angioedema events 


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recorded by the subjects will be reviewed and confirmed or rejected according to a set of 
pre-defined rules prior to inclusion in effectiveness analyses.  
A final study follow-up visit will be scheduled approximately 3 weeks following the last 
administration of study drug (up to Week 104). 
Figure 1: 
Study Schema 
  
Abbreviations: e-diary = electronic diary; QD = once daily. 
4.2. 
Definition of Study Drugs 
BCX7353 110 mg QD is supplied as two 55-mg capsules of BCX7353 per dose for Parts 1 and 
2. 
BCX7353 150 mg QD is supplied as two 75-mg capsules of BCX7353 per dose for Parts 1 and 
2, and as one 150-mg capsule for Part 3. 
Placebo QD is supplied as 2 capsules of matching placebo per dose (Part 1 only).   
4.3. 
Sample Size Considerations 
Power calculations for the primary efficacy endpoint for the current study alone and those for the 
combined analyses with Study 302 are provided in Table 2 and described in Sections 4.3.1 and 
4.3.2, respectively. 
4.3.1. 
Sample Size for Analysis of Study 301 Alone 
Assuming a weekly angioedema event rate for placebo subjects of 0.9 and a common standard 
deviation (SD) of 0.50 angioedema events per week for BCX7353 and placebo and with 
8 subjects per treatment group in the current study alone, the power to detect a ≥ 67% 
angioedema event rate reduction (a treatment difference of 0.6 angioedema events per week) for 
each comparison of angioedema event rates between active and placebo treatment would be 
61%. 


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The primary analysis will be conducted on the Study 301 population.  
4.3.2. 
Sample Size for Combined Analysis of Studies 301 and 302 
The sample size considered feasible for enrollment in Japan has limited statistical power. 
Therefore, all efficacy data for Part 1, where appropriate, will also be analyzed by combining 
data from this study with data from Study 302, to ensure adequate statistical power (Table 2). For 
the combined analysis with Study 302, the sample size is expected to be 48 subjects per 
treatment group. 
Assuming a weekly angioedema event rate for placebo subject of 0.9 and a common SD of 
0.50 angioedema events per week for BCX7353 and placebo, a sample size of 120 subjects 
(40 per treatment group: 8 from Study 301 and 32 from Study 302) will provide > 99% power to 
detect a ≥ 67% angioedema event rate reduction (a treatment difference of 0.6 angioedema 
events per week) between each BCX7353 active dose and placebo, based on a 2-sided test at 
significance level of 0.05. To control for familywise type I error, the Hochberg step-up 
procedure will be used to adjust for the comparison of the active doses to placebo. Note that 
sample size calculations were based on the originally planned sample size for Study 302. Actual 
sample size was slightly larger, indicating that actual power for combined analyses may be 
slightly increased. 
The assumptions underlying the sample size calculations for this study and the combined 
analysis of results from this study and Study 302 are based on the results of Study BCX7353-203 
(Study 203). In Study 203, the mean weekly angioedema event rate during the effective dosing 
period (Days 8 to 29) for placebo subjects in the full analysis set population was 0.939. The 
reduction in angioedema event rate during the effective dosing period for subjects receiving 
125 mg BCX7353 was 73.8%. The model-derived SD of the weekly angioedema event rate was 
0.487. Sample size calculations have been conducted using the weekly angioedema event rate to 
be consistent with Study 203, although the monthly angioedema event rate will be reported for 
this study. The power calculations using the monthly angioedema event rate would be the same. 
See Table 2 for details. 
Table 2: 
Power Calculations to Support Sample Size 
Study 
Sample Size 
Per 
Treatment 
Group 
Event 
Rate for 
Placebo 
Subjects 
(events/ 
week) 
Event Rate 
for Active 
Treatment 
(events/week) 
Common 
SD for 
Event Rate 
Type I 
Error 
Rate 
(α) 
Power for 
Pairwise 
Comparison 
with Placebo 
Study 301 alone 
8 
0.9 
0.3 
0.5 
0.05 
61% 
Combined 
Studies 301 and 302 
40 
0.9 
0.3 
0.5 
0.05 
>99% 
Abbreviations: SD = standard deviation.  
4.4. 
Randomization 
Subjects will be randomized via the interactive response system (IXRS). 


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4.4.1. 
Part 1 Randomization 
Approximately 24 subjects will be randomized in a 1:1:1 (active: active: placebo) ratio to 1 of 
the following treatments in Part 1:  
• Treatment Group 1: BCX7353 110 mg QD administered orally for 24 weeks  
• Treatment Group 2: BCX7353 150 mg QD administered orally for 24 weeks 
• Treatment Group 3: Placebo QD administered orally for 24 weeks 
Randomization will proceed in accordance with a computer-generated randomization schedule 
prepared by an unblinded statistician.  
Sites will randomize eligible subjects in the IXRS, preferably after all baseline assessments to 
reconfirm eligibility have been completed. If required by site procedures (ie, dispensing of 
randomized study drug must occur through a pharmacy), the subject may be randomized on the 
business day prior to the planned baseline visit.  
The sponsor may require review of screening data prior to randomizing a subject 
(eg, concomitant medications); any requirements will be provided to the site separately. 
Enrollment into treatment groups will be stratified by the qualifying angioedema event rate at 
baseline (≥ 2 angioedema events per month vs. < 2 angioedema events per month) entered into 
the IXRS at the time of randomization. The baseline angioedema event rate must be provided 
during randomization and is calculated by: 
(the number of angioedema events meeting the criteria of an angioedema event below 
from the screening visit through the time of randomization *28) divided by the number of 
days during the timeframe from the screening visit through randomization, rounded up to 
2 decimal places 
Angioedema events to be utilized in calculation of the baseline angioedema event rate must meet 
the following criteria: 
• The angioedema events must be unique, which is defined as an angioedema event that 
does not begin within 48 hours of the end of a previous angioedema event. 
• The angioedema events must have either been treated, required medical attention, or 
be documented to cause functional impairment based on subject entry in the e-diary. 
Functional impairment is defined as the subject being unable to perform his or her 
daily activities without restriction (ie, subject records that he or she is at least slightly 
restricted in daily activities during the angioedema event). 
• The angioedema events must include symptoms of swelling. The expert will consider 
that symptoms of swelling, in addition to visible swelling, may also include 
symptoms in the oropharyngeal or abdominal regions that are indicative of internal 
swelling. 
• The angioedema events must be confirmed by an independent expert to be 
angioedema events, based upon the e-diary record and investigator-collected 
information. 


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4.4.2. 
Part 2 Randomization 
Subjects who received active BCX7353 in Part 1 of the study (treatment Groups 1 and 2) will 
continue to receive the same dosing regimen in Part 2. Subjects who received placebo (treatment 
Group 3) during Part 1 will be randomized in a 1:1 ratio to receive a 110 or 150 mg QD dose of 
BCX7353 during Part 2. 
Subjects who received placebo during Part 1 will be automatically randomized for Part 2 in the 
IXRS, which will occur at the time of the Week 24 visit (see Figure 2). Sites will assign drug for 
Part 2 of the study in the IXRS beginning at the Week 24 visit. Sites using a centralized 
pharmacy may assign drug to a subject the day prior to the Part 2 visits. 
Note: Sites will assign 150 mg kits in Part 3 of the study in the IXRS beginning at Week 52. 
Sites using a centralized pharmacy may assign drug to a subject the day prior to a study visit. 
Figure 2: 
Study Randomization 
 
  
Abbreviations: QD = once daily. 
4.5. 
Clinical Assessments 
The schedule of assessments for Parts 1, 2, and 3, are provided in Table 3, Table 4, and Table 5, 
respectively. 


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Table 3: 
Schedule of Assessments: Part 1 of Study 301  
Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
Screening Visita,b 
(up to Week -10) 
Run-in 
Perioda 
Day 1a 
Week 2c 
Day 15 
± 2 days  
Week 4 
Day 29 
± 2 days 
Week 8 
Day 57 
± 2 days 
Week 12 
Day 85 
± 2 days 
Week 18 
Day 127 
± 2 days 
Week 24 
Day 169d 
Informed consentb 
X 
 
 
 
 
 
 
 
 
In-clinic evaluation 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
Telephone contacte 
 
 
Inclusion-exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Medical historyf 
X 
 
X 
 
 
 
 
 
 
HAE medical and medication 
historyf 
X 
 
 
 
 
 
 
 
 
Weight/height/BMIg 
X 
 
X 
 
X 
X 
X 
X 
X 
Drugs of abuse screenh 
X 
 
 
 
 
 
 
 
 
Physical examinationi 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy testj 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signsk 
X 
 
X 
 
X 
X 
X 
X 
X 
FSHl 
X 
 
 
 
 
 
 
 
 
HIV, HCV, HBV serology 
X 
 
 
 
 
 
 
 
 
Diagnosis of HAE 
establishedm 
X 
 
 
 
 
 
 
 
Angioedema events 
eligibility determinationn 
 
X 
 
 
 
 
 
 
 
Safety laboratory 
evaluationsh 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
Troponin I & Troponin T 
 
 
X 
 
X 
X 
X 
X 
X 
C1-INH antigenic level 
X 
 
 
 
 
 
 
 
 
C3  
 
 
X 
 
 
 
 
 
 
HLA typingo 
 
 
X 
 
 
 
 
 
 
Optional sample for possible 
exploratory 
pharmacogenomic testingp 
 
 
X 
 
 
 
 
 
 
NGAL 
 
 
X 
 
X 
X 
X 
X 
X 
CK-MB 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysish 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
12-lead ECGq 
X 
 
X 
 
X 
X 
X 
X 
X 


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Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
Screening Visita,b 
(up to Week -10) 
Run-in 
Perioda 
Day 1a 
Week 2c 
Day 15 
± 2 days  
Week 4 
Day 29 
± 2 days 
Week 8 
Day 57 
± 2 days 
Week 12 
Day 85 
± 2 days 
Week 18 
Day 127 
± 2 days 
Week 24 
Day 169d 
EQ-5D-5Lr,s 
 
 
X 
 
X 
X 
X 
X 
X 
AE-QoL, TSQM, and WPAIs 
 
 
X 
 
X 
X 
X 
X 
X 
Concomitant medications 
AEs 
Randomizationt 
 
 
X 
 
 
 
 
 
X 
e-diary instruction/review/ 
set-upu 
X 
X 
X 
 
X 
X 
X 
X 
X 
e-diary completionv 
Study drug dosingw 
 
 
Investigator review of 
angioedema eventsx 
 
Study drug accountability/ 
dispensing 
 
 
X 
 
X 
X 
X 
X 
X 
Plasma for PK and PD 
analysisy 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; 
AST = aspartate aminotransferase; BMI = body mass index; C1-INH = C1 esterase inhibitor; C3 = complement 3; CK-MB = creatine kinase MB isoenzyme; 
ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; FSH = follicle 
stimulating hormone; GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HLA = human leukocyte antigen; IXRS = interactive (voice/Web) response system; NGAL = neutrophil gelatinase-associated lipocalin; 
PD = pharmacodynamics; PK = pharmacokinetics; QTcF = QT interval corrected by Fridericia’s formula; TSQM = Treatment Satisfaction Questionnaire for 
Medication; WPAI = Work Productivity and Activity Impairment Questionnaire. 
a 
The baseline visit must be held within 10 weeks (70 days) of the screening visit, accommodating a run-in period of 56 days. The investigator must gain 
sponsor approval to enroll subjects who are not randomized within 10 weeks of the screening visit; this may require screening laboratory tests to be redrawn. 
Subjects will not be permitted to rescreen if they did not meet the angioedema event requirements during the run-in period. 
b  
Signing of informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures, including 
e-diary dispensing, are performed. 
c  
The Week 2 visit will consist of monitoring liver function tests only (ALT, AST, GGT, total and direct bilirubin, ALP); urine and additional tubes of blood 
will be required to accommodate possible reflex testing for abnormal GGT, AST, or ALT.  
d 
The last visit in Part 1 (Week 24) must occur the day following 24 weeks of study drug dosing in Part 1. 
e        The investigator (or designee) must call and talk to the subject at least weekly in between the Screening and Baseline visits and on-treatment through 
Week 24; alternative forms of interactive communication such as returned email and cellular text correspondence are acceptable. During all calls, the 
investigator (or designee) will assess the subject’s overall wellbeing, discuss compliance (if applicable), proper recording of angioedema event details 


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(if applicable), or any usability issues with the e-diary. A weekly phone call may be omitted if the subject records an angioedema event as the investigator 
must call and confirm or reject the angioedema event (see Footnote ‘x’). 
f         An HAE medical history form will be completed by the subject at screening. Medical and medication history will be taken at screening and updated at 
baseline.  
g 
BMI calculation and height at screening; weight is to be recorded at each scheduled in-clinic visit during Part 1 except at Week 2. 
h 
Protocol Table 5 lists parameters to be assessed.  
i  
Full physical examinations will be performed at screening, baseline, and Week 24; abbreviated physical examinations targeted to signs and symptoms will 
be performed at all other post-baseline visits except for Week 2. 
j  
For all women of childbearing potential (including adolescents), a serum pregnancy test will be administered at screening. Urine pregnancy tests will be 
assessed at all subsequent visits as indicated in the table. Demonstration of a negative urine pregnancy test will be required prior to the subject taking study 
drug on Day 1.  
k  
To include blood pressure and pulse rate. Temperature and respiratory rate will be captured at screening, baseline, and Week 24 only. Prior to obtaining vital 
signs, subjects should rest in a supine position for at least 5 minutes.  
l  
For women who declare that they have been post-menopausal ≤ 2 years.  
m        A clinical diagnosis of HAE Type 1 or 2 must be demonstrated during screening for this study as outlined in Inclusion Criterion 3 (Protocol Section 8.2.1). 
n         The subject will be determined as eligible for the study based upon screening evaluations and the prospective recording of angioedema events during the 
run-in period of 56 days. The subject must have at least 2 angioedema events during the run-in period as assessed by an independent expert which meet all of 
the following requirements:1) the angioedema events are unique, which is defined as an angioedema event that does not begin within 48 hours of the end of 
a previous angioedema event; 2) the angioedema events must have either been treated, required medical attention, or be documented to cause functional 
impairment based on subject entry in the e-diary; 3) the angioedema events must include symptoms of swelling. The expert will consider that symptoms of 
swelling, in addition to visible swelling, may also include symptoms in the oropharyngeal or abdominal regions that are indicative of internal swelling and; 
4) the angioedema events are otherwise confirmed by an independent expert to be angioedema events (see Footnote ‘x’). 
o 
A blood sample for HLA typing will be drawn at the baseline/Day 1 visit; if a blood sample is not obtained at baseline, the sample may be drawn at any time 
during the study.  
p  
A blood sample for possible exploratory pharmacogenomic testing will be drawn at the Baseline/Day 1 visit only if consent/assent is obtained for this 
optional testing; if a blood sample is not obtained at Baseline, the sample may be drawn at any time during the study following consent obtained from the 
subject.  
q         Bedside 12-lead ECGs will be conducted in triplicate (ie, 3 separate readings) at 1- to 5-minute intervals predose on Day 1 and Week 24, with values for 
these visits calculated from an average of the 3 readings. All other ECGs during the study will be single assessments. Prior to obtaining an ECG, subjects 
should rest quietly in a supine position for at least 10 minutes. ECGs should be obtained prior to any blood sampling. An ECG should be repeated for a 
change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
r        The EQ-5D-5L will be administered once at baseline and 1 to 2 × at Weeks 4, 8, 12, 18, and 24 visits. The subject will fill out the first EQ-5D-5L at baseline 
and on-study to describe their current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a 
recollection of their health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema event 
since the last study visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L. 
s         Where possible, quality of life and health outcome questionnaires should be collected as the first assessments at a visit. 
t       Sites will randomize eligible subjects in the IXRS at the Day 1 visit, preferably after all baseline assessments have been completed. Sites using a centralized 
pharmacy may randomize the subject the day prior to the baseline visit. The baseline event rate generated from the date of screening through the time of 
randomization must be calculated at this time (Protocol Section 9.3.2.1). 


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u  
The investigator (or designee) will set up the e-diary at the screening visit and as needed during the study; any issues (including mediocre or poor 
compliance) warranting e-diary re-education should occur on an as-needed basis. 
v 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details and 
dosing information (as applicable) at least once per day. 
w  
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits. Subjects will take study drug in Part 1 beginning on Day 1 and will complete Part 1 dosing on Study Day 168 (day before 
Week 24 visit). Subjects will take Part 2 active study drug no sooner than the conclusion of the Week 24 visit on Study Day 169, after all other study 
procedures have been completed. 
x  
An independent expert will review the e-diary record in conjunction with investigator-collected details of all angioedema events that occur from screening 
through follow-up and either confirm or reject each event as an angioedema event. At least 2 angioedema events that occur during the run-in period must 
meet the requirements outlined in Footnote ‘n’ in order to qualify the subject to randomize in the study. For all angioedema events that are recorded, subjects 
will be contacted within approximately 2 business days of the end of the angioedema event to discuss the clinical characteristics of the angioedema event, 
any questions the investigator has on the entered data, or to gain additional details on each event not included in the e-diary that the investigator deems 
important to clinically evaluate the event, as applicable. The investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each event recorded in the diary as a confirmed angioedema event. The investigator e-diary data review and subject 
contact summaries will be documented in the source records and made available to an independent expert for their verification (confirmation or rejection) of 
the event.  
y         Concentration and PD blood samples will be drawn on all subjects at the scheduled visits. For at least one of these timepoints, a PK and PD sample should 
be drawn approximately 3 to 6 hours after the last dose of study drug. The remaining timepoints can be drawn with no particular relationship to the timing of 
study drug dosing. The investigator (or designee) must ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary 
(this may also be captured in the eCRF). 
 


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Table 4: 
Schedule of Assessments: Part 2 of Study 301  
Assessment 
Part 2 
Double-Blind, Active Study Drug Administrationa 
 
Week 26b 
Day 183 
± 2 days 
Week 28 
Day 197 
± 2 days 
Week 32 
Day 225 
± 2 days 
Week 36 
Day 253 
± 2 days 
Week 40 
Week 44 
Week 48 
Day 337 
± 7 days 
Week 52 
(Day 365) 
± 2 days 
In-clinic evaluation 
X 
X 
X 
X 
 
 
X 
X 
Telephone contactc 
 
 
 
 
X 
X 
 
 
Subject weight 
 
X 
X 
X 
 
 
X 
X 
Physical examinationd 
 
X 
X 
X 
 
 
X 
X 
Urine pregnancy test 
 
X 
X 
X 
 
 
X 
X 
Vital signse 
 
X 
X 
X 
 
 
X 
X 
Safety laboratory evaluationsf 
Xb 
X 
X 
X 
 
 
X 
X 
Troponin I & troponin T 
 
X 
X 
X 
 
 
X 
X 
NGAL 
 
X 
X 
X 
 
 
X 
X 
CK-MB 
 
X 
X 
X 
 
 
X 
X 
Urinalysisf 
Xb 
X 
X 
X 
 
 
X 
X 
12-lead ECGg 
 
X 
X 
X 
 
 
X 
X 
EQ-5D-5Lh,i 
 
X 
X 
X 
 
 
X 
X 
AE-QoL, TSQM, and WPAIi 
 
X 
X 
X 
 
 
X 
X 
Concomitant medications 
AEs 
e-diary instruction/reviewj 
 
X 
X 
X 
X 
X 
X 
X 
e-diary daily completionk 
Study drug dosingl 
Investigator review of angioedema 
eventsm 
 
Study drug accountability/ dispensing 
 
X 
X 
X 
 
 
X 
X 
Plasma for BCX7353 concentration and 
PD analysisn 
 
X 
X 
X 
 
 
X 
X 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; AST aspartate 
aminotransferase; CK-MB = creatine kinase MB isoenzyme; ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; 
EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; GGT = gamma-glutamyltransferase; HAE = hereditary angioedema; NGAL = neutrophil gelatinase-
associated lipocalin; PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; QTcF = QT interval corrected by Fridericia’s formula; 
TSQM = Treatment Satisfaction Questionnaire for Medication; WPAI = Work Productivity and Activity Impairment Questionnaire. 
a 
Period 2 study drug is to be initiated upon administration of study drug, dispensed at the Week 24 visit. 


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b  
The Week 26 visit will consist of monitoring liver function tests only (ALT, AST, GGT, total and direct bilirubin, ALP); urine and additional tubes of blood 
will be required to accommodate possible reflex testing for abnormal GGT, AST, or ALT (see Protocol Table 5). If preferred by the subject and clinical site, 
laboratory values may be drawn and resulted locally, with results entered into the eCRF. 
c 
The investigator (or designee) must call and talk to the subject during Weeks 40 and 44; alternative forms of interactive communication such as returned 
email and cellular text correspondence are acceptable. During all calls, the investigator (or designee) will assess the subject’s overall wellbeing, discuss 
compliance (if applicable), proper recording of angioedema event details (if applicable), or any usability issues with the e-diary. The phone call may be 
omitted if the subject records an angioedema event as the investigator must call and discuss details of the event (see Footnote ‘m’). 
 
d        Abbreviated physical examinations targeted to signs and symptoms will be performed at post-baseline visits. 
e 
To include blood pressure and pulse rate. Prior to obtaining vital signs, subjects should rest in a supine position for at least 5 minutes.  
f          Protocol Table 5 lists parameters to be assessed. 
g 
ECGs may be single assessments. Prior to obtaining an ECG, subjects should rest quietly in a supine position for at least 10 minutes. ECGs should be 
obtained prior to any blood sampling. An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
h  
The EQ-5D-5L will be administered 1 to 2 × at Weeks 28, 32, 36, 48, and 52. The subject will fill out the first EQ-5D-5L at baseline and on-study to 
describe their current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a recollection of their 
health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema event since the last study 
visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L.  
i          Where possible, QoL and health outcome questionnaires should be collected as the first assessments at a visit. Additional information about long-term 
experience on study may be collected at Week 52. 
j  
Any issues (including mediocre or poor compliance) warranting e-diary re-education should occur on an as-needed basis. 
k 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details and 
dosing information (as applicable) at least once per day. 
l  
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits.  
m 
An independent expert will review the e-diary record in conjunction with investigator-collected details of all angioedema events that occur from screening 
through follow-up during Parts 1 and 2 and either confirm or reject each event as an angioedema event. For all angioedema events that are recorded, subjects 
will be contacted within approximately 2 business days of the end of the angioedema event to discuss the clinical characteristics of the angioedema event, 
any questions the investigator has on the entered data, or to gain additional details on the event that are not included in the e-diary that the investigator deems 
important to clinically evaluate the event, as applicable. The investigator-collected information, in conjunction with the e-diary record, will be used by an 
independent expert to verify or reject each event recorded in the e-diary as a confirmed angioedema event. The investigator e-diary data review and subject 
contact summaries will be documented in the source records and made available to an independent expert for their verification (confirmation or rejection) of 
the event. 
n        PK and PD blood samples will be drawn on all subjects with no particular relationship to the timing of study drug dosing. The investigator (or designee) must 
ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary (this may also be captured in the eCRF). 
 


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Table 5:  
Schedule of Assessments: Part 3 of Study 301 
Assessment 
Part 3 
Open-Label, Active Study Drug Administrationa 
Follow-up/ 
Early 
Termination 
Visit 
Week 107 
+ 1 Week 
Week 56 
Week 60 
Day 421 
± 6 days 
Weeks 64 
and 68 
Week 72 
Day 505 
± 6 days 
Weeks 76 
and 80 
Week 84 
Day 589 
± 6 days 
Weeks 88 
and 92  
Week 96 
Day 673 
± 6 days 
Week 100 
Week 104 
(Day 729 
± 7 days) 
In-clinic evaluation 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Telephone contactb 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Subject weight/heightc 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical examinationd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine pregnancy test 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signse 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Safety laboratory evaluationsf 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Troponin I & troponin T 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NGAL 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CK-MB 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysisf 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECGg 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
EQ-5D-5Lh,i 
 
X 
 
X 
 
X 
 
X 
 
X 
 
AE-QoL, TSQM, and WPAIi 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Concomitant medications 
 
AEs 
 
Diary instruction/reviewj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary daily completionk 
 
Study drug dosingl 
 
 
Study drug accountability/ 
dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
Xm 
Plasma for BCX7353 
concentration and PD analysisn 
 
 
 
 
 
 
 
 
 
 
Xn 
Abbreviations: AE = adverse event; AE-QoL = angioedema quality of life questionnaire; ALP = alkaline phosphatase; ALT = alanine transferase; AST aspartate 
aminotransferase; CK-MB = creatine kinase MB isoenzyme; ECG = electrocardiogram; eCRF = case report form; e-diary = electronic diary; 
EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; HAE = hereditary angioedema; NGAL = neutrophil gelatinase-associated lipocalin; 
PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; QTcF = QT interval corrected by Fridericia’s formula; TSQM = Treatment Satisfaction 
Questionnaire for Medication; WPAI = Work Productivity and Activity Impairment Questionnaire. 
a 
Period 3 study drug is to be initiated upon administration of study drug, dispensed at the Week 52 visit. 


