Conditions: Hereditary Angioedema (HAE)
Keywords: HAE hereditary angioedema kallikrein inhibitor plasma kallikrein
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 58
Healthy volunteers: no

Brief summary:
This 3-part study will evaluate the efficacy and safety of an oral kallikrein inhibitor, BCX7353, in the treatment angioedema attacks in subjects with Type I or II hereditary angioedema (HAE). In each study part, subjects will treat 3 attacks with BCX7353 (2 attacks) or placebo (1 attack), in a randomly allocated order. In Part 1, the dose of 750mg will be assessed relative to placebo in up to 36 patients. If this is shown to be effective, then a further 12 patients will be enrolled at a 500mg dose (Part 1), followed by a further 12 (if efficacy still shown) at a dose of 250mg (Part 3) to determine the minimum effective dose of BCX7353 compared to placebo for treating HAE attacks. Efficacy will be determined by subject diary entries completed at pre-defined times post-dose.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: BCX7353 intervention 2: Placebo
Intervention descriptions: intervention 1: oral liquid formulation intervention 2: oral liquid formulation to match BCX7353

Protocol document:
Prot_001.pdf: 
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1. 
TITLE PAGE 
BIOCRYST 
PHARMACEUTICALS, INC. 
 
 
Protocol No. BCX7353-202 
 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, DOSE-RANGING STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY 
OF SINGLE DOSES OF BCX7353 AS AN ACUTE ATTACK 
TREATMENT IN SUBJECTS WITH HEREDITARY 
ANGIOEDEMA  
 
EudraCT Number: 2016-001424-55 
 
Version 4.0: 16 March 2018 
 
 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703, USA 
Phone: +1 (919) 859-1302 
Fax: +1 (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. 
 
 


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CONFIDENTIAL 
Protocol Number: 
BCX7353-202 
Study Title: 
A randomized, double-blind, placebo-controlled, dose-ranging, study to 
evaluate the efficacy, safety and tolerability of single doses of BCX7353 as an 
acute attack treatment in subjects with hereditary angioedema 
IND Number: 
N/A 
EudraCT No. 
2016-001424-55 
Investigational Product: 
BCX7353 
Indication Studied: 
Hereditary Angioedema 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703, USA 
Development Phase: 
2 
Sponsor Medical Officer: 
Sylvia Dobo, MD 
Executive Director, Product Safety and Clinical Development 
BioCryst Pharmaceuticals 
Office: +1 (919) 226-5860 
Cell: +1 (773) 304-8942 
Email: sdobo@biocryst.com 
Principal Investigator: 
Dr Hilary Longhurst 
 
Email: hlonghurst@doctors.org.uk  
Sponsor Project Manager: Sharon VanDyke 
BioCryst Pharmaceuticals 
Office: +1 (919) 859-7914 
Cell: +1 (919) 830-8019 
Email:sdyke@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) and International Conference on Harmonization 
Guidelines. Essential study documents are currently archived in accordance 
with applicable regulations 
Final Protocol Date: 
Version 1.0: 16 December 2016 
Version 2.0: 24 February 2017 
Version 3.0: 02 August 2017 
Version 4.0: 16 March 2018 
 




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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No:       BCX7353-202 
Protocol Title: A randomized, double-blind, placebo-controlled, dose-ranging, study to 
evaluate the efficacy, safety, and tolerability of single doses of BCX7353 as an 
acute attack treatment in subjects with hereditary angioedema 
Date: 
 
Version 4.0:  16 March 2018 
 
 
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 Conference on Harmonization Guidelines for Good 
Clinical Practices, and all applicable regulatory requirements. 
 
 
_____________________________________________________________________ 
Investigator’s Signature 
Date 
 
 
_________________________________ 
Name (Print) 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. 
Name of Investigational Product: 
BCX7353 
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 randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy, safety and 
tolerability of single doses of BCX7353 as an acute attack treatment in subjects with hereditary 
angioedema 
Study centers: Study centers in Europe and Israel 
Principal Investigator: Dr Hilary Longhurst 
Studied period (years):  
Estimated date first patient enrolled: July 2017 
Estimated date last patient completed: September 2018 
Phase of development:  
2 
Objectives:  
Primary: 
• To evaluate the efficacy of single oral doses of BCX7353 in treating acute attacks in subjects 
with hereditary angioedema (HAE)  
Secondary: 
• To evaluate the safety and tolerability of single oral doses of BCX7353 in subjects with HAE 
• To evaluate the relationship of BCX7353 dose with clinical responses 
• To evaluate subject satisfaction with BCX7353 treatment 
• Substudy: to describe the natural history and temporal pattern of symptoms of untreated 
attacks and those treated with commercially available attack medications 
 
Efficacy Endpoints:   
• 
Proportion of subject attacks with an improved or stable 3-symptom composite visual analogue 
scale (VAS) score at 4 hours post-dose. The 3-symptom composite will be calculated as the 
average of the VAS scores for abdominal pain, skin pain and skin swelling. A subject is 
considered improved or stable if the change from baseline (time of drug administration) in VAS 
is less than or equal to 0.  
• Proportion of subject attacks with a patient global assessment of improved or stable symptoms at 
4 hours post-dose   
• Proportion of subject attacks with no symptoms or mild symptoms of an HAE attack at 4 hours 
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• Proportion of subject attacks requiring standard of care attack treatment through 24 hours post-
dose 
• Time to use of standard of care acute attack treatment through 24 hours 
• Time to stable or improved symptoms by composite VAS score through 24 hours post-dose 
• Time to symptom relief (first documented time point when a subject experiences a 50% 
reduction in the 3-symptom composite VAS score from the pretreatment composite score) 
• Time to almost complete symptom relief (first documented time point when a subject records a 
VAS score < 10 mm in the 3-symptom composite VAS score) 
• Time to initial symptom relief (time from ingestion of study medication to report that the worst 
symptoms of the attack are over) 
• Time to complete symptom relief (time from ingestion of study medication to no HAE attack 
symptoms) 
Methodology:  
This is a 3-part, Phase 2, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy 
and safety of single oral doses of a liquid formulation of BCX7353 in the treatment of acute HAE 
attacks. All subjects enrolled will receive both active and placebo blinded study drug in a randomized 
sequence. Part 1 of the study will evaluate single doses of 750 mg BCX7353; Part 2 will evaluate single 
doses of 500 mg BCX7353 and Part 3 will evaluate single doses of 250 mg BCX7353. 
Randomization 
Up to 36 subjects with Type 1 or 2 HAE with a documented history of HAE attacks will be sequentially 
enrolled into Part 1 of the study and randomized to receive a treatment sequence containing one of the 
following: 
Treatment A1: Single oral dose of BCX7353, 750 mg (Part 1)  
Treatment B: Single oral dose of placebo 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single oral doses 
of BCX7353 500 mg in Part 2; or Treatment A3 = single oral doses of BCX7353 250 mg in Part 3.  
Initially, in Part 1,12 subjects will be randomized to one of 3 treatment sequences (n = 4 per sequence): 
Sequence 1:  ABA 
Sequence 2:  BAA 
Sequence 3:  AAB 
If required, additional subjects will be enrolled into Part 1 (as outlined below) using the same 1:1:1 ratio 
for the 3 sequences, with a maximum total number of 36 subjects for Part 1. 
Part 2 will evaluate a dose of 500 mg (Treatment A2) and placebo (Treatment B). A maximum of 12 
subjects will be enrolled, using the same 1:1:1 ratio for the 3 sequences. Part 3 will evaluate a dose of 
250 mg (Treatment A3) and will enroll a maximum of 12 subjects in a 1:1:1 ratio for each of the 3 
sequences. 
If tolerability issues prevent enrollment of Part 1 as described, additional subjects in Part 1 may be dosed 
with active study drug at a dose of 500 mg. If the dose in Part 1 is reduced and at least 12 subjects are 
treated with an active study drug dose of 500 mg, a 250 mg active dose may be assessed in Part 2. Any 
further dose level changes warranted for Part 2 and Part 3 will be instituted via protocol amendment. 
Enrollment and Analyses 
Up to 36 subjects will be enrolled in Part 1. Upon full enrollment, enrollment into Part 2 of the study 
(maximum of 12 subjects) may immediately commence. Part 3 (n = up to 12) may 
immediately commence upon enrollment of Part 2. 
Following the 12th subject completing Part 1, the treatment effect may be estimated. The predefined 


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endpoint, determined by the Haybittle-Peto method, is the proportion of subjects with a stable or 
improved composite VAS at 4 hours post-dose. A Haybittle-Peto boundary of p < 0.001 is considered 
clinically significant. 
If the Haybittle-Peto analysis is run and the boundary is not crossed with 12 subjects, the treatment 
effect may be estimated with cumulative data after each treated attack in accordance with the fully 
sequential analysis method assessing the estimate of treatment effect using the Haybittle-Peto boundary 
(p < 0.001).  
Alternatively, if the boundary is not crossed with 24 subjects or the Heybittle-Peto analyses are not 
performed, treatment differences may be assessed using available data in Parts 1, 2 and 3 in order to plan 
subsequent studies.  
Study Conduct Overview 
At the Screening visit, subjects will be provided a diary and receive instruction on the correct 
completion of the diary in real-time to record attack symptoms and severity and any medication usage 
during an acute attack. During the 35-day screening period, subjects will be required to: 1) phone the 
Investigator at the onset of pain or swelling associated with an HAE attack; 2) complete diary details in 
real time of this HAE attack; and 3) phone the Investigator at the 4 hour post-call timepoint.  Completion 
of these procedures will confirm that the subject is able and competent to perform on-study requirements 
in early identification of an attack and treating and documenting an appropriate attack with study drug.  
Eligible subjects will return to the clinic to attend a Baseline visit. At the conclusion of the baseline visit, 
subjects will receive their first randomized dose of study drug for treatment of attacks by self-
administration. The investigational medicinal product (IMP; BCX7353 or placebo) is supplied as a 
powder form drug product, presented in a bottle, that will require reconstitution to a liquid formulation 
with vehicle by the subject prior to administration. 
At the Baseline visit, all subjects will be instructed on how to prepare and use study drug to treat a 
protocol-qualified acute HAE attack and will receive further instruction on the correct completion of a 
diary in real-time immediately prior to and after study drug administration.  
Subjects will be instructed to contact the on-call Investigator (or designee) at the first symptom of 
swelling or pain associated with a potentially protocol-qualified HAE attack.  
Protocol-qualified attacks approved for study drug treatment must meet all of the following: 
• 
have pain and/or swelling associated with an HAE attack reported as a symptom 
• 
subject has contacted Investigator within approximately 1 hour of onset time of HAE pain 
and/or swelling not involve pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, icatibant) 
without delay. 
• 
not be an abdominal attack that has already resulted in vomiting. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, icatibant). 
• 
have an identifiable onset time, with the exception that abdominal attacks with an onset 
during sleep may be permitted for study drug treatment. Onset time for abdominal attacks 
will be time the subject woke up with symptoms. Peripheral attacks starting with an onset 
during sleep will not be approvable for study drug treatment. 
• 
occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor antagonist (i.e. 
Firazyr) OR treated with human recombinant C1 INH (i.e. Ruconest) OR any non-


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targeted therapy (i.e. pain medication, anti-spasmodic, anti-emetic, tranexamic acid) 
OR was not treated with any medication: new attack can be treated with IMP if has 
been 48 hours since the complete resolution of all symptoms of the previous HAE 
attack AND the Investigator believes it is a new (de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH (i.e. 
Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent detergent 
plasma): new attack can be treated with IMP if it has been 96 hours since the 
complete resolution of all symptoms of the previous HAE attack 
• 
occur at least 96 hours after complete recovery from a procedure or injury  
• 
occur at least 14 days from a previous dose of study drug 
After approval of the attack for study drug administration, subjects will reconstitute and take study drug 
preferably within one hour of the onset of symptoms. Subjects will complete the diary questionnaire, 
record any additional medications taken, and a 3-component VAS on a 100 mm scale for abdominal 
pain, cutaneous pain, and cutaneous swelling at the time of administration and 1, 2, 3, 4, approximately 
8 and at 24 hours after study drug administration. Subjects will then phone the on-call Investigator (or 
designee) at approximately 4 hours after study medication to review their response to study drug and 
diary completion.  
At each visit following treatment of an attack with study drug, the completed diary will be reviewed and 
any re-education required to ensure correct diary completion will be performed. Safety assessments will 
be completed and the next randomized dose of study drug will be dispensed to the subject.  
Each subject will continue on study to treat 3 attacks with study drug. Clinic visits will be scheduled 10 
to 14 days after each attack that is treated with study drug.  Any additional attacks that occur in the 
intervening periods between study visits may be treated according to standard of care for the subject. 
Subjects will also be asked to track the start and stop times of any attacks not treated with study drug 
that occur after the baseline visit through the last study visit (Post-Attack 3 visit). 
Optional Observational Substudy 
Subjects will be asked to participate in an optional observational substudy to obtain diary data on all 
HAE attacks, through 12 weeks commencing from the last study visit.  Consenting subjects will receive 
a diary and instruction for completion at the Post-Attack 3 visit. For the next 12 weeks, subjects will 
complete their diaries, with periodic subject contact (telephone) to ensure diary adherence. 
A schedule of assessments is presented in Table 4.  
Number of subjects (planned):  
Up to 36 evaluable subjects with Type 1 or 2 HAE are planned to be enrolled in Part 1, up to 12 
evaluable subjects in Part 2 and up to 12 evaluable subjects in Part 3. An evaluable subject is one who 
treats 3 attacks with study drug and for which there is diary information recorded.  
Subjects who complete Part 1 will not be eligible to participate in Parts 2 or 3. Subjects completing Part 
2 will not be eligible to participate in Part 3 of the study. 
Criteria for inclusion: 
1. Able to provide written, informed consent. 
2. Males and non-pregnant, non-lactating females age 18 to 70 years. 


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3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined having a C1 INH 
functional level below 50% of normal and a C4 level below the lower limit of the normal 
reference range, as assessed at the Screening visit. 
4. Access to and ability to use standard of care acute attack treatment. Standard of care acute attack 
treatment is defined as a medication approved by the relevant competent authority for the 
treatment of attacks of HAE (e.g. icatibant, ecallantide, plasma-derived C1INH, recombinant 
C1INH). 
5. Female and male subjects must agree to the contraception requirements and must meet the 
inclusion criteria regarding contraception, and contraception of female partners (as applicable), 
as outlined in Section 8.2. 
6. Any regularly administered concomitant medication recorded at the Screening visit and not 
stated as prohibited must be anticipated to be continued through the entire study and be of a 
stable dose and regimen for the duration of the entire study (screening through follow-up). 
7. In the opinion of the Investigator, the subject is expected to adequately comply with all required 
study procedures for the duration of the study. To be dispensed study drug at baseline, the 
subject must demonstrate adequate compliance with all study procedures required from the 
Screening visit through randomization, including phoning the Investigator and diary recording 
of at least one HAE attack during the screening period. 
8.  Must have a documented HAE attack rate of at least 1 unique attack per month for 3 months (up 
to 93 days) within the 4 months prior to the Screening visit. 
Criteria for exclusion: 
1. No HAE attack reported to the on-call Investigator (or designee) through the 35 days of the 
Screening period. 
2. 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 increase the risk of participation for that subject.  
3. 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. 
4. Clinically significant abnormal electrocardiogram (ECG) at the Screening visit. This includes, 
but is not limited to, a QTcF > 470 msec for women, a QTcF > 450 msec for men, a PR > 220 
msec (both sexes), or ventricular and/or atrial premature contractions that are more frequent than 
occasional, and/or as couplets or higher in grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant 
cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other clinically 
significant cardiovascular abnormality such as poorly controlled hypertension.  
6. Known family history of sudden cardiac death. Family history of sudden death from HAE is not 
exclusionary. 
7. History of or current implanted defibrillator or pacemaker. 
8. Any laboratory parameter at screening that, in the opinion of the Investigator, is clinically 


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significant and relevant for this study. A calculated creatinine clearance of ≤ 60 mL/min or AST 
or ALT value ≥ 2 times the upper limit of the normal reference range value obtained during 
screening is exclusionary. 
9. Suspected C1INH resistance in the opinion of the Investigator and Sponsor. 
10. 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). 
11. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B 
virus (HBV) or hepatitis C virus (HCV). 
12. Pregnant, planning to become pregnant within 30 days of the study, or nursing. 
13. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a prescription). 
14. History of severe hypersensitivity to any medicinal product, which was associated with a non-
HAE related swelling, a severe rash requiring treatment/hospitalization, or anaphylaxis. 
15. Hypersensitivity reaction to BCX7353. 
16. Use of tranexamic acid, androgens or C1 INH for prophylaxis of HAE attacks within the 7 days 
prior to the Screening visit or initiation during the study. Use of a C1 INH therapy for treatment 
of attacks is not excluded at any time, nor is C1 INH for pre-procedure prophylaxis. 
17. 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.  
18. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or planned 
initiation during the study.  
19. 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 baseline or initiation during the 
study. 
20. Current participation in any other investigational drug study or received another investigational 
drug within 30 days of the Screening visit. 
21. An immediate family relationship to either Sponsor employees, the Investigator or employees of 
the study site named on the delegation log. 
Investigational product, dosage and mode of administration:  
BCX7353 powder for reconstitution at doses of 750 mg, 500 mg, and 250 mg.  BCX7353 powder in 
bottle will require reconstitution with vehicle by the subject prior to oral administration. 
All clinical doses of BCX7353 provided in this protocol are in reference to the hydrochloride (HCl) salt. 
Duration of treatment:  
Participating subjects will receive 3 single oral doses of study drug to treat an HAE attack approved for 
study drug treatment: 2 doses of BCX7353 and 1 dose of placebo.  
Reference therapy, dosage and mode of administration:  
Matched placebo powder for reconstitution. Placebo will be lactose monohydrate powder in a bottle that 
will require reconstitution with vehicle by the subject prior to oral administration.  


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Criteria for evaluation: 
Efficacy: 3-symptom composite VAS score, patient global assessment of symptoms, qualitative 
symptom severity, use of standard of care treatment. 
Safety: adverse events (AEs), laboratory analyses [clinical chemistry, hematology, coagulation, 
urinalysis, creatine kinase-MB (CK-MB), troponin I and T], vital signs, ECGs, and physical 
examinations. 
Subject satisfaction:  Treatment Satisfaction Questionnaire for Medication (TSQM)  
Statistical methods: 
Due to the exploratory nature of this study, no formal power or sample size calculations were used to 
determine sample size. Descriptive statistics for disposition, demographics, and baseline characteristics 
will be presented by treatment sequence.  All analyses of efficacy and safety will be attributed to the 
treatment assignment at the time of the assessment. 
Efficacy Analyses: 
Resolution of attacks will be analyzed by treatment arm. The endpoint that may be assessed using a 
Heybittle-Peto boundary for significance is the proportion of subject treated attacks with improved or 
stable composite VAS at 4 hours post-dose in the full analysis set (i.e., all subject treated attacks). The 
number and proportion of subject treated attacks that stabilize or improve at 4 hours will be summarized 
by treatment group. Attacks that require standard of care acute attack treatment prior to the 4-hour time 
point will be considered as failure (i.e., not having a stable or improved VAS at 4 hours). To assess 
treatment differences, a logistic mixed effect model including treatment, period and sequence as fixed 
effects, and subject within sequence as a random effect will be utilized. Other binary endpoints will be 
analyzed in a similar manner.  
The 3-symptom composite VAS and its associated changes from baseline will be summarized by attack, 
time point and treatment group. Treatment differences in the change from baseline values at each time 
point will be assessed with a mixed effect linear model with factors for treatment, period, sequence, and 
baseline value as fixed effects, and subject within sequence as a random effect. Analyses of other 
continuous variables will be analyzed in a similar manner. 
The time to use of standard of care acute attack treatment will be estimated using the Kaplan-Meier 
method.  Subjects who do not use standard of care acute attack treatment will be censored at the end of 
the attack observation period (i.e., 24 hours).  Treatment differences will be assessed using an 
appropriate proportional hazards model. 
Safety Analyses: 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term and system organ classification. The occurrence of treatment-emergent AEs will be summarized by 
treatment group using MedDRA preferred terms, system organ classifications, and severity. Separate 
summaries of treatment-emergent serious adverse events (SAEs) and AEs considered to be related to 
study drug will be generated. All AEs will be listed for individual subjects showing both verbatim and 
preferred terms.  
Descriptive summaries of vital signs, ECG parameters, and clinical laboratory results will be presented 
by study visit and treatment group. Laboratory abnormalities will be graded according to the Division of 
Microbiology and Infectious Diseases [DMID] Adult Toxicity Table [November 2007]. The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by 


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treatment group. Laboratory toxicity shifts from baseline to post-baseline assessments will be 
summarized by study visit and treatment group.  
Physical examination results will be presented in listings.   
Concomitant medications will be coded using the World Health Organization (WHO) dictionary. These 
data will be summarized by treatment group. 
Subject Satisfaction: 
A TSQM global satisfaction score will be calculated as validated. Data on the global score as well as 
relevant subscales will be listed, summarized, and appropriately tested for differences between active 
treatment and placebo and between active and current acute therapy utilized at baseline.  