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b  
The investigator (or designee) must call and talk to the subject during Weeks 56, 64, 68, 76, 80, 88, 92, and 100; alternative forms of interactive 
communication such as returned email and cellular text correspondence are acceptable. During all calls, the investigator (or designee) will assess the 
subject’s overall wellbeing, discuss compliance (if applicable), proper recording of angioedema event details (if applicable), or any usability issues with the 
e-diary. 
 
c 
Adolescent subjects will have height measured at Weeks 48 and 96.  
d        Abbreviated physical examinations targeted to signs and symptoms will be performed at post-baseline visits. 
e 
To include blood pressure and pulse rate. Prior to obtaining vital signs, subjects should rest in a supine position for at least 5 minutes.  
f          Protocol Table 5 lists parameters to be assessed. 
g 
ECGs may be single assessments. Prior to obtaining an ECG, subjects should rest quietly in a supine position for at least 10 minutes. ECGs should be 
obtained prior to any blood sampling. An ECG should be repeated for a change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
h  
The EQ-5D-5L will be administered 1 to 2 × at Weeks 60, 72, 84, 96, and 104. The subject will fill out the first EQ-5D-5L at baseline and on-study to 
describe their current health state today as instructed per the instrument. The subject will also fill out a second EQ-5D-5L based on a recollection of their 
health state during an average angioedema event experienced since the last study visit. If the subject has not had an angioedema event since the last study 
visit, the subject is not required to fill out the second, angioedema event-related EQ-5D-5L.  
i          Where possible, QoL and health outcome questionnaires should be collected as the first assessments at a visit.  
j  
Any issues (including mediocre or poor compliance) warranting e-diary re-education should occur on an as-needed basis. 
k 
At any time the e-diary is in a subject’s possession, they will enter angioedema events (attacks, symptoms or swelling due to HAE) and relevant details (as 
applicable) at least once per day. Subjects are not required to enter dosing information in the e-diary in this part. 
l  
Study drug should be taken at approximately the same time each day, with whichever meal is typically the largest of the day. Subjects are not required to 
take their doses at clinic visits.  
m 
 
Early termination visit only (if occurring during dosing phase). 
n        PK and PD blood samples will be drawn on all subjects with no particular relationship to the timing of study drug dosing through the Week 48 visit only. 
The investigator (or designee) must ensure that the time of the last dose prior to PK and PD draw is recorded in the subject’s e-diary (this may also be 
captured in the eCRF). PK and PD blood samples will be drawn at the ET visit, only if the ET visit occurs prior to Week 48. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
Interim safety analyses may be conducted while Parts 2 and 3 ongoing to support regulatory 
filings. 
5.2. 
Primary Efficacy Analysis at the End of Part 1  
The primary efficacy analysis is planned after all subjects have completed Part 1 of the study 
(Part 1 analysis). Unblinding of the database will occur after database freeze for the Part 1 
analysis (24-week assessment). 
This is a double-blind study throughout both Parts 1 and 2. As such, study drug assignment will 
be blinded to the investigator, study staff, study subjects, and clinical research organization 
(CRO) staff involved with study operations. Part 3 is open-label and all subjects will receive 
BCX7353 150 mg. 
During Part 1, sponsor employees will also be blinded to the treatment allocation of individual 
subjects, with the exception of sponsor staff responsible for managing clinical supplies. 
The sponsor and all other personnel who are blinded to study treatment will remain blinded to 
Part 1 treatment until after the database has been frozen for the primary analysis at the end of 
Part 1. 
As much as possible, sponsor and CRO employees who interact with sites will remain blinded 
during Part 2 of the study; however, unblinding of these staff may occur out of necessity during 
document preparation for regulatory filings of the study. 
5.3. 
Combined Efficacy Analysis at the End of Part 1  
The sample size considered feasible for enrollment in Japan has limited statistical power. 
Therefore, a supplemental statistical analysis will be conducted using combined data from 
Studies 302 and 301 in the comparison of efficacy and other selected endpoints for Part 1 of both 
studies. Investigator-confirmed attacks from Study 302 and expert-confirmed events from 
Study 301 will be considered equivalent for the combined analysis. 
5.4. 
Final Analysis  
The final analysis will occur after the last subject completes Part 3 of the study, the data are 
cleaned, and the database is locked for analysis. Analysis of the 104-week data will be comprised 
of data from the current study alone. 
5.5. 
Other Analyses to Support Safety Review and Regulatory 
Submissions 
Ongoing safety analyses for the purpose of Data Monitoring Committee (DMC) review will be 
conducted. Sponsor and CRO staff who work on the reporting of the study will remain blinded 
during Part 1. See Section 5.2 for discussion of blinding during Part 2. A CRO statistician and 


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CRO programmers separate from the group working on the primary analyses will be unblinded 
for purpose of DMC analyses. Other interim analyses to support regulatory filings may be 
required.  
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
DATA HANDLING 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Tables and listings will be prepared in accordance with the current ICH guidelines (Alberti, 
Pontisso et al. 1995). The information and explanatory notes in the “footer” or bottom of each 
table and listing will include the following information: 
• Date of data extraction 
• Date of output generation 
• SAS® program name, including the path where the program is stored 
• Any other output specific details that require further elaboration 
V9.4 or higher of the SAS system will be used to analyze the data and to generate tables, figures, 
and listings. All SAS programs prepared to analyze the data will be properly annotated to permit 
uninvolved outside statistical experts to replicate all the analyses specified in this SAP. 
Listings for the Part 1 interim analysis will include Part 1 treatment only. These listings will 
generally be sorted by Part 1 treatment, subject identification (ID), and visit, if applicable. 
Listings for the entire study period will include all parts and will generally be sorted by Part 1 
treatment, Part 2 treatment, subject ID and visit, if applicable.  
Adjusted visit (as described in Table 9) will be included on listings that cover the entire study 
period as applicable. Listings will also include visit date, days relative to first dose of Part 1 
treatment, and days relative to first dose of Part 2 treatment, if applicable. 
One exception to the sort order is that laboratory listings will be sorted by laboratory parameter, 
Part 1 treatment, Part 2 treatment (for listings that include the entire study period), subject ID, 
visit, and adjusted visit, if applicable. 
For the Part 1 interim analysis, displays will be summarized by Part 1 treatment. A column that 
combines both active treatments will also be included (see Table 6). 


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Table 6: 
Treatment Descriptors for Part 1 Only Displays 
Sort Order 
Part 1 Treatment Descriptor 
Notes 
1 
110 mg   
110 mg 
2 
150 mg 
150 mg 
3 
All active 
Combined 110 mg and 150 mg groups 
4 
Placebo 
Placebo 
Column order will be in order of ascending dose, combined active doses, and placebo. A total 
column will be included as applicable. Generally, total columns are included on demographic 
and baseline characteristics tables as well as on certain safety tables, such as AE tables. 
Demographic and baseline characteristic displays will be repeated for Part 2 to characterize the 
subset of subjects who continue in Part 2. Total columns will be included. For these displays the 
treatment descriptors will be as shown in Table 7. The descriptors shown in Table 7 also apply to 
any displays specific to Part 3; footnotes will be provided detailing the transition from 110 to 150 mg 
at Week 52 (ie, Part 3). 
Table 7: 
Treatment Descriptors for Part 2 Only Displays 
Sort 
Order 
Part 2 Treatment Descriptor 
Notes 
1 
110 mg    
110 mg 
2 
150 mg  
150 mg 
3 
110 mg after placebo 
For subjects who were originally randomized to placebo and 
were randomized to 110 mg for Part 2 with continuation to 
150 mg in Part 3.a 
4 
150 mg after placebo 
For subjects who were originally randomized to placebo and 
were randomized to 150 mg for Part 2 with continuation to 
150 mg in Part 3.a 
a Footnotes will be provided to detail the transition from 110 to 150 mg at Week 52 (ie, Part 3). 
For tables that cover the entire study period, 110 and 150 mg data in Part 2 from subjects 
assigned to placebo in Part 1 will be separated from 110 and 150 mg data from subjects assigned 
to active treatment in Part 1. For some tables, there will also be columns that combine data from 
each active treatment whether received in Part 2 only or in both Parts 1 and 2. Treatment 
descriptors are provided in Table 8.   


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Table 8: 
Treatment Descriptors for Displays for Entire Study  
Sort Order 
Treatment Descriptor 
Notes 
1 
110 mg 
110 mg (originally randomized) 
2 
110 mg after placebo  
Part 2 data from subjects in Part 2 who 
were originally randomized to placebo 
and were randomized to 110 mg for 
Part 2 
3 
All 110 mg 
Combines 110 mg data from subjects 
originally assigned to placebo with 
110 mg data from subjects originally 
assigned to 110 mg 
4 
150 mg 
150 mg (originally randomized) 
5 
150 mg after placebo 
Data from subjects in Part 2 who were 
originally randomized to placebo and 
were randomized to 150 mg for Part 2 
6 
All 150 mg 
Combines 150 mg data from subjects 
originally assigned to placebo with 
150 mg data from subjects originally 
assigned to 150 mg 
7 
All active 
Combines all data collected for 110 and 
150 mg treatment regardless of original 
randomization of subject. 
8 
Placebo 
Placebo (includes data from Part 1 only) 
Note: Not all columns will be required for any given table. 
For tables produced by visit that combine active treatment data for those originally assigned to 
active treatment with those originally assigned to placebo there will be an adjusted visit that 
corresponds to the time since active dosing (either Day 1 for those originally assigned to active 
dose or Week 24 visit for those originally assigned to placebo; see Table 9). This will allow for 
combining data from active treatments in Part 1 (either 110 or 150 mg) with active treatment in 
Part 2 that followed placebo (either 110 or 150 mg). The adjusted visit for those assigned to 
110 or 150 mg in Part 1 will equal the original visit (ie, Day 1). Subjects who changed from 
110 to 150 mg beginning in Part 3 will continue to be summarized in the same treatment to 
which they were assigned as in Part 2; a footnote will detail the transition from 110 to 150 mg at 
Week 52. 


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Table 9: 
Adjusted Visit for Active Treatment for Subjects Originally Assigned to 
Placebo 
Original Visit 
Adjusted Visit 
Week 24 
Day 1 
Week 26 
Week 2 
Week 28 
Week 4  
Week 32 
Week 8 
Week 36 
Week 12 
Week 48 
Week 24 
Week 52 
Week 28 
Week 60 
Week 36 
Week 72 
Week 48 
Week 84 
Week 60 
Week 96 
Week 72 
Note: There is no visit in Part 2 that corresponds with the Week 18 or Week 26 visit in Part 1. There is no visit in 
Part 3 that corresponds to the Week 52 Visit in Part 2. 
For tables with count data, such as TEAE tables, additional displays based on the number of 
TEAEs per person-years of exposure may also be provided to adjust for the differing periods of 
exposure to active treatment for those originally randomized to placebo with those originally 
randomized to active treatment. 
Summary tables for medications and free-text fields for HAE medication history are coded 
according to the World Health Organization Drug Dictionary (WHODD) version from 
March 2017. AE preferred terms (PT) and system organ classifications (SOC) are coded using 
Medical Dictionary for Regulatory Affairs (MedDRA) v19.1.  
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Tables, listings, and figures will be numbered using a decimal system to indicate the main levels 
of unique displays and sub-levels of replicate displays. The first level represents the appendix 
within which the tables, figures, and listings will appear. This will be 14 for tables and figures 
and 16.2.x for listings. The second level of the numbering represents the type of data; 1 for study 
population, 2 for efficacy, 3 for safety, 4 for health outcomes, 5 for PK, and 6 for PD. The third 
level of numbering represents the type of endpoint within the data type, the fourth level 
represents a count of displays for the endpoint, and the fifth level is used for repeated tables. For 
example, tables may be repeated using a different population or for a subset of subjects. 
Secondary titles will be used to identify the analysis population used for the displays. 
In general, the listings should be sorted and presented by treatment assignment, subject number, 
and visit, if applicable. For Part 1, listings that include visit, visit date, and study day should be 
included on listings. For listings produced for the analysis at the end of Part 3 that include visit, 
displays should include visit, adjusted visit, visit date, study day, and adjusted study day.  


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6.3. 
Data Management 
A data management plan will be developed and approved prior to commencement of data entry. 
Data will be captured using the Medidata electronic data capture system. Electronic validation 
steps (edit checks) will be utilized, and data cleaning will occur in conjunction with each site. 
Prior to transfer of data provided by vendors (eg, laboratory data), a data transfer agreement 
including specifications for the type of file, definitions of variables, and contact information for 
the sending and receiving parties will be developed and finalized. The standard operating 
procedures (SOPs) of PharPoint, the selected statistics and programming vendor for this study, 
will be used. 
Data will be mapped to Study Data Tabulation Model (SDTM)-compliant datasets prior to 
creation of Analysis Data Model (ADaM)-compliant derived datasets for use in the creation of 
summary tables. All analyses will be generated using SAS v9.4 or higher and in accordance with 
PharPoint SOPs.   
6.4. 
Data Presentation Conventions 
Continuous variables (eg, age) are summarized using descriptive statistics (the number of 
subjects with available data, the mean, SD, median, and minimum and maximum). Categorical 
variables (eg, gender) are summarized using counts and percentages. Percentages are calculated 
using the total number of subjects per treatment group unless otherwise specified. 
The following conventions are applied to all data presentations and summaries: 
• For continuous variables, all mean and median values are formatted to 1 more 
decimal place than the measured value. SD values are formatted to 2 more decimal 
places than the measured value. Minimum and maximum values are presented with 
the same number of decimal places as the measured value. 
• For categorical variables, the number and percentage of responses are presented in the 
form XX (XX.X%) where the percentage is in the parentheses. 
• Date variables are formatted as DDMMMYYYY for presentation. Time is formatted 
in military time (24-hour clock) as HH:MM for presentation. Dates missing day are 
denoted as MMMYYYY and dates missing both day and month are denoted as 
YYYY in listings. Handling of partial dates for analysis is discussed in Section 6.8. 
• Wherever possible, data will be decimal aligned. 
The table of contents of statistical displays is provided in Section 17.1 as part of this SAP. Any 
changes to format, layout, titles, numbering, or any other minor deviation will not necessitate a 
revision to the SAP, nor will they be considered as deviations from planned analyses. Only true 
differences in the analysis methods or data handling will necessitate such documentation. The 
appropriate listings supporting the tables will be included and are not necessarily specified in the 
individual sections throughout the document. 


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6.5. 
Analysis Populations  
6.5.1. 
Screen Failures 
Subjects who give informed consent but are not randomized to study treatment and are noted as 
screen failures in the electronic case report form (eCRF) are considered screen failures. Reasons 
for screen failure will be summarized using this population.  
6.5.2. 
Intent-to-Treat Population 
The intent to treat (ITT) population will include all subjects who are randomized, regardless of 
whether study treatment was administered. The ITT population will be used as the primary 
population for efficacy and health outcomes analyses. Subjects will be analyzed based on the 
treatment to which they were randomized. 
6.5.3. 
Safety Population 
The safety population will include all subjects who received at least 1 capsule of study drug. This 
population will be used for all analyses of accountability, demographics, BCX7353 drug 
concentrations, and safety. Subjects will be analyzed based on the actual treatment received at 
first dose for all subjects for Part 1 or at first dose of Part 2 for subjects originally randomized to 
placebo. Per-Protocol Population 
The per protocol (PP) population will include a subset of subjects in the safety population that 
complete Part 1 and have ≥ 85% treatment compliance without any major protocol deviations 
that could impact efficacy measures. A decision will be made prior to database lock on which (if 
any) subjects are to be excluded from the PP population based upon major protocol deviations. In 
the PP analysis, subjects will be assessed based on the actual treatment received on study Day 1 
for Part 1. The PP population may be used as a secondary population for efficacy analyses. 
6.5.5. 
Completers Population 
The subset of subjects in the ITT population who complete Part 1 of the study (as evidenced by 
the completion of the Week 24 visit in the eCRF) will comprise the completers population. The 
completers population will be used for a sensitivity analysis of the primary efficacy analysis for 
Part 1 only. Data will be analyzed according to randomized treatment.Pharmacodynamic 
Population 
The PD population for plasma kallikrein inhibition will include all subjects for whom at least 
1 pre- and post-dose plasma kallikrein inhibition result can be estimated. Data will be analyzed 
according to the actual treatment received. This population will be used for all analyses of 
plasma kallikrein inhibition. 
6.5.7. 
Pharmacokinetic Concentration/Pharmacodynamic Population   
The PK concentration/PD population will include all subjects for whom at least 1 pre- and 
post dose plasma kallikrein inhibition result can be estimated with a corresponding plasma 
BCX7353 concentration (placebo samples not analyzed will be assumed to have a zero 
concentration). This population will be used for all correlation analyses and figures involving 
plasma kallikrein inhibition and plasma BCX7353 concentrations. 


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6.6. 
Baseline Definition 
In general, the baseline value is the last available assessment prior to the time of first dose of 
study drug unless otherwise specified. For tables that include adjusted visit information, the 
baseline for active treatment for subjects who originally were assigned to placebo will be the last 
available assessment prior to the time of first dose of active treatment in Part 2, unless otherwise 
specified.  
6.6.1. 
Baseline Event Rate 
Enrollment into treatment groups is stratified by the baseline HAE event rate as determined by 
the IXRS system based on the number of events and duration of screening as input by the sites 
(≥ 2 events/month vs. < 2 events/month). For analysis purposes, the baseline event rate will be 
calculated from the diary data and expressed as events per month where 1 month = 28 days as 
follows: 
Number of HAE events meeting baseline criteria from Screening to First Dose Date/time ∗28
 Date of First Dose −Screening Date + 1
 
Criteria that must be met for events to qualify for confirmation by the Investigator during the 
baseline period are provided in Section 4.1.  
Baseline event rate will be included in statistical models as appropriate. 
6.6.2. 
Categorized Baseline Event Rate 
The categorized baseline event rate will be determined using the calculated baseline event rate 
(See Section 6.6.1) and will be categorized similarly to the stratification factor: ≥ 2 events/month 
vs. < 2 events/month. 
6.6.3. 
Baseline Age  
Age at time of consent is collected on the demographics form. This will be the baseline age for 
analyses and for determination of whether the subject is classified as an adult (≥ 18 years) or an 
adolescent (12 to 17 years). 
6.7. 
Derived and Transformed Data 
6.7.1. 
Study Day 
In this study, it is possible that the randomization date and date of first dose could differ. Study 
Day 1 is defined as the date of first dose. 
If the date of measurement for a particular endpoint occurs on or after the first dose date, then 
study day will be calculated as (date of measurement – date of first dose) + 1. If the date of 
measurement occurs prior to the first dose date, then study day will be calculated as (date of 
measurement – date of first dose). There is no Day 0.  
6.7.2. 
Change from Baseline 
CFB is calculated as (post-baseline result – baseline result).Percent CFB is calculated as 
((change from baseline/baseline result) * 100). 


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If either the baseline or the post-baseline result is missing, the CFB and/or percentage CFB is set 
to missing as well. 
6.7.3. 
Visit Windows  
For summary purposes in general, records will be assigned to the scheduled visit collected on the 
case report form (CRF). Unscheduled and early termination visits will be assigned to an analysis 
window according to the study day of the actual visit date using the visit windows displayed in 
Table 10. All information collected at an unscheduled visit will be identified as such in the 
listings. 
Table 10: 
Visit Windows (Days) 
Visit 
Relative Target Day 
Protocol-Specified 
Visit Window 
Analysis Visit 
Window 
Screening visit 
 
-70 to -14 
-70 to -14 
Baseline 
1 
1 
1 
Week 2 
15 
13 to 17 
2 to 22 
Week 4 
29 
27 to 31 
23 to 43 
Week 8 
57 
55 to 59 
44 to 71 
Week 12 
85 
83 to 87 
72 to 106 
Week 18 
127 
125 to 129 
107 to 148 
Week 24 
169 
169 
149 to 176 
Week 26 
183 
181 to 185 
177 to 190 
Week 28 
197 
195 to 199 
191 to 211 
Week 32 
225 
223 to 227 
212 to 239 
Week 36 
253 
251 to 255 
240 to 295 
Week 48 
337 
330 to 343 
296 to 351 
Week 52 
365 
364 to 368 
352 to 406 
Week 60 
421 
415 to 427 
407 to 463 
Week 72 
505 
499 to 511 
464 to 547 
Week 84 
589 
583 to 595 
548 to 631 
Week 96 
673 
667 to 679 
632 to 683 
Week 104 
729 
723 to 735 
≥684 
6.7.4. 
Multiple Assessments 
Where multiple planned scheduled measurements are recorded for a given time point 
(eg, electrocardiograms [ECGs]), the mean of the measurements will be calculated and used in 
any derivation of summary statistics. All available data will be listed. 
When multiple visits occur within the same window, the scheduled visit will be used in analysis 
if available. If no scheduled visit occurs within the window and an unscheduled visit(s) and/or 


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early termination visit occur within the window, the analysis visit closest to the target day will be 
selected for use in analysis. If deemed appropriate by the Sponsor (eg, in the case of a retest), 
unscheduled visits may be chosen for analysis given documentation of the desired visit from the 
Sponsor. Results from unscheduled visits will be eligible for inclusion in analyses of worst post-
baseline results. Listings will display all visits as recorded on the CRF, including the date and 
study day. All available data including any totals, domains, or subscales of scale assessments 
summarized will be listed. 
6.7.5. 
Derived Efficacy Endpoints 
6.7.5.1. 
Event Rate 
General Formula for Event Rate 
In general, the formula for computing an event rate is the number of events meeting the event 
criteria divided by the duration of treatment during the reporting period of interest. Duration of 
treatment during the reporting period of interest = the last day in the reporting period – first day 
in the reporting period + 1. 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 ൬𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ൰ 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 
=
 Number of Events ∗28
 Duration of Treatment During Reporting Period in Days 
If the subject discontinues treatment early, any events that occur within 24 hours after last dose 
will be counted in the calculation of event rate and the additional 24-hour period will be included 
in the duration of the reporting period. 
Subject-Reported Event Rate 
Diary entries for events and investigator-collected events that are not captured in the diary are 
considered subject-reported events. The expert reviews each event and either confirms it as an 
event or rejects it as an event. For Part 3, there is no expert review of attacks, but an adjusted 
subject-reported attack rate will be computed based on a list of programmable requirements. 
Subject-reported event rates will be computed for the entire dosing period only (ie, not for the 
effective dosing period or by month) for Parts 1, 2, and 3. 
Adjusted Subject-Reported Attack Rate for Part 3 
Because there is no expert-confirmation of attacks during Part 3, an adjusted subject-reported 
attack rate will be computed. 
Subject-reported attacks must meet the following criteria (applied in order) for inclusion in the 
adjusted subject-reported rate computation: 
• Attack must include at least 1 symptom of swelling 
• Subject response to diary question, “In retrospect, could there be an alternative 
explanation for your symptoms other than an HAE attack (ie, allergic reaction, viral 
cold, etc)?” must be “no” 


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• Attack must be unique (attack begins > 24 hours from end of the prior attack), 
otherwise the event will be combined with and treated as a continuation of the 
preceding attack 
• If untreated, attack must have a duration > 24 hours 
Adjusted subject-reported attack rates will be computed for the following reporting periods and 
expressed in units of attacks/month where 1 month = 28 days: 
• Part 3, by month 
• Part 3, entire dosing period 
For adjusted subject-reported attack rates by month, months will be defined in blocks of 28 days, 
beginning on the first day of dosing in Part 3. If the subject discontinues treatment early, any 
attacks that occur within 24 hours after last dose will be counted in the calculation of 
subject-reported adjusted attack rate and the additional 24 hour-period will be included in the 
duration of the reporting period. 
Confirmed Event Rate 
Confirmed event rates will be computed based on the number of expert-confirmed events that 
occur during the reporting period of interest.   
Confirmed event rates will be computed for the following reporting periods and expressed in 
units of events/month where 1 month = 28 days: 
• Parts 1 and 2, by month 
• Parts 1 and 2, entire dosing period 
• Parts 1 and 2, effective dosing period 
Confirmed event rates will be computed for Part 1 and at the end of Part 2. For confirmed event 
rates by month, months will be defined in blocks of 28 days, beginning on Day 1, the day of first 
dose. The entire dosing period begins on Day 1 or adjusted Day 1 during Part 2 for subjects 
originally randomized to placebo. The effective dosing period similarly begins on Day 8 or 
adjusted Day 8. Part 1 continues until the time of Part 2 dose. Part 2 continues until the time of 
the first dose for Part 3. Expert confirmation is not done in Part 3 and so confirmed event rate will 
not be computed for Part 3. If the subject discontinues treatment early, the reporting period will 
continue through 24 hours post last dose and any events that occur within 24 hours after last dose 
will be counted in the calculation of events rate. If there are confirmed events in the eCRF without 
corresponding diary information, as may happen if a subject verbally reports an event to an 
investigator but does not enter it into the e-diary, the event will be counted. 
For sensitivity analyses for missing data for the Part 1 primary analysis, confirmed event rates 
for the entire dosing period for subjects who discontinue treatment early will be re-computed as a 
weighted average of the observed post-treatment discontinuation event rate and an imputed event 
rate for periods of missing data post-treatment discontinuation. Details are provided in 
Section 6.8.1.  


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Expert-Confirmed Event Rate by Location 
Expert-confirmed abdominal-only, peripheral, and mixed event rates will be computed using the 
location definitions provided in Section 6.7.5.9. 
Adjusted Expert-Confirmed Event Rate 
An adjusted expert-confirmed event rate will be computed for use in the determination of the 
50%, 70%, and 90% responder endpoints comparing post-baseline event rates to baseline event 
rates. For the adjusted expert-confirmed event rate, the 2 additional requirements for 
confirmation of event rates used during screening will be applied to post-baseline 
expert-confirmed events to determine the number of confirmed events meeting the additional 
requirements. The additional requirements are: 
• The events are unique, which is defined as an event that does not begin within 
48 hours of the end of a previous event. 
• The events must have either been treated, required medical attention or be 
documented to cause functional impairment based on subject entry in the diary. 
Functional impairment is defined as the subject being unable to perform their daily 
activities without restriction (ie, subject records that they are at least slightly 
restricted in their daily activities during their HAE event). 
6.7.5.2. 
Number and Percentage of Subjects Who Are Event Free Over Entire Dosing 
Period and Effective Dosing Period 
The following event-free endpoints will be derived for the entire dosing period and for the 
effective dosing period for Parts 1 and 2: 
• The number and percentage of subjects with no confirmed events during the period of 
interest. Subjects with no confirmed events who discontinue before the end of the 
planned treatment period are not considered event-free.  
The event-free rate for active treatment for subjects originally randomized to placebo will be 
based on the initial 24-week period during Part 2. 
6.7.5.3. 
Number and Proportion of Days with Angioedema Symptoms 
The number of days with angioedema symptoms is the sum of the days during the entire dosing 
period prior to discontinuation of treatment for which at least 1 symptom is reported during an 
expert-confirmed HAE event. 
This endpoint will be determined for Parts 1 and 2 as expert-confirmation will not be calculated 
for Part 3. As with the calculation of event rate, if the subject discontinues treatment during the 
reporting period, any symptoms during confirmed attacks that occur within 24 hours after last 
dose will be counted in the calculation of days with angioedema symptoms and the additional 
24-hour period will be included in the duration of the reporting period. 
The percentage of days with angioedema symptoms is derived as the number of days with 
angioedema symptoms divided by the duration of the treatment period of interest. 


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6.7.5.4. 
Responder Endpoint 
A subject is defined as being a responder to study treatment if the rate of adjusted confirmed 
events during study treatment represents at least a 50% relative reduction compared with the 
baseline event rate as defined in Section 6.6.1. 
The relative reduction is calculated for Part 1 as:  
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 
= Baseline event rate − Adjusted confirmed event rate on treatment
Baseline event rate
 × 100% 
where the adjusted confirmed event rate while on study treatment is computed as shown in 
Section 6.7.5.1. 
A subject is classified as a responder if the relative reduction in monthly event rate for Part 1 is 
≥ 50%. Otherwise, the subject is classified as a non-responder.  
Responder analysis will be conducted for Part 1 only. Additional responder analyses will be 
conducted for 70% and 90% relative reduction, defined similarly. 
6.7.5.5. 
Event Duration 
The duration of each confirmed on-treatment event will be calculated in hours, based on the start 
and stop date and time of the confirmed event (time the event finished). Experts have the option 
to count more than one subject-reported event as a single confirmed event. For a confirmed event 
that includes more than 1 subject-reported event, the duration is calculated from the start of the 
first subject-reported event to the end of the last subject-reported event that has been combined 
into 1 event. A similar adjustment for duration will be made for adjusted subject-reported attacks 
that are combinations of two or more subject-reported attacks in Part 3. The duration of the event 
from start of the event to time that the worst was over will also be calculated and summarized. 
6.7.5.6. 
Event Onset Relative to Prior Dose of Study Drug 
For each confirmed on-treatment event, the time to event onset from the time of the prior dose of 
study drug reported in the subject CRF page will be calculated. If there is no dosing time 
reported for the dose taken prior to the event, the event onset time relative to prior dose will be 
missing.  The event onset time relative to prior dose of study drug information is used in the 
listing of event data only. 
6.7.5.7. 
 Medications to Treat HAE Events 
The following medications reported taken as acute treatment in the subject diary will be 
classified in the analyses as targeted medications to treat subject-reported HAE events: Berinert, 
Cinryze, Kalbitor, Firazyr, Ruconest, and fresh frozen plasma. Of these, Berinert and Firazyr are 
approved for use in Japan. Other medications listed in the diary for treatment of HAE events will 
be considered non-targeted medications to treat subject-reported HAE events. 


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6.7.5.8. 
Event Symptoms 
Symptoms reported for confirmed on-treatment events will be included in summaries of event 
characteristics. In addition, listings of diary data will show symptoms for all events, whether 
subject-reported or expert-confirmed. 
6.7.5.9. 
Event Location 
The location of each subject-reported and confirmed event will be determined based on the 
symptoms indicated in the e-diary as shown in Table 11. 
Table 11: 
Determination of Event Location Using Symptoms Collected in the e-Diary 
Abdominal-only event 
Mixed Event 
Peripheral event  
(inclusive of skin and airway swelling) 
Symptoms checked must only come from 
this box: 
• 
Internal Swelling or Symptoms of 
Internal Swelling in the Abdomen: 
• 
Nausea 
• 
Abdominal Discomfort 
• 
Cramps (colicky pain) 
• 
Vomiting 
• 
Abdominal pain 
• 
Diarrheaa 
Must have at least 
1 symptom from left and 
right box (from 
abdominal and 
peripheral event 
characterization) 
Symptoms checked must only come from this 
box: 
• 
Visible Swelling:  
• 
face/head 
• 
neck (outer swelling) 
• 
legs, buttocks/genitals 
• 
eyes 
• 
arms 
• 
feet 
• 
stomach (outside)  
• 
mouth/tongue/lips  
• 
hands 
• 
chest/back 
• 
joints 
• 
Internal Swelling or Symptoms of Internal 
Swelling in the Airways:  
• 
lump in throat/tightness 
• 
change in voice 
• 
difficulty swallowing 
• 
difficulty breathing 
• 
Pink rings (erythema marginatum)a 
Note: headache and fatigue symptoms may be checked but play no role in characterization of a subject-reported or 
confirmed event 
 a Diarrhea, erythema marginatum, headache, and/or fatigue cannot be selected alone or in combination without 
another symptom(s) of swelling or internal swelling to be considered a confirmed event. 
6.7.5.10. Laryngeal Events 
Laryngeal events are those events that have visible swelling in the mouth/tongue/lips or any of 
the following internal swelling symptoms: lump in throat (tightness), difficulty swallowing, 
change in voice, or difficulty breathing, as recorded in the e-diary. 
6.7.5.11. Event Triggers 
All event triggers for each subject-reported event will be included in listings of event data.   


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6.7.5.12. AE-QoL 
The AE-QoL (Wechsler, Fulkerson et al. 2012) consists of 4 domains and a total score. Each 
item answered by the subject scores between 0 and 4 points depending on the answer option 
chosen by the subject. The first answer option gets 0 points, the second option 1 point, the third 
option 2 points, etc.  
Dimensions  
Item 
Functioning 
1. Impairment of work 
2. Impairment of physical activity 
3. Impairment of spare time activities 
Fatigue/Mood 
4. Impairment of social relations 
6. Difficulties of falling asleep 
7. Waking up during the night 
8. Feeling tired during the day 
9. Difficulties in concentrating 
10. Feeling downhearted 
Fears/Shame 
12. Feeling burdened at having swellings 
13. Fear of new suddenly appearing swellings 
14. Fear of increased frequency of swellings 
15. Ashamed to visit public places 
16. Embarrassed by the appearance of swellings 
17. Fear of long-term negative drug effects 
Nutrition 
5. General limitations in foods and eating 
11. Limitations in the selection of food and beverages 
Total Score  
Items 1 to 17 
The AE-QoL domain scores and the AE-QoL total score are calculated using the following 
formula: 
(Σ items)/(max Σ items) × 100 
where 
Σ items = Sum of answered item scores per CRF 
max Σ items = Sum of the maximum possible score for the answered items (ie 4 × the 
number of completed items) 
The calculated AE-QoL ranges from 0 (best) to 100 (worst).  
Since only answered items are included in the computation (and the calculated domain and total 
scores are not raw scores but linear transformations to a 0 to 100 scale), the calculated scores are 
not highly influenced by missing items. An AE-QoL domain score should not be calculated if 
more than 1 item is left unanswered in that domain. The AE-QoL total score should not be 
calculated if more than 25% of items (> 4 items) are left unanswered. Note that subjects who do 
not work were instructed to leave question 1 blank. As long as that is the only question in the 
functioning domain that is missing, the functioning domain can still be calculated. 


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6.7.6. 
Derived Health Outcomes Endpoints 
6.7.6.1. 
EQ-5D-5L 
The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EuroQoL Visual Analogue 
Scale (EQ VAS). The descriptive system is comprised of 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression as shown in Table 12. Each dimension has 
5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The respondent is asked to indicate his/her health state by ticking (or placing a cross) 
in the box against the most appropriate statement in each of the 5 dimensions. This decision 
results in a 1-digit number to express the level selected for that dimension. The digits for 
5 dimensions can be combined in a 5-digit number to describe the respondent’s health state. For 
example, 11122 would represent the health state for someone who has no problems with 
mobility, self-care, or usual activities, but who has slight pain or discomfort and slight anxiety or 
depression. 
Note that this study uses the questionnaire in its validated form for subjects to report their health 
status “today”. If the subject has had an HAE event since their last visit, starting at Week 4, they 
complete it a second time reflecting back on their health status during a “usual event”.  On 
summary tables, the “today” and “usual event” questionnaire results should appear in different 
rows. 


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Table 12: 
EQ-5D-5L Dimensions (UK English Sample Version) 
Dimensions  
Item 
Mobility 
I have no problems in walking about 
I have moderate problems in walking about 
I am unable to walk about 
I have severe problems in walking about 
I am unable to walk about 
Self-Care 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
Usual Activities 
(eg, work, study, 
housework, family or 
leisure activities)  
I have no problems doing my usual activities  
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
Pain/Discomfort 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
Anxiety/Depression 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
Abbreviations: EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; UK = United Kingdom. 
The EQ VAS records the respondent’s self-rated health on a 20-cm vertical visual analog scale 
(VAS). The VAS is numbered from 0 to 100 with 0 meaning ‘the worst health you can imagine’ 
and 100 meaning ‘the best health you can imagine’. This information can be used as a 
quantitative measure of health as judged by the individual respondents. The EQ-5D-5L asks 
respondents to simply ‘mark an X on the scale to indicate how your health is TODAY’ and then 
to ‘write the number you marked on the scale in the box below’. 
For each subject and visit, the 5-digit health state will be converted into a single summary index, 
the EQ-5D Index, using the EQ-5D-5L Index calculator with United States (US) value set 
(Besari, Md Noor et al. 2014). A manual for EQ-5D is available (van Reenen and Janssen 2015).  


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6.7.6.2. 
Treatment Satisfaction Questionnaire for Medication 
The TSQM consists of 14 items of which 13 items are made up of 3 specific scales 
(effectiveness, side effects, and convenience) and a global satisfaction scale (global satisfaction). 
In addition, one item (Item 4) questions whether as a result of taking this medication, the subject 
experienced any side effects at all, which can be answered by yes or no. Scale scores are 
calculated for each scale and are transformed into scores ranging from 0 to 100, with higher 
scores indicating higher satisfaction.  
The 14 questions are detailed in Table 13. 
Table 13: 
List of Questions for TSQM 
Item # 
TSQM Item 
1 a 
How satisfied or dissatisfied are you with the ability of the medication to prevent or treat 
your condition?  
2 a 
How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
3 a 
How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working? 
4 b 
As a result of taking this medication, do you currently experience any side effects at all? 
5 
How bothersome are the side effects of the medication you take to treat your condition? 
6 
To what extent do the side effects interfere with your physical health and ability to function 
(ie, strength, energy levels, etc.)? 
7 
To what extent do the side effects interfere with your mental function (ie, ability to think 
clearly, stay awake, etc.)? 
8 
To what degree have medication side effects affected your overall satisfaction with the 
medication?  
9 
How easy or difficult is it to use the medication in its current form? 
10 
How easy or difficult is it to plan when you will use the medication each time?  
11 
How convenient or inconvenient is it to take the medication as instructed? 
12 
Overall, how confident are you that taking this medication is a good thing for you? 
13 
How certain are you that the good things about your medication outweigh the bad things?  
14 a 
Taking all things into account, how satisfied or dissatisfied are you with this medication?  
Abbreviations: TSQM = Treatment Satisfaction Questionnaire for Medication. 
a These items are scaled on a seven-point bipolar scale from “extremely dissatisfied” to “extremely satisfied”.  
b Item #4 is a dichotomous response option with a conditional skip to Item #9.  
Source: (Atkinson, Sinha et al. 2004) 
Note that higher scores indicate higher satisfaction as the seven-point scale for the individual 
items goes from 1 = extremely dissatisfied to 7 = extremely satisfied. 
The scale scores, also with higher numbers indicating higher satisfaction, are calculated as: 
Effectiveness 
([(Item 1 + Item 2 + Item 3) − 3] ÷ 18) × 100. 
If 1 item is missing: ([(Sum of Available Items) − 2] ÷ 12) × 100. 


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Side Effects 
If Item 4 answer is “No” then score = 100. 
Else… 
([(Sum of Item 5 to Item 8) − 4] divided by 16) × 100. 
If 1 item is missing: ([(Sum of Available Items) − 3] ÷ 12) × 100. 
Convenience 
([(Sum of Item 9 to Item 11) − 3] ÷18) × 100. 
If 1 item is missing: ([(Sum of Available Items) − 2] ÷ 12) × 100. 
Global Satisfaction 
([(Sum of Item 12 to Item 14) − 3] ÷ 14) × 100. 
If Item 12 or Item 13 is missing: 
([(Sum (the two completed items)) – 2] ÷ 10) × 100  
If Item 14 is missing:  
([(Sum of Available Items) − 2] ÷ 8) × 100. 
If more than 1 item is missing from any subscale, then the subscale will not be calculated. 
6.7.6.3. 
Work Productivity and Activity Impairment Questionnaire  
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity (ie, worse outcomes). There are 4 impairment scores. 
The scoring is as follows (Reilly Associates 2002): 
1. Absenteeism: Percent work time missed due to health: 100*[Q2/(Q2+Q4)]. 
2. Presenteeism: Percent impairment while working due to health: 100*[Q5/10]. 
3. Work productivity loss: Percent overall work impairment due to problem: 
100*{Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)]}. 
4. Activity impairment: Percent activity impairment due to health: 100*(Q6/10). 
where, 
Q2 = hours missed due to health problems 
Q3 = hours missed due to other reasons 
Q4 = hours actually worked 
Q5 = degree health affected productivity while working (circle a number from 0 to 10, where 
10 is worst impairment) 
Q6 = degree health affected regular activities (circle a number from 0 to 10, where 10 is 
worst impairment) 
Q1 asks whether the individual works for pay (yes/no). If the answer to that question is ‘No’ then 
the subject is instructed to skip to Q6. 


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6.8. 
Handling of Missing Data 
6.8.1. 
Imputation of Missing Efficacy Endpoints Post Study Treatment 
Discontinuation 
The event rate used in the primary analysis will be based on the observed data until the time of 
treatment discontinuation, if applicable. For the primary analysis at the end of Part 1, missing 
data sensitivity analyses will be conducted for handling of data for subjects who discontinue 
study treatment prior to the end of Part 1 in 2 ways: 
1. Using observed post-treatment discontinuation data where available without imputation 
for missing data. For this analysis, the event rate will be computed through the last date 
of observed data up to the Part 2 treatment start date/time, including data collected after 
treatment discontinuation.    
2. Observed post-treatment discontinuation data will be used in combination with an 
imputed event rate for the time period, post-treatment discontinuation, where data were 
not observed. An imputed rate for the entire 24-week period will be a weighted average 
of the observed rate up to the last day of diary collection (including days post treatment 
discontinuation) and the imputed rate for the time after treatment discontinuation during 
which data were not observed, with weighting based on the fraction of days with 
observed vs. unobserved data. For this rate, actual diary data collected after 
discontinuation of study treatment will be included in the observed rate where it is 
available by extending the time period in the denominator of the event rate calculation to 
the last day that diary data were collected, even if past study treatment discontinuation. 
The only exception to this is if the subject started other prophylactic treatment after 
discontinuation of study treatment. In that case, actual diary data will be used up until the 
time of start of other prophylactic treatment.  
For subjects for whom no diary data is missing post study treatment discontinuation, no 
imputation is necessary. An observed confirmed event rate will be computed to include 
data post study treatment discontinuation as applicable, as long as the subject did not start 
other prophylactic therapy.  
For subjects with missing data post study treatment discontinuation, missing data will be 
imputed as follows: 
𝑓𝑓= 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑜𝑜𝑜𝑜 𝑁𝑁𝑁𝑁𝑁𝑁-𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 
=  Date of Last Day of Diary Collection Prior to Any Other Prophylactic Treatment −Date of First Dose + 1
169
 
𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜
= 𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂  𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀ℎ𝑙𝑙𝑙𝑙 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑛𝑛𝑡𝑡 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 
=
 Number of Events ∗28
 Date of Last Day of Diary Collection Prior to Any Other Prophylactic Treatment −Date of First Dose + 1 
 
𝑟𝑟𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖= 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀ℎ𝑙𝑙𝑙𝑙 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡ℎ𝑒𝑒 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 
 


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= ൜
𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔                                                                                                
𝑖𝑖𝑖𝑖 𝑛𝑛𝑛𝑛𝑛𝑛 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑜𝑜𝑜𝑜 ℎ𝑖𝑖𝑖𝑖ℎ𝑒𝑒𝑒𝑒𝑒𝑒 (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤) 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑗𝑗𝑒𝑒𝑒𝑒𝑒𝑒 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤  
 
𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎=  𝑓𝑓∗𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜+ (1 −𝑓𝑓) ∗𝑟𝑟𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
 
As shown above, if a subject discontinues study treatment or withdraws from the study, 
the imputation of rimputed will differ depending on whether the data are considered missing 
at random or not missing at random based on the reason for study treatment 
discontinuation or study withdrawal as shown in Table 14. Data missing at random will 
be imputed using multiple imputation with 10 separate founds of imputations, randomly 
selecting from observed confirmed event rates of other subjects in the treatment group 
who completed the treatment for Part 1. Data not missing at random will be imputed 
using the median event rate of subjects in the worst quartile of performance (ie, highest 
event rate quartile) with regard to the primary endpoint for the given treatment group or 
the subject’s observed rate over the time period of available data, if worse.   
Table 14: 
Reason for Study Treatment Discontinuation and Whether Data are 
Considered Missing at Random or Not 
Missing Data Considered Missing at Random 
Missing Data Considered Not Missing at Random 
Subsequent determination that inclusion/exclusion 
criteria were not met 
Laboratory abnormality or adverse event 
Intercurrent illness or emergence of new illness/medical 
condition/pregnancy 
Discontinuation due to QT prolongation 
Subject noncompliance with study drug or procedures 
Discontinuation due to rash 
Subject withdrew consent 
Perceived lack of efficacy 
Other a 
Other a 
Sponsor discontinuation a 
Sponsor discontinuation a 
Investigator judgment a 
Investigator judgment a 
a A review of discontinuations for sponsor discontinuation, investigator judgment, or other reason will be completed 
prior to unblinding of Part 1 data for determination of missing at random or not missing at random. 
6.8.2. 
Other Sensitivity Analyses for Missing Data 
The PP population analyses will serve as a sensitivity analysis for missing data by displaying the 
results of analysis for subjects who generally followed the protocol. Analysis of the primary 
efficacy endpoint based on the completers population will also serve as a sensitivity analysis for 
missing data by showing the event rate in subjects who completed Part 1 of the study. 
6.8.3. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
For analysis of medications, a complete date should be established in order to identify 
medication as occurring during treatment or not. For the purpose of handling partially reported 
start and stop dates for medication the following algorithm will be applied: 
• Missing start day, but month and year present: 


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If trial medication had been taken in the same month and year as the occurrence of the 
medication, then the start day of the medication will be assigned to the day of first 
dose of trial medication. 
Otherwise the start day will be set to the first day of the month. 
• Missing start day and month, but year present: 
If trial medication had been taken in the same year as the occurrence of the 
medication, then the start date of the medication will be assigned to the date of first 
application of trial medication. 
Otherwise the start day and month will be set to 01 January. 
• Completely missing start date: 
For HAE medications, the date will be set to corresponding HAE event date. For all 
other concomitant medications, a completely missing date will be set to the treatment 
start date (if prior to the medication end date) or otherwise will be set to the 
medication end date. 
• Missing end day, but month and year present: 
The day will be set to the last day of the month. 
• Missing end day and month, but year present: 
The end day and month will be set to the date of trial termination. 
However, if trial termination year is greater than the year of the event/medication, 
then the day and month will be set to 31 December. 
In subject data listings, start and stop date of medication will be displayed as reported on the 
eCRF. 
6.8.4. 
Missing Start Date, Stop Date, Severity, or Relationship for Adverse Event 
The same conventions to address incomplete dates for prior and concomitant medications will 
also be used for AEs. Should an event have a missing severity or relationship, it will be classified 
as having the highest severity and/or strongest relationship to study treatment. 
6.8.5. 
Missing Time of First Dose or Time of Last Dose  
In case of missing time for first dose, it will be assumed that baseline measures that were to be 
taken prior to first dose according to the protocol were in fact taken prior to dosing. 
In case the time of the last dose is not reported, time of dose will be assigned as the median 
dosing time from all prior doses for the subject, as subjects are to dose once per day at 
approximately the same time each day. 
6.8.6. 
Incomplete Date and Time for a Subject-Reported Event 
For HAE events reported with missing start date and/or time, stop date and/or time, or date 
and/or time reported that the worst symptoms of the event were over (“worst over”), the 
following algorithm will be applied: 


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• Missing start time but start date present: 
The start time will be set to 12:00PM. 
• Missing start date and time: 
The start date will be set to the date for which the question was answered “Yes”. The 
start time will be set to 12:00PM 
• Missing worst over time, but worst over date present:  
The worst over time will be set to 11:59PM. 
• Missing worst over date and time:  
The worst over date will be set to the start date, the worst over time will be set to 
11:59PM 
• Missing stop time, but stop date present: 
The stop time will be set to 11:59PM 
• Missing stop date and time:  
The stop date will be set to the worst over date, or if missing, the event start date, the 
stop time will be set to 11:59PM 
7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
A summary table will be generated to provide the number and percentage (based on subjects 
randomized) of subjects in each of the analysis populations. 
Subject status at the end of Part 1 will be listed and summarized as a Part 1 only display based on 
the ITT population, showing the number and percentage of subjects with early discontinuation of 
study treatment and early withdrawal from the study along with reasons for each item. Subjects 
will be considered to have completed Part 1 if they have a Week 24 visit. A similar summary 
table and listing will be provided at the end the study and will show discontinuations over the 
entire study period. The listings will include whether subjects discontinued from the study drug, 
whether they withdrew from the study and the reasons for the discontinuation of study drug, 
along with the date of first and last dose and the date of completion or discontinuation from the 
study drug and date of study withdrawal. Duration on study treatment and on the study will also 
be provided.  
A CONSORT diagram will be created based on the summary tables for the study report, starting 
with the number of subjects screened. 
A summary of enrollment by investigator site will be provided. 
7.2. 
Screen Failures 
The number of screen failures and percent of screened subjects who are screen failures will be 
summarized along with reasons for screen failure. A summary and listing of demographic 
information for screen failures will be provided.  


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Confirmation of clinical diagnosis of HAE will be summarized based on the protocol inclusion 
criterion: C1 esterase inhibitor (C1-INH) functional levels, complement 4 (C4) levels, 
SERPING-1 gene mutation, and family history. 
Additionally, SERPING result listings will show whether tested subjects were positive or 
negative for the SERPING-1 gene mutation and hence whether they failed screening due to a 
negative SERPING result.  
7.3. 
Protocol Deviations and Listing of Subject Inclusion and Exclusion 
Criteria 
Subjects who were randomized but did not satisfy all inclusion and exclusion criteria will be 
listed. A listing of subjects for whom the treatment blind was broken during the study will also 
be provided, if appropriate.  
Protocol deviations will be included in listings and summaries for the CSR. A separate document 
will detail decision-making guidelines for determining whether a protocol deviation is major or 
minor and, for major protocol deviations, whether they would result in exclusion from the PP 
population. It will also detail a list of categories of protocol deviations. Protocol deviations will 
be reviewed in data review meetings prior to Part 1 unblinding to classify protocol deviations 
into categories, determine whether they are major or minor and to determine whether they will 
result in exclusion from the PP population.   
Analyses based on the PP population will only be produced for Part 1 analysis.  
A summary of all protocol deviations by type of deviation will be provided for Part 1. 
A review of protocol deviations for Part 2 will be conducted prior to database lock for the final 
study report after the last subject has completed Part 2. Protocol deviations for Part 2 will be 
summarized by Part 2 treatment (Table 7) and category of deviation and will be listed but will 
not result in exclusion from the PP population.  
7.4. 
Demographic and Baseline Characteristics 
Demographic summary tables will be provided separately for Part 1 Treatment and Part 2 
Treatment (Table 7). The ITT and PP populations will be the primary populations for analyses of 
demographics. Demographics, including age, gender, race, ethnicity, childbearing potential, 
weight, height, and body mass index (BMI) will be listed and summarized. Age (in years) will be 
reported as the age at consent or assent, as collected in the eCRF. 
BMI (kg/m2) will be calculated using the standard formula:  
BMI (kg/m2) = Weight (kg)/[Height (m)]2 
Confirmation of clinical diagnosis of HAE will be summarized based on the protocol inclusion 
criterion: C1-INH functional levels, C4 levels, SERPING-1 gene mutation, and family history.  
All SERPING results will be listed.  
Baseline C1-INH antigenic levels will be summarized using descriptive statistics for the 
continuous measure and categorized into < lower limit of normal (LLN) and ≥ LLN; subjects 
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the categorization but included in the continuous summary. A scatter plot of baseline C1-INH 
antigenic levels vs. screening C1-INH functional levels will be produced.   
7.5. 
HAE Medical and Medication History 
HAE and HAE medication history will be summarized for the following where possible: 
• HAE history 
• Past on-demand treatments of HAE 
• Current on-demand treatments of HAE 
• Past prophylactic treatments of HAE  
Past on-demand treatments will include those medications that were taken as needed and 
discontinued prior to the initiation of study treatment as recorded on the HAE Medication 
History Page. Past prophylactic treatments will include those medications that were taken as 
prophylaxis and discontinued prior to the initiation of study treatment as recorded on the HAE 
Medication History Page. Current on-demand medications will include those that are noted at 
screening as currently used for on-demand treatment as recorded on the HAE Medication History 
Page. Summaries will include a grouping of any C1-INH medication as well as displays of 
individual medications. The C1-INH grouping will include plasma-derived C1-INH replacement 
(brand names = Cinryze, Berinert, HAEgarda), recombinant C1-INH replacement (brand 
name = Ruconest), icatibant (Brand name = Firazyr), and fresh frozen plasma. The summary of 
androgens will include androgens (unspecified), oxandrolone, danazol (brand 
name = Danocrine), and stanozolol. 
All HAE medical and medication history collected on the CRF will be listed. Summaries will 
include a grouping of any C1-INH medication as well as displays of individual medications. 
7.6. 
Medical History and Medical Conditions Present at Entry 
Past or current relevant medical history information will be summarized and listed. 
7.7. 
Prior and Concomitant Non-HAE and HAE Medications  
Medication use is collected for the period from 30 days prior to Screening to study completion, 
except for contraceptives which are collected from 60 days prior. Medications collected in the 
eCRF that were received and stopped prior to the date of first dose will be considered prior 
medications. Medications will be considered as concomitant if the start date of the medication is 
on or after the date of first intake of study drug or if the start date is prior to the first date of study 
drug but the medication is ongoing during the treatment period in the study. Medications taken at 
any time during Part 1 of the study will be considered with Part 1 treatment. Similarly, 
medications taken at any time during Part 2 of the study will be considered with Part 2 treatment. 
For example, a medication which is started during Part 1 while a subject is assigned to a Part 1 
treatment of placebo will appear in the Part 1 only summary under the placebo column. If that 
treatment is continued into Part 2 where the subjects is assigned to a treatment of 110 mg, the 
medication will also be summarized in the treatment column labeled “110 mg after placebo” in 
the summary of concomitant medications for the entire study period. 