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
 
1. 
TITLE PAGE ................................................................................................................1 
1.1. 
Protocol Approval Signature Page ................................................................................3 
1.2. 
Clinical Study Protocol Agreement ..............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background .................................................................................................................23 
5.2. 
Nonclinical Findings for BCX7353 ............................................................................25 
5.3. 
Clinical Findings for BCX7353 ..................................................................................26 
5.3.1. 
Study BCX7353-101 ..................................................................................................26 
5.3.2. 
Study BCX7353-102 ..................................................................................................27 
5.3.3. 
Study BCX7353-203 ..................................................................................................28 
5.3.4. 
Study BCX7353-109 ..................................................................................................28 
5.4. 
Rationale for Study .....................................................................................................29 
5.4.1. 
Rationale for Study Drug Doses .................................................................................29 
5.4.1.1. 
Rationale for Achievement and Maintenance of Target Concentrations 
Proposed as Efficacious ..............................................................................................29 
5.4.1.2. 
Rationale for Proposed Doses .....................................................................................30 
5.4.2. 
Rationale for Study Design .........................................................................................32 
5.4.3. 
Study Population Rationale ........................................................................................33 
5.4.3.1. 
Rationale for Use of Standard of Care Attack Medication .........................................33 
5.4.4. 
BCX7353 Risk/Benefit Analysis ................................................................................34 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions ............................................................34 
5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 ....................................................35 
5.4.5. 
Benefits of Trial Participation ....................................................................................39 
5.4.6. 
Overall Benefit-Risk Assessment ...............................................................................39 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................40 
6.1. 
Objectives ...................................................................................................................40 


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7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.1.1. 
Enrollment and Analyses ............................................................................................42 
7.1.2. 
Study Conduct Overview ............................................................................................42 
7.2. 
Endpoints ....................................................................................................................45 
7.2.1. 
Efficacy Endpoints ......................................................................................................45 
7.2.2. 
Safety Endpoints .........................................................................................................45 
7.2.3. 
Other Secondary Endpoints ........................................................................................46 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................47 
8.1. 
Number of Subjects ....................................................................................................47 
8.2. 
Subject Selection ........................................................................................................47 
8.2.1. 
Inclusion Criteria ........................................................................................................47 
8.2.2. 
Exclusion Criteria .......................................................................................................49 
8.3. 
Subject Withdrawal Criteria .......................................................................................51 
8.3.1. 
Subject Discontinuation from Study ...........................................................................51 
8.3.2. 
Subject Discontinuation from Study Drug .................................................................51 
8.3.2.1. 
Discontinuation Due to QT Prolongation ...................................................................51 
8.3.2.2. 
Discontinuation Due to Rash ......................................................................................52 
8.3.2.3. 
End of Trial Definition ...............................................................................................52 
9. 
TREATMENT OF SUBJECTS ..................................................................................53 
9.1. 
Description of Study Drug ..........................................................................................53 
9.2. 
Description of Study Drug Packaging, Labeling and Storage ....................................53 
9.3. 
Blinding and Randomization ......................................................................................54 
9.3.1. 
Blinding ......................................................................................................................54 
9.3.2. 
Randomization ............................................................................................................54 
9.4. 
Study Drug (Investigational Medicinal Product) Reconstitution and 
Administration ............................................................................................................55 
9.5. 
Study Drug Dose Modification ...................................................................................55 
9.6. 
Study Drug (Investigational Medicinal Product) Accountability ...............................55 
9.7. 
Concomitant Medications and Other Restrictions ......................................................56 
9.7.1. 
Prohibited Medications/Restrictions ...........................................................................56 
10. 
STUDY CONDUCT ...................................................................................................58 
10.1. 
Overview .....................................................................................................................58 


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10.2. 
Schedule of Assessments ............................................................................................58 
10.3. 
Study Visits .................................................................................................................62 
10.3.1. 
Screening ....................................................................................................................62 
10.3.2. 
Baseline .......................................................................................................................63 
10.3.3. 
Telephone Contacts ....................................................................................................64 
10.3.4. 
Clinic Visits Following Study Drug Administration ..................................................65 
10.3.5. 
Early Termination Visits .............................................................................................66 
10.3.6. 
Optional Observational Substudy ...............................................................................66 
11. 
ASSESSMENTS.........................................................................................................67 
11.1. 
Investigator-Completed Assessments .........................................................................67 
11.1.1. 
HAE Medical and Medication History .......................................................................67 
11.1.2. 
Physical Examination .................................................................................................67 
11.1.3. 
Weight/Body Mass Index ...........................................................................................67 
11.1.4. 
12-lead Electrocardiograms ........................................................................................67 
11.1.5. 
Vital Signs ..................................................................................................................68 
11.1.6. 
Clinical Laboratory Assessments ...............................................................................68 
11.1.8. 
Pregnancy Testing ......................................................................................................70 
11.1.9. 
C1 INH Testing ...........................................................................................................70 
11.1.10. 
Other Laboratory Assessments ...................................................................................70 
11.1.11. 
Rash Assessment ........................................................................................................70 
11.2. 
Subject-Completed Assessments ................................................................................71 
11.2.1. 
Treatment Satisfaction Questionnaire .........................................................................71 
11.2.2. 
HAE Attack Diaries and Phone Calls .........................................................................71 
11.2.2.1. 
Screening through Post-Attack 3 Visit .......................................................................71 
11.2.2.2. 
Optional Observational Substudy ...............................................................................75 
12. 
ASSESSMENT OF SAFETY .....................................................................................76 
12.1. 
Adverse Events ...........................................................................................................76 
12.1.1. 
Definitions ..................................................................................................................76 
12.1.1.1. 
Adverse Event .............................................................................................................76 
12.1.1.2. 
Serious Adverse Event ................................................................................................77 
12.1.1.3. 
Adverse Events of Special Interest .............................................................................77 
12.1.3. 
Definition of Severity .................................................................................................78 


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12.1.4. 
Definition of Relationship to Study Drug (Investigational Medicinal 
Product) .......................................................................................................................79 
12.1.5. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................80 
12.1.5.1. 
Reporting Events of Special Interest ..........................................................................81 
12.1.6. 
Pregnancy ...................................................................................................................81 
12.1.7. 
Serious Breaches .........................................................................................................81 
12.1.8. 
Emergency Procedures ...............................................................................................82 
12.2. 
Toxicity Management .................................................................................................82 
12.2.1. 
Rash ............................................................................................................................82 
12.2.2. 
Overdose .....................................................................................................................82 
12.3. 
Data Monitoring Committee .......................................................................................83 
13. 
STATISTICS ..............................................................................................................84 
13.1. 
Sample Size Considerations .......................................................................................84 
13.2. 
Hypothesis Testing .....................................................................................................84 
13.3. 
Statistical Methods ......................................................................................................84 
13.3.1. 
Analysis Populations ..................................................................................................84 
13.3.1.1. 
Full Analysis Set .........................................................................................................84 
13.3.1.2. 
Safety Population ........................................................................................................84 
13.3.2. 
Subject Demographic and Disposition Data ...............................................................84 
13.3.3. 
Analysis of Efficacy Variables ...................................................................................85 
13.3.4. 
Analysis of Safety Variables ......................................................................................85 
13.3.5. 
Subject Satisfaction Analyses .....................................................................................86 
13.3.6. 
Interim Monitoring and Statistical Stopping Rules ....................................................86 
14. 
STUDY ADMINISTRATION ...................................................................................87 
14.1. 
Regulatory and Ethical Considerations ......................................................................87 
14.1.1. 
Regulatory Authority Approvals ................................................................................87 
14.1.2. 
Institutional Review Board and Ethics Committee Approvals ...................................87 
14.1.3. 
Subject Informed Consent ..........................................................................................87 
14.1.4. 
Payment to Subjects ....................................................................................................88 
14.1.5. 
Investigator Reporting Requirements .........................................................................88 
14.2. 
Study Monitoring ........................................................................................................88 
14.3. 
Quality Assurance .......................................................................................................88 


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14.4. 
Study Termination and Site Closure ...........................................................................89 
14.5. 
Records Retention .......................................................................................................89 
14.6. 
Confidentiality of Information ....................................................................................90 
14.7. 
Study Publication ........................................................................................................90 
15. 
REFERENCES ...........................................................................................................91 
APPENDICES ...............................................................................................................................94 
15.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) .........................94 


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LIST OF TABLES 
Table 1. 
Abbreviations and specialist terms .............................................................................19 
Table 2. 
Simulated first time postdose to achieve BCX7353 concentration ≥71 ng/mL 
following single dose administration of 250, 500, and 750 mg BCX7353 ................32 
Table 3. 
Simulated duration of BCX7353 concentrations exceeding target 
concentration of 71ng/mL following single dose administration of 250, 500, 
and 750 mg BCX7353 ................................................................................................32 
Table 4. 
Schedule of Assessments for Study BCX7353-202 ...................................................59 
Table 5. 
Schedule of Assessments for Optional Observational Substudy ................................62 
Table 6. 
Clinical Laboratory Evaluations .................................................................................68 
 
 
LIST OF FIGURES 
Figure 1. 
Simulated Mean Exposure of BCX7353 over Target Concentration .........................31 
Figure 2.  Study Design Through Follow-up (Post-Attack 3 Visit) ............................................42 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1. 
Abbreviations and specialist terms 
Abbreviation  
Explanation 
AAS 
angioedema activity score 
ABW 
actual body weight 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0−t 
area under the concentration versus time curve from time zero to time “t” 
AUC0-inf 
area under the concentration versus time curve extrapolated to infinite time 
AUCtau 
area under the plasma concentration versus time curve over the dosing interval (tau) 
% AUCexp 
percentage of AUC extrapolated between AUC0-last and AUC0-inf 
BCRP 
Breast cancer resistance protein 
BID 
twice daily 
BK 
bradykinin 
BMI 
body mass index 
BMP 
Bis(mono)acylglycerol phosphate 
C1 INH 
C1 esterase inhibitor 
Clast 
last measurable concentration of drug 
CK-MB 
creatine kinase-MB 
CLcr 
creatinine clearance 
CLr 
renal clearance of unchanged drug in a specific interval (CLr[interval]) or 
cumulatively over all collection intervals 
Cmax 
maximum plasma concentration of the drug 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CRO 
clinical research organization 
Cav,ss 
average steady-state plasma drug concentration during multiple-dose administration 
Ctau 
observed drug concentration at the end of the dosing interval (tau) 
CYP 
cytochrome P450 
DMC 
Data monitoring committee 


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Abbreviation  
Explanation 
DMID 
Division of Microbiology and Infectious Diseases 
% Doseexcreted 
percentage of given dose excreted in the urine as unchanged drug 
eCRF 
Electronic case report form 
EC50 
Half-maximal effective concentration 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQoL five-dimensional, 5-level questionnaire 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulation hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HAE 
hereditary angioedema 
HBV 
hepatitis B virus 
HCl 
hydrochloride 
HDPE 
High density polyethylene 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HK 
high-molecular weight kininogen 
IB 
Investigator’s brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IMPD 
investigational medicinal product dossier 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 


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Abbreviation  
Explanation 
IUS 
intrauterine system 
IV 
intravenous 
Ka 
absorption rate constant 
Ki 
inhibition constant value 
KRBC/P 
partitioning constant between erythrocytes and plasma 
λz 
terminal elimination rate constant 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MCH 
mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NGAL 
neutrophil gelatinase–associated lipocalin 
P-gp 
p-glycoprotein 
PBMC 
Peripheral blood mononuclear cell 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PKK 
prekallikrein 
PLD 
phospholipidosis 
PO 
oral 
PR 
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex, representing time for atrial and ventricular depolarization, respectively 
PT 
prothrombin time 
QD 
once daily 
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 
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 


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Abbreviation  
Explanation 
SUSAR 
suspected unexpected severe adverse reaction 
T1/2 
estimate of the terminal elimination half-life of the drug 
TEAE 
treatment emergent adverse event 
Tmax 
time to maximum plasma concentration 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
Vz/F 
apparent volume of distribution of the drug 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background 
Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent 
episodes of swelling of the skin, pharynx, larynx, gastrointestinal tract, genitals, and extremities 
(Longhurst and Cicardi 2012). The frequency of attacks varies between subjects, 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 (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 acute attacks of HAE 
(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 (FXIIa) 
forming the active protease kallikrein. Kallikrein in turn cleaves HK, producing BK (Kaplan and 
Ghebrehiwet 2010). The activation of the bradykinin B2 receptor by BK ultimately results in 
vasodilatation, increased vascular permeability, and smooth muscle contraction, all of which lead 
to the tissue swelling that characterizes HAE (Kaplan 2010). 
The primary inhibitor of kallikrein in plasma is the SERPING1 gene product, C1 esterase 
inhibitor (C1 INH) (Cicardi and Johnston 2012). C1 INH is a serine protease inhibitor (serpin) 
that normally prevents uncontrolled contact activation and BK production by covalently binding 
to and inactivating kallikrein (Patston, Gettins et al. 1991). Patients with HAE have mutations in 
the regulatory or coding regions of the C1 INH gene that result in either a failure to produce 
C1 INH or the production of nonfunctional C1 INH (Pappalardo, Cicardi et al. 2000). The 
amount of functional C1 INH produced by the unaffected allele is insufficient to control serine 
protease activity, including that of kallikrein, that is induced by even asymptomatic levels of 
vascular endothelial contact activation (Cicardi and Johnston 2012). As a result, even when a 
patient does not experience any symptoms, plasma HK levels may be lower than normal and BK 
is detectable (Cugno, Hack et al. 1993, Nussberger, Cugno et al. 1998, Kaplan, Joseph et al. 
2002, Nussberger, Cugno et al. 2002, Suffritti, Zanichelli et al. 2014). During symptomatic 
attacks, which may be triggered by trauma, infection, changes in hormone levels (e.g., with oral 
contraceptive use or with the menstrual cycle), or emotional stress, kallikrein activation, HK 
cleavage and BK production increase, and circulating BK levels are dramatically elevated 
(Cugno, Nussberger et al. 2003, Bork, Meng et al. 2006, Cicardi and Johnston 2012, Martello, 
Woytowish et al. 2012).  


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The effective management of HAE involves the prevention and/or treatment of symptomatic 
attacks (Cicardi, Bork et al. 2012). Kallikrein is a proven target in the treatment of HAE.  
As noted above, C1 INH is a covalent kallikrein inhibitor, and plasma-derived purified C1 INH 
(Cinryze®, Berinert®) and a human recombinant C1 INH (Ruconest®) are licensed for the 
treatment of acute HAE attacks in the European Union (EU). In the United States (US), 
Berinert® and Ruconest® are licensed for this indication. Kalbitor® (ecallantide) is an engineered 
recombinant protein noncovalent binding kallikrein inhibitor with homology to tissue factor 
pathway inhibitor and is licensed in the US for treatment of acute attacks of HAE by 
subcutaneous injection (Martello, Woytowish et al. 2012, Riedl 2012). In addition, Firazyr® 
(icatibant) is a bradykinin B2 receptor antagonist and is licensed in the EU and the US for 
treatment of acute attacks of HAE by subcutaneous injection.  
The goal of acute treatment is to resolve angioedema symptoms as quickly as possible. There are 
no comparative (head-to-head) studies of therapies to treat an acute attack. Double-blind, 
randomized placebo-controlled trials have demonstrated superiority of Berinert, Cinryze 
Ruconest, Firazyr, and Kalbitor over placebo. These data are briefly described below. 
Data from both the Berinert and the Cinryze trials suggest that higher doses (i.e., 20 U/kg 
Berinert, and more than 1 dose of Cinryze 1000 U) have a shorter median time to onset of relief 
with secondary outcomes consistently supported by the efficacy of the higher doses (Craig, Levy 
et al. 2009, Zuraw, Busse et al. 2010, Wasserman, Levy et al. 2011). With C1 INH, serious 
arterial and venous thromboembolic events have been reported at the recommended dose of 
C1 INH products. A general concern over transmission of blood-borne infections is inevitable 
when using human plasma–derived products. Hypersensitivity and allergic/pseudo-allergic 
systemic reactions have also been reported in a few patients. Berinert is approved in Europe for 
self-administration to treat all acute attacks and in the US to treat facial, laryngeal and abdominal 
attacks. Cinryze is approved in Europe to treat all acute attacks. 
Ruconest also demonstrated a treatment effect and the time to minimal symptoms was 
significantly shorter in patients receiving rhC1 INH compared to placebo with no subject in the 
rhC1 INH treatment group experiencing therapeutic failure (Zuraw, Cicardi et al. 2010). 
Hypersensitivity, including anaphylaxis in a single healthy volunteer with an undisclosed rabbit 
allergy, has been reported with the use of Ruconest. Ruconest is approved in Europe for 
treatment for all acute attacks and the US package insert has a limitation of use clause in the 
indication statement that states effectiveness was not established in HAE patients with laryngeal 
attacks. 
Icatibant (Firazyr) is also an acute attack medication option for most patients in the US and EU. 
Icatibant is a subcutaneously-administered synthetic peptide that works distinctly from the other 
HAE treatments in that it functions as a bradykinin B2 receptor antagonist. In 3 published 
multicenter clinical trials (FAST 1, 2, and 3) patients were randomized to icatibant or comparator 
(placebo or tranexamic acid). Time to almost complete resolution was shorter with icatibant than 
with the comparator in all 3 trials and was statistically significant in the FAST 2 and FAST 3 
trials (Cicardi, Levy et al. 2010, Lumry, Li et al. 2011). Open label studies have shown the 
benefit of different treatments for attacks at all sites. However, approximately 10% of patients 
require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial 
treatment (Longhurst 2010). Icatibant was generally well tolerated and is approved for the 
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Kalbitor (ecallantide) demonstrated a significantly higher improvement over placebo by using 
2 measures of patient-reported outcomes and demonstrated efficacy at all attack locations (Riedl, 
Campion et al. 2010). The open-label extension phase of the studies suggested that the majority 
of patients benefited from a single dose of ecallantide, although in 29% of attacks a second dose 
was necessary due to incomplete efficacy (Levy, Lumry et al. 2010). Hypersensitivity (including 
anaphylaxis) is a known risk of ecallantide treatment for acute HAE attacks and is a black box 
warning label in the prescribing information, with a 4% incidence in treated patients. Ecallantide 
is approved for the treatment of all acute attacks of HAE. 
BCX7353 is a potent, synthetic, second-generation small molecule inhibitor of plasma kallikrein 
discovered at BioCryst. In contrast to the parenterally administered options outlined above, 
inhibition of kallikrein with an orally bioavailable small molecule such as BCX7353 may offer 
the advantage of oral administration in the rapid and successful treatment of acute HAE attacks.  
5.2. 
Nonclinical Findings for BCX7353 
The results of nonclinical pharmacology, pharmacokinetics, and toxicology studies of BCX7353 
are described briefly below; additional details can be found in the Investigator’s Brochure (IB). 
BCX7353 is a potent and highly specific inhibitor of human plasma kallikrein activity with a 
50% inhibitory concentration (IC50) of BCX7353 against plasma kallikrein of 0.88 nM.  
In activated plasma from subjects with HAE, the mean half-maximal effective concentration 
(EC50) value was 15.9 ± 0.57 nM.  
Safety pharmacology studies were negative except for a positive human ether-à-go-go-related 
gene (hERG) signal. Doses > 30 mg/kg increased the duration of ECG intervals including the 
QTc interval, but these effects were not considered adverse as the maximum increase was 10% 
versus the pretest group mean.  
In nonclinical species, orally dosed BCX7353 is recovered in the bile, feces, and urine, and the 
terminal half-life is long. In the rat and monkey, BCX7353 is metabolized by oxidative 
deamination, oxidation, and/or conjugation of cyclopropanecarboxylic acid.  
In vitro, BCX7353 inhibits cytochrome P450 (CYP) 2C9 and CYP2C19, CYP2D6 and CYP3A. 
The time-dependent inhibition screen with BCX7353 suggests it may irreversibly inhibit 
CYP3A, but not CYP2C9 or CYP2C19. BCX7353 is also an inhibitor of the transport protein p-
glycoprotein (P-gp) and also breast cancer resistance protein (BCRP), MATE1, and MATE2-K 
at micromolar concentrations. BCX7353 is a substrate of P-gp and BCRP.  
BCX7353 has a low concern for genotoxicity and has no phototoxic potential. 
In rats and cynomolgus monkeys, the effects of repeated, daily oral doses for durations of 28 
days and 13 weeks have been investigated, in accordance with the OECD Test Guidelines and 
Principles of Good Laboratory Practice (GLP). Twenty-eight day studies in rats and monkeys 
suggest that the primary target organs of BCX7353 toxicity were liver (both hepatocyte necrosis 
and bile duct hyperplasia), kidney, and skeletal muscle, with toxicities also observed in cardiac 
and smooth muscle, and the lymphoid system. However, with longer duration of dosing (13 
weeks; a different drug lot than used in the 28-day studies was utilized) there were no significant 
adverse effects noted. In monkeys administered the highest dose (20 mg/kg/day) for 13 weeks, 
there were no adverse effects noted. In rats dosed at this same dose level, bile duct hypertrophy, 


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hyperplasia and vacuolated macrophages in the liver were noted but not considered adverse.  
Further details can be found in the IB. 
Single oral dose non-GLP studies have also been conducted in rats and monkeys. Doses of 150, 
250 and 450 mg/kg administered to rats were well tolerated; there were no deaths and no clinical 
observations. At the highest dose of 750 mg/kg mortality and clinical signs were noted, mainly in 
females. At the highest tolerated single dose of 450 mg/kg, the mean plasma exposures (Cmax and 
AUC0-24) were 560 ng/mL and 11,900 ng•hr/mL, respectively. A single oral dose of BCX7353 to 
one male and one female cynomolgus monkey was evaluated at 75, 150, 300, 500 and 
700 mg/kg. BCX7353 was tolerated at all dose levels but vomiting was noted at 300 mg/kg and 
higher which may have limited the systemic exposure and hence the toxicity. At 300 mg/kg, the 
mean plasma exposures (Cmax and AUC0-24) were 1,030 ng/mL and 14,400 ng•hr/mL, 
respectively. Exposures were lower at higher doses.  
Definitive embryo-fetal development studies were conducted in pregnant Sprague Dawley rats 
and New Zealand White rabbits. In rats and rabbits there was no evidence of embryo-fetal 
mortality, fetotoxicity, or dysmorphogenesis at any dose level. There was no evidence of adverse 
maternal toxicity at 25 mg/kg/day in rats and at 50 mg/kg/day in rabbits. 
5.3. 
Clinical Findings for BCX7353 
Two studies in human subjects have completed (Study BCX7353-101 and Study BCX7353-102) 
and 2 studies are currently ongoing (Studies BCX7353-203 and BCX7353-109). Brief 
summaries are provided below.  
5.3.1. 
Study BCX7353-101 
Study BCX7353-101 was a first-in human, 3-part, Phase 1, double-blind, placebo-controlled 
dose-ranging study of BCX7353 (solid dosage form) conducted in 96 healthy subjects. Part 1 and 
Part 2 of the study assessed the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of a 
single ascending dose of BCX7353 (10 mg–1000 mg) or multiple ascending doses of BCX7353 
given to healthy Western subjects over 7 to 14 days (125mg–500 mg once daily [QD]), 
respectively. Part 3 of the study evaluated the safety, PK, and PD of single (100 and 500 mg) and 
multiple doses of BCX7353 250 mg given over 7 days in healthy Japanese subjects.  
BCX7353 was generally safe and well tolerated with no treatment-emergent serious adverse 
events (TESAEs) or Grade 4 treatment emergent adverse events (TEAEs). Most TEAEs were 
Grade 1 in severity. In the multiple dose portion (Part 2), one subject (500-mg group) 
experienced a Grade 3 TEAE. The TEAE was a diffuse, cutaneous maculo-papular rash with no 
mucosal involvement, no desquamation, or constitutional symptoms or laboratory abnormalities 
that was diagnosed after the subject completed 7 days of treatment. This event was consistent 
with a Type IV hypersensitivity reaction, and resolved following treatment with oral and topical 
steroids. The event was assessed as probably related to BCX7353. In addition, a Japanese subject 
treated with BCX7353 250 mg for 7 days experienced a Grade 2 maculo-papular rash after 
completing treatment; the subject had no mucosal involvement, no desquamation, or 
constitutional symptoms or clinically significant laboratory abnormalities. The event resolved 
following treatment with antihistamine and was assessed as probably related to BCX7353. 