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Medication verbatim text will be coded using the WHODD, March 2017. A summary by Part 1 
treatment of recently discontinued medications taken within 30 days of screening but 
discontinued prior to dosing will be provided.  
Separate summaries of concomitant medications for Part 1 only and for the entire study period 
will be presented using the treatment descriptors in Table 6 and Table 8, respectively. The 
number and percentages of subjects taking each medication will be summarized by WHO 
preferred name. Multiple uses of the same medication (by preferred name) will be counted once 
only per subject per study treatment. No inferential statistics will be provided. 
HAE-related medications will be similarly summarized for Part 1 only and for the entire study 
period.  
An event-level summary will also be provided showing the number of expert-confirmed events 
for which the various HAE-related medications were taken based on the subject diary. 
All medication data will be listed. 
7.8. 
Baseline Physical Examination 
Physical examination data will be listed. 
7.9. 
Baseline Primary and Secondary Efficacy Evaluations 
All events will be listed. The baseline event rate and the categorized baseline event rate will be 
summarized by Part 1 treatment using descriptive statistics for baseline event rate and n [%] for 
the categorized baseline event rate. The proportion of days with HAE symptoms during the 
baseline period will also be included in the summary. 
Similarly, a summary of baseline of AE-QoL total and domain scores will be provided by Part 1 
treatment. 
8. 
EFFICACY  
8.1. 
General Considerations 
Data from all centers will be combined for analysis. 
Hypothesis tests will be 2-sided. Hypotheses comparing each of the 2 active dose groups to 
placebo will be separately tested for the primary efficacy endpoint for Part 1 of the current study 
and the combined Studies 301 and 302 using the ITT populations. Analyses of Part 2 data will be 
descriptive and will be reported for the current study only. No hypotheses will be tested for 
Part 2 nor will hypothesis testing be conducted to compare the 2 active dose groups. 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline 
A summary of subgroup membership for the current study and for the combined Studies 301 and 
302 will be provided by Part 1 treatment. Subgroups are listed in Section 8.4. In addition, the 
duration of baseline period, baseline event rate, categorized baseline event rate 
(≥ 2 events/month vs. < 2 events/month), and baseline AE-QoL will be summarized by Part 1 
treatment. 


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8.3. 
Statement of the Null and Alternate Hypotheses 
Hypothesis testing will be conducted for Part 1 only. The primary null and alternative 
hypotheses, for each active dose separately, are: 
• Ho: RA = RP; active treatment does not have a differential effect on the rate of 
expert-confirmed HAE events 
• HA: RA ≠ RP; active treatment does have a differential effect on the rate of 
expert-confirmed HAE events 
where RA is the monthly event rate for active treatment and RP is the monthly event rate 
for placebo treatment. 
Secondary hypotheses are (in order of hierarchical testing): 
1. Proportion of days with angioedema symptoms 
• Ho: β = 0; active treatment does not have a differential effect on the proportion of 
days with angioedema symptoms over the entire treatment period 
• HA: β ≠ 0; active treatment does have a differential effect on the proportion of days 
with angioedema symptoms over the entire treatment period 
where β is the parameter representing treatment effect for the dose of interest in an 
analysis of covariance (ANCOVA) model. 
2. Rate of expert-confirmed HAE events during the effective dosing period (beginning on 
Day 8 through 24 weeks) 
• Ho: RA = RP; active treatment does not have a differential effect on the rate of 
expert-confirmed HAE events during the effective dosing period 
• HA: RA ≠ RP; active treatment does have a differential effect on the rate of 
expert-confirmed HAE events during the effective dosing period 
where RA is the monthly event rate for active treatment and RP is the monthly event rate 
for placebo treatment during the effective dosing period. 
3. AE-QoL 
• Ho: β = 0; active treatment does not have a differential effect on the change from 
baseline AE-QoL at Week 24 
• HA: β ≠ 0; active treatment does have a differential effect on the change from baseline 
AE-QoL at Week 24 
where β is the parameter representing treatment effect for the dose of interest in a 
mixed-effects model with repeated measures (MMRM). 
8.4. 
Subgroup Analyses for Combined Study Analysis 
For the combined study analysis, subgroup analyses for the primary and secondary endpoints 
will be provided by: 
1. Sex 


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2. Race (white vs. other) 
3. Baseline event rate (≥ 2 events/month vs. < 2 events/month)  
4. Age group (12 - 17, 18 to 64, ≥ 65 years) 
5. Region (North America vs. Japan vs. rest of world) 
6. Weight (< median vs. ≥ median) 
7. BMI (18.5 to 24.9 kg/m2 vs. 25 to 29.9 kg/m2 vs. ≥ 30 kg/m2) 
8. Prior androgen use (yes vs. no) 
A summary of TEAEs by age group will also be provided. 
8.5. 
Multiple Comparisons and Multiplicity 
There are 4 endpoints being tested in the combined analysis, the primary endpoint and 3 
secondary endpoints. For each endpoint, there are 2 potential doses to be tested. The Type I error 
rate will be controlled at the study level by using a combination of hierarchical testing and the 
Hochberg procedure. The 4 endpoints will be tested in a hierarchical fashion and the 2 doses will 
be tested using the Hochberg step-up procedure at each level of the hierarchy to which both 
doses progress through the hierarchy. 
The first endpoint to be tested is the primary endpoint, the rate of expert-confirmed angioedema 
events during dosing in the entire 24-week treatment period of Part 1. Using the Hochberg 
step-up procedure, each of the 2 doses will be tested at the α = 0.05 level, comparing active 
treatment to placebo. If the maximum of the 2 p-values is ≤ 0.05, the null hypotheses of no 
difference between the rate of angioedema events for subjects on active and placebo treatment 
will be rejected for both doses and testing will proceed to the next endpoint in the hierarchy with 
α = 0.05. If the maximum of the 2 p-values is > 0.05 but the minimum of the 2 p-values is 
< 0.025, the null hypothesis for the dose with p < 0.025 will be rejected and testing for that dose 
only will proceed to the next endpoint in the hierarchy with α = 0.025. Otherwise, the null 
hypotheses for both doses will not be rejected, testing will stop, and the hypothesis for the next 
endpoint in the hierarchy will not be tested. 
The first, second, third, and fourth endpoints in the hierarchy are: 
1. The rate of expert-confirmed HAE events during dosing in the entire 24-week treatment 
period (Day 1 to Day 168) 
2. Number and proportion of days with angioedema symptoms through 24 weeks 
3. Rate of expert-confirmed HAE events during dosing in the effective dosing period 
(beginning on Day 8 through 24 weeks) 
4. Change from baseline in AE-QoL at Week 24 (total score) 
The process described above will be continued for each endpoint in the hierarchy until either all 
4 endpoints have been tested or testing has stopped due to non-rejection of the null hypotheses 
for both doses for endpoints earlier in the hierarchy. At each level of the hierarchy, the Hochberg 
step-up procedure is used to control Type I error rates if 2 doses are to be tested. Otherwise, if 
only one dose is being tested, the single test is conducted with α = 0.025. 


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The sample size considered feasible for enrollment in Japan has limited statistical power. 
Therefore, a supplemental statistical analysis will be conducted in the same manner as above 
using the combined data from Studies 301 and 302. The combined rate of HAE events will 
utilize investigator-confirmed attacks from Study 302 and expert-confirmed events from 
Study 301. 
8.6. 
Analysis of the Primary Efficacy Endpoint 
8.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint for Part 1 of the study is the rate of expert-confirmed HAE events 
during dosing in the entire 24-week dosing period during Part 1 (Day 1 to first dose of Part 2). 
The first dose in Part 2 is expected on Day 169. The primary efficacy analysis will be produced 
using the ITT population. The estimand will be based on data from subjects who are on study 
treatment and this analysis will not include data post treatment discontinuation. 
The number of expert-confirmed HAE events for Part 1 will be analyzed by treatment group 
using appropriate descriptive statistics for the confirmed event rate (expressed as events/month) 
based on the 24-week dosing period or until study treatment discontinuation, if applicable. An 
additional summary of confirmed event rate by month, including CFB event rate and percentage 
CFB event rate by month, will be produced. The primary efficacy analysis will be conducted 
using Part 1 data and the primary efficacy endpoints will be summarized and listed by Part 1 
treatment group.  
The angioedema event rate and the treatment comparisons between each BCX7353 dose and 
placebo in the rate of expert-confirmed angioedema events during the entire dosing period will 
be analyzed using a negative binomial regression model. The number of expert-confirmed 
angioedema events will be included as the dependent variable, the treatment will be included as a 
fixed effect, the stratification variable (baseline monthly angioedema event rate) and study (for 
the combined study analysis) will be included as covariates, and the logarithm of duration on 
treatment will be included as an offset variable. The estimated rate of angioedema events for 
each treatment group, the treatment differences expressed as the angioedema event rate ratio 
(BCX7353 over placebo rate ratio), and their associated 95% confidence intervals (CIs) will be 
provided from the negative binomial regression model. Monthly will be defined as 28 days. 
The percentage reduction from placebo will be calculated for each dose as:  
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟= ( 1 −𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟) ∗100 = (1 −RA
RP
) ∗100 
Where RP is the estimated event rate for Placebo treatment and RA is the estimated event rate for 
Active treatment. 
Example SAS pseudo-code for the negative binomial regression analysis is as follows: 
proc genmod data = datasetname; 
   class trt01p /param=glm; 
   model ecevents = trt01p blatk /dist=negbin link=log offset=logdurtrt; 
run; 


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All statistical tests will be two-sided. Multiplicity adjustments for Part 1 analyses for the two 
dose groups are discussed in Section 8.5 along with handling of testing of multiple endpoints. 
Plots of mean confirmed event rate by month and scatter plots of baseline event rate vs. 24-week 
event rate will be produced with a different color for each treatment. Plots of mean event rate per 
month will be updated to include the Part 2 data at the end of Part 2. Adjusted subject-reported 
event rate data per month will be plotted separately for Part 3, as Part 3 does not include expert 
confirmation of events. A scatterplot will be produced for the difference between the baseline 
confirmed event rate and the confirmed event rate for Part 1 vs. the baseline confirmed event 
rate. This scatterplot will also be produced by gender. A plot of confirmed events by study day 
for Part 1 will be presented for individual subjects by treatment group and will display the length 
of each event and will include the use of on-demand medication. A plot of individual event rates 
showing the baseline and the Part 1 confirmed event rate will be presented by treatment group. A 
plot of individual event rates showing the baseline and confirmed event rates for each month will 
be presented by treatment group.  
The sample size considered feasible for enrollment in Japan has limited statistical power. 
Therefore, a supplemental statistical analysis will be conducted in the same manner as above 
using the combined monthly angioedema event rate (investigator-confirmed attacks in Study 302 
and expert-confirmed events in Study 301) in the entire treatment period in the ITT population. 
The relationship of selected baseline characteristics with the expert-confirmed events will be 
explored using an appropriate model-building method for Part 1. 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Results 
Primary efficacy analysis will be based on the ITT population with a sensitivity analyses for 
efficacy based on the PP and completers populations. A second analysis using the ITT 
population with subject-reported rather than expert-confirmed events will also be conducted. 
In addition, there will be 2 sensitivity analyses to examine the effect of missing data.  
1. A missing data sensitivity analysis will be conducted in which observed data post study 
drug discontinuation are included in event rate determination. The estimand for this 
analysis is referred to as the de facto estimand. Details on the determination of the event 
rate are provided in Section 6.8.1. 
2. A missing data sensitivity analysis will be conducted in which observed data post study 
drug discontinuation are used in combination with imputed data for subjects who 
discontinue study treatment prior to the end of Part 1 and do not continue to provide 
event information. The method of imputation will depend upon whether the data are 
considered missing at random or not missing at random. Details on the imputation 
methodology are provided in Section 6.8.1. 
A forest plot will be provided to visually compare the results obtained using these methods of 
sensitivity analyses to the primary efficacy result.   
Sensitivity analyses will also be conducted for the combined study. 


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8.7. 
Analysis of the Secondary Efficacy Endpoints 
Analysis of the secondary efficacy endpoints will be conducted for the combined study. 
8.7.1. 
Angioedema Quality of Life (Total and Domain Scores) 
CFB in AE-QoL questionnaire at Week 24 (total score) is a secondary endpoint for Part 1. 
Durability in AE-QoL questionnaire scores is a secondary endpoint for Part 2. 
The actual and change from baseline domain and total scores will be summarized by visit and 
treatment. For Part 1, changes from baseline in AE-QoL will be assessed with a MMRM model 
with fixed effects for treatment, baseline event rate, baseline AE-QoL, visit, and a visit by 
treatment interaction and a random effect for subject. An unstructured covariance structure will 
be used. The estimated treatment difference comparing each active treatment to placebo at each 
post-baseline visit (Weeks 4, 6, 12, 18, and 24) will be displayed together with the 95% CI and 
the associated p-value. Least squares means (LSM) for each visit will also be presented with the 
standard error and the number of subjects contributing to the LSM. Total and domain scores will 
be listed for each subject and visit. The responses to the individual AE-QoL questions will also 
be listed. 
Figures of mean actual and change from baseline AE-QoL total and domain scores will be 
produced with one line per treatment group. In addition, a cumulative distribution plot of 
AE-QoL Total Score at Week 24 will be provided. 
Final analyses at the end of Part 2 will also include data from visits at Weeks 28, 32, 36, 48, and 
52. Summaries will be updated to include the additional information. An additional descriptive 
summary of change from Week 24 will be provided for Part 2 visits for subjects originally 
randomized to placebo treatment. 
A summary and analysis of the number and percent of subjects with at least a six-point decrease 
(Minimum Clinically Important Difference [MCID]) in total AE-QoL score will be performed by 
visit for Part 1. The summary will be repeated at the end of Part 2. The analysis for Part 1 will be 
based on a logistic model with response of achievement of the MCID (yes/no), baseline event 
rate and baseline AE-QoL total score as covariates and a fixed effect for treatment. 
8.7.2. 
Number and Proportion of Days with Angioedema Symptoms  
The number of proportion of days with angioedema symptoms through 24 weeks is a secondary 
endpoint for Part 1. The number and proportion of days with angioedema symptoms is also a 
secondary endpoint for Part 2. Definitions of the endpoints are provided in Section 6.7.5.3. 
For Part 1, the number and proportion of days with angioedema symptoms through Week 24 will 
be determined. Both the number and proportion of days will be summarized. The proportion of 
days with angioedema symptoms through Week 24 will be analyzed using an ANCOVA model 
with baseline event rate as a covariate and treatment included as a fixed effect. The estimated 
treatment difference comparing each active treatment to placebo will be displayed together with 
the 95% CI and the associated p-value. LSMs will be presented with the standard error and the 
number of subjects contributing to the LSM. The number and proportion of days with 
angioedema symptoms will be listed for each subject. A similar analysis will be conducted based 
on the effective dosing period, beginning on Day 8 and continuing through Week 24. 


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Final analyses at the end of Part 2 will include a summary of the number and proportion of days 
with angioedema symptoms through Week 52 for those subjects originally randomized to active 
treatment and a summary through adjusted Week 24 for active treatment for subjects originally 
randomized to placebo. Only subjects who received at least one dose of study treatment in Part 2 
of the study will be included in this summary. The subject listing will be updated to include the 
number and proportion of days with angioedema symptoms through the end of the study. The 
number and proportion of days with angioedema symptoms during Part 3 of the study will be 
reported separately from Part 2. 
8.7.3. 
Rate of Expert-Confirmed HAE Events during Dosing in the Effective Dosing 
Period 
The rate of expert-confirmed HAE events during dosing in the effective dosing period is a 
secondary endpoint for Part 1. 
Summaries and analysis of the expert-confirmed event rate using the ITT population for the 
effective dosing period (Day 8 through Week 24, inclusive) will be conducted using negative 
binomial regression, similar to what is done for the primary efficacy endpoint analysis.  
Summary displays will be updated at the end of Part 2 to include data collected during Part 2 of 
the study. For subjects originally randomized to placebo, data on active treatment will be 
summarized using the adjusted visits. 
8.7.4. 
Use of HAE Event Medications 
The use of HAE event medications over 24 weeks is an exploratory efficacy endpoint for Part 1 
and a secondary endpoint for Part 2. Use of HAE medications based on diary data will be 
summarized separately from concomitant medications. In addition, summaries and analyses of 
the rate of expert-confirmed HAE events requiring treatment will be provided for Part 1 and for 
the entire study period. The analysis will be performed similarly to the analysis of rate of 
confirmed HAE events. For a list of medications that qualify as HAE event medications, see 
Section 6.7.5.7. Separate summaries of HAE event medication use for Part 3 will be produced based 
on adjusted subject-reported attacks. 
A Kaplan-Meier (KM) plot of time to first use of targeted HAE rescue medication to treat an 
expert-confirmed event and corresponding summary table will be produced for Part 1. 
The rate of the use of any HAE medications (ie medication rate) used to treat expert-confirmed 
events will be calculated as doses taken for expert-confirmed events per month (28 days), similar 
to the calculation of the event rate. This will be analyzed using a negative binomial regression 
analysis in the same manner as the primary endpoint, with the number of rescue medication 
doses included as the dependent variable, treatment included as a fixed effect, baseline 
expert-confirmed event rate included as a covariate, and the logarithm of duration on treatment 
included as an offset variable. This analysis will also be conducted for the medication rate for 
subject-reported events. 
A summary of expert-confirmed events requiring treatment with targeted HAE medications that 
will display the first medication taken and number of uses of any other targeted medications for 
each attack will be presented. 


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8.7.5. 
Discontinuations due to Lack of Efficacy 
Discontinuation due to lack of efficacy is a secondary endpoint for Part 2. 
A summary of the number of subjects who discontinue due to lack of efficacy will be provided 
with subject disposition. The summary will include the number and percent of subjects who 
discontinue due to lack of efficacy during Part 1 and Part 2 as well as overall. 
8.8. 
Analysis of Additional Exploratory Efficacy Endpoints 
8.8.1. 
Number and Proportion of Subjects with No Events  
The number and proportion of subjects with no events over 24 weeks is an exploratory endpoint 
for Part 1. This information will be descriptively summarized. The summary will be repeated at 
the end of Part 2 as a summary of the number and proportion of subjects with no events over the 
entire dosing period of 52 weeks for those originally randomized to active treatment. A summary 
of 24-Week data at the end of Part 2 will be conducted including subjects originally randomized 
to placebo. The summary will show the number and proportion of subjects with no events during 
the first 24 weeks of active treatment, whether received in Part 1 or Part 2 and separately for 
those who started active treatment in Part 2. Subjects who discontinue treatment prior to the end 
of the reporting period of interest will not be considered event-free. A separate summary of the 
number and proportion of subjects with no adjusted subject-reported events in Part 3 will be 
provided. 
 For Part 1, a chi-squared test will be used to test whether there is a difference in the proportion 
of subjects with no events comparing each active dose to placebo. For the chi-squared analysis, if 
the expected number of subjects in any individual cell is < 5, Fisher’s exact test will be used 
instead the chi-squared test.  
A KM plot and corresponding summary of time to first event will be produced for Part 1 for both 
the entire dosing period and the effective dosing period (Day 8 to Week 24). 
8.8.2. 
Proportion of Responders to Study Drug. 
Subjects will be classified as responders or non-responders for Part 1 as discussed in 
Section 6.7.5.4. A responder is defined as a subject who has at least a 50% relative reduction in 
the rate of expert-confirmed HAE events meeting the stricter screening criteria during treatment 
compared with the baseline event rate. A summary of the number and proportion of responders 
by study treatment will be produced. Logistic regression with responder status as the outcome 
variable and treatment and baseline event rate as independent variables in the model will be used 
to compare each active treatment to placebo treatment. Point estimates of the odds ratios for 
response comparing 110 mg to placebo and 150 mg to placebo will be calculated along with 
corresponding 95% CIs. If the proportion of responders is near zero for the placebo treatment (or 
for either active treatment), logistic regression may not be an appropriate methodology for 
analysis and Fisher’s exact test will be used in place of logistic regression. This analysis will also 
be conducted for responders with at least 70% and 90% relative reduction and conducted by 
subgroups for 50%, 70%, and 90% relative reduction. Forest plots will be produced to 
accompany the subgroup analyses. 


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A waterfall plot of relative reduction by treatment will be produced. For the combined study, this 
plot will include differentiation in the bar fill for Japan and the rest of the world. 
A listing of expert-confirmed events that are not included in any adjusted expert-confirmed 
events will be provided. 
The relationship of selected baseline characteristics with the proportion of responders with at 
least 50% and 70% relative reduction, respectively, will be explored using an appropriate 
model-building method for Part 1. 
8.8.3. 
Event Characteristics 
Characteristics of events including location of event (see Section 6.7.5.9), laryngeal events (see 
Section 6.7.5.10), duration of events from start to finish and from start to the time the worst 
symptoms of the event were over, time since last dose, triggers, swelling, other symptoms, 
whether the event was treated, severity as assessed by the patient and by the investigator, ability 
to do daily activities, appearance affected, professional care sought, and location of professional 
care will be summarized and listed. 
A summary of duration of event for abdominal, peripheral, and mixed events will also be 
provided (see Table 11). 
8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses 
A listing of subjects excluded from the PP population will be provided along with reason for 
exclusion. 
9. 
HEALTH OUTCOMES 
9.1. 
EQ-5D-5L 
EQ-5D-5L is a health outcomes endpoint for Part 1 and a secondary endpoint for Part 2. The 
5-digit numbers representing the health state of each subject will be listed along with the VAS 
score and computed index value (Section 6.7.6.1). The VAS score and computed EQ-5D-5L 
index value will be summarized descriptively for Part 1 and for the entire study period. 
Note that this study uses the questionnaire in its validated form for subjects to report their health 
status “today”. If the subject has had an HAE event since the last visit, starting at Week 4, the 
subject completes the questionnaire a second time to reflect back on health status during a “usual 
event”.  On summary tables, the “today” and “usual event” questionnaire results will appear in 
different rows and analyses should be separated. 
For Part 1, MMRM will be used to compare each active dose to placebo for each time point. For 
this analysis, either the CFB VAS score or EQ-5D-5L index value using the “today” 
questionnaire will be included as the dependent variable in the model with fixed effects for 
treatment, baseline event value, baseline VAS or EQ-5D-5L index score as appropriate, visit, 
visit by treatment interaction, and a random effect for subject included as independent variables. 
An unstructured covariance structure will be used.   


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Analyses at the end of Part 2 will be descriptive and will cover the entire study period. 
For Part 1 and entire study period analyses, categorical summaries by treatment group and visit 
will be provided for responses to each individual question.  In addition, summaries of VAS and 
index scores during a “usual event” will be provided. 
Plots of VAS and EQ-5D-5L index mean scores over time and CFB mean scores will be 
provided for Part 1 analysis and at end of Part 2 analysis using the health status “today”. For 
Part 2, plots of mean scores over time by treatment will be shown separately for active treatment 
for the subjects originally randomized to placebo. 
9.2. 
Treatment Satisfaction Questionnaire for Medication 
TSQM is a health outcomes endpoint for Part 1 and a secondary endpoint for Part 2. TSQM is 
measured at baseline. 
TSQM scores for Effectiveness, Side Effects, Convenience, and Global Satisfaction will be 
calculated for each visit as discussed in Section 6.7.6.2. The TSQM scores will be summarized 
by score, treatment, and visit with separate summaries for Part 1 and for the entire study period. 
For Part 1, MMRM will be used to compare each active dose to placebo for each time point. For 
this analysis, the TSQM CFB score of interest will be included as the dependent variable in the 
model with fixed effects for treatment, baseline event value, baseline TSQM score, visit, visit by 
treatment interaction and a random effect for subject included as independent variables. An 
unstructured covariance structure will be used.  
Separate figures of Effectiveness, Side Effects, Convenience, and Global Satisfaction mean 
scores over time with one line per treatment group will be provided. There will be one set of 
figures for Part 1 and another for the entire study period. For the analysis at the end of Part 2, the 
figure will have separate lines for active treatment for subjects originally randomized to placebo, 
showing mean scores over time by treatment. 
In addition, categorical summaries by treatment group and visit will be provided for responses to 
each individual question.  
9.3. 
Work Productivity and Activity Impairment 
WPAI is a health outcomes endpoint for Part 1 and a secondary endpoint for Part 2. 
Absenteeism, presenteeism, work productivity loss, and activity impairment will be calculated as 
described in Section 6.7.6.3. WPAI scores will be summarized descriptively by treatment group 
and visit for Part 1 and for the entire study period. For Part 1, MMRM will be used to compare 
each active dose to placebo for each time point. For this analysis, the CFB WPAI score of 
interest will be included as the dependent variable in the model with fixed effects for treatment, 
baseline event value, baseline WPAI score, visit, visit by treatment interaction and a random 
effect for subject included as independent variables. An unstructured covariance structure will be 
used.     
In addition, summaries statistics by treatment group and visit will be provided for responses to 
each individual question (Q2 to Q6) with a categorical summary provided for Q1. 
Separate figures of each of the WPAI mean scores and CFB mean scores over time with one line 
per treatment group will be provided. There will be one set of figures for Part 1 and another for 


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the entire study period. For the plots produced at the end of Part 2, the figure will have separate 
lines for active treatment for subjects originally randomized to placebo. 
10. 
SAFETY AND TOLERABILITY 
Analysis of safety data will be conducted for the current study alone. 
The safety analyses will be analyzed separately for Part 1; available data from all parts of the 
study will be combined for a long-term safety assessment. 
10.1. 
Adverse Event Preferred Term and System Organ Class Summary 
Tables 
The following are Part 1 safety endpoints and Part 2 primary endpoints: 
• Number and proportion of subjects with a TEAE 
• Number and proportion of subjects who discontinue due to a TEAE 
• Number and proportion of subjects who experience a TESAE  
• Number and proportion of subjects who experience a Grade 3 or 4 TEAE 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality. 
In addition, the proportion of subjects with a treatment-emergent, treatment-related AE 
consistent with a drug rash will also be summarized 
AEs will be mapped to the MedDRA version 19.1 preferred term (PT) and SOC. AEs are 
assessed by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 
(life-threatening) according to Division of Microbiology and Infectious Diseases (DMID) using 
the November 2007 criteria. If a subject experiences multiple events that map to a single PT, the 
greatest severity grade according to the DMID criteria and strongest investigator assessment of 
relation to study medication will be assigned to the PT for the appropriate summaries. All AEs 
will be listed for individual subjects showing both verbatim and preferred terms.  
TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in 
Part 1 or Part 2, and will be assigned to the relevant treatment depending on when the TEAE 
began (Part 1 or Part 2 treatment). AEs occurring 30 days after the last dose for subjects who 
discontinue study treatment in Part 1 or up to 30 days after last dose in Part 2 will be considered 
as TEAEs and will be associated with Part 1 or Part 2 respectively. Note that investigators are 
not required to contact subjects after the last follow-up if it occurs prior to 30 days from last 
dose. All AEs that occurred prior to the initiation of study treatment or those recorded more than 
30 days after the last dose of study treatment will be excluded from the tables but will be 
included in the listings. 
Drug-related events are defined as those AEs that the investigator believes were possibly, 
probably, or definitely related to the study drug. 


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10.1.1. 
Summaries of Adverse Event Incidence Rates for All Subjects and Incidence 
Rates for Serious Adverse Events, Discontinuations due to Adverse Events, and 
Deaths 
A brief summary of TEAEs will show, by treatment group, the number and percentage of 
subjects who 1) had any TEAE, 2) had any drug-related event, 3) permanently discontinued from 
study drug due to a TEAE, 4) had any TESAE, 5) had any Grade 3 or higher TEAE, 6) had any 
Grade 3 or higher drug-related TEAE, 7) had any TEAE leading to interruption of study drug, or 
8) had a drug-related TESAE. This summary will be reproduced for TEAEs by month 
(1 month = 28 days) for the first 7 months of the study, eg Month 1 will include events which 
have a start date between Day 1 and Day 28 of the study, Month 2 will include events between 
Day 29 and Day 56, etc. Subjects at risk for each month will include those who are receiving 
drug in the period of interest or who have discontinued drug within 30 days of the start of the 
period. Figures presenting the categories by month will also be produced. 
AEs will be summarized by treatment group. For each SOC and PT, the number and percentage 
of subjects reporting an event will be calculated. In summary tables, SOCs and events within a 
SOC will be presented by decreasing frequency count based on the total number of events. 
Multiple events (by subject or SOC as appropriate) will be counted only once per subject per 
dose in each summary. For summaries that use severity grade, the most severe event will be 
selected. 
The following summary tables (number and percentage of subjects) of TEAEs (by SOC and PT) 
will be provided by treatment group: 
• Overall summary of TEAEs 
• Summary of TEAEs 
• Summary of drug-related TEAEs 
• Summary of TEAEs by severity 
• Summary of treatment-emergent Grade 3 or Grade 4 AEs 
• Summary of drug-related, treatment-emergent Grade 3 or Grade 4 AEs 
• Summary of TESAEs 
• Summary of TEAEs leading to permanent discontinuation of study treatment 
• Summary of TEAEs leading to interruption of study treatment 
• Summary of drug-related TESAEs 
In addition, a summary of frequent AEs will be provided by PT (not by SOC and PT), in 
decreasing order of frequency. Frequent AEs will be defined as events that occur in 2 or more 
subjects in the clinical trial. 
Data listings will be provided for all AE data. In addition to listing all AEs, distinct data listings 
will also be provided for the following: 
• Grade 3 or Grade 4 AEs  
• AEs leading to permanent study discontinuation 


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• SAEs (fatal and non-fatal) 
A forest plot of most-frequent treatment-emergent AEs sorted by risk difference will be 
produced using the format recommended by the FDA/Industry/Academia Safety Graphics 
working group (https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). 
A listing of subjects for whom narratives are required will be provided and will include the 
reason for the narrative.  
10.1.2. 
Investigator-Identified Rash Events of Special Interest and Gastrointestinal 
Abdominal-Related Adverse Events 
The following is a Part 2 primary endpoint: 
• The proportion of subjects with a treatment-emergent, treatment-related AE 
consistent with a drug rash 
All rashes, regardless of assessed causality or severity are reported as events of special interest 
(EOSIs) by investigators in a protocol defined manner. However, the endpoint of interest is the 
proportion of subjects with a treatment-emergent, treatment-related AE consistent with drug 
rash. 
Gastrointestinal (GI) abdominal-related TEAEs are also of interest, although these are not EOSIs 
for investigator reporting purposes. There are no appropriate standardized MedDRA queries in 
MedDRA to evaluate GI abdominal-related AEs that are appropriate to assess potential AEs 
associated with BCX7353 use. To create a list of PTs that are pertinent, the events to be analyzed 
have been prospectively defined as all PTs within the MedDRA v19.1 hierarchy under the high-
level group terms (HLGTs) of 1) gastrointestinal signs and symptoms and 2) gastrointestinal 
motility and defaecation conditions. See Section 17.3 for a detailed list of PTs, high level terms, 
and HLGTs. This selection is broad enough so that GI events are appropriately identified and 
analyzed but excludes terms that, although in the GI SOC, are not representative of the events of 
concern such as oral or esophageal events.  
For the investigator-identified rashes and the GI abdominal-related events, separate listings will 
be provided. In addition, for both investigator-identified rashes and GI abdominal-related events 
there will be a summary that shows, by treatment group, the number and percentage of subjects 
with: 
• A TEAE  
• A drug-related TEAE 
• Permanent discontinuation from study drug due to the TEAE 
• An AE that was considered an TESAE 
• Any Grade 3 or higher TEAE 
• Any Grade 3 or higher drug-related TEAE 
• Any TEAE leading to interruption of study drug 
• A TEAE that was considered a drug-related TESAE 
• A TEAE that required use of concomitant medication 


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For treatment-emergent investigator-identified rashes and GI abdominal-related AEs, time to 
development of the TEAE will be estimated using the KM method. The results will be displayed 
in summary tables as well as in a KM plot. Subjects who do not experience the event of interest 
will be censored at the date of the last dose. Summary displays for the investigator-identified 
rashes and GI abdominal-related TEAEs will include a count of the number of TEAEs as well as 
the number of subjects who experience each AE. 
A KM plot and summary of duration of event will be provided for the investigator-identified 
rashes and GI abdominal TEAEs. The summary display will provide the median duration of 
event by treatment group, with the event as the unit of interest rather than the subject. 
A separate analysis will be conducted in which the number and proportion of subjects with either 
a GI abdominal-related TEAE or an unconfirmed abdominal-only event is presented. The 
number of events will also be included in the summary. 
10.1.3. 
Missing and Partial Adverse Event Onset Dates 
See Section 6.8.4. 
10.1.4. 
Summaries of Adverse Event Incidence Rates per Person-Year of Exposure to 
Study Treatment 
For this study, the duration of exposure to study treatment will vary depending on whether the 
subject is initially assigned to placebo. Because of this, certain AE tables will be repeated using 
the number of TEAEs per 100 person-years of exposure instead of using a count, where 
1 year = 365.25 days of exposure. These tables will not be created for the Part 1 primary efficacy 
analysis since the same amount of exposure is expected per treatment group for Part 1 analysis. 
To determine the rate of TEAEs per 100 person-years of exposure, the duration of treatment 
exposure will be computed for each subject and treatment. The rate of TEAEs per person-year 
will then be calculated as the count of TEAEs divided by the duration of treatment exposure.  
This value will then be multiplied by 100 to compute the rate per 100 person-years of exposure. 
For subjects initially randomized to placebo, there will be exposure time for placebo treatment 
and a separate exposure time for treatment with either 110 or 150 mg. The total exposure for the 
treatment group of interest will sum the individual subject exposure time for each treatment 
group.  
The following summary tables of rate of TEAEs per 100 person-years of exposure will be 
provided by treatment group (by SOC and PT): 
• Summary of TEAE rate per 100 person-years of exposure 
• Summary of drug-related, TEAE rate per 100 person-years of exposure 
• Summary of TESAEs per 100 person-years of exposure 
A listing of person-years of exposure to study treatment will be provided by subject and 
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10.2. 
Exposure to Study Treatment and Treatment Compliance 
The number of subjects exposed to study treatment, the number of subjects who discontinue 
treatment early, and the reasons for early discontinuation will be presented on the disposition 
table. A summary of exposure to study treatment will be also be presented and will include a 
summary of person-years of exposure to study treatment as described in Section 10.1.4. Listings 
of exposure to study treatment and of drug accountability will be provided by subject and 
treatment. KM plots of duration of study treatment will be provided. Treatment compliance will 
be computed based on drug accountability by determining the number of capsules taken relative 
to the number of capsules that should have been administered.  
For compliance (%) for the study period of interest based on the drug accountability page of the 
eCRF: 
number of capsules taken= number of capsules dispensed – number of capsules returned 
expected number of capsules taken = 2*(date of the last dose-date of the first dose+1) 
If the number of capsules taken per day changes due to formulation or lot changes at any time 
(eg, from 2 per day to 1 per day), the expected number of capsules will be adjusted accordingly 
at the date of the change. 
Treatment compliance based on dispensing information will be calculated for each study 
treatment that the subject received as follows: 
Treatment compliance (dispensing)= 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∗100 
Treatment compliance will be listed and summarized for Part 1 for all subjects and for Day 1 to 
Week 24, Day 1 to Week 48, and Day 1 to Week 52, for subjects who have completed the 
respective visit. For subjects initially assigned to placebo, treatment compliance will be 
computed for placebo treatment and separately for the active treatment received in Part 2.  
A categorical summary of treatment compliance will be produced with the following categories 
shown in Table 15. 
Table 15: 
Definition of Compliance Categories 
Compliance 
Range of Compliance (%) 
Poor compliance 
< 80% 
Acceptable compliance 
80% to < 90% 
Good compliance 
90% to 110% 
Over-dosing 
> 110% 
A plot of CFB event rate by % compliance will be produced for Part 1, with treatment groups 
overlaid. 
Treatment compliance will also be calculated between scheduled visits (or between the final 
dispense date and the final return date) similar to above with the following changes. The 
expected number of capsules will be computed as the number of capsules expected between 
scheduled dispense dates. Drug will be assumed to have been taken during the period after the 


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drug was dispensed, as long as the bottle is returned, regardless of the return date. Visits for 
which no bottles are returned at any time are considered missing data and compliance is not 
calculated in these cases. Note that this calculation does not take into account any 
protocol-allowable study drug interruptions. 
10.3. 
Concomitant and Other Medications 
Association of concomitant medications with treatment and coding of concomitant medications 
is described in Section 7.7. Concomitant medications will be summarized by treatment and 
WHO preferred name for Part 1 and for the entire study period. Multiple medication use (by 
preferred name) will be counted once only per subject. Concomitant medications started more 
than 30 days post last dose will not be included in summary displays but will be listed. 
Concomitant medications that were used for HAE-related indications will also be summarized 
separately for Part 1 and for the entire study period.     
All medication data will be listed. 
10.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
See Section 6.8.3. 
10.4. 
Laboratory Data 
The following endpoint is a Part 1 safety endpoint and Part 2 primary endpoint: 
• Number and proportion of subjects who experience a treatment-emergent Grade 3 or 
4 laboratory abnormality 
A listing of clinical laboratory evaluations is provided in the Protocol, Section 11.2.6.  
Clinical laboratory assessments and corresponding changes from baseline will be summarized 
for each laboratory panel by treatment group and visit. Laboratory abnormalities will be graded 
according to the DMID Adult Toxicity Table (publish date: November 2007; see Protocol 
Appendix 16.1). Any graded abnormality that occurs following the initiation of study drug and 
represents at least one-grade increase from the baseline assessment is defined as treatment emergent. 
Urinalysis results will be summarized by treatment and visit and listed by subject and treatment.   
The number and percentage of subjects experiencing treatment-emergent graded toxicities will 
be summarized. Treatment-emergent Grade 3 or 4 laboratory abnormalities will be summarized 
separately. Laboratory toxicity shifts from baseline to worst postbaseline assessments will be 
summarized.  
The number and percentage of subjects who have post-baseline elevations in liver transaminase 
(alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or bilirubin abnormalities 
in relation to fold above the upper limit of normal will be summarized according to the US Food 
and Drug Administration’s (FDA’s) Premarketing Clinical Evaluation on Drug-Induced Liver 
Injury Guidance for Industry (DHHS 2009).  
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments (where “and” indicates elevations occurring at 
the same visit). Within each treatment group and laboratory parameter grouping, a subject may 


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be counted once per elevation criteria using the worst-case result. That is, a subject with a 
worst-case ALT elevation >3 × the upper limit of normal (ULN) for a given treatment group 
would be counted once in the ALT > 1.5 × ULN category and once in the ALT > 3 × ULN 
category, regardless of how many ALT elevations the subject had that met the > 3 × ULN and 
> 1.5 × ULN elevation criteria. 
• ALT and/or AST > 3 × ULN and total bilirubin > 1.5 or 2 × ULN 
• AST > 1.5, 3, 5, 10, and 20 × ULN 
• ALT > 1.5, 3, 5, 10, and 20 × ULN  
• Total bilirubin > 1, 1.5, or 2 × ULN  
• Alkaline phosphatase (ALP) > 1.5 × ULN 
The summary display of abnormal hepatic laboratory values will be repeated by prior use of 
androgens (yes/no) based on medical history. Detailed listings of prior androgen use will be 
provided for subjects with any elevation in the indicated categories. 
Profiles of liver enzymes and bilirubin over time will be graphically displayed for subjects with 
any Grade 3 or 4 abnormality in these analytes. In addition, a listing of all liver function test 
(ALT, AST, bilirubin, ALP, gamma-glutamyl transferase) results for subjects experiencing a 
treatment-emergent Grade 3 or 4 liver function test will be provided.  
In addition, a Hy’s law plot, a shift plot showing liver safety panel tests over time (baseline vs. 
on-study), and distribution plots of ALT, AST, ALP, bilirubin, cholesterol, and triglycerides over 
time will be produced using the format recommended by the FDA/Industry/Academia Safety 
Graphics working group (https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The 
plots to be included are the scatter plot of maximum transaminase vs. maximum bilirubin, the 
liver test safety panel over time and the distribution of ALT by time and treatment. The 
distribution plots for AST, ALP, bilirubin, cholesterol, and triglycerides will use the same format 
as is used for ALT. 
Separate KM plots of time to event for a Grade 3 or higher ALT, AST, or bilirubin will be 
produced.   
A listing of AEs of nausea, vomiting, anorexia, abdominal pain, or fatigue occurring within 
24 hours of an elevation of AST or ALT will be produced. 
10.4.1. 
Prior Androgen Use and Liver Function Test Abnormalities 
The summary display of abnormal hepatic laboratory values will be repeated by prior use of 
androgens (yes/no) at any time in the past based on medical history. Detailed listings of prior 
androgen use will be provided for subjects with any elevation in the indicated categories. 
10.4.2. 
Complement Factors and HAE Diagnosis  
Laboratory results related to HAE diagnosis, including complement factors C1-INH antigenic 
level, C1-INH functional level, complement 3 (C3), and C4 will be included in summaries of 
laboratory data. Criteria used to confirm diagnosis of HAE Type 1 or 2 will be summarized and 
listed as described in Section 7.4. 


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10.4.3. 
Laboratory Assessments for Rash 
For subjects with rash, peripheral blood mononuclear cells will be collected for analysis of 
possible drug-specific immune responses and possible drug-responsive T cells.  
Other laboratory assessments taken at the time of a rash, including clinical chemistry, 
hematology with differential, C3 level, and urine eosinophils will be included in laboratory 
listings. 
10.5. 
Pregnancy 
A listing of pregnancy test results will be provided.   
10.6. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and respiratory rate) 
and body weight and corresponding changes from baseline will be summarized by treatment 
group and visit using descriptive statistics. These data will be listed by subject, treatment, and 
visit. 
Distribution plots of systolic and diastolic blood pressure over time will be produced using the 
format recommended by the FDA/Industry/Academia Safety Graphics working group 
(https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The graph format to be used is 
the same as the graph provided for the distribution of ALT by time and treatment. 
A scatter plot of baseline values vs. all observed changes relative to baseline recorded at any 
time will be produced. 
10.7. 
12-lead Electrocardiograms  
Baseline (pre-dose) and Week 24 ECGs will be obtained in triplicate (ie, three separate readings) 
at 1- to 5-minute intervals, with baseline values calculated from an average of the 3 readings. All 
other ECGs will be single assessments.  
An ECG should be repeated for a CFB in corrected QT interval using Fridericia’s method 
(QTcF) > 60 msec or a QTcF interval > 500 msec. 
ECGs and corresponding CFB will be summarized by treatment group and visit using descriptive 
statistics.  
ECG findings will be summarized. 
The CFB in QTcF will be determined by routine ECGs. At each time point where ECGs are 
analyzed, an individual subject’s CFB will be calculated as: 
∆ik= (QTcF for subject i at time point k – Baseline QTcF)  
QTcF measurements will be the average of triplicate ECGs at baseline and Week 24 and single 
values at all other time points.  
A distribution plot of QTcF over time will be produced using the format recommended by the 
FDA/Industry/Academia Safety Graphics working group 
(https://www.ctspedia.org/do/view/CTSpedia/StatGraphHome). The graph format to be used is 
the same as the graph provided for the distribution of ALT by time and treatment. 


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A scatter plot of baseline values vs. all observed changes relative to baseline recorded at any 
time will be produced. 
For routine ECGs, the number and proportion of subjects with QTcF ≤ 450, > 450 to ≤ 480, 
> 480 to ≤ 500, and > 500 msec; or changes of ≤ 30, > 30 to ≤ 60, or > 60 msec will be 
summarized. Unscheduled ECG results will be included in this summary table. 
All ECG values and findings will be listed by subject, treatment, and visit.   
10.8. 
Physical Examination 
A full physical examination is conducted at Screening, Baseline, and at Week 24. 
Symptom-directed physicals are done at all other study visits except Week 2 and Week 26. 
Physical examination data will be listed by subject and treatment. 
10.9. 
Study Termination Status 
Study termination status will be presented on the subject disposition table. 
11. 
PHARMACOKINETICS 
Analyses of concentration data will be performed using the safety population. PK concentration 
data will be listed by subject, treatment, day, and time for Part 1 and for the entire study period at 
the end of Part 2. Note that PK concentration data collected at each visit will not be summarized 
by visit as the timing of PK data collected was not pre-specified. 
The following summary displays will be produced: 
• Summary of number and percentage of collected samples > 4 × half-maximal effective 
concentration (EC50) > 6 × EC50, and > 8 × EC50 at each visit and overall  
• Summary of number and percentage of samples within a subject > 4 × EC50, > 6 × EC50, 
and > 8 × EC50 
The value of EC50 used will be 9 ng/mL. 
12. 
PHARMACODYNAMICS 
Analyses of concentration data will be performed using the PD population. The baseline 
amidolytic activity mean will be summarized by treatment for all subjects and for males and 
females separately. 
Plasma kallikrein inhibition (KKI) data will be expressed as percent inhibition compared to 
subject baseline activity (%KKI).  The formula for percent inhibition is: 
%KKI = 100 – (postbaseline value) 
where the values are the mean amidolytic activity (%) at each time point. The mean amidolytic 
activity is set as 100% at baseline. Multiple assessments of amidolytic activity from samples at a 
single time point will be handled as described in Section 6.7.4. 


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%KKI data will be listed by subject, treatment, day, and time. This analysis will be conducted for 
Part 1 and then repeated for the entire study period. 
The following summary displays will be produced: 
• Summary of number and percentage of collected samples with > 50% and > 80% 
inhibition at each visit and overall  
• Summary of number and percentage of samples within a subject with > 50% and > 80% 
inhibition  
13. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
A scatter plot of %KKI (y-axis) by PK concentration/4 (x-axis) will be produced at the time of 
the Part 1 analysis and for the entire study period, using the PK/PD population for the current 
study alone. Note the division by 4 of the concentration corrects for the dilution of the plasma 
required for the PD assay. This analysis will be conducted for the current study alone and for 
combined Studies 301 and 302. 
14. 
PHARMACOGENETICS 
Pharmacogenetic samples will be collected on all subjects who are willing to participate in 
pharmacogenetic testing. If a decision is made to analyze the samples and conduct a statistical 
analysis of the results, the statistical analysis will be the subject of a separate SAP. 
Results of human leukocyte antigen typing may be evaluated in a separate cross-study analysis. 
15. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
The following changes from protocol-specified analyses are as follows: 
• The definition of the screen failure population has changed from subjects not dispensed 
treatment to those who are not randomized and are reported as screen failures in the eCRF. 
• The definition of the PP population has been altered to include ≥ 85% treatment 
compliance as an inclusion requirement. 
• Part 1 is defined as Day 1 to first dose of Part 2 rather than Day 1 through Day 168. 
• The entire dosing period for Part 1 is defined as Day 1 to first dose of Part 2 rather than 
Day 1 through Day 168 and Day 1 through Day 168 + 24 hours. 
• The negative binomial regression model will be used instead of the Poisson regression 
model for all applicable analyses. The Poisson regression that was originally proposed is a 
special case of the negative binomial regression model. For Study 302, the required 
assumptions of the Poisson model were not met, and the negative binomial model was 
used instead.  For this reason and because there will be a combined analysis of the current 
study with Study 302, the negative binomial model results for the current study will be 
provided. 


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16. 
REFERENCES 
Alberti, A., P. Pontisso, L. Chemello, G. Fattovich, L. Benvegnu, F. Belussi and M. S. De Mitri 
(1995). "The interaction between hepatitis B virus and hepatitis C virus in acute and chronic liver 
disease." J Hepatol 22(1 Suppl): 38-41. 
Atkinson, M. J., A. Sinha, S. L. Hass, S. S. Colman, R. N. Kumar, M. Brod and C. R. Rowland 
(2004). "Validation of a general measure of treatment satisfaction, the Treatment Satisfaction 
Questionnaire for Medication (TSQM), using a national panel study of chronic disease." Health 
Qual Life Outcomes 2: 12. 
Besari, A. M., S. S. Md Noor and Y. Y. Lee (2014). "The deadly ebola threat in the midst of an 
overwhelming dengue epidemic." Malays J Med Sci 21(6): 9-13. 
DHHS (2009). "Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation." 
Reilly Associates (2002). "WPAI Scoring ". 
van Reenen, M. and B. Janssen (2015). "EQ-5D-5L User Guide Version 2.1." 
Wechsler, M. E., P. C. Fulkerson, B. S. Bochner, G. M. Gauvreau, G. J. Gleich, T. Henkel, R. 
Kolbeck, S. K. Mathur, H. Ortega, J. Patel, C. Prussin, P. Renzi, M. E. Rothenberg, F. Roufosse, 
D. Simon, H. U. Simon, A. Wardlaw, P. F. Weller and A. D. Klion (2012). "Novel targeted 
therapies for eosinophilic disorders." J Allergy Clin Immunol 130(3): 563-571. 
 