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Overall, 2 subjects (both enrolled in Part 2) discontinued treatment due to Grade 2 TEAEs upper 
abdominal pain and diarrhea in 1 subject (500-mg group) and upper abdominal pain in 1 subject 
(350-mg group).  
There was no apparent dose response regarding any individual AE; however, more 
gastrointestinal AEs were reported in the higher dose cohorts. Across all parts of the study, there 
were no trends in laboratory abnormalities.  
Electrocardiograms extracted from the 12-lead Holter monitoring data provided evidence of a 
dose-dependent increase in mean QTcF occurring after multiple doses of BCX7353 at dose 
levels of 350 mg QD and higher (250 mg QD in Japanese subjects). This was not seen in the 
single dose cohorts. 
Following single and multiple oral doses of BCX7353, Cmax was reached approximately 2 to 
6 hours after dosing. There was approximately 3- to 5-fold accumulation in BCX7353 plasma 
exposure with 7 or 14 days of BCX7353 dosing, which is consistent with the observed long 
half-lives ranging from 67 to 79 hours. Analysis of trough values indicated that steady-state 
conditions were achieved from 6 to 12 days post first dose. 
Cmax and AUC0-inf indicated that both Cmax and AUC0-inf  increased in a more than dose-
proportional manner over the 30 mg to 1000 mg dose range while reasonable 
dose-proportionality between 250 mg and 500 mg for Cmax was observed. There was a slightly 
greater than dose proportional increase in exposure (AUCtau and Cmax) following multiple dose 
exposure over the 125-mg to 500-mg dose range.  
After a high-fat breakfast, AUC0-last and AUC0-inf appeared to be modestly increased although the 
90% CIs were wide. No significant changes were observed in the geometric mean Cmax values.  
The effect of BCX7353 on plasma kallikrein activity was generally dose dependent. Higher 
doses of BCX7353 (≥ 250 mg QD) provided more potent inhibition that was more consistently 
sustained through a dosing interval, achieving approximately 90% inhibition across an interval 
on average. Exposure-response analyses demonstrated a high correlation between ex-vivo 
kallikrein inhibition activity and plasma concentrations of BCX7353 (r = 0.921). The BCX7353 
concentration and kallikrein inhibition relationship was well described by a sigmoidal Emax 
model with predicted EC50 value of 9.71 ng/mL. 
There were no clinically relevant safety, PK, or PD differences and/or trends observed between 
Western and Japanese subjects following dosing with BCX7353. 
5.3.2. 
Study BCX7353-102 
Study BCX7353-102 evaluated the effect of multiple oral doses of BCX7353 (solid dosage form) 
on hepatic and intestinal metabolism by CYP3A4 (as assessed by pharmacokinetics of 
intravenous [IV] and oral [PO] midazolam, respectively), CYP2C9 (tolbutamide), CYP2C19 
(omeprazole) and CYP2D6 (dextromethorphan) enzyme activity using probe substrate drugs in 
healthy subjects. Study BCX7353-102 has completed dosing.  
A total of 21 subjects were enrolled and 18 subjects completed the study; withdrawal from study 
drug were for nonstudy-drug related reasons. BCX7353 was generally safe and well tolerated. 
Most AEs were Grade 1 in severity and no SAEs or Grade 3 or 4 AEs were reported. There was 
1 Grade 2 TEAE assessed as probably related to BCX7353: a subject developed a diffuse 


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maculo-papular rash 48 hours after completing 9 days of BCX7353. The rash was pruritic with 
no mucosal involvement, no desquamation, and no abnormalities on exam. The subject had no 
constitutional symptoms or clinically significant lab abnormalities. The rash resolved rapidly 
following a single dose of cetirizine 10 mg.  
Preliminary analysis of the PK data indicate that BCX7353 is an inhibitor of CYP3A4, CYP2C9, 
CYP2C19, and CYP2D6 to varying degrees. Following administration of ≥ 8 days of BCX7353, 
exposure of all probe substrates were increased, indicating that metabolism was inhibited. Based 
on the draft US Food and Drug Administration (FDA) Drug Interaction Guidance and 
preliminary PK of the probe substrates, BCX7353 is a strong inhibitor of CYP2D6 (> 5-fold 
increase in AUC), a moderate inhibitor of CYP2C9, CYP2C19, and intestinal CYP3A4 
(exposure increased between 2- and 5-fold), and a weak inhibitor of hepatic CYP3A4 (< 2-fold 
increase in exposure). 
5.3.3. 
Study BCX7353-203 
Study BCX7353-203 is an ongoing Phase 2, randomized, double-blind, placebo-controlled, 
2-part, parallel-group, dose- response study to evaluate the safety, tolerability, PK, PD, and 
efficacy of BCX7353 (solid dosage form) in subjects with HAE. Up to 36 eligible subjects are to 
be randomized in Part 1 of the study to BCX 7353 350 mg QD or placebo QD orally for 28 days. 
In Part 2, approximately 14 eligible subjects will be randomized into 1 of the following 
3 treatment groups: 1) placebo QD orally for 28 days, 2) BCX7353 125 mg QD orally for 
28 days, and 3) BCX7353 250 mg QD orally for 28 days. 
As of 16 December 2016, 29 subjects have been randomized and treated in Part 1 of the study. 
Fifteen subjects have completed through 28 days of dosing and 2 subjects have discontinued 
study drug prematurely due to TEAEs, one due to a concurrent illness and one due to a TEAE. 
The first subject discontinued due to persistently elevated liver enzyme levels that were present 
at baseline and assessed as not related to study drug by the investigator. The other subject 
discontinued due to elevated liver enzymes that occurred in the setting of gastroenteritis. To date, 
no SAEs have been reported.  
5.3.4. 
Study BCX7353-109 
Study BCX7353-109, is an ongoing, open-label study in subjects with Type 1 or 2 HAE to 
evaluate the single dose pharmacokinetics and pharmacodynamics of BCX7353.  A single dose 
of BCX7353 is administered with 2 dose regimens tested. Subjects may participate in one or 
more of the regimens, although it is preferred to have a subject participate in both regimens. Six 
subjects will be enrolled in each regimen to receive the following treatments, separated by at 
least a 14-day washout period:   
Regimen A: Single oral dose of BCX7353 350 mg in capsule formulation 
Regimen B: Single oral dose of BCX7353 750 mg in capsule formulation 
Regimen C: Single oral dose of BCX7353 750 mg in liquid dose formulation 
Three subjects have currently screened for enrollment. Regimen B (750 mg capsules) will be 
administered first given ready availability of IMP for this dosing level. One subject has received 
Regimen B. 


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5.4. 
Rationale for Study 
BCX7353 is a second-generation small molecule developed as an orally administered inhibitor of 
plasma kallikrein that is being evaluated for the treatment of acute angioedema attacks in adult 
patients with HAE. Kallikrein is a proven target for the treatment of HAE; the kallikrein inhibitor 
ecallantide is approved in the US for subcutaneous injection for the treatment of acute HAE 
attacks, and C1 INH treatments also target kallikrein. BCX7353 has activity at low nM 
concentrations against plasma kallikrein (see Section 5.4.1).  Phase I PK data describe a plasma 
concentration profile that supports treatment of acute attacks: following oral administration, 
BCX7353 is rapidly absorbed and has a long terminal elimination half-life.  
Study BCX7353-202 is an initial proof-of-concept study of BCX7353 in the oral treatment of 
acute attacks in adult subjects with HAE. Administration of a liquid formulation of BCX7353 
was chosen for this study to eliminate the time required for disintegration of capsules and 
dissolution of powdered drug substance, in order to optimize the time to effective drug levels in 
the systemic circulation after oral dosing.  
This study is designed to evaluate the treatment effect of BCX7353 750 mg on the resolution of 
acute attacks. Up to 2 additional doses of BCX7353 (500 mg and 250 mg) will be evaluated in 
the dose-ranging parts of the study.  
5.4.1. 
Rationale for Study Drug Doses  
5.4.1.1. 
Rationale for Achievement and Maintenance of Target Concentrations Proposed 
as Efficacious 
In healthy subjects in Study BCX7353-101, inhibition of plasma kallikrein was highly correlated 
with plasma BCX7353 concentrations (r = 0.92). Therefore, achieving BCX7353 concentrations 
at or above an appropriate target level is hypothesized to effectively treat attacks in HAE 
subjects with little or no functional C1 INH, the endogenous inhibitor of kallikrein and 
ultimately, bradykinin production.  Moreover, maintaining these concentrations over the target 
level for a duration of time to prevent recurrence of an attack will be required.  
Selection of appropriate target plasma level of BCX7353 
In the plasma kallikrein inhibition assay using HAE patient plasma, the EC50 of C1 INH was 
measured to be 213 nM and for BCX7353 was 15.9 nM, a 13.4-fold potency difference. The 
lower limit of the normal range (LLN) of C1 INH is approximately 1680 nM; therefore, the LLN 
for C1 INH corresponds to a BCX7353 concentration of approximately 125 nM, or 71 ng/mL. It 
would be expected that BCX7353 concentrations above approximately 71 ng/mL, would restore 
phenotypically normal total plasma kallikrein inhibitory activity.   
Selection of duration that BCX7353 concentrations must exceed the target plasma level 
To abate an attack, it is desirable to exceed the target plasma concentrations of BCX7353 as 
quickly as possible after a dose. HAE attacks typically follow a predictable time course. Swelling 
classically worsens slowly but relentlessly over the first 24 hours, and gradually subsides over 
the subsequent 48 to 72 hours. Following administration of a single dose formulated in a capsule 
in Study BCX7353-101, BCX7353 was rapidly absorbed. Mean plasma concentrations exceeded 
71 ng/mL by 0.5 to 1 hour postdose at doses ranging from 250 to 1000 mg. Administration of a 


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liquid formulation in the current study is expected to achieve target levels earlier. In summary, 
target concentrations of BCX7353 are achievable early in the development of an HAE attack. 
Current treatments for acute attacks of angioedema in HAE patients are administered 
parenterally, and sometimes retreatment is required after a period to time due to a lack of 
symptom relief. The label for Firazyr (icatibant) specifies that patients should administer 
additional doses every 6 hours if symptoms have not improved, and analysis of the open-label 
extension period of FAST-1 showed that 11.8% of treated attacks required more than one 
injection of Firazyr (icatibant) (Malbran, Riedl et al. 2014). The need for redosing could indicate 
that adequate plasma concentrations of icatibant are not of a sufficient duration to alleviate the 
symptoms of the attack or that a rebound effect is occurring. For an acute treatment, it would be 
advantageous to rapidly achieve plasma concentrations of BCX7353 at levels that lead to potent 
inhibition of plasma kallikrein, and maintain these concentrations above this level for longer than 
6 hours.  
Given that BCX7353 is rapidly absorbed from the gastrointestinal tract and has a long half-life 
(approximately 50 hours after a single dose), it is expected that BCX7353 plasma concentrations 
could be maintained above the target of 71 ng/mL for up to 24 hours with an appropriate dose. 
Following administration of a single 250-mg dose in Study BCX7353-101, BCX7353 was 
rapidly absorbed, and mean plasma concentrations exceeded 71 ng/mL by 1 hour postdose and 
fell below target by 8 hours. After administration of a 500-mg dose, mean BCX7353 plasma 
concentrations exceeded 71 ng/mL after 0.5 hours postdose and remained above that 
concentration through 12 hours. Mean plasma concentrations were above 71 ng/mL at 1 hour 
postdose and remained above this level until the 24-hour time point following administration of 
the 1000-mg dose. In addition, rapid inhibition of plasma kallikrein was observed following a 
single dose of BCX7353 at doses of 250 mg or higher. At doses of 500 and 1000 mg, maximal 
inhibition of plasma kallikrein was sustained through 24 hours postdose.  
The rapid onset and maintenance of kallikrein inhibition with a single dose gives support that 
BCX7353 could be a potent oral option for treatment of acute HAE attacks.  
5.4.1.2. 
Rationale for Proposed Doses 
This study will evaluate the safety and efficacy of a single dose treatment of BCX7353 for an 
acute HAE attack at doses of 750 mg, 500 mg, and 250 mg compared to placebo. The rationale 
for selection of these doses is based upon the safety observed in Study BCX7353-101 and the 
achievement and maintenance of potentially efficacious BCX7353 plasma concentrations. Single 
doses of up to 1000 mg were generally safe and well-tolerated in healthy subjects. 
Gastrointestinal effects were reported more frequently at higher dose levels, although these 
events were predominantly mild. No other dose-related safety concerns were noted, and the 
maximum tolerated dose was not reached in Study BCX7353-101, supporting selection of single 
doses up to 750 mg for clinical evaluation in the current study.  Assuming linear exposure 
between a single 500 mg dose and a 1000 mg dose administered in Study BCX7353-101, the 
AUC0-24  for a single 750 mg dose is predicted to be approximately 4219 ng*h/mL with a Cmax of 
approximately 330 ng/mL. This exposure is expected to be less than the steady-state exposure at 
a 350 mg and 500 mg daily dose as measured in the first in human study (517 ng/mL [Cmax] and 
8230 ng*h/mL [AUCtau] for a 500 mg dose administered for 7 days and 363 ng/mL [Cmax] and 


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5720 ng*h/mL [AUCtau] for a 350 mg dose administered for 14 days). As previously mentioned, 
the doses of BCX7353 imparting this exposure were well-tolerated. 
 
Simulation of plasma drug levels over a range of doses of BCX7353 after single dose 
administration 
Superposition with linear extrapolation was first used to simulate individual plasma 
concentration-time profiles of BCX7353 following single dose administration at dose levels 
ranging from 250 to 750 mg using available pharmacokinetic data from Study BCX7353-101. 
The main purpose of this simulation was to obtain more concentration-time points of BCX7353 
at early times following the dose administration. Simulated mean concentrations (Figure 1) 
facilitated determination of the percentage of theoretical subjects predicted to have 
concentrations over a target concentration of 71 ng/mL at various timepoints postdose (SAS 
Version 9.2 [SAS, USA)], assuming a normal distribution, with 1000 simulations performed at 
each time point for each dose level). These data are presented in Table 2. Following 
administration of a capsule-formulated dose of 750 mg, plasma concentrations are predicted to 
exceed the target concentration of 71 ng/mL within 1.2 hours of dosing in approximately 90% of 
subjects. At this dose, plasma concentrations are predicted to be sustained above 71 ng/mL for 
24 hours, which also provide sustained levels of kallikrein inhibition (Table 3).   
Figure 1. 
Simulated Mean Exposure of BCX7353 over Target Concentration 
 


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Table 2. 
Simulated first time postdose to achieve BCX7353 concentration ≥71 ng/mL 
following single dose administration of 250, 500, and 750 mg BCX7353 
Dose 
(mg) 
Mean time 
(hr) to first 
achieving 
target 
BCX7353 
concentration  
(≥71 ng/mL) 
Estimated percentiles (1st percentile to 99th percentile) of simulated subjects 
(1,000 at each dose level) for time (hr) to first achieving target drug 
concentration (≥71 ng/mL), based on plasma concentrations observed in study 
BCX7353-101 after dosing solid dosage form (powder in capsule) 
p1 
p5 
p10 
p25 
p50 
p75 
p90 
p95 
p99 
250 
1.56 
0.00 
0.20 
0.36 
0.87 
1.56 
2.22 
2.75 
2.99 
3.66 
500 
0.92 
0.00 
0.12 
0.30 
0.59 
0.91 
1.25 
1.56 
1.70 
2.18 
750 
0.76 
0.00 
0.17 
0.29 
0.53 
0.76 
1.02 
1.23 
1.36 
1.56 
 
Table 3. 
Simulated duration of BCX7353 concentrations exceeding target 
concentration of 71ng/mL following single dose administration of 250, 500, 
and 750 mg BCX7353 
Dose 
(mg) 
Mean duration 
(hr) of 
BCX7353 
concentration  
≥ target (71 
ng/mL)  
Estimated percentiles (1st percentile to 99th percentile) of simulated subjects 
(1,000 at each dose level) for duration (hr) at or above the target drug 
concentration (≥71 ng/mL), based on plasma concentrations observed in study 
BCX7353-101 after dosing solid dosage form (powder in capsule) 
p1 
p5 
p10 
p25 
p50 
p75 
p90 
p95 
p99 
250 
4.0 
0.0 
0.2 
1.1 
2.4 
4.1 
5.6 
6.9 
8.0 
9.6 
500 
17.7 
6.3 
9.5 
11.1 
14.2 
17.6 
21.0 
24.0 
24.0 
24.0 
750 
21.2 
12.6 
15.0 
16.5 
18.5 
21.2 
23.8 
24.0 
24.0 
24.0 
 
5.4.2. 
Rationale for Study Design 
This is a Phase 2 study designed to assess the efficacy and safety of single oral doses of 
BCX7353 for the treatment of acute attacks in subjects with Type 1 or Type 2 HAE.  
A dose-ranging design that incorporates sequential testing was chosen to ensure that a treatment 
effect could be demonstrated while allowing exploration of the potential utility of a range of 
doses. Further, evaluating a total of 3 attacks for each subject (1 of which is treated with placebo) 
enhances the ability to detect a treatment effect at each dose. The study allows for initial 
evaluation of the treatment effect during Part 1, the highest planned dose level (750 mg), and 
employs a Haybittle-Peto boundary for detection of drug effect. Treatment effect will be 
measured by comparing BCX7353-treated and placebo-treated attacks, using the proportion of 
subjects with a stable or improved composite visual analogue scale (VAS) of HAE attack 
symptoms at 4 hours postdose. If conducted, a convincing treatment effect will be demonstrated 
if the p value for the comparison crosses the Haybittle-Peto boundary of < 0.001. This treatment 
effect may be estimated beginning when 12 subjects completing the study at the 750-mg dose 


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level and. If the boundary is not crossed, the treatment effect may be re-estimated based on 
cumulative data after data on each additional attack on study are available.  
Given the Cmax levels achieved with the BCX7353 doses proposed in this study and its long 
terminal half-life, a washout period of at least 14 days between treatments is necessary to 
minimize carryover of a previously administered active dose.  
Risk mitigation built into the protocol includes medical assessment of suitability of the attack, 
prohibiting treatment with study drug of any attack involving the throat or mouth, or any 
abdominal attack that has already resulted in vomiting. Lastly, subjects are allowed to self-treat 
with a standard of care attack medication 4 hours after dosing with study drug or sooner if the 
subject feels that the attack is progressing rapidly after administration of study drug.  
A 3-month optional substudy, commencing at the conclusion of the study drug phase of the 
study, is included with the goal to learn more about the progression of untreated attacks and 
those treated with commercially available attack medications. 
5.4.3. 
Study Population Rationale 
The current study is limited to adults of both sexes with HAE. Adolescents and children are 
excluded from participation since the long term benefit/risk profile has not been sufficiently 
characterized in adults. 
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 males and females in this clinical trial to gain an early assessment of 
potential safety and efficacy differences. Based on past and ongoing studies conducted in HAE 
patients, it is anticipated that female subjects will comprise at least 50% of the patient population 
in this study. 
Although there is no evidence of embryofetal developmental toxicity with BCX7353 in 
reproductive toxicology studies, appropriate precautions are still warranted with respect to 
administering BCX7353 to women of reproductive age, in accordance with International 
Conference on Harmonization) ICH guidelines. Women of childbearing potential may be 
enrolled in this trial provided they meet the contraceptive requirements and have negative 
pregnancy tests prior to receiving each dose of study drug. 
As BCX7353 is early in clinical development, the benefit/risk profile has not been sufficiently 
characterized to allow pregnant women to receive BCX7353, therefore pregnant women will be 
excluded from participation. 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. 
5.4.3.1. 
Rationale for Use of Standard of Care Attack Medication 
In the current study, all participants must have access to effective, approved treatments for acute 
attacks of angioedema as part of their routine medical care. Each subject will continue to use 


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their prescribed acute attack medication to treat any acute attacks that do not meet the eligibility 
requirements for treatment in this study. For the protection of the safety of the subjects, subjects 
will not utilize study drug to treat any HAE attack with the symptoms of pain or swelling 
involving the throat or mouth; for these attacks, subjects will be instructed to use their standard 
of care acute attack treatment. Abdominal attacks that have resulted in vomiting may be expected 
to reduce or abrogate absorption of an orally administered drug, and are therefore also restricted 
from study drug treatment. For these attacks, subjects will be instructed to use their standard of 
care acute attack treatment. Lastly, subjects who experience progression or do not experience 
improvement of the HAE attack will also be instructed to use their acute attack treatment per 
their standard of care.  
Subjects will be requested to treat early with study drug (within approximately 1 hour of 
symptom onset) and use standard of care, if necessary, no sooner than 4 hours post-study drug 
administration. Requesting a delay in administration of standard of care for 4 hours after 
administration of study drug and maximally 5 hours after the onset of known symptoms is 
necessary for demonstration of a treatment effect of BCX7353 versus placebo and is a reasonable 
request of subjects as part of the protocol for the following reasons: 
1. An HAE attack develops with a worsening of swelling over the first 24 hours with a 
resorption of the edema over the subsequent 48-72 hours. Therefore, four to five hours 
from the onset of symptoms to administration of standard of care attack treatment is 
within a symptom-modifiable timeframe based upon the development of symptoms of 
HAE. 
2. A four to five hour timeframe from the onset of symptoms to administration of standard 
of care attack treatment in the current study is less than the delay in treatment observed in 
pivotal studies of acute attack medications in which treatments were found to be 
efficacious. For instance, in the FAST-3 study of icatibant, the mean (SD) time from 
onset of symptoms to blinded study drug treatment in 43 subjects was 7.07 (3.17) hours; 
in FAST-3, icatibant-treated attacks had a median time to onset of symptom relief of 
2 hours (Lumry, Li et al. 2011).   
 