 
 


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17. 
APPENDIX 
17.1. 
Table of Contents for Data Display Specifications 
17.1.1. 
Tables 
17.1.1.1. BCX7353-301 Only 
Output Number 
Population Title 
Output Title 
14.1.1.1 
All Subjects 
Summary of Subject Disposition by Site, Part 1 
14.1.1.1.ES 
All Subjects 
Summary of Subject Disposition by Site, Entire Study 
14.1.2.1 
ITT Population 
Summary of Analysis Populations 
14.1.2.2 
ITT Population 
Summary of Subgroups 
14.1.2.3.1 
ITT Population 
Summary of Inclusion/Exclusion Criteria Violations 
14.1.2.3.2 
Screen Failures 
Summary of Inclusion/Exclusion Criteria Violations 
14.1.2.4 
ITT Population 
Summary of Protocol Deviations, Part 1 
14.1.2.4.ES 
ITT Population 
Summary of Protocol Deviations that Occurred During Part 2 
14.1.2.5 
All Subjects 
Summary of Confirmation of Diagnosis of HAE Type I or II 
14.1.3.1.1 
ITT Population 
Summary of Demographic Characteristics 
14.1.3.1.1.ES 
ITT Population 
Summary of Demographic Characteristics - Subjects Who Transitioned to Part 2 
14.1.3.1.2 
PP Population 
Summary of Demographic Characteristics 
14.1.3.1.3 
Screen Failures 
Summary of Demographic Characteristics 
14.1.3.2 
ITT Population 
Summary of Subject-Reported HAE Baseline Characteristics - HAE Medical History 
14.1.3.3 
ITT Population 
Summary of Past Prophylactic Treatments of HAE 
14.1.3.4 
ITT Population 
Summary of Primary Reason for Discontinuation of Past Prophylactic Treatments of 
HAE 
14.1.3.5 
ITT Population 
Summary of Current On-Demand Treatments of HAE 
14.1.3.6 
ITT Population 
Summary of Subject-Reported HAE Baseline Characteristics - Primary Acute Event 
Treatment Information 
14.1.3.7 
ITT Population 
Summary of Pre-Treatment Expert-Confirmed Event Rates and Angioedema 
Symptoms 
14.1.3.8 
ITT Population 
Summary of C1-INH Antigenic Levels 
14.1.4.1 
ITT Population 
Summary of Medications Taken within 30 Days Prior to Screening and Discontinued 
Prior to Dosing 
14.1.4.2 
ITT Population 
Summary of Concomitant Medications, Part 1 
14.1.4.2.ES 
ITT Population 
Summary of Concomitant Medications, Entire Study 
14.1.4.3 
ITT Population 
Summary of Concomitant Medications for HAE, Part 1 
14.1.4.3.ES 
ITT Population 
Summary of Concomitant Medications for HAE, Entire Study 
14.1.4.3.P3 
ITT Population 
Summary of Concomitant Medications for HAE, Part 3 
14.1.4.4 
ITT Population 
Summary of Concomitant Medications for Acute Treatment of Angioedema Events - 
Event Level [1] 
14.1.4.4.ES 
ITT Population 
Summary of Concomitant Medications for Acute Treatment of Angioedema Events - 
Event Level [1], Entire Study 
14.1.4.4.P3 
ITT Population 
Summary of Concomitant Medications for Acute Treatment of Angioedema Events – 
Event Level, Part 3 
14.1.4.5 
ITT Population 
Summary of Expert-Confirmed Events Requiring Treatment with Targeted HAE 
Medications, Part 1 
14.1.4.5.ES 
ITT Population 
Summary of Expert-Confirmed Events Requiring Treatment with Targeted HAE 
Medications, Entire Study 


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Output Number 
Population Title 
Output Title 
14.1.5.1 
Safety 
Population 
Summary of Treatment Exposure, Part 1 
14.1.5.1.ES 
Safety 
Population 
Summary of Treatment Exposure, Entire Study 
14.1.5.3 
Safety 
Population 
Summary of Treatment Compliance, Part 1 
14.1.5.3.ES 
Safety 
Population 
Summary of Treatment Compliance, Entire Study 
14.2.1.1 
ITT Population 
Summary of Hierarchical Testing for Efficacy Endpoints 
14.2.1.2.1 
ITT Population 
Overall Event Summary During Part 1 
14.2.1.2.1.ES 
ITT Population 
Overall Event Summary During Entire Study 
14.2.1.2.2 
PP Population 
Overall Event Summary During Part 1 
14.2.1.3.1 
ITT Population 
Overall Event Summary During the Effective Dosing Period, Part 1 
14.2.1.3.1.ES 
ITT Population 
Overall Event Summary During the Effective Dosing Period, Entire Study 
14.2.1.3.2 
PP Population 
Overall Event Summary During the Effective Dosing Period, Part 1 
14.2.1.4.1 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Part 1 
14.2.1.4.1.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Entire Study 
14.2.1.4.2 
PP Population 
Summary of Rate of Expert-Confirmed Events During Part 1 
14.2.1.4.3 
Completers 
Population 
Summary of Rate of Expert-Confirmed Events During Part 1 
14.2.1.4.4 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Part 1, Including Observed 
Data Post Treatment Discontinuation  
14.2.1.4.5 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Part 1, Including Observed 
Data Post Treatment Discontinuation and Missing Data Post Treatment 
Discontinuation are Imputed 
14.2.1.11.1 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Effective Dosing Period, Part 
1 
14.2.1.11.1.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Effective Dosing Period, 
Entire Study 
14.2.1.11.2 
PP Population 
Summary of Rate of Expert-Confirmed Events During Effective Dosing Period, Part 
1 
14.2.1.14 
ITT Population 
Summary of Rate of Expert-Confirmed Events Requiring Treatment During Part 1 
14.2.1.14.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Events Requiring Treatment During Entire 
Study 
14.2.1.15 
ITT Population 
Summary of Rate of Expert-Confirmed Abdominal-Only Events During Part 1 
14.2.1.15.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Abdominal-Only Events During Entire Study 
14.2.1.16 
ITT Population 
Summary of Rate of Expert-Confirmed Peripheral-Only Events During Part 1 
14.2.1.16.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Peripheral-Only Events During Entire Study 
14.2.1.17 
ITT Population 
Summary of Rate of Expert-Confirmed Mixed Location Events During Part 1 
14.2.1.17.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Mixed Location Events During Entire Study 
14.2.1.18 
ITT Population 
Summary of Rate of Subject-Reported Events During Part 1 
14.2.1.18.ES 
ITT Population 
Summary of Rate of Subject-Reported Events During Entire Study 
14.2.1.18.P3 
ITT Population 
Summary of Rate of Subject-Reported Events During Part 3 
14.2.1.19.P3 
ITT Population 
Summary of Rate of Subject-Reported Events Requiring Treatment During Part 3 
14.2.1.20 
ITT Population 
Subject-Reported and Expert-Confirmed Events During Part 1 
14.2.1.20.ES 
ITT Population 
Subject-Reported and Expert-Confirmed Events During Entire Study 
14.2.1.22 
ITT Population 
Relationship of Baseline Characteristics and the Rate of Expert-Confirmed Events, 
Part 1 
14.2.2.1 
ITT Population 
Summary of Rate of Expert-Confirmed Events by Month During Part 1 
14.2.2.1.ES 
ITT Population 
Summary of Rate of Expert-Confirmed Events by Month During Entire Study 


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Output Number 
Population Title 
Output Title 
14.2.2.1.P3 
ITT Population 
Summary of Rate of Adjusted Events By Month During Part 3 
14.2.3.1.1 
ITT Population 
Summary of AE-QoL Scores by Visit, Part 1 
14.2.3.1.1.ES 
ITT Population 
Summary of AE-QoL Scores by Visit, Entire Study 
14.2.3.1.2 
PP Population 
Summary of AE-QoL Scores by Visit, Part 1 
14.2.3.7 
ITT Population 
Number and Percent of Subjects Achieving the MCID (Decrease in Total AE-QoL 
Score), Part 1 
14.2.3.7.ES 
ITT Population 
Number and Percent of Subjects Achieving the MCID (Decrease in Total AE-QoL 
Score), Entire Study 
14.2.4.1 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert-Confirmed Event-
Free, Part 1 
14.2.4.1.ES 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert-Confirmed Event-
Free, Entire Study 
14.2.4.2 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert-Confirmed Event-
Free in the Effective Dosing Period, Part 1 
14.2.4.2.ES 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert-Confirmed Event-
Free in the Effective Dosing Period, Entire Study 
14.2.5.1.1 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert-Confirmed Events, Part 1  
14.2.5.1.1.ES 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert-Confirmed Events, Entire Study 
14.2.5.1.1.P3 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Adjusted Events, Part 3 
14.2.5.1.2 
PP Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert-Confirmed Events, Part 1  
14.2.5.1.3 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert-Confirmed Events During Effective Dosing Period, Part 1 
14.2.5.1.3.ES 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert-Confirmed Events During Effective Dosing Period, Entire Study  
14.2.6.1.1 
ITT Population 
Summary of Relative Reduction from Baseline in Adjusted Expert-Confirmed Event 
Rate, Part 1 
14.2.6.1.2 
PP Population 
Summary of Relative Reduction from Baseline in Adjusted Expert-Confirmed Event 
Rate, Part 1 
14.2.6.3 
ITT Population 
Relationship of Baseline Characteristics and the Proportion of Subjects with at least a 
50% Relative Reduction in Adjusted Expert- or Investigator-Confirmed Events, Part 
1 
14.2.6.4 
ITT Population 
Relationship of Baseline Characteristics and the Proportion of Subjects with at least a 
70% Relative Reduction in Adjusted Expert- or Investigator-Confirmed Events, Part 
1 
14.2.7.1 
ITT Population 
Event-Level Duration of Expert-Confirmed Events (hours) from Start of Event to the 
Time the Event Finished, Part 1 
14.2.7.1.ES 
ITT Population 
Event-Level Duration of Expert-Confirmed Events (hours) from Start of Event to the 
Time the Event Finished, Entire Study 
14.2.7.2 
ITT Population 
Event-Level Duration of Expert-Confirmed Events (hours) from Start of Event Until 
Worst Was Over, Part 1 
14.2.7.2.ES 
ITT Population 
Event-Level Duration of Expert-Confirmed Events (hours) from Start of Event Until 
Worst Was Over, Entire Study 
14.2.8.1 
ITT Population 
Summary of Time (Days) to First Expert-Confirmed Event 
14.2.9.1 
ITT Population 
Summary of Time (Days) to First Use of Targeted HAE Rescue Medication to Treat 
an Expert-Confirmed Event 
14.2.10.1 
ITT Population 
Summary of Event Characteristics for Expert-Confirmed Events, Part 1  
14.2.10.1.ES 
ITT Population 
Summary of Event Characteristics for Expert-Confirmed Events, Entire Study  
14.2.11.1 
ITT Population 
Summary of Event Locations for Expert-Confirmed Events, Part 1  


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
87 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.2.11.1.ES 
ITT Population 
Summary of Event Locations for Expert-Confirmed Events, Entire Study 
14.2.12.1 
ITT Population 
On-demand Rescue Medication Rate for Expert-Confirmed Events, Part 1 
14.2.12.2 
ITT Population 
On-demand Rescue Medication Rate for Subject-Reported Events, Part 1 
14.3.1.1 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events, Part 1 
14.3.1.1.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events, Entire Study 
14.3.1.2 
Safety 
Population 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, 
Part 1 
14.3.1.2.ES 
Safety 
Population 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, 
Entire Study 
14.3.1.3 
Safety 
Population 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term, Part 1 
14.3.1.3.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term, Entire Study 
14.3.1.4 
Safety 
Population 
Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred 
Term, Part 1 
14.3.1.4.ES 
Safety 
Population 
Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred 
Term, Entire Study 
14.3.1.5 
Safety 
Population 
Drug-Related Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term, Part 1 
14.3.1.5.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term, Entire Study 
14.3.1.6 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System Organ Class and 
Preferred Term, Part 1 
14.3.1.6.ES 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System Organ Class and 
Preferred Term, Entire Study 
14.3.1.7 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System 
Organ Class and Preferred Term, Part 1 
14.3.1.7.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System 
Organ Class and Preferred Term, Entire Study 
14.3.1.8 
Safety 
Population 
Treatment-Emergent Adverse Events Leading to the Interruption of Study Drug by 
System Organ Class and Preferred Term, Part 1 
14.3.1.8.ES 
Safety 
Population 
Treatment-Emergent Adverse Events Leading to the Interruption of Study Drug by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.9 
Safety 
Population 
Treatment-Emergent Adverse Events Leading to the Discontinuation of Study Drug 
by System Organ Class and Preferred Term, Part 1 
14.3.1.9.ES 
Safety 
Population 
Treatment-Emergent Adverse Events Leading to the Discontinuation of Study Drug 
by System Organ Class and Preferred Term, Entire Study 
14.3.1.10 
Safety 
Population 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Severity, Part 1 
14.3.1.10.ES 
Safety 
Population 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Severity, Entire Study 
14.3.1.12 
Safety 
Population 
Summary of Frequent Adverse Events, Part 1 
14.3.1.12.ES 
Safety 
Population 
Summary of Frequent Adverse Events, Entire Study 
14.3.1.14 
Safety 
Population 
Summary of Drug-Related Frequent Adverse Events, Part 1 
14.3.1.14.ES 
Safety 
Population 
Summary of Drug-Related Frequent Adverse Events, Entire Study 
14.3.1.15 
Safety 
Population 
Overall Summary of Treatment-Emergent Investigator-Identified Rash (Event of 
Special Interest), Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
88 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.1.15.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Investigator-Identified Rash (Event of 
Special Interest), Entire Study 
14.3.1.16 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) by 
System Organ Class and Preferred Term, Part 1 
14.3.1.16.ES 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.17 
Safety 
Population 
Drug-Related Treatment-Emergent Investigator-Identified Rash (Event of Special 
Interest) by System Organ Class and Preferred Term, Part 1 
14.3.1.17.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Investigator-Identified Rash (Event of Special 
Interest) by System Organ Class and Preferred Term, Entire Study 
14.3.1.18 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Serious 
Adverse Events by System Organ Class and Preferred Term, Part 1 
14.3.1.18.ES 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Serious 
Adverse Events by System Organ Class and Preferred Term, Entire Study 
14.3.1.19 
Safety 
Population 
Drug-Related Treatment-Emergent Investigator-Identified Rash (Event of Special 
Interest) Serious Adverse Events by System Organ Class and Preferred Term, Part 1 
14.3.1.19.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Investigator-Identified Rash (Event of Special 
Interest) Serious Adverse Events by System Organ class and Preferred Term, Entire 
Study 
14.3.1.20 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 Investigator-Identified Rash (Event of 
Special Interest) by System Organ Class and Preferred Term, Part 1 
14.3.1.20.ES 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 Investigator-Identified Rash (Event of 
Special Interest) by System Organ Class and Preferred Term, Entire Study 
14.3.1.21 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or 4 Investigator-Identified Rash (Event 
of Special Interest) by System Organ Class and Preferred Term, Part 1 
14.3.1.21.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or 4 Investigator-Identified Rash (Event 
of Special Interest) by System Organ Class and Preferred Term, Entire Study 
14.3.1.22 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Leading 
to the Interruption of the Study Drug by System Organ Class and Preferred Term, 
Part 1 
14.3.1.22.ES 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Leading 
to the Interruption of the Study Drug by System Organ Class and Preferred Term, 
Entire Study 
14.3.1.23 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Leading 
to the Discontinuation of Study Drug by System Organ Class and Preferred Term, 
Part 1 
14.3.1.23.ES 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) Leading 
to the Discontinuation of Study Drug by System Organ Class and Preferred Term, 
Entire Study 
14.3.1.24 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) 
Requiring the Use of Concomitant Medication by System Organ Class and Preferred 
Term, Part 1 
14.3.1.24.ES 
Safety 
Population 
Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) 
Requiring the Use of Concomitant Medication by System Organ Class and Preferred 
Term, Entire Study 
14.3.1.25 
Safety 
Population 
Summary of Time (Days) to Development of Investigator-Identified Rash (Event of 
Special Interest), Part 1 
14.3.1.25.ES 
Safety 
Population 
Summary of Time (Days) to Development of Investigator-Identified Rash (Event of 
Special Interest), Entire Study 
14.3.1.27 
Safety 
Population 
Summary of Duration (Days) of Investigator-Identified Rash (Event of Special 
Interest), Part 1 
14.3.1.27.ES 
Safety 
Population 
Summary of Duration (Days) of Investigator-Identified Rash (Event of Special 
Interest), Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
89 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.1.29 
Safety 
Population 
Overall Summary of Treatment-Emergent GI Abdominal-Related Adverse Events, 
Part 1 
14.3.1.29.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent GI Abdominal-Related Adverse Events, 
Entire Study 
14.3.1.30 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class 
and Preferred Term, Part 1 
14.3.1.30.ES 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class 
and Preferred Term, Entire Study 
14.3.1.31 
Safety 
Population  
Drug-Related Treatment-Emergent GI Abdominal-Related Adverse Events by System 
Organ Class and Preferred Term, Part 1 
14.3.1.31.ES 
Safety 
Population  
Drug-Related Treatment-Emergent GI Abdominal-Related Adverse Events by System 
Organ Class and Preferred Term, Entire Study 
14.3.1.32 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Events Serious Adverse Events by 
System Organ Class and Preferred Term, Part 1 
14.3.1.32.ES 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Events Serious Adverse Events by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.33 
Safety 
Population 
Drug-Related Treatment-Emergent GI Abdominal-Related Serious Adverse Events 
by System Organ Class and Preferred Term, Part 1 
14.3.1.33.ES 
Safety 
Population 
Drug-Related Treatment-Emergent GI Abdominal-Related Serious Adverse Events 
by System Organ Class and Preferred Term, Entire Study 
14.3.1.34 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 GI Abdominal-Related Adverse Events by 
System Organ Class and Preferred Term, Part 1 
14.3.1.34.ES 
Safety 
Population 
Treatment-Emergent Grade 3 or Grade 4 GI Abdominal-Related Adverse Events  by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.35 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or 4 GI Abdominal-Related Adverse 
Events by System Organ Class and Preferred Term, Part 1 
14.3.1.35.ES 
Safety 
Population 
Drug-Related Treatment-Emergent Grade 3 or 4 GI Abdominal-Related Adverse 
Events by System Organ Class and Preferred Term, Entire Study 
14.3.1.36 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Leading to the 
Interruption of Study Drug by System Organ Class and Preferred Term, Part 1 
14.3.1.36.ES 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Leading to the 
Interruption of Study Drug by System Organ Class and Preferred Term, Entire Study 
14.3.1.37 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Leading to the 
Discontinuation of Study Drug by System Organ Class and Preferred Term, Part 1 
14.3.1.37.ES 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Leading to the 
Discontinuation of Study Drug by System Organ Class and Preferred Term, Entire 
Study 
14.3.1.38 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Requiring the Use of 
Concomitant Medication by System Organ Class and Preferred Term, Part 1 
14.3.1.38.ES 
Safety 
Population 
Treatment-Emergent GI Abdominal-Related Adverse Events Requiring the Use of 
Concomitant Medication by System Organ Class and Preferred Term, Entire Study 
14.3.1.39 
Safety 
Population 
Summary of Time (Days) to Development of GI Abdominal-Related Adverse Events, 
Part 1  
14.3.1.39.ES 
Safety 
Population 
Summary of Time (Days) to Development of GI Abdominal-Related Adverse Events, 
Entire Study  
14.3.1.41 
Safety 
Population 
Duration (Days) of GI Abdominal-Related Adverse Events, Part 1 
14.3.1.41.ES 
Safety 
Population 
Duration (Days) of GI Abdominal-Related Adverse Events, Entire Study 
14.3.1.44 
Safety 
Population 
Summary of GI Abdominal-Related Adverse Events and Unconfirmed HAE Events 
with Abdominal-Only Symptoms, Part 1 
14.3.1.44.ES 
Safety 
Population 
Summary of GI Abdominal-Related Adverse Events and Unconfirmed HAE Events 
with Abdominal-Only Symptoms, Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
90 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.1.45.ES 
Safety 
Population 
Summary of Treatment-Emergent Adverse Event Rate Per 100 Person-Years of 
Exposure, Entire Study 
14.3.1.46.ES 
Safety 
Population 
Summary of Drug-Related Treatment-Emergent Adverse Event Rate Per 100 Person-
Years of Exposure, Entire Study 
14.3.1.47.ES 
Safety 
Population 
Summary of Treatment-Emergent Serious Adverse Event Rate Per 100 Person-Years 
of Exposure, Entire Study 
14.3.1.48.1 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 1, Part 
1 
14.3.1.48.1.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 1, 
Entire Study 
14.3.1.48.2 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 2, Part 
1 
14.3.1.48.2.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 2, 
Entire Study 
14.3.1.48.3 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 3, Part 
1 
14.3.1.48.3.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 3, 
Entire Study 
14.3.1.48.4 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 4, Part 
1 
14.3.1.48.4.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 4, 
Entire Study 
14.3.1.48.5 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 5, Part 
1 
14.3.1.48.5.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 5, 
Entire Study 
14.3.1.48.6 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 6, Part 
1 
14.3.1.48.6.ES 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events Occurring in Month 6, 
Entire Study 
14.3.5.1 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Clinical 
Chemistry, Part 1 
14.3.5.1.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Clinical 
Chemistry, Entire Study 
14.3.5.2 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Hematology 
and Coagulation, Part 1 
14.3.5.2.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Hematology 
and Coagulation, Entire Study 
14.3.5.3 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Complement 
Factors, Part 1 
14.3.5.3.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Complement 
Factors, Entire Study 
14.3.5.4 
Safety 
Population 
Summary of Observed and Change from Baseline Laboratory Data: Additional Tests, 
Part 1 
14.3.5.4.ES 
Safety 
Population 
Summary of Observed and Change from Baseline Laboratory Data: Additional Tests, 
Entire Study 
14.3.5.5 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Continuous 
Urinalysis Parameters, Part 1 
14.3.5.5.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in Laboratory Data: Continuous 
Urinalysis Parameters, Entire Study 
14.3.5.6 
Safety 
Population 
Summary of Observed Laboratory Data: Categorical Urinalysis Parameters, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
91 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.5.6.ES 
Safety 
Population 
Summary of Observed Laboratory Data: Categorical Urinalysis Parameters, Entire 
Study 
14.3.5.7 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Clinical Chemistry, Part 1 
14.3.5.7.ES 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Clinical Chemistry, Entire 
Study 
14.3.5.8 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Hematology and 
Coagulation, Part 1 
14.3.5.8.ES 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Hematology and 
Coagulation, Entire Study 
14.3.5.9 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Urinalysis, Part 1 
14.3.5.9.ES 
Safety 
Population 
Shift from Baseline to Worst Post-Baseline Assessment: Urinalysis, Entire Study 
14.3.5.10 
Safety 
Population 
Summary of Treatment-Emergent Graded Laboratory Abnormalities, Part 1 
14.3.5.10.ES 
Safety 
Population 
Summary of Treatment-Emergent Graded Laboratory Abnormalities, Entire Study 
14.3.5.11 
Safety 
Population 
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities, Part 1 
14.3.5.11.ES 
Safety 
Population 
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities, Entire 
Study 
14.3.5.12 
Safety 
Population 
Summary of Treatment-Emergent Laboratory Toxicity Grade Increases from 
Baseline, Part 1 
14.3.5.12.ES 
Safety 
Population 
Summary of Treatment-Emergent Laboratory Toxicity Grade Increases from 
Baseline, Entire Study 
14.3.5.13 
Safety 
Population 
Summary of Fold x ULN for Liver Function Tests, Part 1 
14.3.5.13.ES 
Safety 
Population 
Summary of Fold x ULN for Liver Function Tests, Entire Study 
14.3.5.14 
Safety 
Population 
Summary of Fold Change from Baseline for Liver Function Tests, Part 1 
14.3.5.14.ES 
Safety 
Population 
Summary of Fold Change from Baseline for Liver Function Tests, Entire Study 
14.3.5.15 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Part 1 
14.3.5.15.ES 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Entire Study 
14.3.5.16 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Part 1 - Subjects with 
Prior Androgen Use 
14.3.5.16.ES 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Entire Study - 
Subjects with Prior Androgen Use 
14.3.5.17 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Part 1 - Subjects with 
No Prior Androgen Use 
14.3.5.17.ES 
Safety 
Population 
Summary of Elevations in Post-Baseline Liver Function Tests, Entire Study - 
Subjects with No Prior Androgen Use 
14.3.5.18 
Safety 
Population 
Summary of Treatment-Emergent Elevations in Post-Baseline Liver Function Tests, 
Part 1 
14.3.5.18.ES 
Safety 
Population 
Summary of Treatment-Emergent Elevations in Post-Baseline Liver Function Tests, 
Entire Study 
14.3.5.24 
Safety 
Population 
Summary of Time (Days) to First Occurrence of Grade 3 or 4 ALT, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
92 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.5.26 
Safety 
Population 
Summary of Time (Days) to First Occurrence of Grade 3 or 4 AST, Part 1 
14.3.5.28 
Safety 
Population 
Summary of Time (Days) to First Occurrence of Grade 3 or 4 Total Bilirubin, Part 1 
14.3.5.30 
Safety 
Population 
Summary of Treatment-Emergent Graded Laboratory Abnormalities by Greatest 
Post-Baseline Severity, Part 1 
14.3.5.30.ES 
Safety 
Population 
Summary of Treatment-Emergent Graded Laboratory Abnormalities by Greatest 
Post-Baseline Severity, Entire Study 
14.3.5.31 
Safety 
Population 
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities by 
Greatest Post-Baseline Severity, Part 1 
14.3.5.31.ES 
Safety 
Population 
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities by 
Greatest Post-Baseline Severity, Entire Study 
14.3.6.1 
Safety 
Population 
Summary of Observed and Change from Baseline in Vital Signs, Part 1 
14.3.6.1.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in Vital Signs, Entire Study 
14.3.6.3 
Safety 
Population 
Summary of Diastolic and Systolic Blood Pressure, Part 1; Baseline and All Post-
Baseline Observations 
14.3.6.3.ES 
Safety 
Population 
Summary of Diastolic and Systolic Blood Pressure, Part 2; Baseline and All Post-
Baseline Observations 
14.3.7.1 
Safety 
Population 
Summary of Observed and Change from Baseline in ECG Interval Values, Part 1 
14.3.7.1.ES 
Safety 
Population 
Summary of Observed and Change from Baseline in ECG Interval Values, Entire 
Study 
14.3.7.2 
Safety 
Population 
Summary of QTcF Baseline and All Post-Baseline Observations, Part 1 
14.3.7.2.ES 
Safety 
Population 
Summary of QTcF Baseline and All Post-Baseline Observations, Part 1 
14.3.7.3 
Safety 
Population 
Summary of ECG Findings, Part 1 
14.3.7.3.ES 
Safety 
Population 
Summary of ECG Findings, Entire Study 
14.3.7.4 
Safety 
Population 
Summary of QTcF Observed and Change from Baseline in Categorical Findings, Part 
1 
14.3.7.4.ES 
Safety 
Population 
Summary of QTcF Observed and Change from Baseline in Categorical Findings, 
Entire Study 
14.3.7.5 
Safety 
Population 
Summary of QTcF Observed and Change from Baseline in Categorical Findings, Part 
1; Baseline and All Post-Baseline Observations 
14.3.7.5.ES 
Safety 
Population 
Summary of QTcF Observed and Change from Baseline in Categorical Findings, 
Entire Study; Baseline and All Post-Baseline Observations 
14.4.1.1 
ITT Population 
Summary of WPAI Scores, Part 1 
14.4.1.1.ES 
ITT Population 
Summary of WPAI Scores, Entire Study 
14.4.1.4 
ITT Population 
Summary of Responses to WPAI Individual Questions, Part 1 
14.4.1.4.ES 
ITT Population 
Summary of Responses to WPAI Individual Questions, Entire study 
14.4.2.1 
ITT Population 
Summary of EQ-5D-5L VAS Scores, Part 1 
14.4.2.1.ES 
ITT Population 
Summary of EQ-5D-5L VAS Scores, Entire Study 
14.4.2.11 
ITT Population 
Summary of Responses to EQ-5D-5L Individual Questions, Part 1 
14.4.2.11.ES 
ITT Population 
Summary of Responses to EQ-5D-5L Individual Questions, Entire study 
14.4.2.12 
ITT Population 
Summary of Responses to EQ-5D-5L Individual Questions from Usual Event, Part 1 
14.4.2.12.ES 
ITT Population 
Summary of Responses to EQ-5D-5L Individual Questions from Usual Event, Entire 
study 
14.4.2.4 
ITT Population 
Summary of EQ-5D-5L VAS Scores from Usual Event, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
93 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.4.2.4.ES 
ITT Population 
Summary of EQ-5D-5L VAS Scores from Usual Event, Entire Study 
14.4.2.6 
ITT Population 
Summary of EQ-5D-5L Index Scores, Part 1 
14.4.2.6.ES 
ITT Population 
Summary of EQ-5D-5L Index Scores, Entire Study  
14.4.2.9 
ITT Population 
Summary of EQ-5D-5L Index Scores from Usual Event, Part 1 
14.4.2.9.ES 
ITT Population 
Summary of EQ-5D-5L Index Scores from Usual Event, Entire Study  
14.4.3.1 
ITT Population 
Summary of TSQM Scores, Part 1 
14.4.3.1.ES 
ITT Population 
Summary of TSQM Scores, Entire Study  
14.4.3.4 
ITT Population 
Summary of Responses to TSQM Individual Questions, Part 1 
14.4.3.4.ES 
ITT Population 
Summary of Responses to TSQM Individual Questions, Entire study 
14.5.1.1 
Safety 
Population 
Summary of Plasma BCX7353 Concentration (ng/mL), Part 1 
14.5.1.1.ES 
Safety 
Population 
Summary of Plasma BCX7353 Concentration (ng/mL), Entire Study 
14.5.2.1 
Safety 
Population 
Plasma BCX7353 Concentration (ng/mL) Samples above Kallikrein Inhibition EC50, 
Part 1 
14.5.2.1.ES 
Safety 
Population 
Plasma BCX7353 Concentration (ng/mL) Samples above Kallikrein Inhibition EC50, 
Entire Study 
14.6.1.1 
PD Population 
Summary of Plasma Kallikrein Inhibition (%), Part 1 
14.6.1.1.ES 
PD  Population 
Summary of Plasma Kallikrein Inhibition (%), Entire Study 
14.6.2.1 
PD Population 
Plasma Kallikrein Inhibition Samples above 50% and 80%, Part 1 
14.6.2.1.ES 
PD Population 
Plasma Kallikrein Inhibition Samples above 50% and 80%, Entire Study 
14.6.2.2 
PD Population 
Summary of Baseline Mean Amidolytic Activity Overall and by Gender 
17.1.1.2. BCX7353-301 and BCX7353-302 Combined Study Output 
Output Number 
Population Title 
Output Title 
14.1.1.1.C 
All Subjects 
Summary of Subject Disposition by Country and Site, Part 1 
14.1.2.1.C 
ITT Population 
Summary of Analysis Populations 
14.1.2.2.C 
ITT Population 
Summary of Subgroups 
14.1.2.3.1.C 
ITT Population 
Summary of Inclusion/Exclusion Criteria Violations 
14.1.2.4.C 
ITT Population 
Summary of Protocol Deviations, Part 1 
14.1.2.5.C 
All Subjects 
Summary of Confirmation of Diagnosis of HAE Type I or II 
14.1.3.1.1.C 
ITT Population 
Summary of Demographic Characteristics 
14.1.3.1.2.C 
PP Population 
Summary of Demographic Characteristics 
14.1.3.2.C 
ITT Population 
Summary of Subject-Reported HAE Baseline Characteristics - HAE Medical History 
14.1.3.3.C 
ITT Population 
Summary of Past Prophylactic Treatments of HAE 
14.1.3.4.C 
ITT Population 
Summary of Primary Reason for Discontinuation of Past Prophylactic Treatments of 
HAE 
14.1.3.5.C 
ITT Population 
Summary of Current On-Demand Treatments of HAE 
14.1.3.6.C 
ITT Population 
Summary of Subject-Reported HAE Baseline Characteristics - Primary Acute Event 
Treatment Information 
14.1.3.7.1.C 
ITT Population 
Summary of Pre-Treatment Expert- or Investigator-Confirmed Event Rates and 
Angioedema Symptoms 
14.1.3.7.2.C 
ITT Population 
Summary of Pre-Treatment Expert- or Investigator-Confirmed Event Rates and 
Angioedema Symptoms by Subgroups 
14.1.3.8.C 
ITT Population 
Summary of C1-INH Antigenic Levels 
14.1.4.1.C 
ITT Population 
Summary of Medications Taken within 30 Days Prior to Screening and Discontinued 
Prior to Dosing 
14.1.4.2.C 
ITT Population 
Summary of Concomitant Medications, Part 1 
14.1.4.3.C 
ITT Population 
Summary of Concomitant Medications for HAE, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
94 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.1.4.4.C 
ITT Population 
Summary of Concomitant Medications for Acute Treatment of Angioedema Events - 
Event Level [1] 
14.1.5.1.C 
Safety 
Population 
Summary of Treatment Exposure, Part 1 
14.1.5.3.C 
Safety 
Population 
Summary of Treatment Compliance, Part 1 
14.2.1.1.C 
ITT Population 
Summary of Hierarchical Testing for Efficacy Endpoints 
14.2.1.2.1.C 
ITT Population 
Overall Event Summary During Part 1 
14.2.1.2.2.C 
PP Population 
Overall Event Summary During Part 1 
14.2.1.3.1.C 
ITT Population 
Overall Event Summary During the Effective Dosing Period, Part 1 
14.2.1.3.2.C 
PP Population 
Overall Event Summary During the Effective Dosing Period, Part 1 
14.2.1.4.1.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Part 1 
14.2.1.4.2.C 
PP Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Part 1 
14.2.1.4.3.C 
Completers 
Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Part 1 
14.2.1.4.4.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Part 1, 
Including Observed Data Post Treatment Discontinuation  
14.2.1.4.5.C 
ITT Population 
Summary of Rate of Expert-Confirmed Events During Part 1, Including Observed 
Data Post Treatment Discontinuation and Missing Data Post Treatment 
Discontinuation are Imputed 
14.2.1.6.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Part 1 by 
Subgroups 
14.2.1.11.1.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Effective 
Dosing Period, Part 1 
14.2.1.11.2.C 
PP Population 
Summary of Rate of Expert- or Investigator-Confirmed Events During Effective 
Dosing Period, Part 1 
14.2.1.14.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events Requiring Treatment 
During Part 1 
14.2.1.15.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Abdominal-Only Events 
During Part 1 
14.2.1.16.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Peripheral-Only Events 
During Part 1 
14.2.1.17.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Mixed Location Events 
During Part 1 
14.2.1.18.C 
ITT Population 
Summary of Rate of Subject-Reported Events During Part 1 
14.2.1.19.C 
ITT Population 
Subject-Reported and Expert- or Investigator-Confirmed Events During Part 1 
14.2.1.21.C 
ITT Population 
Relationship of Baseline Characteristics and the Rate of Expert- or Investigator-
Confirmed Events, Part 1 
14.2.2.1.C 
ITT Population 
Summary of Rate of Expert- or Investigator-Confirmed Events by Month During Part 
1 
14.2.3.1.1.C 
ITT Population 
Summary of AE-QoL Scores by Visit, Part 1 
14.2.3.1.2.C 
PP Population 
Summary of AE-QoL Scores by Visit, Part 1 
14.2.3.2.C 
ITT Population 
Summary of AE-QoL Total Scores, Part 1 by Subgroups 
14.2.3.7.C 
ITT Population 
Number and Percent of Subjects Achieving the MCID (Decrease in Total AE-QoL 
Score), Part 1 
14.2.4.1.C 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert- or Investigator-
Confirmed Event-Free, Part 1 
14.2.4.2.C 
ITT Population 
Summary of Number and Proportion of Subjects Who are Expert- or Investigator-
Confirmed Event-Free in the Effective Dosing Period, Part 1 
14.2.5.1.1.C 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert- or Investigator-Confirmed Events, Part 1  


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
95 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.2.5.1.2.C 
PP Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert- or Investigator-Confirmed Events, Part 1  
14.2.5.1.3.C 
ITT Population 
Summary of Number and Proportion of Days with Angioedema Symptoms from 
Expert- or Investigator-Confirmed Events During Effective Dosing Period, Part 1 
14.2.6.1.1.C 
ITT Population 
Summary of Relative Reduction from Baseline in Adjusted Expert- or Investigator-
Confirmed Event Rate, Part 1 
14.2.6.1.2.C 
PP Population 
Summary of Relative Reduction from Baseline in Adjusted Expert- or Investigator-
Confirmed Event Rate, Part 1 
14.2.6.3.C 
ITT Population 
Relationship of Baseline Characteristics and the Proportion of Subjects with at least a 
50% Relative Reduction in Adjusted Expert- or Investigator-Confirmed Events, Part 
1 
14.2.6.4.C 
ITT Population 
Relationship of Baseline Characteristics and the Proportion of Subjects with at least a 
70% Relative Reduction in Adjusted Expert- or Investigator-Confirmed Events, Part 
1 
14.2.6.5.C 
ITT Population 
Summary of Relative Reduction from Baseline in Adjusted Expert- or Investigator-
Confirmed Event Rate by Subgroups, Part 1 
14.2.7.1.C 
ITT Population 
Event-Level Duration of Expert- or Investigator-Confirmed Events (hours) from Start 
of Event to the Time the Event Finished, Part 1 
14.2.7.2.C 
ITT Population 
Event-Level Duration of Expert- or Investigator-Confirmed Events (hours) from Start 
of Event Until Worst Was Over, Part 1 
14.2.8.1.C 
ITT Population 
Summary of Time (Days) to First Expert- or Investigator-Confirmed Event 
14.2.9.1.C 
ITT Population 
Summary of Time (Days) to First Use of Targeted HAE Rescue Medication to Treat 
an Expert- or Investigator-Confirmed Event 
14.2.10.1.C 
ITT Population 
Summary of Event Characteristics for Expert- or Investigator-Confirmed Events, Part 
1  
14.2.11.1.C 
ITT Population 
Summary of Event Locations for Expert- or Investigator-Confirmed Events, Part 1  
14.2.12.1.C 
ITT Population 
On-demand Rescue Medication Rate for Expert or Investigator-Confirmed Events, 
Part 1 
14.2.12.2.C 
ITT Population 
On-demand Rescue Medication Rate for Subject-Reported Events, Part 1 
17.1.2. 
Listings (BCX7353-301 Only) 
Output Number 
Population Title 
Output Title 
16.2.1.1 
All Subjects 
Informed Consent and Screen Failures 
16.2.1.2 
All Subjects 
Subject Randomization and Site 
16.2.1.3 
Safety 
Population 
Planned and Actual Treatment Assignments for Subjects with Incorrect Treatment, 
Part 1 
16.2.1.3.ES 
Safety 
Population 
Planned and Actual Treatment Assignments for Subjects with Incorrect Treatment, 
Entire Study 
16.2.1.4 
ITT Population 
Subject Disposition, Part 1 
16.2.1.5 
All Subjects 
Confirmation of Clinical Diagnosis of HAE 
16.2.1.6 
ITT Population 
Analysis Populations 
16.2.1.7 
ITT Population 
Subgroups Based on Baseline Characteristics 
16.2.1.8 
ITT Population 
IXRS Reported Event Rate and Baseline Event Rate 
16.2.2.1 
ITT Population 
Protocol Deviations, Part 1 
16.2.2.1.ES 
ITT Population 
Protocol Deviations Occurring During Part 2 of the Study 
16.2.2.2 
Safety 
Population 
Subjects for Whom the Treatment Blind Was Broken, Part 1 
16.2.2.2.ES 
Safety 
Population 
Subjects for Whom the Treatment Blind Was Broken, Entire Study 
16.2.4.1 
ITT Population 
Inclusion/Exclusion Criteria Not Met 
16.2.4.2.1 
All Subjects 
Demography 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
96 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
16.2.4.2.2 
All Subjects 
Demography - Contraception 
16.2.4.3.1 
ITT Population 
Medical History 
16.2.4.3.2 
ITT Population 
HAE Baseline Characteristics - HAE Medical History 
16.2.4.3.3 
Safety 
Population 
HAE Medication History: Past and Current On-Demand HAE Treatment 
16.2.4.3.4 
Safety 
Population 
HAE Medication History: Past Prophylactic HAE Treatment 
16.2.4.4.1 
Safety 
Population 
Medications Taken within 30 Days Prior to Screening and Discontinued Prior to 
Dosing 
16.2.4.4.2 
Safety 
Population 
Concomitant Medication Use, Part 1 
16.2.4.4.2.ES 
ITT Population 
Concomitant Medication Use, Entire Study 
16.2.4.4.3 
Safety 
Population 
Use of Concomitant Medications for HAE, Part 1 
16.2.4.4.3.ES 
ITT Population 
Use of Concomitant Medications for HAE, Entire Study 
16.2.4.5 
ITT Population 
Pre-Treatment Expert-Confirmed Event Rates and Angioedema Symptoms 
16.2.5.1 
Safety 
Population 
Drug Accountability, Part 1 
16.2.5.1.ES 
Safety 
Population 
Drug Accountability, Entire Study 
16.2.5.2 
Safety 
Population 
Dosing Diary, Part 1 
16.2.5.2.ES 
Safety 
Population 
Dosing Diary, Entire Study 
16.2.5.3 
Safety 
Population 
Person-Years of Exposure, Part 1 
16.2.5.3.ES 
Safety 
Population 
Person-Years of Exposure, Entire Study 
16.2.5.4 
Safety 
Population 
Treatment Compliance, Part 1 
16.2.5.5 
Safety 
Population 
Subjects Who Switched from 110 mg to 150 mg During the Study 
16.2.6.1.1 
ITT Population 
HAE Event Diary and Investigator Confirmation for All Events, Part 1 
16.2.6.1.1.ES 
ITT Population 
HAE Event Diary and Investigator Confirmation for All Events, Entire Study 
16.2.6.1.2 
ITT Population 
HAE Event Diary and Investigator Confirmation (Expert-Confirmed Events Only), 
Part 1 
16.2.6.1.2.ES 
ITT Population 
HAE Event Diary and Investigator Confirmation (Expert-Confirmed Events Only), 
Entire Study 
16.2.6.1.3 
ITT Population 
HAE Event Diary Detail - Subject-Reported Events, Part 1 
16.2.6.1.3.ES 
ITT Population 
HAE Event Diary Detail - Subject-Reported Events, Entire Study 
16.2.6.1.4 
ITT Population 
HAE Event Diary Detail - Expert-Confirmed Events, Part 1 
16.2.6.1.4.ES 
ITT Population 
HAE Event Diary Detail - Expert-Confirmed Events, Entire Study 
16.2.6.1.5 
ITT Population 
HAE Event Level Summary - Subject-Reported Events, Part 1 
16.2.6.1.5.ES 
ITT Population 
HAE Event Level Summary - Subject-Reported Events, Entire Study 
16.2.6.1.6 
ITT Population 
HAE Event Level Summary - Expert-Confirmed Events, Part 1 
16.2.6.1.6.ES 
ITT Population 
HAE Event Level Summary - Expert-Confirmed Events, Entire Study 
16.2.6.1.7 
ITT Population 
Event Rate, Part 1 
16.2.6.1.7.ES 
ITT Population 
Event Rate, Entire Study 
16.2.6.1.8 
ITT Population 
Imputed Expert-Confirmed Event Rates for Subjects with Missing Data, Part 1 
16.2.6.1.9 
ITT Population 
Subjects Who Are Expert-Confirmed Event-Free During Entire Dosing Period and 
Effective Dosing Period, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
97 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
16.2.6.1.9.ES 
ITT Population 
Subjects Who Are Expert-Confirmed Event-Free During Entire Dosing Period and 
Effective Dosing Period, Entire Study 
16.2.6.1.10 
ITT Population 
Days with Angioedema Symptoms from Expert-Confirmed Events, Part 1 
16.2.6.1.10.ES 
ITT Population 
Days with Angioedema Symptoms from Expert-Confirmed Events, Entire Study 
16.2.6.1.11.1 
ITT Population 
Subject-Level Efficacy Endpoint Profile, Part 1 
16.2.6.1.11.2 
ITT Population 
Subject-Level Additional Derived Endpoint Profile, Part 1 
16.2.6.1.12 
ITT Population 
HAE Event Diary Detail - Expert-Confirmed Laryngeal Events, Part 1 
16.2.6.1.13 
ITT Population 
Expert-Confirmed Attacks Not Included in Adjusted Expert-Confirmed Attacks 
16.2.6.2.1 
ITT Population 
AE-QoL: Individual Question Responses and Days Missed, Part 1 
16.2.6.2.1.ES 
ITT Population 
AE-QoL: Individual Question Responses and Days Missed, Entire Study 
16.2.6.2.2 
ITT Population 
AE-QoL: Domain Scores, Part 1 
16.2.6.2.2.ES 
ITT Population 
AE-QoL: Domain Scores, Entire Study 
16.2.6.3.1 
ITT Population 
TSQM Global Satisfaction Individual Responses, Part 1 
16.2.6.3.1.ES 
ITT Population 
TSQM Global Satisfaction Individual Responses, Entire Study 
16.2.6.3.2 
ITT Population 
TSQM Global Satisfaction, Effectiveness, Side Effects, and Convenience Subscale 
Scores, Part 1 
16.2.6.3.2.ES 
ITT Population 
TSQM Effect, Side Effect, Convenience and Global Satisfaction Scores, Entire 
Study 
16.2.6.4.1 
ITT Population 
EQ-5D-5L Individual Question Responses, Part 1 
16.2.6.4.1.ES 
ITT Population 
EQ-5D-5L Individual Question Responses, Entire Study 
16.2.6.4.2 
ITT Population 
EQ-5D-5L Descriptive, VAS, and Index Scores, Part 1 
16.2.6.4.2.ES 
ITT Population 
EQ-5D-5L Descriptive, VAS, and Index Scores, Entire Study 
16.2.6.4.3 
ITT Population 
EQ-5D-5L for Usual Event Individual Question Responses, Part 1 
16.2.6.4.3.ES 
ITT Population 
EQ-5D-5L for Usual Event Individual Question Responses, Entire Study 
16.2.6.4.4 
ITT Population 
EQ-5D-5L for Usual Event Descriptive, VAS, and Index Scores, Part 1 
16.2.6.4.4.ES 
ITT Population 
EQ-5D-5L for Usual Event Descriptive, VAS, and Index Scores, Entire Study 
16.2.6.5.1 
ITT Population 
WPAI Individual Question Responses, Part 1 
16.2.6.5.1.ES 
ITT Population 
WPAI Individual Question Responses, Entire Study 
16.2.6.5.2 
ITT Population 
WPAI Absenteeism, Presenteeism, Work Productivity Loss, and Activity 
Impairment Scores, Part 1 
16.2.6.5.2.ES 
ITT Population 
WPAI Absenteeism, Presenteeism, Work Productivity Loss, and Activity 
Impairment Scores, Entire Study 
16.2.7.1 
Safety 
Population 
Adverse Events, Part 1 
16.2.7.1.ES 
Safety 
Population 
Adverse Events, Entire Study 
16.2.7.2 
Safety 
Population 
Serious Adverse Events, Part 1 
16.2.7.2.ES 
Safety 
Population 
Serious Adverse Events, Entire Study 
16.2.7.3 
Safety 
Population 
Grade 3 or 4 Adverse Events, Part 1 
16.2.7.3.ES 
Safety 
Population 
Grade 3 or 4 Adverse Events, Entire Study 
16.2.7.4 
Safety 
Population 
Adverse Events Leading to Permanent Discontinuation of Study Drug, Part 1 
16.2.7.4.ES 
Safety 
Population 
Adverse Events Leading to Permanent Discontinuation of Study Drug, Entire Study 
16.2.7.5 
Safety 
Population 
Fatal Serious Adverse Events, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
98 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
16.2.7.5.ES 
Safety 
Population 
Fatal Serious Adverse Events, Entire Study 
16.2.7.6 
Safety 
Population 
Adverse Events Leading to Interruption of Study Drug, Part 1 
16.2.7.6.ES 
Safety 
Population 
Adverse Events Leading to Interruption of Study Drug, Entire Study 
16.2.7.7 
Safety 
Population 
Investigator-Identified Rash (Event of Special Interest), Part 1 
16.2.7.7.ES 
Safety 
Population 
Investigator-Identified Rash (Event of Special Interest), Entire Study 
16.2.7.8 
Safety 
Population 
GI Abdominal-Related Adverse Events, Part 1 
16.2.7.8.ES 
Safety 
Population 
GI Abdominal-Related Adverse Events, Entire Study 
16.2.7.9 
Safety 
Population 
Adverse Events Occurring with 24 Hours of an LFT Elevation for Subjects with an 
LFT Elevation, Part 1 
16.2.7.9.ES 
Safety 
Population 
Adverse Events For Subjects with Elevated LFTs Occurring within 24 hours of the 
Elevation, Entire Study 
16.2.7.10 
ITT Population 
Listing of GI Abdominal-Related Adverse Events and Unconfirmed HAE Events 
with Abdominal-Only Symptoms, Part 1 
16.2.7.10.ES 
ITT Population 
Listing of GI Abdominal-Related Adverse Events and Unconfirmed HAE Events 
with Abdominal-Only Symptoms, Entire Study 
16.2.7.11 
ITT Population 
Listing of Subjects For Whom Narratives are Required, Part 1 
16.2.7.11.ES 
ITT Population 
Listing of Subjects For Whom Narratives are Required, Entire Study 
16.2.7.12.ES 
Subjects 
Randomized to 
BCX7353 110 
mg who Switch 
to BCX7353 150 
mg 
Adverse Events Occurring Following 110 mg Switch to 150 mg, Entire Study 
16.2.8.1 
Safety 
Population 
Clinical Chemistry, Part 1 
16.2.8.1.ES 
Safety 
Population 
Clinical Chemistry, Entire Study 
16.2.8.2 
Safety 
Population 
Hematology, Part 1 
16.2.8.2.ES 
Safety 
Population 
Hematology, Entire Study 
16.2.8.3 
Safety 
Population 
Coagulation, Part 1 
16.2.8.3.ES 
Safety 
Population 
Coagulation, Entire Study 
16.2.8.4 
Safety 
Population 
Urinalysis, Part 1 
16.2.8.4.ES 
Safety 
Population 
Urinalysis, Entire Study 
16.2.8.5 
Safety 
Population 
Other Laboratory Tests, Part 1 
16.2.8.5.ES 
Safety 
Population 
Other Laboratory Tests, Entire Study 
16.2.8.6 
Safety 
Population 
Complement Factors C3, C4, and C1-INH, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
99 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
16.2.8.6.ES 
Safety 
Population 
Complement Factors C3, C4, and C1-INH, Entire Study 
16.2.8.7 
ITT Population 
SERPING Results 
16.2.8.8 
ITT Population 
Pregnancy Tests, Part 1 
16.2.8.8.ES 
ITT Population 
Pregnancy Tests, Entire Study 
16.2.8.9 
Safety 
Population 
Laboratory Abnormalities, Part 1 
16.2.8.9.ES 
Safety 
Population 
Laboratory Abnormalities, Entire Study 
16.2.8.10 
Safety 
Population 
Grade 3 or Grade 4 Laboratory Abnormalities, Part 1 
16.2.8.10.ES 
Safety 
Population 
Grade 3 or Grade 4 Laboratory Abnormalities, Entire Study 
16.2.8.11 
Safety 
Population 
All Liver Function Test Results for Subject Experiencing a Treatment-Emergent 
Grade 3 or 4 Liver Function Test, Part 1 
16.2.8.11.ES 
Safety 
Population 
All Liver Function Test Results for Subject Experiencing a Treatment-Emergent 
Grade 3 or 4 Liver Function Test, Entire Study 
16.2.8.12 
Safety - Subjects 
with Prior 
Androgen Use 
All Liver Function Test Results for Subject Experiencing a Treatment-Emergent 
Grade 3 or 4 Liver Function Test, Part 1 
16.2.8.12.ES 
Safety - Subjects 
with Prior 
Androgen Use 
All Liver Function Test Results for Subject Experiencing a Treatment-Emergent 
Grade 3 or 4 Liver Function Test, Entire Study 
16.2.8.13.ES 
Subjects 
Randomized to 
BCX7353 110 
mg who Switch 
to BCX7353 150 
mg 
Grade 3 or 4 Liver Function Test Results Occurring Following 110 mg Switch to 
150 mg, Entire Study 
16.2.8.14 
Safety 
Population 
Vital Signs, Part 1 
16.2.8.14.ES 
Safety 
Population 
Vital Signs, Part 1, Entire Study 
16.2.8.15 
Safety 
Population 
12-Lead Electrocardiogram, Part 1 
16.2.8.15.ES 
Safety 
Population 
12-Lead Electrocardiogram, Entire Study 
16.2.8.16 
Safety 
Population 
QTcF Values > 450 msec or QTcF Change from Baseline Values > 30 msec, Part 1 
16.2.8.16.ES 
Safety 
Population 
QTcF Values > 450 msec or QTcF Change from Baseline Values > 30 msec, Entire 
Study 
16.2.8.17 
Safety 
Population 
Physical Exam, Part 1 
16.2.8.17.ES 
Safety 
Population 
Physical Exam, Entire Study 
16.2.8.18 
Safety 
Population 
Pharmacokinetic Sample Collection, Part 1 
16.2.8.18.ES 
Safety 
Population 
Pharmacokinetic Sample Collection, Entire Study 
16.2.8.19 
PD Population 
Plasma Kallikrein Inhibition (%), Part 1 
16.2.8.19.ES 
PD Population 
Plasma Kallikrein Inhibition (%), Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
100 
CONFIDENTIAL 
17.1.3. 
Figures 
17.1.3.1. BCX7353-301 Only 
Output Number 
Population Title 
Output Title 
14.1.1.2 
All Subjects 
CONSORT Diagram, Part 1 
14.1.1.2.ES 
All Subjects 
CONSORT Diagram, Entire Study 
14.1.3.9 
Safety 
Population 
Plot of Baseline C1-INH Antigenic Levels vs. Screening C1-INH Functional Levels 
14.1.5.2 
Safety 
Population 
Plot of Duration of Exposure to Study Drug [1], Part 1 
14.1.5.2.ES 
Safety 
Population 
Plot of Duration of Exposure to Study Drug, Entire Study 
14.1.5.4 
Safety 
Population 
Histogram Plot of Treatment Compliance, Part 1 
14.1.5.4.ES 
Safety 
Population 
Histogram Plot of Treatment Compliance, Entire Study 
14.2.1.7 
ITT Population 
Box Plot of Expert-Confirmed Event Rate By Dose for Entire Dosing Period, Part 1 
14.2.1.7.ES 
ITT Population 
Box Plot of Expert-Confirmed Event Rate By Dose for Entire Dosing Period, Entire 
Study 
14.2.1.8 
ITT Population 
Cumulative Distribution Plot of Individual Expert-Confirmed Event Rate for Entire 
Dosing Period, Part 1 
14.2.1.8.ES 
ITT Population 
Cumulative Distribution Plot of Individual Expert-Confirmed Event Rate for Entire 
Dosing Period, Entire Study 
14.2.1.9 
ITT Population 
Forest Plot of Results of Sensitivity Analyses of Expert-Confirmed Event Rate for 
Entire Dosing Period, Part 1 
14.2.1.10 
ITT Population 
Forest Plot of Results of Subgroup Analyses of Expert-Confirmed Event Rate for 
Entire Dosing Period, Part 1 
14.2.1.12 
ITT Population 
Box Plot of Expert-Confirmed Event Rate By Dose for Effective Dosing Period, 
Part 1 
14.2.1.12.ES 
ITT Population 
Box Plot of Expert-Confirmed Event Rate By Dose for Effective Dosing Period, 
Entire Study 
14.2.1.13 
ITT Population 
Cumulative Distribution Plot of Individual Expert-Confirmed Event Rate for 
Effective Dosing Period, Part 1 
14.2.1.13.ES 
ITT Population 
Cumulative Distribution Plot of Individual Expert-Confirmed Event Rate for 
Effective Dosing Period, Entire Study 
14.2.1.21 
ITT Population 
Plot of Expert-Confirmed Events and Use of On-Demand Medication, Part 1 
14.2.2.2 
ITT Population 
Histogram Plot of Baseline Expert-Confirmed Event Rate, Part 1 
14.2.2.3 
ITT Population 
Plot of Mean Expert-Confirmed Event Rate by Month, Part 1 
14.2.2.3.ES 
ITT Population 
Plot of Mean Expert-Confirmed Event Rate by Month, Entire Study 
14.2.2.3.P3 
ITT Population 
Plot of Mean Adjusted Event Rate by Month, Part 3 
14.2.2.4 
ITT Population 
Scatterplot of On-Study Expert-Confirmed Event Rate vs Baseline Expert-
Confirmed Event Rate, Part 1 
14.2.2.4.ES 
ITT Population 
Plot of On-Study Expert-Confirmed Event Rate vs Baseline Expert-Confirmed 
Event Rate, Entire Study 
14.2.2.5 
ITT Population 
Plot of Change from Baseline Expert-Confirmed Event Rate vs. Baseline Expert-
Confirmed Event Rate, Part 1 
14.2.2.6 
ITT Population 
Plot of Change from Baseline Expert-Confirmed Event Rate vs. Percent 
Compliance, Part 1 
14.2.2.7 
ITT Population 
Plot of Change from Baseline Expert-Confirmed Event Rate vs. Baseline Expert-
Confirmed Event Rate by Gender, Part 1 
14.2.2.8 
ITT Population 
Plot of Baseline and Expert-Confirmed Attack Rate By Subject 
14.2.2.9 
ITT Population 
Plot of Individual Expert-Confirmed Attack Rate by Month 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
101 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.2.2.10 
ITT Population 
Plot of Change from Baseline Expert-Confirmed Attack Rate vs. Baseline Expert-
Confirmed Attack Rate, Part 1 By Gender 
14.2.3.3 
ITT Population 
Plot of Mean AE-QoL Scores Over Time, Part 1 
14.2.3.3.ES 
ITT Population 
Plot of Mean AE-QoL Scores Over Time, Entire Study 
14.2.3.4 
ITT Population 
Plot of Mean Change from Baseline AE-QoL Scores Over Time, Part 1 
14.2.3.4.ES 
ITT Population 
Plot of Mean Change from Baseline AE-QoL Scores Over Time, Entire Study 
14.2.3.5 
ITT Population 
Cumulative Distribution of Total AE-QoL Change from Baseline at Week 24 
14.2.3.6 
ITT Population 
Forest Plot of Results of Subgroup Analyses of Total AE-QOL Change from 
Baseline at Week 24, Part 1 
14.2.6.2 
ITT Population 
Waterfall Plot of Relative Reduction from Baseline in Adjusted Expert-Confirmed 
Event Rate, Part 1 
14.2.8.2 
ITT Population 
Kaplan-Meier Plot of Time to First Expert-Confirmed Event, Part 1 
14.2.9.2 
ITT Population 
Kaplan-Meier Plot of Time to First Use of Targeted HAE Rescue Medication to 
Treat an Expert-Confirmed Event, Part 1 
14.3.1.13 
Safety 
Population 
Forest Plot of Treatment-Emergent Adverse Events Sorted by Risk Difference, Part 
1 
14.3.1.13.ES 
Safety 
Population 
Forest Plot of Treatment-Emergent Adverse Events Sorted by Risk Difference, 
Entire Study 
14.3.1.26 
Safety 
Population 
Kaplan-Meier Plot of Time to Development of Investigator-Identified Rash (Event 
of Special Interest), Part 1 
14.3.1.26.ES 
Safety 
Population 
Kaplan-Meier Plot of Time to Development of Investigator-Identified Rash (Event 
of Special Interest), Entire Study 
14.3.1.28 
Safety 
Population 
Kaplan-Meier Plot of Duration of Investigator-Identified Rash (Event of Special 
Interest), Part 1 
14.3.1.28.ES 
Safety 
Population 
Kaplan-Meier Plot of Duration of Investigator-Identified Rash (Event of Special 
Interest), Entire Study 
14.3.1.40 
Safety 
Population 
Kaplan-Meier Plot of Time to First Occurrence of a GI Abdominal-Related Adverse 
Event, Part 1 
14.3.1.40.ES 
Safety 
Population 
Kaplan-Meier Plot of Time to First Occurrence of a GI Abdominal-Related Adverse 
Event Entire Study 
14.3.1.42 
Safety 
Population 
Kaplan-Meier Plot of Duration of GI Abdominal-Related Adverse Events, Part 1 
14.3.1.42.ES 
Safety 
Population 
Kaplan-Meier Plot of Duration of GI Abdominal-Related Adverse Events Entire 
Study 
14.3.1.43 
Safety 
Population 
Plot of Occurrence of Treatment-Emergent GI Abdominal-Related Adverse Events, 
Part 1 