3. After administration of study drug, subjects may treat an attack with their standard of 
care attack medication before 4 hours post administration of study drug, if they feel that 
the attack symptoms warrant earlier treatment.  
Exclusion of approved kallikrein inhibitor attack prophylaxis with C1 INH is required to clearly 
demonstrate proof of concept of BCX7353. Additionally, use of androgens is prohibited due to 
possible interference of androgen metabolism by CYP3A4 from the inhibitory effect of 
BCX7353, resulting in higher androgen concentrations (see Section 9.7.1).  
5.4.4. 
BCX7353 Risk/Benefit Analysis 
5.4.4.1. 
Risks for Potential Severe Adverse Reactions 
BCX7353 is a small molecule kallikrein inhibitor and given the previous experience with this 
class of agents in man, there is an acceptably low risk of severe adverse reactions, especially 
with two single active doses separated by at least 14 days. Potential risks are outlined below. 


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5.4.4.2. 
Risks of Potential Adverse Events with BCX7353 
Initial toxicology studies in rats and monkeys suggest that the primary target organs of BCX7353 
toxicity were liver (both hepatocyte necrosis and bile duct hyperplasia), kidney, and skeletal 
muscle, with toxicities also observed in cardiac and smooth muscle, and the lymphoid system. 
However, with longer duration of dosing (13 weeks) (albeit with a different drug lot than used in 
the 28-day studies) there were no significant adverse effects noted. In monkeys dosed 
20 mg/kg/day, and for 13 weeks, there were no adverse effects noted. In rats dosed at 
20 mg/kg/day, only bile duct hypertrophy, hyperplasia and vacuolated macrophages in the liver 
were noted and these were not considered adverse. No clinically significant toxicities in these 
organs have been noted during the first in human trial. Mild gastrointestinal symptoms, including 
diarrhea, abdominal pain, and nausea were noted with single doses, particularly at higher doses. 
With multiple days of dosing, similar gastrointestinal effects were seen as well as a delayed 
hypersensitivity drug rash, both occurring in the higher dose cohorts. In addition, at multiple 
dosing with 350 mg and higher, QT prolongation was seen. While the mechanisms of delayed 
hypersensitivity drug rash and QT prolongation following multiple dosing with BCX7353 have 
not yet been elucidated, it is currently considered unlikely that either of these findings will occur 
following administration of single doses of study drug. 
Liver: At 20 mg/kg/day of BCX7353 dosed to rats for 13 weeks, liver bile duct hypertrophy, 
hyperplasia, and vacuolated macrophages were present in the liver with evidence of 
phospholipidosis (PLD) in Kupffer cells on EM. There were no hepatic enzyme or biliary lab 
marker changes and all these effects were reversible as evidenced in the 6-week recovery 
animals. At 25 mg/kg/day of BCX7353 dosed to rats for 28 days, there was minimal to mild bile 
duct degeneration/necrosis and inflammation. At higher doses of 75 mg/kg day, there was 
minimal bile duct hyperplasia, hepatocyte necrosis, and hepatocellular vacuolation that 
correlated to increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) on 
clinical chemistry.  
At 20 mg/kg/day dosed to monkeys for 13 weeks, ALT levels were mildly increased in both 
sexes at Week 4 but demonstrated partial resolution at the terminal collection despite continued 
dosing, lacked correlative microscopic changes in the liver at the terminal necropsy, and were 
normal at the recovery collection. In the previous study where monkeys were dosed for 28 days 
there were enlarged hepatocytes with foamy to large cytoplasmic vacuoles and hyperplasia of 
oval cells at 100 mg/kg/day. Hepatocellular necrosis was noted at 30 mg/kg/day, but only those 
effects at 100 mg/kg/day were considered adverse. These changes also correlated with increased 
transaminases on clinical chemistry. In addition, monkeys had mild decreases in albumin and 
mild increases in globulin levels at 100 mg/kg/day.  
Liver enzymes, bilirubin, gamma-glutamyltransferase (GGT) and alkaline phosphatase are being 
followed closely in clinical trials to monitor for any hepatocellular and biliary system changes. 
There have been no clinically significant abnormalities observed in any of these analytes during 
the completed and unblinded Phase 1 studies. In the 68 subjects treated with BCX7353 for 7 to 
14 days, the highest ALT (104 IU/L) and AST (48 IU/L) occurred on Day 14 in 1 subject who 
was in the 350 mg × 14-day cohort. There was no evidence of any clinically significant 
abnormality in hepatic synthetic function as monitored by prothrombin time, albumin, and total 
protein levels in blood. 


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Liver function will be monitored after each dose administered in this study, although no toxicity is 
anticipated from single doses of study drug, separated by 14 days at a minimum. 
Kidney: Although there was no evidence for any renal injury in the 13-week studies in either rats 
or monkeys, in the 28-day studies both rats and monkeys had renal tubular degeneration/ 
regeneration with vacuolated cells, which was adverse at 75 mg/kg/day for rats and 100 
mg/kg/day for monkeys. This appeared to correlate to glycosuria noted in the 28-day monkey 
study. In addition, female monkeys had significant mononuclear infiltration resulting in a 35% 
increase in kidney weight from controls at 100 mg/kg/day. 
In the Phase 1 trials, no clinically significant abnormalities of renal function, as measured by 
serum creatinine and creatinine clearance have been found. Additional measurements to date of 
renal injury were also performed; serial evaluations of spot urine microalbumin to creatinine 
ratio, a marker for glomerular injury, and neutrophil gelatinase–associated lipocalin (NGAL), a 
novel marker for tubular injury, did not demonstrate any evidence of renal injury. 
Renal assessments including creatinine and urine microalbumin will be assessed after each dose 
of study drug administered in this study, although no toxicity is anticipated from single doses of 
study drug, separated by 14 days at a minimum.  
Skeletal muscle: Although there was no evidence for any skeletal muscle injury in the 13-week 
studies in either rats or monkeys, in the 28-day studies both rats and monkeys had 
degeneration/necrosis and/or regeneration noted in multiple skeletal muscle groups. In the rat, 
these changes were also noted in cardiac muscle. Both the skeletal and cardiac muscle changes 
were adverse at 75 mg/kg/day in rats. The skeletal muscle changes were adverse in the monkey 
at 100 mg/kg/day. The muscle degeneration was suspected to contribute to the elevated AST on 
serum chemistry.  
In the Phase 1 trials neither AST nor creatine phosphokinase (CPK) demonstrated any clinically 
significant elevations. All CPK changes were associated with muscular exertions. In addition, no 
subjects have experienced any AEs of potential muscular injury. 
Given the preclinical data, AST and CPK will be monitored after each dose of study drug 
administered in this study, although no toxicity is anticipated from single doses of study drug, 
separated by 14 days at a minimum. 
Heart: Although there was no evidence for any cardiac muscle injury in the 13-week studies in 
either rats or monkeys, in the 28-day study in rats, degeneration/necrosis and/or regeneration 
were noted in cardiac muscle and was considered adverse at 75 mg/kg/day. At high doses of 
BCX7353, monkeys did have decreases in blood pressure and heart rate, with corresponding 
ECG changes consisting of slowing of the heart rate and lengthening of the RR, QT and QTc 
intervals and QRS duration.  
In addition to cardiac muscle changes and physiologic changes in heart rate and blood pressure, 
it should be noted that there is a small risk of hERG channel inhibition, although the cardiac 
action potential was not prolonged.  
In the Phase 1 study BCX7353-101 study, no single ECG in subjects dosed with BCX7353 had a 
clinically significant abnormality. All QRS intervals were < 120 msec. There was a small but 
discernible QT prolongation seen only with multiple day dosing at doses higher than 250 mg; no 
QT prolongations were noted following single doses of BCX7353 up to 1000 mg. After multiple 


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daily doses, there was a dose-dependent increase in QTcF evident at 350 mg QD and higher in 
Western subjects and at 250 mg QD in Japanese subjects, and a concentration-dependent 
increase that was not predicted by analysis of QTcF data for single high doses that produced 
overlapping BCX7353 concentrations. No subject dosed in this study had an absolute QTcF 
value > 448 msec or change from baseline > 37 msec. There were 9 subjects in the entire trial 
with 21 events of QTcF change from baseline > 30 msec. The majority (16/21) of events 
occurred in 4 subjects after 7 days of dosing with 500 mg. The rest of the events occurred in 
5 subjects at lower doses at a single timepoint. In summary, these data indicate that the change 
observed with multiple doses is not likely to be clinically significant in any population with 
normal QTcF and no underlying cardiac conductivity issues, even at a supratherapeutic daily 
doses such as 500 mg QD. 
Troponin T values were normal at all time points in all Phase 1 subjects. One subject in the 
single-dose 1000-mg group had a transient elevation in Troponin I on Day 2 to 0.06 µg/L 
(ULN = 0.04 µg/L) that returned to within normal limits on Day 4 and remained < 0.01 µg/L 
through follow-up. The subject was clinically asymptomatic, had no Troponin T or CK-MB 
elevations, and had no ECG evidence of ischemia.  
Six subjects treated with BCX7353 in the Phase 1 study BCX7353-101 study had treatment 
emergent elevations from baseline of CK-MB, 2 receiving single doses of 100 mg,2 subjects 
receiving 250 mg for 7 days, 1 subject receiving 500 mg for 7 days and 1 subject receiving 
350 mg for 14 days. In 5 of the 6 subjects this corresponded to elevated CK ranging from 1.3 to 
7.6 × ULN. In addition, 3 of these 5 subjects had elevated CK-MB at baseline. None of these 
subjects had an elevation of Troponin I or Troponin T or any evidence of ischemia or cardiac 
muscle damage. In all cases this was noted at the follow-up visit after sequestration was 
complete. In 1 subject receiving 350 mg for 14 days, the CK-MB was elevated to 6.5 µg/L 
(normal range = 0.0–2.9 µg/L) at the follow-up visit which was not due to an abnormal CK level. 
This subject had an elevated CK-MB at baseline of 4.0 µg/L, which improved during study drug 
dosing. All other labs were normal at the follow-up visit. In particular, Troponin I and Troponin 
T were normal and there was no evidence of cardiac ischemia. It is unclear why the CK-MB was 
elevated in this subject but cardiac ischemia is unlikely. No significant ECG or laboratory 
changes were seen in BXC7353-102 study. 
As a precaution, this study will exclude subjects with evidence of cardiac disease as indicated by 
medical history, family history of sudden death or abnormal screening ECG. ECGs, troponin and 
CK-MB will be regularly monitored in this study. No cardiac toxicity or QT prolongation is 
anticipated from single doses of study drug, separated by 14 days at a minimum.  
Lymphoid system: Although there was no evidence for any lymphoid system abnormalities in 
the 13 week studies in either rats or monkeys, in the rat 28-day study lymphoid depletion was 
noted in the thymus and spleen at 75 mg/kg/day. In contrast, the monkeys generally had 
hyperplastic lymphoid tissue (spleen and lymph nodes) which was not considered adverse.  
In the Phase 1 studies, no clinically significant changes in any hematologic parameter or 
lymphoid tissue were noted. No organomegaly and no lymphadnopathy were noted on physical 
exam.  
In this study, complete blood counts and general physical examinations will be monitored after 
each dose of study drug administered. 


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Presumed Phospholipidosis (PLD):  
In the 28 day studies in both rats and monkeys, foamy macrophages and vacuolated infiltrates 
were found in multiple organs and various tissues, and presumed to be signs of PLD. PLD can 
only be confirmed with electron microscopy which was not done in the 28 day study. In most 
tissues, these infiltrates did not appear to be adverse and there were no clinical or blood 
chemistry findings that correlated. Importantly, the infiltrates were fully or partially reversible in 
both species. The partial reversibility in monkeys may have been due to the continued presence 
of BCX7353 in plasma even at Day 50 of the 28-day dosing study. 
In the 13-week studies in rats, the liver showed vacuolated macrophages with electron 
microscopic features consistent with PLD. In the monkey 13-week study there were no 
microscopic abnormalities, and no foamy macrophages or vacuolated cellular infiltrates were 
observed. Increased urinary levels of di-docosahexaenoyl (22:6)-Bis(mono)acylglycerol 
phosphate (BMP), an investigational biomarker for PLD, were demonstrated in both rats and 
monkeys dosed with BCX7353 for 13 weeks. This increase was dose related and reversible upon 
cessation of BCX7353 in both species. These data suggest that the urinary BMP changes induced 
by BCX7353 in both rats and monkeys may not be associated with PLD, given the differences 
seen microscopically between the two species.   
PLD is not adverse in and of itself and there are many approved products that cause this 
phenomenon without any unmanageable toxicities. Since PLD requires accumulation of drug, it 
is highly unlikely that subjects are at any risk of this phenomenon with individual doses of study 
drug, separated by at least 14 days at a minimum. The primary method of ensuring subject safety 
will be to monitor organ toxicity and subject well-being through adverse event reporting and 
vital signs including weight.  Since phospholipidosis is not toxic in and of itself, organ health 
including function and signs of inflammation will be monitored. Monitoring of renal, liver, 
cardiac, and muscle health will be achieved with routine safety assessments, including ECGs.  
Gastrointestinal (GI) symptoms: Gastrointestinal symptoms, all mild, were noted in half of the 
subjects receiving a single 1000 mg single dose in the Phase 1 BCX7353-101 study. The events 
were both upper GI (nausea, dyspepsia, and vomiting) and lower GI (diarrhea). The events 
resolved without treatment. No pertinent GI events occurred in the 500 mg single dose cohort but 
2 subjects reported GI symptoms at 100 mg.  During multiple day dosing (part 2), all cohorts 
experienced GI symptoms when BCX7353 was given over 7 to 14 days. Symptoms were 
primarily lower gastrointestinal (diarrhea and flatulence) at 500 mg QD × 7 days and primarily 
upper gastrointestinal (abdominal pain, dyspepsia) at 350 mg QD × 14 days without any 
pertinent laboratory or physical exam findings. In the Japanese 250 mg × 7-day cohort, a single 
subject had abdominal pain. All subjects reporting these events took study drug in a fasting state. 
Two subjects discontinued study drug, one after a single 500-mg dose of BCX7353 due to 
diarrhea and abdominal pain, and one after 10 days of 350 mg BCX7353 due to abdominal pain. 
Neither subject had any clinically significant laboratory abnormalities. The Phase 1 study 
demonstrated no adverse impact on the extent of drug exposure from taking BCX7353 with food 
in 6 subjects who received a dose of BCX7353 (250 mg) under fed and fasting conditions. 
However, the time to achieve maximal blood concentrations was delayed when BCX7353 was 
administered with food (median Tmax increased from 2 to 5 hours, with 4 of 6 subjects 
experiencing a delay in Tmax with food relative to fasting). Therefore, since food may materially 
delay achievement of effective blood levels and the gastrointestinal effects to date have been a 


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tolerability issue but not a safety issue, BCX7353 is recommended to be taken without food and 
to delay food at least one hour (to allow for gastric emptying). However, due to the 
unpredictability of onset and location of HAE attacks, recent food intake will not necessarily 
prohibit an attack from being approved for treatment with study drug in this study. The time of 
the last meal prior to the attack will be captured to assess whether recent food ingestion prior to 
an attack may affect efficacy.  
Subject well-being with respect to possible gastrointestinal symptoms will be monitored through 
adverse event reporting and laboratory assessment. 
Drug rash: A benign maculopapular exanthema consistent with a delayed type drug rash has been 
seen in 3 subjects taking multiple doses of BCX7353 to date. In Studies BCX7353-101 and 
BCX7353-102, a total population of BCX7353 exposed subjects who have received at least 7 
days of BCX7353 doses is 68, equating to an incidence rate of 4.4%.  In all cases, symptoms 
were observed or reported approximately 2 days after daily BCX7353 dosing ended: one subject 
who completed 500 mg QD BCX7353 x 7 days (Study BCX7353-101), one subject of Japanese 
heritage who completed 250 mg QD BCX7353 x 7 days (Study BCX7353-101), and one subject 
who recently completed 9 days of BCX7353 350 mg QD (Study BCX7353-102). In all cases, no 
systemic or constitutional symptoms, no organ involvement, no desquamation or mucosal 
involvement was observed, no clinically significant laboratory abnormities were present and the 
rash rapidly resolved. Two subjects received an oral antihistamine and 1 subject received oral 
and topical steroids. 
Hypersensitivity is a risk with any drug. In all three cases, the rashes have been limited and 
resolved quickly. Subjects should report any rashes, pruritus, or skin changes. Evaluation of any 
suspected drug-induced rash will be required with high resolution photography and clinical 
laboratory assessments in order to better define this risk; skin biopsy of a fresh lesion should be 
obtained for histopathologic examination, where possible. The management of rash is 
specifically addressed in Section 11.1.11. It is unknown if repeat exposure of single doses will 
result in hypersensitivity. 
5.4.5. 
Benefits of Trial Participation 
Study subjects will receive regular medical care for the duration of the study. Subjects may 
experience a resolution in their acute attacks after receiving active study drug; however, subjects 
will be blinded to their treatment sequence so they will not know if they are receiving BCX7353 
or placebo for any given treated attack.  
The development of BCX7353 may be of benefit to the wider community/patients with HAE.  
5.4.6. 
Overall Benefit-Risk Assessment 
The risks seen to date in both preclinical and clinical studies at the study doses were primarily 
mild, monitorable, and reversible. Although there may be no direct benefit to any individual 
subject, the information obtained from this study will support the development of BCX7353 for 
treatment of acute attacks in patients with HAE, a life-threatening disease. The overall risk 
benefit balance is therefore considered to be acceptable. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Objectives 
The primary objective of this study is as follows:  
• To evaluate the efficacy of single oral doses of BCX7353 in treating acute attacks in 
subjects with HAE  
The secondary objectives of this study are as follows:  
• To evaluate the safety and tolerability of single oral doses of BCX7353 in subjects 
with HAE 
• To evaluate the relationship of BCX7353 dose with clinical responses 
• To evaluate subject satisfaction with BCX7353 treatment 
• Substudy: to describe the natural history and temporal pattern of symptoms of 
untreated attacks and those treated with commercially available attack medications 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design  
This is a 3-part, Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to 
evaluate the efficacy and safety of single oral doses of a liquid formulation of BCX7353 in the 
treatment of acute HAE attacks. All subjects enrolled will receive both active and placebo 
blinded study drug in a randomized sequence. Part 1 of the study will evaluate single doses of 
BCX7353 750 mg; Part 2 will evaluate single doses of BCX7353 500 mg and Part 3 will 
evaluate single doses of BCX7353 250 mg.  
HAE patients with a documented recent history of angioedema attacks who have provided 
written informed consent will be evaluated for participation in this study at a screening visit.  
Up to 36 subjects with Type 1 or 2 HAE with a documented history of HAE attacks will be 
sequentially enrolled into Part 1 of the study and randomized to a treatment sequence containing 
the following: 
• Treatment A1: Single oral dose of BCX7353 750 mg  
• Treatment B: Single oral dose of placebo 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single 
oral doses of BCX7353 500 mg in Part 2; or Treatment A3 = single oral doses of BCX7353 
250 mg in Part 3. 
Initially in Part 1, 12 subjects will be randomized 1:1:1 to 1 of 3 treatment sequences 
(n = 4 subjects per treatment sequence): 
• Sequence 1:  ABA 
• Sequence 2:  BAA 
• Sequence 3:  AAB 
Both subjects and site staff will be blinded to which treatment sequence a subject is randomized 
to receive. 
If required, additional subjects will be enrolled into Part 1 (see below) using the same 1:1:1 ratio 
for the 3 treatment sequences, with a maximum total number of 36 subjects for Part 1. 
Part 2 will evaluate a dose of 500 mg (Treatment A2) and placebo (Treatment B). A maximum of 
12 subjects will be enrolled, using the same 1:1:1 ratio for the 3 sequences. Part 3 will evaluate a 
dose of 250 mg (Treatment A3) and will enroll a maximum of 12 subjects in a 1:1:1 ratio for 
each of the 3 treatment sequences.  
If tolerability issues prevent enrollment of Part 1 as described, additional subjects in Part 1 may 
be dosed with active study drug at a dose of 500 mg. If the Part 1 dose is reduced and at least 
12 subjects are treated with an active study drug dose of 500 mg, a 250 mg active dose may be 
assessed in Part 2. Any further dose level changes warranted for Part 2 and Part 3 will be 
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The overall study design is presented in Figure 2. 
Figure 2.  
Study Design Through Follow-up (Post-Attack 3 Visit) 
    Screening                          Study Drug Treatment                  Follow-Up 
Sequence 1: A1, B, A1
Randomize 1:1:1
n = 36 (Part 1)
n = 12 (Parts 2 and 3)
Sequence 2: B, A1, A1
Sequence 3: A1, A1, B
A1 = BCX7353 750 mg x1 (Part 1) 
A2 = BCX7353 500 mg x1 (Part 2)
A3 = BCX7353 250 mg x1 (Part 3)
B  = Placebo x1
 
7.1.1. 
Enrollment and Analyses 
Up to 36 subjects will be enrolled in Part 1. Upon full enrollment, enrollment into Part 2 of the 
study (maximum of 12 subjects) may immediately commence. Likewise, Part 3 (n = up to 12) 
may immediately commence upon enrollment of Part 2. 
Following the 12th subject completing Part 1, the treatment effect may be estimated. The 
predefined endpoint, determined by the Haybittle-Peto method, is the proportion of subjects with 
a stable or improved composite VAS at 4 hours postdose of an HAE attack. A Haybittle-Peto 
boundary of p < 0.001 is considered clinically significant. 
If the Haybittle-Peto analysis is run and the boundary is not crossed with 12 subjects, the 
treatment effect may be re-estimated with cumulative data after each treated attack in accordance 
with the fully sequential analysis method. At each evaluation, the treatment effect may be 
assessed using the Haybittle-Peto boundary (p < 0.001).  
Alternatively, if the boundary is not crossed with 24 subjects enrolled or the Heybittle-Peto 
analyses are not performed, treatment differences may be assessed using available data in Parts 
1, 2 and 3 in order to plan subsequent studies. 
7.1.2. 
Study Conduct Overview 
At the Screening visit, potential subjects will be given a diary and receive instruction on the 
correct completion of the diary in real-time to record attack symptoms and severity and any 
medication usage during an attack. During the 35-day screening period, subjects will be required 
to: 1) phone the on-call Investigator (or designee) at the onset of pain or swelling associated with 
an HAE attack; 2) complete details in real time of this HAE attack; and 3) phone the on-call 
Investigator (or designee) again in at least 4 hours time.  Completion of these procedures will 
confirm that the subject is able and competent to perform on-study requirements in early 
identification of an attack and treating and documenting an HAE attack.  
Eligible subjects will return to the clinic to attend a Baseline visit. At the conclusion of the 
Baseline visit, subjects will receive their first (single) randomized dose of study drug for 
treatment of attacks by self-administration. The IMP is supplied as a powder form of drug in a 
bottle that will require reconstitution to a liquid formulation with vehicle, by the subject, prior to 
self-administration. 


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At the Baseline visit, all subjects will be instructed on how to prepare and use study drug to treat 
a protocol-qualified HAE attack and will receive further instruction on the correct completion of 
a diary in real-time immediately prior to and after study drug administration.  
Specifically, subjects will be instructed with respect to treatment of attacks with study drug by 
self-administration as follows: 
1. At the first symptom of swelling or pain known to be associated with a potentially 
protocol-qualified attack, the subject will phone their on-call study Investigator (or 
designee) who will review the subject’s symptoms by phone. The Investigator will 
confirm that their symptoms constitute an acute attack that qualifies for treatment with 
study drug.  
Protocol-qualified attacks approved for study drug treatment must meet all of the 
following: 
• have pain and/or swelling associated with an HAE attack reported as a symptom 
• subject has contacted Investigator within approximately 1 hour of onset time of 
HAE pain and/or swelling  
• not involve pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant) without delay. 
• not be an abdominal attack that has already resulted in vomiting. Such attacks 
should be treated using the subject’s standard of care acute attack treatment (e.g., 
C1 INH, icatibant). 
• have an identifiable onset time, with the exception that abdominal attacks with an 
onset during sleep may be permitted for study drug treatment. Onset time for 
abdominal attacks will be time the subject woke up with symptoms. Peripheral 
attacks starting with an onset during sleep will not be approvable for study drug 
treatment. 
• occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor 
antagonist (i.e. Firazyr) OR treated with human recombinant C1 INH (i.e. 
Ruconest) OR any non-targeted therapy (i.e. pain medication, anti-spasmodic, 
anti-emetic, tranexamic acid) OR was not treated with any medication: new 
attack can be treated with IMP if has been 48 hours since the complete 
resolution of all symptoms of the previous HAE attack AND the Investigator 
believes it is a new (de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH 
(i.e. Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent 
detergent plasma): new attack can be treated with IMP if it has been 96 hours 
since the complete resolution of all symptoms of the previous HAE attack 
• occur at least 96 hours after complete recovery from a procedure or injury  


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• occur at least 14 days from a previous dose of study drug 
2. Only after receiving confirmation by the on-call Investigator (or designee) should a 
subject reconstitute study drug with vehicle and take it to treat the HAE attack.  
Reconstitution and ingestion of the study drug should occur almost immediately (within 
5 minutes) following the phone call, with the goal for subjects to take study drug within 
approximately one hour of the onset of symptoms. 
3. At 4 hours post study drug intake, subjects who are not experiencing improvement or 
who are experiencing progression of the HAE attack can use their standard of care acute 
attack treatment, if warranted. However, if the subject feels that an attack is progressing 
rapidly after administration of study drug or intraoral symptoms develop, the subject 
may treat the attack with their standard of care attack medication prior to 4 hours.  
4. The subject will call the on-call study Investigator (or designee) at least 4 hours after 
taking study medication (or earlier if they have any concerns over the course of their 
symptoms) to review their response to study drug and diary completion. The on-call 
study Investigator (or designee) will call the subject if they have not heard from the 
subject within 5 hours of their initial phone call. Subjects who did not require standard 
of care at 4 hours will be reminded at the telephone call, by the Investigator, that they 
may use standard of care at any time point at their own discretion if not experiencing 
improvement or if they are experiencing progression of the HAE attack. An exception to 
the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours 
post-study medication. In this case, the subject will be required to call the on-call 
Investigator (or designee) upon waking.  
Subjects will complete a diary questionnaire and a 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling immediately prior to study drug 
administration and at 1, 2, 3, 4, approximately 8 and at 24 hours after study drug administration. 
Subjects sleeping during these timepoints (see #4 exception above) will be required to complete 
the diary questionnaire upon waking. Subjects will also be asked to track the start and stop times 
of any attacks not treated with study drug that occur after the baseline visit through the last study 
visit (Post-Attack 3 visit). 
At each clinic visit following treatment of an attack with study drug, the diary will be reviewed. 
Any re-education required to ensure correct diary completion will be performed and safety 
assessments will be completed. At Post-Attack 1 and Post-Attack 2 clinic visits, the subject will 
be dispensed their next randomized dose of study drug and a new attack diary. Completed diaries 
will be collected at each visit to avoid subjects referencing back to previous attack entries.   
Each subject will continue on study to treat 3 protocol-qualifying attacks with study drug. Clinic 
visits will be scheduled 10 to 14 days after each attack that is treated with study drug. Any 
additional attacks that occur in the intervening periods between study visits may be treated 
according to standard of care for the subject. 
Sites must attempt to contact subjects every 7 days from the last clinic visit to inquire about the 
occurrence of an attack if the subject has not contacted the site during this timeframe.  


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Subjects will be asked to participate in an optional observational substudy to obtain diary data on 
all HAE attacks, commencing from the Post-Attack 3 visit.  Consenting subjects will receive a 
diary and instruction for completion at the Post-Attack 3 visit. For the next 12 weeks, subjects 
will complete diaries provided on an as-needed basis with periodic subject contact to ensure 
adherence with diary completion. 
7.2. 
Endpoints 
7.2.1. 
Efficacy Endpoints 
The efficacy endpoints of this study are as follows: 
• Proportion of subject attacks with an improved or stable 3-symptom composite VAS 
score at 4 hours post-dose. The 3-symptom composite will be calculated as the 
average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject 
is considered improved or stable if the change from baseline (time of drug 
administration) in VAS is less than or equal to 0 
• Proportion of subject attacks with a patient global assessment of improved or stable 
symptoms at 4 hours post-dose   
• Proportion of subject attacks with no symptoms or mild symptoms of an HAE attack 
at 4 hours post-dose 
• Proportion of subject attacks requiring standard of care attack treatment through 
24 hours post-dose 
• Time to use of standard of care acute attack treatment through 24 hours post-dose 
• Time to stable or improved symptoms by composite VAS score through 24 hours 
post-dose 
• Time to symptom relief (first documented time point when a subject experiences a 
50% reduction in the 3-symptom composite VAS from the pretreatment composite 
score) 
• Time to almost complete symptom relief (first documented time point when a subject 
records a VAS score < 10 mm in the 3-symptom composite VAS score) 
• Time to initial symptom relief (time from ingestion of study medication to report that 
the worst symptoms of the attack are over) 
• Time to complete symptom relief (time from ingestion of study medication to no 
HAE attack symptoms) 
7.2.2. 
Safety Endpoints 
Safety endpoints will include the number and proportion of subjects who: discontinue due to a 
treatment-emergent AE; experience a treatment-emergent SAE; experience a Grade 3 or 4 
treatment-emergent AE; and experience a treatment emergent Grade 3 or 4 laboratory 
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7.2.3. 
Other Secondary Endpoints 
Other secondary endpoints will include treatment satisfaction, as assessed by the TSQM. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Subjects 
Up to 36 evaluable subjects with Type 1 or 2 HAE are planned to be enrolled in Part 1, up to 
12 evaluable subjects in Part 2, and up to 12 evaluable subjects in Part 3. An evaluable subject is 
one who treats 3 attacks with study drug and for which there is diary information recorded for 
each treated attack.  
Subjects who complete Part 1 will not be eligible to participate in Parts 2 or 3. Likewise, subjects 
who complete Part 2 will not be permitted to participate in Part 3. 
Subjects who prematurely withdraw from the study may be replaced at the Sponsor’s discretion. 
Any subject who has withdrawn from the study as a result of a treatment-emergent AE 
(regardless of severity or causality) may not be replaced. 
The following inclusion and exclusion criteria will be used to screen subjects for 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. Able to provide written, informed consent 
2.  Males and non-pregnant, non-lactating females age 18 to 70 years 
3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined having a C1 
INH functional level below 50% of normal and a C4 level below the lower limit of the 
normal reference range, as assessed at the Screening visit. 
Should the C4 level be within the normal range, as is the case in a small percentage of 
subjects with HAE, C4 may be drawn during an attack for re-testing or the SERPING-1 
gene may be analyzed for a known mutation associated with HAE Types 1 or 2. Either 
will be considered confirmation of eligibility. 
4. Access to and ability to use standard of care acute attack treatment. Standard of care 
acute attack treatment is defined as a medication approved by the relevant competent 
authority for the treatment of attacks of HAE (e.g., icatibant, ecallantide, plasma-derived 
C1INH, recombinant C1INH). 
5. Female participants must meet at least 1 of the following requirements: 
a. Be a woman of childbearing potential (defined as a nonmenopausal female who 
has not had a hysterectomy, bilateral oophorectomy, or documented ovarian 
failure) who agrees to use an acceptable effective contraceptive method during the 
study and for a duration of 30 days after last dose of study drug. One or more of 
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 surgical sterilization (i.e., bilateral tubal ligation or vasectomy of male 
partner) 
 placement of an intrauterine device (IUD) or intrauterine system (IUS) 
(implanted any time prior to or during screening) 
 progesterone-only (implantable or injectable only) hormonal 
contraception associated with inhibition of ovulation, initiated at least 
60 days prior to the screening visit 
 male or female condom with or without spermicide 
 use of an occlusive cap [diaphragm, or cervical/vault caps] with 
spermicide (foam/gel/film/cream/suppository) 
Female subjects who report being postmenopausal for ≤ 2 years and have a 
screening follicle-stimulating hormone (FSH) ≤ 40 mIU/mL must agree to use an 
acceptable effective contraceptive method (as defined 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 a screening FSH > 40 mIU/mL if postmenopausal ≤ 2 years or have 
had a hysterectomy, bilateral oophorectomy, or documented ovarian failure). 
c. Be a woman declaring herself as either sexually abstinent or exclusively having 
female sexual partners. Abstinence in this study is defined as "true abstinence: 
when this is in line with the preferred and usual lifestyle of the subject."  
6. Male participants must comply with the following requirements through the end of the 
study: 
a. Subjects with female partners of childbearing potential (defined as 
postmenopausal ≤ 2 years or a nonmenopausal female who has not had a 
hysterectomy, bilateral oophorectomy, or documented ovarian failure) must agree 
to utilize an acceptable effective contraceptive method. At least 1 or more of the 
following methods are acceptable:  
 surgical sterilization (ie, vasectomy or bilateral tubal ligation of a 
female partner) 
 partner’s placement of an IUD or IUS 
 partner’s use of any form of hormonal contraception that is associated 
with inhibition of ovulation (oral, injectable, intravaginal, implantable 
or transdermal) 
 use of a condom with or without spermicidal 
foam/gel/film/cream/suppository 
 partner’s use of an occlusive cap [diaphragm, or cervical/vault caps] 
with spermicidal (foam/gel/film/cream/suppository) 
b. Male subjects who declare themselves as sexually abstinent or exclusively having 
male sexual partners are acceptable for the purposes of this study. Abstinence in 


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this study is defined as “true abstinence: when this is in line with the preferred 
and usual lifestyle of the subject.”  
7. Any regularly administered concomitant medication recorded at the Screening visit and 
not stated as prohibited must be anticipated to be continued through the entire study and 
be of a stable dose and regimen for the duration of the entire study (screening through 
follow-up). 
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. To be dispensed study drug at 
baseline, the subject must demonstrate adequate compliance with all study procedures 
required from the Screening visit through randomization, including phoning the 
investigator and diary recording of at least one HAE attack during the screening period. 
9. Must have an HAE attack rate of at least 1 unique attack per month for 3 months (up to 
93 days) within the 4 months prior to the Screening visit. A unique attack is defined as 
an attack that is not recorded on contiguous days to another attack. For the purposes of 
this protocol, two attacks that are recorded on contiguous days are one attack with an 
onset day/time of the first attack. 
Any of the following will be acceptable source records of HAE attacks: clinic notes with 
a numerical rate of attacks, acute attack medicine administration records, or a 
historically-completed subject record of attacks. This record should indicate the dates of 
attacks, at a minimum.  
8.2.2. 
Exclusion Criteria 
Subjects must meet none of the following exclusion criteria to be eligible for participation in this 
study: 
1. No HAE attack reported to the on-call Investigator (or designee) during the 35-day 
screening period. 
2. 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 increase the risk of participation for that subject.   
3. 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. 
4. 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, a PR > 220 
msec (both sexes), or ventricular and/or atrial premature contractions that are more 
frequent than occasional, and/or as couplets or higher in grouping. 
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any 
other clinically significant cardiovascular abnormality such as poorly controlled 
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6. Known family history of sudden cardiac death from causes other than HAE. Family 
history of sudden death from HAE is not exclusionary. 
7. History of or current implanted defibrillator or pacemaker. 
8. Any laboratory parameter at screening that, in the opinion of the Investigator, is 
clinically significant and relevant for this study. A calculated creatinine clearance of 
≤ 60 mL/min or AST or ALT value ≥ 2 times the upper limit of the normal reference 
range value obtained during screening is exclusionary. 
9. Suspected C1 INH resistance in the opinion of the Investigator and Sponsor. 
10. 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). 
11. Positive serology for human immunodeficiency virus (HIV) or active infection with 
hepatitis B virus (HBV) or hepatitis C virus (HCV). 
12. Pregnant, planning to become pregnant within 30 days of the study, or nursing. 
13. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a 
prescription). 
14. History of severe hypersensitivity to any medicinal product, which was associated with 
swelling, a severe rash requiring treatment/hospitalization, or anaphylaxis. 
15. Hypersensitivity reaction to BCX7353.  
16. Use of tranexamic acid, androgens or C1 INH for prophylaxis of HAE attacks within the 
7 days prior to the Screening visit or initiation during the study. Use of a C1 INH 
therapy for treatment of attacks is not excluded at any time, nor is C1 INH for pre-
procedure prophylaxis. 
17. 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. For the purpose of this protocol, these include, but 
are not limited to the following: warfarin, phenytoin, s-mephenytoin, thioridazine, 
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfenadine and desogestrel. 
18. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study.  
19. 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 baseline 
or initiation during the study. 
20. Current participation in any other investigational drug study or received another 
investigational drug within 30 days of the Screening visit. 
21. An immediate family relationship to either Sponsor employees, the Investigator or 
employees of the study site named on the delegation log. 
Medications prohibited for use during the study are addressed in Section 9.7.1. 


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8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Subject Discontinuation from 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 prior to study 
completion will be requested to attend an early termination visit to complete all end-of-study 
evaluations. In all cases, the reason for withdrawal from the study must be recorded in the 
subject’s medical records (source documents) and also in the electronic case report form (eCRF). 
If at any point in the study the clinic is unable to contact the subject after appropriate attempts 
have been made according to local clinic standards, the subject will be considered to have 
withdrawn consent. 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.   
Once subjects have discontinued 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 their treating physician and according to the accepted standard of 
care. 
8.3.2. 
Subject Discontinuation from Study Drug 
A subject will be withdrawn from study drug for any of the following bulleted reasons, which 
will be recorded in the source documents and eCRF. In all cases, subjects who discontinue study 
drug will be requested to complete an Early Termination visit and all procedures as outlined in 
Section 10.3.5. 
• 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 
degree 
• Subsequent determination that inclusion/exclusion criteria were not met 
• 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 due to an altered risk/benefit profile 
• Subject noncompliance with study drug or to the protocol 
• Discontinuation at the request of the Sponsor, competent authorities in the Member 
State(s) concerned, or the institutional review board (IRB)/independent ethics 
committee (IEC)  
• Criteria outlined in Sections 8.3.2.1 and 8.3.2.2. 
8.3.2.1. 
Discontinuation Due to QT Prolongation 
Any subject will be discontinued from further dosing if the following QTcF criteria are met: 
• The subject has a QTcF > 500 msec (confirmed on repeat testing) 
or  


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• The subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
from the value obtained predose at baseline 
8.3.2.2. 
Discontinuation Due to Rash 
All subjects with a suspected drug rash should undergo specific rash evaluation as described in 
Section 11.1.11. Subjects with a study drug related Grade 3 or 4 rash as described by the DMID 
criteria “Skin-mucocutaneous” will be discontinued from study drug and treated according to 
best medical practice. 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 or necrosis requiring surgery 
Subjects with a Grade 1 or 2 study-drug related rash may be continued on BCX7353 if both 
investigator and subject deem it appropriate.  
8.3.2.3. 
   End of Trial Definition 
The end of the trial will be defined as when the last subject completes the Post-Attack 3 visit. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
The study drug or IMP in this study consists of BCX7353 powder and matching placebo powder 
for reconstitution as oral solutions. Subjects will be randomized to 1 of 3 treatment sequences 
and will receive 2 single doses of BCX7353 and 1 single dose of matching placebo: 
• Two single oral doses of BCX7353 750 mg and one oral dose of matching placebo 
(Part 1) 
• Two single oral doses of BCX7353 500 mg and one oral dose of matching placebo 
(Part 2) 
• Two single oral doses of BCX7353 250 mg and one oral dose of matching placebo 
(Part 3) 
The active ingredient for this study is BCX7353. All clinical doses of BCX7353 provided in this 
protocol are in reference to the hydrochloride (HCl) salt. BCX7353 is a white to tan powder. The 
IMP is formulated as a single unit dose drug in a bottle formulation that will be reconstituted 
with an oral vehicle prior to dosing.  The oral vehicle to be used for reconstitution is a 
SyrPalta:Sterile Water for Irrigation solution and is supplied with the IMP. 
The taste-masked placebo for this study is lactose monohydrate which is an off-white powder. 
The IMP is formulated as a single unit dose drug in a bottle formulation that will be reconstituted 
with an oral vehicle prior to dosing. The oral vehicle to be used for reconstitution is a SyrPalta, 
Sterile Water for Irrigation and Bitrex® 0.256%w/v (50ppm) solution and is supplied with the 
IMP. 
Quotient Clinical (Nottingham, UK) will manufacture the IMP.   
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 
Oral vehicle and study drug will each be packaged in appropriately sized high density 
polyethylene (HDPE) bottles with tamper evident polypropylene lids.  Each kit dispensed to a 
subject will contain one of each bottle.   
Each kit will be labelled with the information required by local law and may include: Sponsor 
name, study protocol number, description of the contents, a statement regarding the 
investigational (clinical trial) use of the study drug, expiry date and/or kit treatment number.   
The IMP will be stored according to the Investigational Medicinal Product Dossier (IMPD).   
Study drug will be stored between 15°C−25°C (room temperature). 


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9.3. 
Blinding and Randomization 
9.3.1. 
Blinding 
This is a double-blind study. As such, study drug treatment sequence will be blinded to the 
Investigator, study staff, study subjects, and clinical research organization (CRO) staff. Sponsor 
employee(s) not regularly interacting with the clinical sites will also be blinded to the treatment 
sequence of individual subjects, with the exception of Sponsor staff responsible for managing 
clinical supplies.  
The project statistician performing the analyses with a Haybittle-Peto boundary for significance 
may become unblinded after the 12th subject completes Part 1. Sponsor employees may be 
unblinded at the same time or at any point thereafter. 
9.3.2. 
Randomization 
Up to 36 subjects will be sequentially enrolled into Part 1 of the study and randomized to receive 
a treatment sequence containing one of the following: 
• Treatment A1: Single oral dose of BCX7353 750 mg (Part 1)  
• Treatment B: Single oral dose of placebo 
Initially in Part 1, 12 subjects will be randomized 1:1:1 to the following treatment sequences 
(n = 4 subjects per treatment sequence): 
• Sequence 1:  ABA 
• Sequence 2:  BAA 
• Sequence 3:  AAB 
Note: Treatment A1 = single oral doses of BCX7353 750 mg in Part 1; Treatment A2 = single 
oral doses of BCX7353 500 mg in Part 2; and Treatment A3 = single oral doses of BCX7353 
250 mg in Part 3. 
A subject will be randomized to a treatment sequence at or prior to the Baseline visit.  
Subject randomization will occur only after the following steps have been completed and 
reviewed by the Sponsor: 
a) The following data is provided to the Sponsor: qualifying historical HAE attack data, 
concomitant and past medications, C1INH function and C4 level (or SERPING-1 
mutation), and the data collected on the HAE medical and medication history form.  
AND 
b) A site-documented screening HAE attack has occurred (i.e., subject phones Investigator 
prior to the attack and approximately 4 hours later) 
For the documented attack, the completed diary does not have to be collected to randomize a 
subject; however, the on-call Investigator (or designee) should ensure the subject has 
competently completed the attack diary. 
Specific details of the randomization and kit shipment processes will be communicated to the 
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Study drug will be dispensed to subjects in a quantity sufficient for the treatment of one acute 
attack. Each subject will be assigned study drug a total of 3 times, which will be dispensed at 
Baseline and at the clinic visits following the first and second attack.  
Information on unblinding in the event of a SAE is provided in Section 12.1.8. 
9.4. 
Study Drug (Investigational Medicinal Product) Reconstitution and 
Administration  
Subjects will take all study drug doses by self-administration after approval from the on-call 
Investigator or designee. After authorization to treat the attack, subjects should reconstitute and 
ingest study drug and the rinse (see below). Reconstitution and ingestion of the study drug 
should occur almost immediately (within 5 minutes) following the phone call, with the goal for 
subjects to take study drug within or approximately one hour of the onset of symptoms. 
To prepare drug to ingest, subjects should reconstitute their study drug by pouring the entire 
contents of the vehicle (liquid) into the bottle containing the powder. The bottle containing the 
liquid and powder should be recapped and shaken vigorously for at least 15 seconds. After 
drinking the entire volume of the reconstituted study drug, subjects will rinse the bottle with 
water (not provided in the study drug kit) by shaking for 5 seconds and ingest the rinse. To the 
extent possible, the entire dose of study drug plus the rinse should be taken within 5 minutes 
from the time of reconstitution. 
Where practical, study drug is recommended to be taken without food and to delay food at least 
one hour (to allow for gastric emptying).  If the subject desires to further cleanse their pallet after 
ingesting the water rinse, hard candy, mouthwash, tongue or teeth brushing or chewing gum is 
recommended. Further instructions on subject preparation of study drug will be provided. 
9.5. 
Study Drug Dose Modification 
Subjects will be instructed to take the entire study drug dose as indicated by the protocol.   
If tolerability issues prevent enrollment of Part 1 at the 750 mg dose, the Sponsor may reduce the 
dose of study drug for new subjects in Part 1 to a dose of 500 mg. Written instructions will be 
communicated to all sites on documentation of the dose to be given to new subjects in Part 1 if 
this occurs. If the Part 1 dose is reduced and at least 12 subjects are treated with an active study 
drug dose of 500 mg, a 250 mg active dose may be assessed in Part 2. Any further dose level 
changes warranted for Part 2 and Part 3 will be instituted via protocol amendment.   
9.6. 
Study Drug (Investigational Medicinal Product) Accountability 
Accountability of returned study drug bottles will be performed by site personnel at the study 
visits following each attack. Returned drug bottles must be retained and reviewed during 
monitoring visits by the clinical research associate (CRA) (Section 14.2). 
The Investigator/pharmacist must maintain accurate records (including date) of the disposition of 
all IMPs received from the Sponsor. The Sponsor will supply a specific drug accountability form 
to each site. At the end of the study, information describing study drug supplies and disposition 
of supplies for each subject must be provided, signed by the Investigator or designee, and 
collected by the study monitor. If any errors or irregularities in any shipment of study medication 


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to the site are discovered at any time, the CRO Project Manager and/or Sponsor must be 
contacted immediately. 
At the end of the study, all medication not dispensed or administered will be collected under 
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 and Other Restrictions 
All subjects in the study must refrain from taking prohibited concomitant medications as outlined 
in Section 9.7.1.  
Any regularly administered concomitant medication at screening must be anticipated to be 
continued through the study and be of a stable dose and regimen for the duration of the study. 
Details of all prior (within 30 days of screening) and concomitant medication use, including all 
medications administered for the treatment of AEs, will be recorded in the source 
documentation/eCRF.  
9.7.1. 
Prohibited Medications/Restrictions 
 
The following medications are excluded during the study (Section 8.2.2): 
• 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. For the purposes of this protocol, these include: 
warfarin, phenytoin, s-mephenytoin, thioridazine, alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine, androgens and desogestrel. 
Additional medications may be added to this list of excluded CYP substrate medications 
as the Sponsor becomes aware of evolving data. The Sponsor may add to the 
exclusionary list based upon review of regulatory labelling for individual medications, 
regulatory guidances, peer-reviewed publications, and regularly-updated drug interaction 
reference databases (e.g., University of Washington School of Pharmacy Drug Interaction 
Database Program).  Any updates to the excluded list will be shared with clinical sites. 
• Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or 
planned initiation during the study (potential for exacerbation of HAE).  
• Use of C1 INH, tranexamic acid or androgens for prophylaxis of HAE attacks within the 
7 days prior to the screening visit or initiation during the study. Use of a C1 INH therapy 
for treatment of attacks is not excluded at any time. 
• 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 baseline 
or initiation during the study.  
A list of these medications will be shared with the clinical sites. In order to construct this 
list, drugs with a known risk of torsades de pointes from the Arizona Center for 


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Education and Research on Therapeutics (https://www.crediblemeds.org) will be 
examined against labelling for CYP substrate specificity.  
 
• Current participation in any other investigational drug study or having received another 
investigational drug within 30 days of the Screening visit  
The following classes of medications are restricted during the study based upon in vitro 
transporter data: 
• Daily use (more than 5 consecutive days) of a medication that is known to induce or 
inhibit drug transporters P-gp or BCRP to a clinically significant degree 7 days prior to 
baseline or subsequent initiation during the study. This includes foods or beverages 
containing grapefruit or Seville oranges 
• Use of a medication (more than 5 consecutive days) that primarily relies upon BCRP or 
P-gp transport proteins for systemic disposition 7 days prior to baseline or subsequent 
initiation during the study that is known or suspected to have clinically significant safety 
concerns with increased exposure. 
The Sponsor will compile and provide a spreadsheet outlining these restricted medications 
based upon regulatory labelling for individual medications, regulatory guidances, peer-
reviewed publications and regularly-updated drug interaction reference databases (e.g., 
University of Washington School of Pharmacy Drug Interaction Database Program). 
A drug interaction study designed to elucidate the clinical relevance of the inhibition 
potential of BCX7353 on BCRP and P-gp transport and whether the pharmacokinetics of 
BCX7353 is affected by P-gp or BCRP inhibitors is planned. If the results of this study 
indicate that there is no clinically significant transport inhibition on or by BCX7353, these 
restricted medications will be permissible for use on study. A memo outlining the findings 
and impact will be sent to each study Investigator. 


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10. 
STUDY CONDUCT 
10.1. 
Overview 
This is a randomized, double-blind, placebo-controlled study. The duration of a subject’s 
participation in this study is dependent on the timing and frequency of on-study acute attacks 
eligible for treatment with study drug. Assuming that subjects will have 1 eligible attack every 
4 weeks, it is anticipated that minimally a subject’s participation would be approximately 
19 weeks (inclusive of the screening period, wash-out periods of 10 to 14 days in duration in 
between treated attacks, and a final follow-up visit [at least 16 days after the third attack]). Each 
eligible subject who consents to participate in the study will receive a total of 2 single doses of 
BCX7353 and 1 dose of matching placebo. All subjects will undergo a screening period of up to 
35 days, and 4 clinic visits; visits will occur at Baseline, within 10 to 14 days after the first and 
second study drug treated attacks, and at least 16 days following the last study drug treated 
attack. Subjects who consent to the optional observational substudy after the last study visit 
(Post-Attack 3 visit) will participate in study activities for approximately 12 additional weeks. 
After the Baseline visit, at the first symptom of swelling or pain associated with an attack, the 
subject will be asked to phone the on-call study Investigator (or designee) who will review the 
subject’s symptoms by phone and confirm that they constitute an appropriate acute attack that 
qualifies for treatment with study drug, including ensuring that the subject is in an environment 
that he/she deems suitable for completion of the timed diary. Following confirmation by the 
Investigator, subjects should use study drug to treat the HAE attack, within approximately 1 hour 
from the onset of the first symptoms.  
Subjects will fill out a diary questionnaire and a 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling prior to and at 1, 2, 3, 4, approximately 
8, and at 24 hours after record of study drug administration.  
If the subject prematurely discontinues from the study, they will be requested to attend an early 
termination visit. 
10.2. 
  Schedule of Assessments 
The schedule of assessments for this study is summarized in Table 4; the optional substudy 
assessment schedule can be found in Table 5. 
 


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Table 4. 
Schedule of Assessments for Study BCX7353-202 
 
Screening 
Day  
−35 to −1 
Baseline 
Attack 1 
Telephone 
Contacts  
Post-
Attack 1 
Visit (10-
14 days) 
Attack 2 
Telephone 
Contacts  
Post- 
Attack 2 
Visit (10-
14 days) 
Attack 3 
Telephone 
Contacts  
Post-
Attack 3 
Visit/ 
Follow-up 
(16 days + 
3 days) 
 
 
Early 
Termination  
Visit 
Informed consenta 
X 
 
 
 
 
 
 
X 
 
Telephone contactb 
X 
 
X 
  
X 
  
X 
 
 
Clinic visitsc 
X 
X 
  
X 
 
X 
 
X 
X 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
HAE attack frequency 
confirmation 
X 
 
 
 
 
 
 
 
 
HAE medical and 
medication history 
X 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
Xd 
 
 
 
 
 
 
Xd 
Drugs of abuse screene 
X 
 
 
 
 
 
 
 
 
HIV/HCV/HBV serology 
X 
 
 
 
 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
C1 INH function and C4 
X 
 
 
 
 
 
 
 
 
Pregnancy testg 
X 
X 
 
X 
 
X 
 
X 
X 
Safety laboratory evaluations 
and urinalysis testingh 
X 
X 
 
X 
 
X 
 
X 
X 
Troponin I & Troponin T 
 
X 
 
X 
 
X 
 
X 
X 
CK-MB 
 
X 
 
X 
 
X 
 
X 
X 
C3 
 
X 
 
 
 
 
 
 
 
C1 INH antigen level 
 
X 
 
 
 
 
 
 
 


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Screening 
Day  
−35 to −1 
Baseline 
Attack 1 
Telephone 
Contacts  
Post-
Attack 1 
Visit (10-
14 days) 
Attack 2 
Telephone 
Contacts  
Post- 
Attack 2 
Visit (10-
14 days) 
Attack 3 
Telephone 
Contacts  
Post-
Attack 3 
Visit/ 
Follow-up 
(16 days + 
3 days) 
 
 
Early 
Termination  
Visit 
Randomizationi 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
Xj 
 
Xj 
 
Xj 
Xj 
ECGk 
X 
X 
 
X  
 
X 
 
X 
X 
Vital signsl 
X 
X 
 
X 
 
X 
 
X 
X 
Diary dispensing/ 
instruction/review/ 
collectionm 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary completion 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing/accountability 
and reconstitution 
instructionn 
 
X 
 
X 
 
X 
 
X 
X 
TSQMo 
 
X 
 
X 
 
X 
 
X 
 
a 
Signing of informed consent may occur in advance of the screening visit, which is defined as the visit where site-conducted screening procedures are 
performed. Informed consent for the observational substudy may be obtained at the follow-up visit or earlier. 
b 
Screening telephone contact: Subjects are instructed to contact the site as soon as they become aware of the onset of symptoms of pain or swelling 
associated with an HAE attack during the screening period. The on-call Investigator (or designee) will review the subject’s symptoms by phone and 
confirm the date of the call. The Investigator may fill out a form to document the conversation. Approximately 4 hours after the initial call, the subject will 
again contact the on-call Investigator as is expected during the study. 
         Attack 1, 2, 3 contact: Subjects are instructed to contact the on-call Investigator (or designee) as soon as they become aware of the onset of symptoms of 
pain or swelling associated with a potentially protocol-qualified HAE attack. The on-call Investigator (or designee) will review the subject’s symptoms by 
phone and confirm that they constitute an acute attack that qualifies for treatment with study drug, including ensuring that the subject is in an environment 
that he/she deems suitable for completion of the timed diary. The Investigator will fill out a form to document the conversation. Following treatment of the 
attack, the subject will again contact the on-call Investigator (or the Investigator will contact the subject) at least 4 hours after treatment with study drug to 
review the subject’s response to treatment and to confirm adequate documentation of the attack in the Diary. The on-call Investigator (or designee) will call 


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the subject if the subject has not contacted the on-call Investigator (or designee) within 4-5 hours of the initial phone call. A follow-up visit to the clinic will 
be scheduled. Sites must attempt to contact subjects every 7 days from the last clinic visit to inquire about the occurrence of an attack. 
c 
Clinic visits are scheduled for Screening, Baseline and 10 to 14 days following the first and second attack treated with study drug. The Post-Attack 3 visit 
suffices as the end of study visit and will be held approximately 16 days after the third attack. Study drug cannot be authorized for administration for at 
least 14 days from a previously treated attack. 
d 
 Weight only. 
e 
Analytes to be measured can be found in Table 6. 
f 
Follicle-stimulating hormone will be measured in women declaring themselves postmenopausal ≤ 2 years. 
g 
A serum pregnancy test will be administered to women of childbearing potential or who are postmenopausal ≤ 2 years at screening; all other pregnancy 
tests performed during the study may be urine pregnancy tests (for women of childbearing potential only). 
h 
Safety laboratory parameters and urinalysis testing as described in Table 6. 
i 
 Randomization to a treatment sequence should occur prior to or during the Baseline visit, following confirmation of eligibility and Sponsor approval.  
j 
Post-baseline, physical examinations will be targeted to reported signs and symptoms.  
k 
ECGs will be captured as single assessments. Any scheduled blood draws should occur after obtaining the ECG. Subjects should rest quietly for 10 minutes 
in a supine position prior to ECGs being performed. 
l 
Vital signs include measurement of heart rate, blood pressure and temperature.  
m 
Diaries will be dispensed at Screening, Baseline, and Post-Attack Visits 1 and 2. The Investigator (or designee) will provide diary instruction at Screening 
and will review diary entries on an ongoing basis. During each visit, any issues warranting diary re-education must occur on an as-needed basis. The 
completed diary will be collected at Baseline and Post-attack Visits 1 to 3. For subjects participating in the observational substudy, a diary will be dispensed 
at the Post-Attack 3 visit. 
n 
Subject will be dispensed study drug for self-administration at Baseline, Post-Attack 1 visit and the Post-Attack 2 visit. Reconstitution and dosing 
instructions will be reviewed with the subject. Accountability will be conducted at the Post-Attack visits. 
o     At baseline, the TSQM will be completed in reference to the subject’s currently used acute attack medication prescribed/authorized by their HAE treater; at 
each subsequent study visit, the TSQM will be completed in reference to the attack previously treated with study drug.


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Table 5. 
Schedule of Assessments for Optional Observational Substudy 
 
Post-Attack 
3 Visit 
Week 4 of 
Observational 
Perioda 
Week 8 of 
Observational 
Perioda 
Week 12 of 
Observational 
Perioda 
Informed consentb 
X 
 
 
 
Telephone contactc 
 
X 
X 
X  
Clinic visits 
X 
 
 
 
Diary 
dispensing/instruction/review/collectiond 
X 
X 
X 
X 
Diary completion 
 
 
AE assessment 
X 
Xe 
Xe 
Xe 
a 
The 12-week observational period begins from dispensation of HAE diary for recording of all attacks after 
completion of the Post-Attack 3 visit. 
b 
Signing of informed consent for the optional observational study may occur at the Post-Attack 3 visit or any 
time prior to this visit. Subjects will be asked to participate in the substudy following completion of Post-
Attack 3 visit if approved by the Sponsor. 
c 
During the substudy, subjects will be primarily contacted via telephone; however, a clinic visit is allowed to 
replace the telephone contact if warranted.    
d 
Diaries to record details of all HAE attacks occurring after the Post-Attack 3 visit will be dispensed at the Post-
Attack 3 visit and as needed thereafter. Completed diaries will be collected from the subject (in-person or via 
post) approximately every 4 weeks. The Investigator (or designee) will provide diary instruction at the Post-
Attack 3 visit and will review diary entries upon collection for correct completion and follow-up with the 
subject as needed. 
e       Only AEs assessed as possibly, probably or definitely related to the previously taken study drug administered 
will be recorded. 
10.3. 
Study Visits 
10.3.1. 
Screening 
Prospective subjects should be screened within 35 days prior to baseline.  
Written informed consent 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 are performed.  
The Investigator (or designee) will conduct the following assessments at the screening visit, 
including:  
• Review of inclusion and exclusion criteria  
• Review of HAE attack frequency documentation 
• HAE, medical, and medication history  
• Complete physical exam 


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• 12-lead ECG  
• Height/weight/body mass index (BMI) estimation  
• Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• Serum pregnancy test for female subjects of child-bearing potential 
• Blood collection for clinical chemistry, hematology, coagulation, HBV/HIV/HCV 
serology, C4 and C1 INH functional level, FSH (for women who declare that they 
have been postmenopausal ≤ 2 years) 
• Urine collection for urinalysis and drugs of abuse screen 
• Recording of AEs and concomitant medications  
• Dispensing of HAE attack diary and any applicable subject instruction sheets 
• Instructions on procedures to take during at least one HAE attack during the 
screening period: phoning the on-call Investigator (or designee) at the outset of HAE-
associated pain or swelling, completing the diary, and placing a second call to the on-
call Investigator (or designee) approximately four hours after the initial call.  
All screening procedures are outlined in Table 4 and are described in Section 11.  
A subject will be randomized to a treatment sequence at or prior to the Baseline visit. Subject 
randomization will occur after the subject has been fully determined to be eligible during 
screening (see Section 9.3.2).  
If the Investigator has not received a call for an HAE attack through Day 35 of the screening 
period, the subject is considered a screening failure. If agreed by the Sponsor or designee, 
subjects having an attack late in the course of the screening period may prolong the screening 
period beyond 35 days to allow for randomization and shipment time of study drug to the clinical 
site, if applicable.  
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 with the Sponsor. Any 
screening ECGs may be repeated if the results suggest operator or machine error. Retesting of 
specific laboratory tests within the screening period without entirely rescreening a subject is 
permitted.  
A reason for screen failure will be recorded in the screening eCRF for all subjects who do not 
enter the study. 
10.3.2. 
Baseline  
Subjects who meet all study eligibility criteria, who agree to participate, have demonstrated 
competence in phoning an investigator for an HAE attack and completing an attack diary during 
the screening period and who are authorized for randomization by the Sponsor will be asked to 
return for a Baseline visit. Inclusion/ exclusion criteria will be reviewed to ensure continued 
subject eligibility. Subjects are asked to fast overnight for at least 8 hours prior to the blood draw 
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The following assessments will be completed: 
• Review of inclusion and exclusion criteria 
• Review of medical history 
• Review of concomitant medications  
• Administration of the TSQM (the TSQM will be completed in reference to the 
subject’s currently used acute attack medication prescribed/authorized by their HAE 
treater) 
• Weight  
• Vital signs (heart rate, blood pressure and temperature) 
• 12-lead ECG 
• Complete physical exam  
• Assessment of any AEs that occurred since the Screening visit 
• Urine collection for urinalysis and urine pregnancy test for female subjects of 
child-bearing potential 
• Blood collection for clinical chemistry, hematology, and coagulation 
• Blood collection for C1 INH antigen level, C3, CK-MB, Troponin I, and Troponin T 
• Study drug dispensing for treatment of an acute HAE attack by self-administration 
• Instruction on reconstitution of study drug and administration 
• Screening HAE diary collection and review 
• HAE diary dispensing for recording Attack 1, daily HAE diary and any applicable 
subject instruction sheets 
• Instructions on treatment of attacks by self-administration with study drug. Subjects 
should also be taught to record start and stop time and treatment of any additional 
HAE attacks that occur following the Baseline visit. 
10.3.3. 
Telephone Contacts  
Subjects will be instructed to contact site personnel at the first symptom of swelling or pain 
associated with a potentially protocol-qualified HAE attack, and if treated with study drug, at 
approximately 4 hours following treatment. If the subject has not contacted the on-call study 
Investigator (or designee) within 5 hours, the on-call Investigator will call the subject. The on-
call Investigator (or designee) will review the treatment and progression of the HAE attack with 
the subject and document the conversation.  Subjects who did not require standard of care at 4 
hours will be reminded at the telephone call by the Investigator that they may use standard of 
care at any time point at their own discretion if not experiencing improvement or who are 
experiencing progression of the HAE attack. Subjects will also be reinstructed on diary 
completion. AEs and concomitant medications will also be collected by phone. Exceptions to the 
return phone call at 4 hours are discussed in Section 11.2.2. 


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The site staff will schedule a clinic visit within 10 to 14 days after the administration of study 
drug and remind the subject to bring their HAE attack diary and study drug containers to their 
next visit.  
Sites must attempt to contact subjects approximately every 7 days from the last clinic visit (i.e., 
after the Baseline visit, Post-Attack 1 clinic visit, and Post-Attack 2 clinic visit) to inquire about 
the occurrence of an attack if the subject has not contacted the site during this time frame.  
10.3.4. 
Clinic Visits Following Study Drug Administration  
Subjects will return to the clinic following the administration of study drug to treat an acute 
attack. Subjects will attend a total of 3 on-study clinic visits: Post-Attack 1 clinic visit, Post-
Attack 2 clinic visit, and Post-Attack 3 clinic visit. After Attack 1 and Attack 2, subjects will 
return to the clinic 10-14 days after administration of study drug. Subjects will not be authorized 
to treat a subsequent attack until at least 14 days have elapsed since the last study drug 
administration. After Attack 3, subjects will return to the clinic for a follow-up visit 16 days after 
their last use of study drug (visit window permissible up to 19 days). 
The following assessments will be performed at each visit: 
• Targeted physical examination   
• Vital signs (blood pressure, heart rate and temperature) 
• 12-lead ECG (including comparison of QTcF to Baseline value) 
• Review of concomitant medications and AEs 
• Administration of TSQM questionnaire (TSQM will be completed in reference to the 
attack previously treated with study drug) 
• Blood collection for clinical chemistry, hematology and coagulation 
• Blood collection for CK-MB, Troponin I and Troponin T  
• Urine collection for urinalysis and urine pregnancy test for female subjects of 
child-bearing potential 
• Study drug accountability  
• Post-Attack 1 and 2 clinic visits only: dispense study drug  
• Collection of subject-completed HAE attack diary and review 
• Post-Attack 1 and 2 clinic visits only: HAE diary dispensing for recording Attacks 2 
and 3, daily HAE diaries and any applicable subject instruction sheets 
• Review/re-education, as applicable, of completion of HAE attack diary, dosing 
instructions, phone call(s) to investigators (Post-Attack 1 and 2 clinic visits only). 
Subjects should record start and stop time and treatment of any additional HAE 
attacks that occur prior to the Post-Attack 3 visit. 
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o Signing of informed consent for participation in the optional observational 
study (consent may be signed prior to this visit) 
o Instruct and dispense diary to record details of any HAE attacks that occur 
10.3.5. 
Early Termination Visits 
Subjects who discontinue treatment early (i.e., prior to the treatment of 3 acute attacks) must 
complete an early termination visit as outlined in Section 10.3.5. 
Assessments to be performed at this visit are described in Section 11. In the event that there are 
clinically significant findings from safety assessments that are ongoing at the time of the visit, 
the subject will be followed at additional unscheduled study visits until the findings are resolved 
or stabilized at a new baseline. 
The following assessments will be performed at the early termination visit: 
• Subject weight  
• Targeted physical examination   
• Vital signs (blood pressure, heart rate and temperature) 
• 12-lead ECG (including comparison of QTcF to Baseline value) 
• Review of concomitant medications and AEs 
• Blood collection for clinical chemistry, hematology, and coagulation 
• Urine collection for urinalysis and urine pregnancy test for female subjects of child-
bearing potential 
• Blood collection for CK-MB, Troponin I and Troponin T 
• Study drug accountability  
• Review and collection of the diary  
10.3.6. 
Optional Observational Substudy 
Subjects who complete the study will be offered an opportunity to participate in an observational 
substudy at the Post Attack 3 visit. The subjects will provide consent and will record details of 
all HAE attacks into an HAE diary, dispensed at the Post-Attack 3 visit that occur for 
approximately 12 weeks.  
The following assessments will be performed after the Post-Attack 3 visit: 
• Week 4, 8, 12 of the observational period: phone call to discuss completion of the 
HAE attack diary, collection of completed diaries (in person or via mail) and whether 
additional diaries are needed. In addition, AEs assessed as possibly, probably or 
definitely related to study drug will also be collected 
• Week 4, 8, 12: review of completed HAE diaries for correctness/completeness  


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11. 
ASSESSMENTS 
The schedule of procedures/assessments to be conducted is outlined by study day in Table 4 with 
details on the conduct of the procedures/assessments provided below. 
11.1. 
Investigator-Completed Assessments 
Demographic information, including year of birth, sex, race or ethnicity, and medical history will 
be captured for each subject participating in the study at the Screening visit. Medical history and 
review of inclusion and exclusion criteria will also be rechecked at the Baseline visit.  
Contraceptive methods enabling eligibility will be captured in source documentation at the 
screening visit. 
11.1.1. 
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 Sponsor confirmation of the subject 
and randomization (see Section 9.3.2). 
11.1.2. 
Physical Examination 
A full physical examination should be conducted at Screening and Baseline. All subsequent 
physical examinations may be targeted (i.e., symptom-driven). Genitourinary and breast 
examinations may be omitted when not required by normal site practice. 
11.1.3. 
Weight/Body Mass Index 
For determination of height and weight, subjects should be dressed, without shoes. Body mass 
index should be calculated using the following formula: 
 
BMI = weight (kg)/height (m)2 
11.1.4. 
12-lead Electrocardiograms 
A standard bedside 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 must 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 postdose ECGs, 
change from baseline). For all ECGs, the clinical interpretation of the ECG should be recorded 
directly on a hard copy of the ECGs. Copies of the ECGs may be requested by the Sponsor. 
All ECGs will be captured as single assessments.  
An ECG should be repeated during the clinic visit if possible for a change from baseline in QTcF 
> 60 msec or a QTcF interval > 500 msec for confirmation of the change. 


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11.1.5. 
Vital Signs 
Blood pressure (systolic and diastolic) and heart 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 will also be obtained at all visits.  
11.1.6. 
Clinical Laboratory Assessments 
Blood and urine samples will be obtained per the schedule of events. Individual laboratory tests 
to be performed are provided in Table 6. Laboratory samples should be obtained in the fasted 
state. 
Laboratory samples will be routinely analysed by a centralized laboratory with the exception of 
urine pregnancy tests which will be assessed locally at the site. A laboratory reference manual 
will be provided to the site detailing laboratory kit contents reordering instructions, 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 lab 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.  
Table 6. 
Clinical Laboratory Evaluations 
Chemistry 
Hematology 
• Albumin 
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Bilirubin (total and direct) 
• Blood glucose (fasting) 
• Blood urea nitrogen (BUN) 
• Electrolytes (calcium, sodium, potassium, 
chloride, phosphorus)  
• Creatine kinase 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• MCH 
• MCHC 
• MCV 
• White blood cell count, with differential 
(lymphocytes, monocytes, neutrophils, 
eosinophils, and basophils) 
• Platelets 
• Creatinine and calculated creatinine 
clearance 
• Gamma-glutamyltransferase (GGT) 
• Lactate dehydrogenase (LDH) 
• Total serum protein 
• Uric acid 
• Amylase  
*reflex to lipase for amylase > 2x ULN 
 


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Pregnancy Test 
Serum (screening) and urine (other scheduled 
visits) βHCG for women of childbearing potential 
only  
Drug screen 
• Amphetamines 
• Barbiturates 
• Benzodiazepines 
• Cocaine 
• Opiates 
• Methamphetamine 
• Ecstasy 
Urinalysis 
• Specific gravity 
• Blood  
• Bilirubin 
• Glucose  
• Leukocytes 
• Ketones 
• Nitrates 
• pH 
• Protein 
• Urobilinogen 
• Microalbumin to creatinine ratio 
• Microscopy if dipstick is abnormal  
Additional Tests 
• Follicle-stimulating hormone (FSH; screening) 
for women postmenopausal ≤ 2 years 
• Hepatitis B surface antigen, Hepatitis C 
antibody, HIV antibody (screening) 
• Troponin I 
• Troponin T 
• CK-MB 
• C1 INH function 
• C4  
• C1 INH antigen 
• C3 
Coagulation 
• Prothrombin time (PT) and international 
normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
 
Creatinine clearance (CLcr) will be calculated using the Cockcroft-Gault formula and actual body 
weight (ABW): 
CLcr (mL/min) = (140 – age in years)  ABW (kg) ( 0.85 for females) 
72  serum creatinine (in mg/dL) 
11.1.7. 
Screening for Human Immunodeficiency Virus, Hepatitis B, and Hepatitis 
Serology 
Blood samples will be collected at screening for serologic testing for evidence of HIV, chronic 
hepatitis B, and hepatitis C infection. Subjects with a positive Hepatitis C antibody but have no 
evidence for HCV RNA upon reflex testing are eligible for study participation. 


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11.1.8. 
Pregnancy Testing 
Follicle stimulating hormone 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.  
A serum pregnancy test will be administered to women of childbearing potential or who are 
postmenopausal ≤ 2 years at Screening; all other pregnancy tests performed during the study may 
be urine pregnancy tests (for women of childbearing potential only). A serum pregnancy test 
should immediately be drawn and sent for analysis for any positive urine pregnancy test. 
11.1.9. 
 C1 INH Testing 
C1 INH functional level and C4 will be measured at screening to establish the laboratory 
diagnosis of HAE Type 1 or 2. These tests should be drawn at least 3 days after a previous dose 
of C1 INH. 
Should C4 be normal, as is the case in a small percentage of subjects with HAE, C4 may be 
drawn during an attack or the SERPING-1 gene may be analyzed and the subject confirmed 
eligible if a known mutation associated with HAE Types 1 or 2 is identified. 
C1 INH antigen level will be drawn for demography on enrolled subjects at the Baseline visit.  
11.1.10. 
Other Laboratory Assessments 
Troponin I, Troponin T and CK-MB will be measured in this study at all time points beginning at 
Baseline (i.e., Post-Attack 1, 2, and 3 clinic visits and early termination visit [if applicable]). C3 
levels will be taken at Baseline on all subjects and will only be drawn on-study if required for 
AE assessment (see Section 11.1.11). 
11.1.11. 
Rash Assessment 
Because of the potential for a study drug-related rash (see Section 5.3), all sites are required to 
have the ability to obtain high resolution photographs and obtain an appropriate skin biopsy. 
These can be performed by experienced site physicians or a dermatologist on retainer for this 
study.  
Subjects should be medically evaluated within 24 to 36 hours of awareness of any treatment-
emergent rash, regardless of grade or causality, and the site must inform the Sponsor medical 
monitor at the time the rash is diagnosed via the Event of Special Interest Form 
(Section 12.1.5.1). In the event the site is notified of a rash on the weekend or holiday, the 
medical evaluation and Sponsor notification can be performed on the next working day. 
The following assessments must be completed for all subjects with a rash, regardless of 
causality, as soon as logistically possible:   
• Full dermatological exam to include the anatomical location(s) of the rash, vital signs, 
and mucosal examination. The notes documenting the examination should include 
detailed description of the rash, presence or absence of blistering and if present, its 
extent and presence or absence of mucosal involvement and if present, its extent and 
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• 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, clinical and 
laboratory assessments, treatment and interpretation of the event needs to be reported 
on an SAE/Event of Special Interest Report form as per Section 12.1.5.1.  
The following assessments must be completed for all subjects with a rash assessed as possibly, 
probably, or definitely related to study drug by the Investigator as soon as logistically possible: 
• Blood taken for clinical chemistry, hematology including differential, and C3 level. 
Table 6 outlines the clinical chemistry and hematology analytes to be assessed. 
• Urine sent to local laboratory for urine eosinophils (if evaluation is available locally) 
• Subjects will also be requested 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 
1-3 months after occurrence of the rash. Information on PBMC collection, processing 
and shipment will be communicated to sites prior to sample collection.  
 
11.2. 
Subject-Completed Assessments 
11.2.1. 
Treatment Satisfaction Questionnaire 
To assess treatment satisfaction of the medication a TSQM will be administered once at Baseline 
and at each clinic visit following treatment of an acute attack with study drug. At Baseline, the 
TSQM will be completed in reference to the subject’s currently used acute attack medication 
prescribed/authorized by their HAE treater; at each subsequent study visit, the TSQM will be 
completed in reference to the attack previously treated with study drug 
For all subject-completed forms, clinic staff should ensure the subject reads the instructions and 
completes the questionnaires in full prior to filing in the source documentation.  
11.2.2. 
HAE Attack Diaries and Phone Calls 
11.2.2.1. 
Screening through Post-Attack 3 Visit 
The Sponsor will supply an attack diary for subject documentation of one HAE attack occurring 
during the screening period and for each of 3 study-drug treated attacks. To ensure compliance 
with on-study requirements in treating an appropriate attack with study drug after the Baseline 
visit, subjects will be required to complete timed attack details of at least 1 HAE attack during 
the screening period after approval of the on-call Investigator (or designee). Subjects will also be 
required to complete the details of three HAE attacks that are treated with study drug, each after 
approval from the on-call Investigator (or designee). 
All attacks for which acute attack diaries are completed by the subject will be included in the 
eCRF. 


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Apart from the principal Investigator at each clinical site, the Sponsor will approve on-call study 
Investigators (or designees). Approval will be based upon demonstration that the proposed on-
call Investigator (or designee) ordinarily has oversight of the care of HAE patients.  
The diaries will be composed of a questionnaire and 3-component VAS on a 100 mm scale for 
abdominal pain, cutaneous pain, and cutaneous swelling. The questionnaire includes queries 
about symptom location, severity/limitation of activities and a global assessment that 
qualitatively compares HAE symptomatology against that experienced prior to study drug intake. 
The diaries will include questions/VAS to be completed prior to study drug administration and 1, 
2, 3, 4, approximately 8 and at 24 hours post study drug intake (or post call for a screening 
attack). All medications used from the time of symptom onset through 24 hours postdose will 
also be captured in the diary, including standard of care treatment for acute attacks and any 
symptomatic treatments such as analgesics. 
At the Screening, Baseline, and Post-Attack 1 and Post-Attack 2 visits, attack diaries will be 
dispensed and the subject will be instructed on completing the diary (written instructions may 
also be provided). In addition, subjects will be informed of what is expected regarding attacks 
likely to be approved for study drug treatment by the Investigator and also administration of 
standard of care rescue medication on a continuing basis. 
At the Baseline and Post-Attack 1, 2, and 3 visits, sites must collect and review the diary for 
completeness and plausibility; any re-education required to ensure correct diary completion will 
be performed. Study staff are not permitted to make any entries into the diary regarding HAE 
attack information.  
Diary instruction will include demonstration on how to properly complete the VAS, review of all 
questions for understanding, and those questions that allow more than one response. Subjects 
must be instructed to complete all questions unless medically prevented from doing so or the 
subject is sleeping after a treated attack, and the importance of completing the diary at the 
scheduled time points must be stressed.   
Following the Baseline visit and prior to the Post-Attack 3 visit, subjects will be asked to record 
the start and stop time of all HAE attacks that occur and any standard of care administration. 
11.2.2.1.1. Documented Screening Attack 
The documented screening attack is intended as a practice for on-study requirements in the 
identification, approval, and documentation of an HAE attack treated with study drug. As such, 
the steps required in identifying, approving and documenting the attack should be as close to as 
would be expected or required after the Baseline visit. All steps must take place (initial call for 
HAE symptom review, HAE attack diary documentation, return call) to assess a subject’s 
understanding and compliance with the study requirements. The Investigator (or designee) may 
request that the subject complete more than one documented screening attack if he or she is not 
satisfied that the subject has demonstrated compliance with the procedures required for treating 
and documenting attacks. 
At the first symptom of swelling or pain associated with at least one HAE attack occurring 
during the Screening period, the subject will phone their on-call study Investigator (or designee) 
who will review the subject’s symptoms by phone. It is preferable that the subject call the 
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on-study (see Section 11.2.2.1.2). Subjects will not be asked to avoid standard of care attack 
treatment for four hours from the phone call.  
During the documented Screening HAE attack, subjects will record the occurrence and details of 
the HAE attack in the diary immediately after the call to the Investigator as well as any 
medications used since the onset of symptoms. Subjects will fill out the diary questionnaire and a 
3-component VAS at 1, 2, 3, 4, approximately 8 and at 24 hours after the phone call. Any 
questions regarding study drug administration may be left blank.  
The subject will be asked to phone the on-call study Investigator (or designee) at least 4 hours 
after the phone call to review diary completion. The on-call study Investigator will call the 
subject if they have not heard from the subject within 5 hours of their initial phone call.  
An exception to the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours post-study 
medication. In this case, the subject will be required to call the on-call Investigator (or designee) 
upon waking. The on-call Investigator (or designee) and subject may agree at the initial attack 
approval phone call that the subject will try to rest to avoid an Investigator call 5 hours later. For 
subjects who were sleeping during diary-required timepoints after the phone call, only the 4 hour 
timepoint in the diary questionnaire is required to be completed at the time they awake and any 
medications taken. 
The on-call Investigator (or designee) will document the details of both calls. 
11.2.2.1.2. On-Study Attacks 
After the Baseline and Attack 1 and 2 visits, the subject will phone their on-call study 
Investigator (or designee) at the first symptom of swelling or pain associated with a potentially 
protocol-qualified HAE attack. The Investigator (or designee) will review the subject’s 
symptoms and confirm that they constitute an acute attack that qualifies for treatment with study 
drug, including ensuring that the subject is in an environment that he/she deems suitable for 
completion of the timed diary.  
Protocol-qualified attacks approved for treatment must meet all of the following: 
• have pain and/or swelling associated with an HAE attack reported as a symptom 
• subject has contacted Investigator within approximately 1 hour of onset time of HAE 
pain and/or swelling 
• not involve HAE pain or swelling in the throat or mouth. Such attacks should be 
treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant). 
• not be an abdominal attack that has already resulted in vomiting. Such attacks should 
be treated using the subject’s standard of care acute attack treatment (e.g., C1 INH, 
icatibant). 
• have an identifiable onset time, with the exception that abdominal attacks with an 
onset during sleep may be permitted for study drug treatment. Onset time for 
approved abdominal attacks will be time the subject woke up with symptoms. 


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Peripheral attacks starting with an onset during sleep are not to be authorized for 
study drug treatment. 
• 
occur during an HAE symptom-free period as follows: 
o if the previous HAE attack was treated with a bradykinin B2 receptor antagonist 
(i.e. Firazyr) OR treated with human recombinant C1 INH (i.e. Ruconest) OR 
any non-targeted therapy (i.e. pain medication, anti-spasmodic, anti-emetic, 
tranexamic acid) OR was not treated with any medication: new attack can be 
treated with IMP if has been 48 hours since the complete resolution of all 
symptoms of the previous HAE attack AND the Investigator believes it is a new 
(de novo) attack. 
OR 
o if the previous HAE attack was treated with plasma-derived purified C1 INH (i.e. 
Berinert or Cinryze) OR plasma preparation (fresh frozen or solvent detergent 
plasma): new attack can be treated with IMP if it has been 96 hours since the 
complete resolution of all symptoms of the previous HAE attack 
• 
occur at least 96 hours after complete recovery from a procedure or injury 
• 
occur at least 14 days from a previous dose of study drug 
Following confirmation by the Investigator that an attack may be treated with study drug, 
subjects should reconstitute and take study drug almost immediately (within 5 minutes) 
following the approval phone call, with the goal for subjects to take study drug within or 
approximately one hour of the onset of symptoms. Subjects will be asked to avoid food for at 
least one hour after taking study drug and will be asked to withhold standard of care attack 
treatment for four hours from administration of study drug (see Section 9.2). If symptoms are 
progressing rapidly or if intraoral symptoms occur, subjects may treat the attack with their 
standard of care attack medication prior to 4 hours. 
The subject will be asked to phone the on-call study Investigator (or designee) at least 4 hours 
after taking study medication (or earlier if they have any concerns over the course of their 
symptoms) to review their response to study drug and diary completion, unless they are sleeping. 
The on-call study Investigator will call the subject if they have not heard from the subject within 
5 hours of their initial phone call. Subjects who did not require standard of care at 4 hours will be 
reminded at the telephone call by the Investigator that they may use standard of care at any time 
point at their own discretion if not experiencing improvement or who are experiencing 
progression of the HAE attack.  
An exception to the requirement of a phone call follow-up at 4 hours may be made if the 4 hour 
timepoint occurs during the typical period of sleep and the subject is asleep at 4 hours post-study 
medication. In this case, the subject will be required to call the on-call Investigator (or designee) 
upon waking. The on-call Investigator (or designee) and subject may agree at the initial attack 
approval phone call that the subject will try to rest to avoid an Investigator call 5 hours later. 
Subjects will record the occurrence and details of the HAE attack immediately prior to treating 
the approved HAE attack with study drug. Subjects will also fill out the diary questionnaire and a 
3-component VAS at 1, 2, 3, 4, approximately 8 and at 24 hours after record of study drug 


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administration. All medications taken after study drug administration through 24 hours will also 
be captured. For subjects who were sleeping during these timepoints after administration of study 
drug, subjects are only required to fill out the 4 hour timepoint in the diary questionnaire and any 
medications taken at the time they awake.   
The on-call Investigator will document the details of both calls involving approval of and 
follow-up after study drug treatment. If duplicate data is collected on this form and in the HAE 
diary, the HAE diary will always be source documentation. In the event that a diary field is 
empty when reviewed subsequently at the Post-Attack 1, 2, or 3 visit, the details of the 
Investigator form may serve as source documentation. 
11.2.2.2. 
Optional Observational Substudy 
Subjects who complete randomized dosing and who provide consent will be offered an 
opportunity to participate in an observational substudy. Consenting subjects will be provided an 
HAE attack diary at the Post-Attack 3 visit and will record details of all HAE attacks that occur 
for approximately 12 weeks. Resupply of diaries will be provided as needed. Completed diaries 
should be returned to the site, in person or via mail, approximately every 4 weeks. 
Subjects will be provided further instruction on completing the diaries at home for any attacks 
that occur for subsequent 12 weeks. Subjects will record the occurrence and details of each HAE 
attack in the diary, beginning from the time of onset of pain or swelling associated with an HAE 
attack. Subjects will fill out the diary questionnaire and a 3-component VAS at 1, 2, 3, 4, 
approximately 8 and at 24 hours after the attack started, as well as any medications used since 
the onset of symptoms.   
During Weeks 4, 8, 12 of the observational period, the Investigator (or designee) will phone the 
subject to discuss completion of the HAE attack diary, collection of completed diaries and 
whether additional diaries are needed. In addition, AEs assessed as possibly, probably or 
definitely related to study drug will also be collected. After receipt of the Week 4, 8, 12 diaries, 
the Investigator (or designee) will review completed HAE diaries for correctness/completeness. 
   


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12. 
ASSESSMENT OF SAFETY 
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. Full details on recording and reporting AEs are provided in 
Section 12.1.2. 
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/ IMP 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 (e.g, requiring unscheduled diagnostic procedures or treatment 
measures, or resulting in withdrawal from the study) are considered to be AEs. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period (see Section 12.1), including medical triggers resulting in an 
HAE attack. 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 only be reported 
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 
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, HAE attacks and their associated symptoms will not be defined 
as AEs, unless they meet the criteria for a SAE. HAE attacks and associated symptoms will be 
recorded in the subject’s diary. The events that may trigger a HAE attack such as an infection or 
trauma are considered AEs and should be reported as such. 
Surgical procedures should not be reported as AEs. The condition for which the surgery is 
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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. 
Adverse events 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 (i.e., there is a substantial 
disruption of a person's ability to carry out normal life functions) 
• 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.  
Overdose 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 12.2.2). 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. 
BioCryst also considers abortions, whether elective or spontaneous, fetal demise, and still births 
as SAEs. 
12.1.1.3. Adverse Events of Special Interest 
For this protocol, nonserious treatment-emergent rashes will be considered events of special 
interest. This event in and of itself will not be considered serious unless it meets the criteria 
above. Events of rash regardless of severity or suspected relationship to study drug/IMP must be 
reported to the Sponsor Medical Monitor as described in Section 12.1.5.1. Management of rash 
possibly, probably or definitely suspected to be related to study drug/IMP, is provided in 
Section 12.2.1. 


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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 until the post –attack 3 visit of the study drug phase. All 
AEs and SAEs are to be reported on the AE CRF. For subjects who continue in the optional 
observational substudy, only those AEs deemed possibly, probably or definitely related to the 
previously taken study drug need to be recorded on the AE CRF. These AEs will be recorded in 
the same manner and include the same information as AEs during the study phase. 
AEs should be documented on eCRFs as Investigators become aware of them. AEs are to be 
followed until the event resolves. If an event is ongoing at the last follow-up visit in the main 
study, 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/IMP (see Section 12.1.3 for AE grading). For all Grade 3 and 
4 events or events deemed possibly, probably or definitely related to use of study drug/IMP, 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 submission of an SAE report form via fax or email, 
and entering the event onto the AE eCRF within 24 hours of their knowledge of the event (see 
Section 12.1.5). The SAE report form is a detailed, written report on the SAE provided by the 
Sponsor or designee. 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. The immediate and follow-up reports 
shall identify subjects by unique code numbers assigned to the latter to ensure that the Sponsor 
shall have the necessary information to continuously assess the benefit-risk profile of the study 
drug/IMP in clinical trial. 
12.1.3. 
Definition of Severity 
All AEs will be assessed (graded) for severity and classified using the Division of Microbiology 
and Infectious Diseases (DMID) criteria for grading AEs (see Appendix 15.1). Any AEs not 
covered by the DMID criteria will be assessed and classified into 1 of 4 clearly defined 
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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. 
12.1.4. 
Definition of Relationship to Study Drug (Investigational Medicinal Product) 
The Investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug/IMP 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/IMP and the event. 
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/IMP 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 study drug/IMP 
administration, abates upon discontinuation of the study drug/IMP, 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/IMP 
administration, follows a known or suspected response pattern to the study drug/IMP, 
is confirmed by improvement upon stopping the study drug/IMP (dechallenge), and 
reappears upon repeated exposure (rechallenge, if rechallenge is medically 
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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 in writing via 
email or fax using the SAE/Event of Special Interest report form within 24 hours of the 
Investigator’s awareness of the SAE. In addition, all SAEs must be recorded on the AE eCRF in 
real time. All additional follow-up evaluations of the SAE must be reported to BioCryst or its 
designee as soon as they are available. The SAE report forms should be sent to the following 
email addresses or fax numbers: 
Sylvia Dobo, MD, Medical Monitor 
Cell number (24 hours) +1 773-304-8942 
Email: safety@biocryst.com; sdobo@biocryst.com 
Safety Fax: +1 919-226-5888 
 
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/IMP in clinical trial, if the relevant 
information was not already available and provided in the initial report. 
Investigators or designees at each site are responsible for retaining copies of all suspected 
unexpected severe adverse reaction (SUSAR) reports (initial and follow-up) and other safety 
information (eg, revised IB) in their files. 
BioCryst or its designee will submit all SUSAR reports (initial and follow-up) or other safety 
information (eg, revised IB) to the IEC and central IRBs. 
BioCryst shall ensure that all relevant information about SUSARs that are fatal or life-
threatening is recorded and reported as soon as possible to all competent authorities, and to the 
IECs, and central IRBs, in any case no later than 7 calendar days after knowledge by BioCryst of 
such a case, and that relevant follow-up information is subsequently communicated within an 
additional 8 days. All other SUSARs shall be reported to the competent authorities concerned 
and to the IECs/IRBs concerned as soon as possible but in no case later than 15 calendar days of 
first knowledge by BioCryst. BioCryst or designee shall also inform all Investigators. 


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12.1.5.1. Reporting Events of Special Interest 
Although not an SAE, all events of treatment-emergent rash regardless of severity or relationship 
to study drug/IMP must be reported by phone or email to the Sponsor Medical Monitor and in 
writing via email or fax using the SAE/Event of Special Interest report form within 24 hours of 
the Investigator’s assessment of the event. In addition, the event must be recorded on the AE 
eCRF in real time. All additional follow-up evaluations of the event must be reported to BioCryst 
or its designee on the form as soon as they are available. The SAE/Event of Special Interest 
report form should be sent to the following email addresses or fax numbers: 
Sylvia Dobo, MD, Medical Monitor 
Cell number (24 hours) +1 773-304-8942 
Email: safety@biocryst.com; sdobo@biocryst.com 
Safety Fax: +1 919-226-5888 
 
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 event. In addition, the report form will allow a full clinical 
description and information regarding the evaluation that cannot be reported in the EDC.  
The follow-up report should contain information about the clinical course, medical evaluation, 
photographs, biopsy, and laboratory results. 
12.1.6. 
Pregnancy 
Any female subject who becomes pregnant during the course of the study should have study 
drug/IMP 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 study partners 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 
It is the responsibility of the Sponsor to notify the competent authority of any serious breach 
which 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 notified to the relevant 


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competent authority within 7 days. The reporting to the Sponsor will be performed by the party 
who suspects the serious breach.  
12.1.8. 
Emergency Procedures 
Access to study drug/IMP assignment will be available immediately if the Investigator deems it 
necessary to break the study blind in the interest of a subject’s medical safety. In addition, the 
blind may be broken 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 unblinding of the subject; however, the final 
decision to break the treatment code in emergency situations resides solely with the Investigator. 
Detailed instructions for immediate unblinding in the interactive web response system used by 
the site to randomize a subject will be provided. 
12.2. 
Toxicity Management 
The Investigator (or qualified designee) will grade clinically significant events and laboratory 
abnormalities (if considered AEs) 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/IMP discontinuation, unless such a delay is not consistent with 
good medical practice. 
In the event that 2 subjects experience similar Grade 3 or 4 treatment-emergent laboratory 
abnormality or AE that is suspected to be IMP related as determined by the Investigator and not 
otherwise physiologically explained, a DMC meeting will be immediately convened by the 
Sponsor. 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  
Management of rash should be based on best medical practice and address the subject’s 
presentation. If a subject experiences a Grade 3 or4 rash suspected to be due to study drug/IMP, 
the subject should have study drug/IMP stopped as per Section 8.3.2.2. 
In the event that 2 subjects experience a rash that is suspected to be study drug/IMP related as 
determined by the Investigator and not otherwise physiologically explained, a DMC meeting will 
be convened by the Sponsor. 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. 
Special evaluation of drug rash is required as per Section 12.1.1.3 and special reporting is 
described in Section 12.1.5.1.  
12.2.2. 
Overdose  
To date there is no experience with overdose of oral BCX7353. Only one dose of study drug is 
provided to each subject at a time, so overdose is not of concern in the study. The maximum dose 
to be administered in the current study is 750 mg. Single doses of up to 1000 mg, 7 days of 


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dosing up to 500 mg/day, and 14 days of dosing with 350 mg/day revealed no clinically 
significant safety concerns in healthy subjects in Study BCX7353-101.   
12.3. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will review safety data on an as needed 
basis. The DMC will be convened upon meeting the criteria listed in Section 12.2 or at 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. 


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13. 
STATISTICS 
13.1. 
Sample Size Considerations 
Given the exploratory nature of this study, the sample size was not chosen based on statistical 
considerations, but rather to provide preliminary safety and efficacy data on BCX7353 in 
subjects with HAE when treated in accordance with this study.  
13.2. 
Hypothesis Testing 
An analysis may be conducted during Part 1, using the Heybittle-Peto boundary for significance, 
to determine whether there is a clinically important treatment effect with BCX7353. The 
endpoint for this analysis is the proportion of subject attacks with a stable or improved VAS at 4 
hours postdose in the full analysis set.  The null hypothesis evaluated (H0) is that the proportion 
of subject attacks treated with BCX7353 with stable or improved VAS at 4 hours postdose is the 
same as proportion of subject attacks treated with placebo with stable or improved VAS at 4 
hours postdose (i.e., no treatment difference). The alternative hypothesis (H1) is that the 
proportion of subject attacks treated with BCX7353 with stable or improved VAS at 4 hours 
postdose is greater than the proportion of subject attacks treated with placebo with stable or 
improved VAS at 4 hours postdose (i.e., treatment difference). 
13.3. 
Statistical Methods 
A detailed statistical analysis plan (SAP) will be developed and finalized prior to database lock. 
The SAP will describe the methods of analyses/summaries, including all endpoints, time points, 
populations, missing data, etc. Any deviation from the analyses outlined in the SAP will be 
described in the final clinical study report. 
13.3.1. 
Analysis Populations 
The analysis populations are defined below.   
13.3.1.1. Full Analysis Set  
The Full Analysis Set (FAS) population will include all subjects/subject attacks treated. 
Subjects/subject attacks will be analyzed according to the treatment randomized. The FAS 
population will be the primary population for efficacy analyses. 
13.3.1.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment received. This population will be used for 
all analyses of accountability, demographics, and safety. 
13.3.2. 
Subject Demographic and Disposition Data 
Demographic data and baseline characteristics including age, gender, race or ethnicity, height at 
screening, weight at screening, and BMI at screening will be summarized by treatment sequence 
using descriptive statistics. 


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Disease and treatment characteristics including years since initial diagnosis of HAE, number of 
days since last HAE attack, documented attack frequency, and pattern of on-demand therapy will 
be summarized by treatment sequence using descriptive statistics. 
Subject disposition will be presented for all subjects. The number of subjects who completed the 
study and discontinued 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 will be 
presented. 
13.3.3. 
Analysis of Efficacy Variables 
As this is the first study of BCX7353 in the treatment of acute attacks, the analysis of attack 
resolution will be described in a number of ways which will be fully detailed in the SAP. The 
endpoint that may be utilized to first examine efficacy is the proportion of subject attacks with a 
stable or improved VAS at 4 hours postdose in the full analysis set. The number and proportion 
of subject attacks with a stable or improved VAS at 4 hours postdose will be summarized by 
treatment group. Attacks that require standard of care medication prior to the 4 hour time point 
will be considered as failure (i.e., not having a stable or improved VAS at 4 hours postdose). To 
assess treatment differences, a logistic mixed effect model including treatment, period and 
sequence as fixed effects, and subject within sequence as a random effect will be utilized. Other 
binary endpoints will be analyzed in a similar manner.  
The 3-symptom composite VAS and its associated changes from baseline will be summarized for 
each attack by time point and treatment group. Treatment differences in the change from baseline 
values at each time point will be assessed with a mixed effect linear model with factors for 
treatment, period, sequence, and baseline value as fixed effects, and subject within sequence as a 
random effect. Analyses of other continuous variables will be analyzed in a similar manner. 
The time to use of standard of care medication will be estimated using the method of 
Kaplan-Meier. For each attack, subjects who do not use standard of care medication will be 
censored at the end of the attack observation period (i.e., 24 hours). Treatment differences will 
be assessed using an appropriate proportional hazards model. Analyses of other type to event 
variables will be analyzed in a similar manner. 
Location of attacks, duration of attacks, and number of acute HAE medications administered will 
be summarized for each treatment group. 
13.3.4. 
Analysis of Safety Variables 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. Any event reported on the subject’s study record 
that occurs on or after the initiation of study drug within a given treatment period is defined as 
treatment emergent. Additionally, it is assumed that an AE that is reported to have started on the 
day of subject dosing to treat an attack without an associated onset time may have occurred after 
the initiation of study drug. Hence, AEs occurring on the day of subject dosing to treat an attack 
with no associated onset time will be assumed to be treatment emergent. AEs will be attributed 
to the corresponding treatment assignment of the corresponding treatment period.  The 
occurrence of treatment-emergent AEs will be summarized by treatment group using MedDRA 
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emergent SAEs and AEs considered to be related to study drug will be generated. All AEs will 
be listed for individual subjects showing both verbatim and preferred terms.  
Descriptive summaries of vital signs, weight, ECG parameters, and clinical laboratory results 
will be presented separately for each treatment group. Laboratory abnormalities will be graded 
according to the DMID Adult Toxicity Table (Publish Date: Draft, November 2007, see 
Appendix 15.1). Any graded abnormality that occurs following the initiation of study drug and 
represents at least 1-grade increase from the baseline assessment for a given treatment period is 
defined as treatment emergent. The number and percentage of subjects experiencing treatment-
emergent graded toxicities will be summarized by treatment group. Laboratory toxicity shifts 
from baseline to post-baseline assessments will be summarized by treatment group.  
Clinically significant abnormal morphological ECG findings will be summarized by treatment 
group. 
Physical examination results will be presented in listings. 
Concomitant medications will be coded using the World Health Organization (WHO) dictionary. 
These data will be summarized by treatment group. 
13.3.5. 
Subject Satisfaction Analyses 
The change from baseline in the TSQM global satisfaction score as well as effectiveness, side 
effects, and convenience subscales will be summarized. Data will be listed, summarized, and 
appropriately tested for differences between active treatment and placebo and between active and 
current acute therapy utilized at baseline. 
13.3.6. 
Interim Monitoring and Statistical Stopping Rules 
The study’s design is intended to identify the dose or doses of BCX7353 shows an efficacy 
benefit over placebo.  Dosing in the study will commence at the 750 mg dose level and lower 
doses (500 mg and 250 mg) will be evaluated in successive parts of the study.   
After 12 subjects have completed Part 1 of the study, the proportion of subject attacks with a 
stable or improved VAS at 4 hours postdose may be estimated for BCX7353 750 mg and placebo 
by the study statistician using the analysis method described in Section 13.3.3. A test of no 
treatment difference is considered statistically significant with p < 0.001 (i.e., Haybittle-Peto 
boundary is crossed). Treatment differences may also be assessed using available data in Parts 1, 
2 and 3 in order to plan for future studies.  
 


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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; Good Clinical Practices (GCPs), 
including International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines (ICH E6); EMA regulatory 
requirements; 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. 
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 study drug 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 substantial modification of the protocol, the ICF, the written information provided 
to subjects, and/or other procedures. After the protocol has been submitted, any amendment must 
be agreed by the Investigator after discussion with the Sponsor and will be formally documented. 
All substantial amendments will be submitted for an opinion as required by current regulations.  
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 to be completed once 
the last subject completes their 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 BioCryst. 
14.1.3. 
Subject Informed Consent 
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.  


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The ICF that is used must be approved both by BioCryst 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 BioCryst policy. 
If an ICF is updated as a result of a substantial protocol amendment, the new IRB/IEC-approved 
versions will be used to re-consent currently enrolled subjects and must be provided to additional 
subjects prior to their entry into the study.  
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. 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 nonenrollment. 
14.1.4. 
Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
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, BioCryst 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 on the eCRF is accurate. The Investigator and institution will 
allow BioCryst representatives, monitors, or its designees direct access to source documents to 
perform this verification. 
It is important that the Investigator and their relevant personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
14.3. 
Quality Assurance 
The Investigator may be subject to visits by the IRB/IEC, and/or by a quality assurance group for 
audits performed by BioCryst, 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. 


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14.4. 
Study Termination and Site Closure 
Formal stopping rules for individual subjectsare listed below and also defined in Section 8.3.2.  
• 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 
degree 
• Subsequent determination that inclusion/exclusion criteria were not met 
• 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 due to an altered risk/benefit profile 
• Subject noncompliance with study drug or to the protocol 
• Discontinuation at the request of the Sponsor, competent authorities in the Member 
State(s) concerned, or the institutional review board (IRB)/independent ethics 
committee (IEC)  
• A subject has a QTcF > 500 msec (confirmed on repeat testing) 
• A subject has a QTcF increase of more than 60 msec (confirmed by repeat ECG) 
from the value obtained predose at the baseline visit 
• A subject has a study drug related Grade 3 or 4 rash as described by the DMID 
criteria “Skin-mucocutaneous”  
 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, will be terminated for any of the following reasons: 
• Request of a Competent Authority 
• Recommendation of the independent DMC 
• Inaccurate or incomplete data recording 
• Non-compliance with study protocol 
BioCryst 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 BioCryst, all study materials must be collected and all eCRFs 
completed to the greatest extent possible. 
14.5. 
Records Retention 
To enable evaluations and/or audits from regulatory authorities or BioCryst, 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 eCRFs, and 
detailed records of study drug accountability and treatment disposition. The records should be 


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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 BioCryst. The Investigator must obtain BioCryst’s written permission before 
disposing of any records and must notify BioCryst before transferring any records to another 
facility. 
All correspondence related to records retention, destruction or transfer of study documents 
should be sent directly to BioCryst study personnel, copying the email archives@biocryst.com. 
14.6. 
Confidentiality of Information 
BioCryst 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 BioCryst. However, in compliance with federal regulations, BioCryst requires the Investigator 
to permit BioCryst’s representatives and, when necessary, representatives of the FDA 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, including the Health Insurance Portability and Accountability Act (HIPAA), 
where this rule is applicable, and the requirements of the Data Protection Act in the EU, where 
applicable. 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. HIPAA authorizations are required for US sites only. 
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 written 
agreement between BioCryst, independent analysis and/or publication of these data by the 
Investigator or any member of his/her staff is not permitted without prior written consent of 
BioCryst. 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 
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 e481-484. 
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. 
Cicardi, M. and D. T. Johnston (2012). "Hereditary and acquired complement component 1 
esterase inhibitor deficiency: a review for the hematologist." Acta Haematol 127(4): 208-220. 
Cicardi, M., R. J. Levy, D. L. McNeil, H. H. Li, A. L. Sheffer, M. Campion, P. T. Horn and W. 
E. Pullman (2010). "Ecallantide for the treatment of acute attacks in hereditary angioedema." N 
Engl J Med 363(6): 523-531. 
Craig, T. J., R. J. Levy, R. L. Wasserman, A. K. Bewtra, D. Hurewitz, K. Obtulowicz, A. Reshef, 
B. Ritchie, D. Moldovan, T. Shirov, V. Grivcheva-Panovska, P. C. Kiessling, H. O. Keinecke 
and J. A. Bernstein (2009). "Efficacy of human C1 esterase inhibitor concentrate compared with 
placebo in acute hereditary angioedema attacks." J Allergy Clin Immunol 124(4): 801-808. 
Cugno, M., C. E. Hack, J. P. de Boer, A. J. Eerenberg, A. Agostoni and M. Cicardi (1993). 
"Generation of plasmin during acute attacks of hereditary angioedema." J Lab Clin Med 121(1): 
38-43. 
Cugno, M., J. Nussberger, M. Cicardi and A. Agostoni (2003). "Bradykinin and the 
pathophysiology of angioedema." Int Immunopharmacol 3(3): 311-317. 
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. 
Kaplan, A. P., K. Joseph and M. Silverberg (2002). "Pathways for bradykinin formation and 
inflammatory disease." J Allergy Clin Immunol 109(2): 195-209. 


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Levy, R. J., W. R. Lumry, D. L. McNeil, H. H. Li, M. Campion, P. T. Horn and W. E. Pullman 
(2010). "EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for 
acute attacks of hereditary angioedema." Ann Allergy Asthma Immunol 104(6): 523-529. 
Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-481. 
Longhurst, H. J. (2010). "Management of acute attacks of hereditary angioedema: potential role 
of icatibant." Vasc Health Risk Manag 6: 795-802. 
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. 
Lumry, W. R., H. H. Li, R. J. Levy, P. C. Potter, H. Farkas, D. Moldovan, M. Riedl, H. Li, T. 
Craig, B. J. Bloom and A. Reshef (2011). "Randomized placebo-controlled trial of the 
bradykinin B(2) receptor antagonist icatibant for the treatment of acute attacks of hereditary 
angioedema: the FAST-3 trial." Ann Allergy Asthma Immunol 107(6): 529-537. 
Malbran, A., M. Riedl, B. Ritchie, W. B. Smith, W. Yang, A. Banerji, J. Hebert, G. J. Gleich, D. 
Hurewitz, K. W. Jacobson, J. A. Bernstein, D. A. Khan, C. H. Kirkpatrick, D. Resnick, H. Li, D. 
S. Fernandez Romero and W. Lumry (2014). "Repeat treatment of acute hereditary angioedema 
attacks with open-label icatibant in the FAST-1 trial." Clin Exp Immunol 177(2): 544-553. 
Martello, J. L., M. R. Woytowish and H. Chambers (2012). "Ecallantide for treatment of acute 
attacks of hereditary angioedema." Am J Health Syst Pharm 69(8): 651-657. 
Nussberger, J., M. Cugno, C. Amstutz, M. Cicardi, A. Pellacani and A. Agostoni (1998). 
"Plasma bradykinin in angio-oedema." Lancet 351(9117): 1693-1697. 
Nussberger, J., M. Cugno and M. Cicardi (2002). "Bradykinin-mediated angioedema." N Engl J 
Med 347(8): 621-622. 
Pappalardo, E., M. Cicardi, C. Duponchel, A. Carugati, S. Choquet, A. Agostoni and M. Tosi 
(2000). "Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with 
angioedema." J Allergy Clin Immunol 106(6): 1147-1154. 
Patston, P. A., P. Gettins, J. Beechem and M. Schapira (1991). "Mechanism of serpin action: 
evidence that C1 inhibitor functions as a suicide substrate." Biochemistry 30(36): 8876-8882. 
Riedl, M. (2012). "Hereditary angioedema therapies in the United States: movement toward an 
international treatment consensus." Clin Ther 34(3): 623-630. 
Riedl, M., M. Campion, P. T. Horn and W. E. Pullman (2010). "Response time for ecallantide 
treatment of acute hereditary angioedema attacks." Ann Allergy Asthma Immunol 105(6): 430-
436 e432. 
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. 
Suffritti, C., A. Zanichelli, L. Maggioni, E. Bonanni, M. Cugno and M. Cicardi (2014). "High-
molecular-weight kininogen cleavage correlates with disease states in the bradykinin mediated 
angioedema due to hereditary c1-inhibitor deficiency." Clin Exp Allergy. 


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Wasserman, R. L., R. J. Levy, A. K. Bewtra, D. Hurewitz, T. J. Craig, P. C. Kiessling, H. O. 
Keinecke and J. A. Bernstein (2011). "Prospective study of C1 esterase inhibitor in the treatment 
of successive acute abdominal and facial hereditary angioedema attacks." Ann Allergy Asthma 
Immunol 106(1): 62-68. 
Zuraw, B., M. Cicardi, R. J. Levy, J. H. Nuijens, A