14.3.1.43.ES 
Safety 
Population 
Plot of Occurrence of Treatment-Emergent GI Abdominal-Related Adverse Events, 
Entire Study 
14.3.1.49 
Safety 
Population 
Plot of Treatment-Emergent Adverse Events by Study Month, Part 1 
14.3.1.50 
Safety 
Population 
Plot of Drug-Related Treatment-Emergent Adverse Events by Study Month, Part 1 
14.3.1.51 
Safety 
Population 
Plot of Treatment-Emergent Serious Adverse Events by Study Month, Part 1 
14.3.1.52 
Safety 
Population 
Plot of Treatment-Emergent Grade 3 or Grade 4 Adverse Events by Study Month, 
Part 1 
14.3.1.53 
Safety 
Population 
Plot of Drug-Related Treatment-Emergent Grade 3 or Grade 4 Adverse Events by 
Study Month, Part 1 
14.3.1.54 
Safety 
Population 
Plot of Treatment-Emergent Adverse Events Leading to the Interruption of Study 
Drug by Study Month, Part 1 
14.3.1.55 
Safety 
Population 
Plot of Treatment-Emergent Adverse Events Leading to the Discontinuation of 
Study Drug by Study Month, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
102 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.3.1.56 
Safety 
Population 
Plot of Treatment-Emergent Investigator-Identified Rash (Event of Special Interest) 
by Study Month, Part 1 
14.3.1.57 
Safety 
Population 
Plot of Treatment-Emergent GI Abdominal-Related Adverse Events by Study 
Month, Part 1 
14.3.1.58 
Safety 
Population 
Plot of Treatment-Emergent GI Abdominal-Related Adverse Events Leading to 
Discontinuation of Study Drug by Study Month, Part 1 
14.3.5.19 
Safety 
Population 
Plot of Liver Function Test Profiles for Subjects with Grade 3 or 4 Liver 
Abnormalities, Part 1 
14.3.5.20 
Safety 
Population 
Hy's Law Plot of Maximum Total Bilirubin vs. Maximum ALT, Part 1 
14.3.5.20.ES 
Safety 
Population 
Hy's Law Plot of Maximum Total Bilirubin vs. Maximum ALT, Entire Study 
14.3.5.21 
Safety 
Population 
Liver Test Safety Panel Over Time, Baseline vs. On-Study, Part 1 
14.3.5.21.ES 
Safety 
Population 
Liver Test Safety Panel Over Time, Baseline vs. On-Study, Entire Study 
14.3.5.22 
Safety 
Population 
Distribution of Liver Tests Over Time: ALP, ALT, AST, and Bilirubin, Part 1 
14.3.5.22.ES 
Safety 
Population 
Distribution of Liver Tests Over Time: ALP, ALT, AST, and Bilirubin, Entire Study 
14.3.5.23 
Safety 
Population 
Distribution of Cholesterol and Triglycerides Over Time, Part 1 
14.3.5.23.ES 
Safety 
Population 
Distribution of Cholesterol and Triglycerides Over Time, Entire Study 
14.3.5.25 
Safety 
Population 
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 ALT, Part 1 
14.3.5.27 
Safety 
Population 
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 AST, Part 1 
14.3.5.29 
Safety 
Population 
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 Total Bilirubin, Part 
1 
14.3.6.2 
Safety 
Population 
Distribution of Diastolic and Systolic Blood Pressure Over Time, Part 1 
14.3.6.2.ES 
Safety 
Population 
Distribution of Diastolic and Systolic Blood Pressure Over Time, Entire Study 
14.3.6.4 
Safety 
Population 
Distribution of Diastolic and Systolic Blood Pressure, Part 1; Baseline and All Post-
Baseline Observations 
14.3.6.4.ES 
Safety 
Population 
Distribution of Diastolic and Systolic Blood Pressure, Entire Study; Baseline and All 
Post-Baseline Observations 
14.3.7.6 
Safety 
Population 
Distribution of QTcF Observed Changes Relative to Baseline Over Time, Part 1 
14.3.7.6.ES 
Safety 
Population 
Distribution of QTcF Observed Changes Relative to Baseline Over Time, Entire 
Study 
14.3.7.7 
Safety 
Population 
Distribution of QTcF Observed Changes Relative to Baseline, Part 1; Baseline and 
All Post-Baseline Observations 
14.3.7.7.ES 
Safety 
Population 
Distribution of QTcF Observed Changes Relative to Baseline, Entire Study; 
Baseline and All Post-Baseline Observations 
14.4.1.2 
ITT Population 
Plot of Mean WPAI Scores Over Time, Part 1 
14.4.1.2.ES 
ITT Population 
Plot of Mean WPAI Scores Over Time, Entire Study 
14.4.1.3 
ITT Population 
Plot of Mean Change from Baseline WPAI Scores Over Time, Part 1 
14.4.1.3.ES 
ITT Population 
Plot of Mean Change from Baseline WPAI Scores Over Time, Entire Study 
14.4.2.2 
ITT Population 
Plot of Mean EQ-5D-5L VAS Scores Over Time, Part 1 
14.4.2.2.ES 
ITT Population 
Plot of Mean EQ-5D-5L VAS Scores Over Time, Entire Study 
14.4.2.3 
ITT Population 
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores Over Time, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
103 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.4.2.3.ES 
ITT Population 
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores Over Time, Entire 
Study 
14.4.2.5 
ITT Population 
Plot of Mean EQ-5D-5L VAS Scores from Usual Event Over Time, Part 1 
14.4.2.5.ES 
ITT Population 
Plot of Mean EQ-5D-5L VAS Scores from Usual Event Over Time, Entire Study 
14.4.2.7 
ITT Population 
Plot of Mean EQ-5D-5L Index Scores Over Time, Part 1 
14.4.2.7.ES 
ITT Population 
Plot of Mean EQ-5D-5L Index Scores Over Time, Entire Study 
14.4.2.8 
ITT Population 
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Part 1 
14.4.2.8.ES 
ITT Population 
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Entire 
Study 
14.4.2.10 
ITT Population 
Plot of Mean EQ-5D-5L Index Scores from Usual Event Over Time, Part 1 
14.4.2.10.ES 
ITT Population 
Plot of Mean EQ-5D-5L Index Scores from Usual Event Over Time, Entire Study 
14.4.3.2 
ITT Population 
Plot of Mean TSQM Scores Over Time, Part 1 
14.4.3.2.ES 
ITT Population 
Plot of Mean TSQM Scores Over Time, Entire Study 
14.4.3.3 
ITT Population 
Plot of Mean Change from Baseline TSQM Scores Over Time, Part 1 
14.4.3.3.ES 
ITT Population 
Plot of Mean Change from Baseline TSQM Scores Over Time, Entire Study 
14.6.1.2 
PK-PD 
Population 
Scatterplot of Kallikrein Inhibition (%) and BCX7353 Plasma Concentration/4 by 
Study Visit, Part 1 
14.6.1.2.ES 
PK-PD 
Population 
Scatterplot of Kallikrein Inhibition (%) and BCX7353 Plasma Concentration/4 by 
Study Visit, Entire Study 
17.1.3.2. 
BCX7353-301 and BCX7353-302 Combined Study Output 
Output Number 
Population Title 
Output Title 
14.1.1.2.C 
All Subjects 
CONSORT Diagram, Part 1 
14.1.5.2.C 
Safety 
Population 
Plot of Duration of Exposure to Study Drug [1], Part 1 
14.1.5.4.C 
Safety 
Population 
Histogram Plot of Treatment Compliance, Part 1 
14.2.1.7.C 
ITT Population 
Box Plot of Expert- or Investigator-Confirmed Event Rate By Dose for Entire 
Dosing Period, Part 1 
14.2.1.8.C 
ITT Population 
Cumulative Distribution Plot of Individual Expert- or Investigator-Confirmed Event 
Rate for Entire Dosing Period, Part 1 
14.2.1.9.C 
ITT Population 
Forest Plot of Results of Sensitivity Analyses of Expert- or Investigator-Confirmed 
Event Rate for Entire Dosing Period, Part 1 
14.2.1.10.C 
ITT Population 
Forest Plot of Results of Subgroup Analyses of Expert- or Investigator-Confirmed 
Event Rate for Entire Dosing Period, Part 1 
14.2.1.12.C 
ITT Population 
Box Plot of Expert- or Investigator-Confirmed Event Rate By Dose for Effective 
Dosing Period, Part 1 
14.2.1.13.C 
ITT Population 
Cumulative Distribution Plot of Individual Expert- or Investigator-Confirmed Event 
Rate for Effective Dosing Period, Part 1 
14.2.1.20.C 
ITT Population 
Plot of Investigator-Confirmed Events and Use of On-Demand Medication, Part 1 
14.2.2.2.C 
ITT Population 
Histogram Plot of Baseline Expert- or Investigator-Confirmed Event Rate, Part 1 
14.2.2.3.C 
ITT Population 
Plot of Mean Expert- or Investigator-Confirmed Event Rate by Month, Part 1 
14.2.2.4.C 
ITT Population 
Scatterplot of On-Study Expert- or Investigator-Confirmed Event Rate vs Baseline 
Expert- or Investigator-Confirmed Event Rate, Part 1 
14.2.2.5.C 
ITT Population 
Plot of Change from Baseline Expert- or Investigator -Confirmed Event Rate vs. 
Baseline Expert-Confirmed Event Rate, Part 1 
14.2.2.6.C 
ITT Population 
Plot of Change from Baseline Expert- or Investigator -Confirmed Event Rate vs. 
Percent Compliance, Part 1 
14.2.2.7.C 
ITT Population 
Plot of Change from Baseline Expert- or Investigator-Confirmed Event Rate vs. 
Baseline Expert- or Investigator-Confirmed Event Rate by Gender, Part 1 
14.2.2.8.C 
ITT Population 
Plot of Baseline and Expert- or Investigator-Confirmed Attack Rate By Subject 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
104 
CONFIDENTIAL 
Output Number 
Population Title 
Output Title 
14.2.2.9.C 
ITT Population 
Plot of Individual Expert-Confirmed Attack Rate by Month 
14.2.2.10.C 
ITT Population 
Plot of Change from Baseline Expert- or Investigator-Confirmed Attack Rate vs. 
Baseline Expert- or Investigator-Confirmed Attack Rate, Part 1 By Gender 
14.2.3.3.C 
ITT Population 
Plot of Mean AE-QoL Scores Over Time, Part 1 
14.2.3.4.C 
ITT Population 
Plot of Mean Change from Baseline AE-QoL Scores Over Time, Part 1 
14.2.3.5.C 
ITT Population 
Cumulative Distribution of Total AE-QoL Change from Baseline at Week 24 
14.2.3.6.C 
ITT Population 
Forest Plot of Results of Subgroup Analyses of Total AE-QOL Change from 
Baseline at Week 24, Part 1 
14.2.6.2.C 
ITT Population 
Waterfall Plot of Relative Reduction from Baseline in Adjusted Expert-Confirmed 
Event Rate, Part 1 
14.2.6.4.C 
ITT Population 
Forest Plot of Results of Additional Subgroup Analysis for Proportion of Subjects 
with a 50% Relative Reduction from Baseline in Adjusted Expert-Confirmed Event 
Rate , Part 1 
14.2.6.5.C 
ITT Population 
Forest Plot of Results of Additional Subgroup Analysis for Proportion of Subjects 
with a 70% Relative Reduction from Baseline in Adjusted Expert- or Investigator-
Confirmed Event Rate , Part 1 
14.2.6.6.C 
ITT Population 
Forest Plot of Results of Additional Subgroup Analysis for Proportion of Subjects 
with a 90% Relative Reduction from Baseline in Adjusted Expert- or Investigator-
Confirmed Event Rate , Part 1 
14.2.8.2.C 
ITT Population 
Kaplan-Meier Plot of Time to First Expert- or Investigator-Confirmed Event, Part 1 
14.2.9.2.C 
ITT Population 
Kaplan-Meier Plot of Time to First Use of Targeted HAE Rescue Medication to 
Treat an Expert- or Investigator-Confirmed Event, Part 1 
14.6.1.2.C 
PK-PD 
Population 
Scatterplot of Kallikrein Inhibition (%) and BCX7353 Plasma Concentration/4 by 
Study Visit, Part 1 
17.2. 
Data Display Specifications 
Table, Listing, and Figure shells will be stored in a separate document. 
17.3. 
List of Preferred Terms, High Level Terms, and High Level Group 
Terms for GI Abdominal-Related AEs 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10000059 
Abdominal 
discomfort 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000060 
Abdominal 
distension 
Flatulence, bloating and 
distension 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000077 
Abdominal 
mass 
Abdominal findings abnormal 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10049714 
Abdominal 
migraine 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000081 
Abdominal 
pain 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000084 
Abdominal 
pain lower 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000087 
Abdominal 
pain upper 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
105 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10052489 
Abdominal 
rebound 
tenderness 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000090 
Abdominal 
rigidity 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10060926 
Abdominal 
symptom 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000097 
Abdominal 
tenderness 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000133 
Abnormal 
faeces 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10058938 
Acetonaemic 
vomiting 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10000647 
Acute 
abdomen 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10052813 
Aerophagia 
Flatulence, bloating and 
distension 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10077605 
Anal 
incontinence 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10006326 
Breath odour 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10051650 
Chilaiditi's 
syndrome 
Abdominal findings abnormal 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10062937 
Cyclic 
vomiting 
syndrome 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10013810 
Dumping 
syndrome 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10013946 
Dyspepsia 
Dyspeptic signs and symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10013950 
Dysphagia 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10053155 
Epigastric 
discomfort 
Dyspeptic signs and symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10015137 
Eructation 
Dyspeptic signs and symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10050248 
Faecal volume 
decreased 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10049939 
Faecal volume 
increased 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10064670 
Faecal 
vomiting 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10056988 
Faecalith 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10056325 
Faecaloma 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10016100 
Faeces 
discoloured 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10016101 
Faeces hard 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
106 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10016102 
Faeces pale 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10074859 
Faeces soft 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10074216 
Fixed bowel 
loop 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10016766 
Flatulence 
Flatulence, bloating and 
distension 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10017999 
Gastrointestina
l pain 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10067715 
Gastrointestina
l sounds 
abnormal 
Abdominal findings abnormal 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10075724 
Gastrointestina
l wall 
thickening 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10075726 
Gastrointestina
l wall thinning 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10021746 
Infantile colic 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10063338 
Infantile 
spitting up 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10075315 
Infantile 
vomiting 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10073530 
Intestinal 
calcification 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10065611 
Intestinal 
congestion 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10067576 
Malignant 
dysphagia 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10028140 
Mucous stools 
Faecal abnormalities NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10069369 
Myochosis 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10028813 
Nausea 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10053634 
Oesophageal 
discomfort 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10065567 
Oesophageal 
food impaction 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10030180 
Oesophageal 
pain 
Gastrointestinal and 
abdominal pains (excl oral and 
throat) 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10034647 
Peristalsis 
visible 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10057030 
Pneumatosis 
intestinalis 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10064711 
Portal venous 
gas 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10066220 
Post-tussive 
vomiting 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
107 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10067171 
Regurgitation 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10038776 
Retching 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10078474 
Scaphoid 
abdomen 
Abdominal findings abnormal 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10047700 
Vomiting 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10047708 
Vomiting 
projectile 
Nausea and vomiting 
symptoms 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10078438 
White nipple 
sign 
Gastrointestinal signs and 
symptoms NEC 
Gastrointestinal signs 
and symptoms 
Gastrointestinal 
disorders 
10063541 
Bowel 
movement 
irregularity 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10007645 
Cardiospasm 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10008399 
Change of 
bowel habit 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10057078 
Colonic 
pseudo-
obstruction 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10010774 
Constipation 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10012110 
Defaecation 
urgency 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10051153 
Diabetic 
gastroparesis 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10012735 
Diarrhoea 
Diarrhoea (excl infective) 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10012741 
Diarrhoea 
haemorrhagic 
Diarrhoea (excl infective) 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10012743 
Diarrhoea 
neonatal 
Diarrhoea (excl infective) 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
108 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10060865 
Duodenogastri
c reflux 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10051244 
Dyschezia 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10013924 
Dyskinesia 
oesophageal 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10017367 
Frequent 
bowel 
movements 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10017753 
Gastric atony 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10017779 
Gastric 
dilatation 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10052406 
Gastric 
hypermotility 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10062931 
Gastric 
hypertonia 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10052405 
Gastric 
hypomotility 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10052402 
Gastrointestina
l hypermotility 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10052105 
Gastrointestina
l hypomotility 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10061173 
Gastrointestina
l motility 
disorder 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10017885 
Gastrooesopha
geal reflux 
disease 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
109 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10062879 
Gastrooesopha
geal sphincter 
insufficiency 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10021333 
Ileus paralytic 
Non-mechanical ileus 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10021335 
Ileus spastic 
Non-mechanical ileus 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10021518 
Impaired 
gastric 
emptying 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10059158 
Infrequent 
bowel 
movements 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10022642 
Intestinal 
dilatation 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10023003 
Irritable bowel 
syndrome 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10027110 
Megacolon 
Non-mechanical ileus 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10072286 
Narcotic 
bowel 
syndrome 
Non-mechanical ileus 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10058934 
Neonatal 
intestinal 
dilatation 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10076953 
Obstructive 
defaecation 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10030136 
Oesophageal 
achalasia 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10071554 
Oesophageal 
atony 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-301 
Statistical Analysis Plan Version 0.1 
 
4 November 2019 
110 
CONFIDENTIAL 
Code 
Preferred 
Term (PT) 
High Level Term (HLT) 
High Level Group 
Term (HLGT) 
SOC 
10067752 
Oesophageal 
hypomotility 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10072419 
Oesophageal 
motility 
disorder 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10030184 
Oesophageal 
spasm 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10060696 
Presbyoesopha
gus 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10075246 
Pseudoachalasi
a 
Gastrointestinal dyskinetic 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10073166 
Pyloric 
sphincter 
insufficiency 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10037628 
Pylorospasm 
Gastrointestinal spastic and 
hypermotility disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10066142 
Sandifer's 
syndrome 
Gastrointestinal atonic and 
hypomotility disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders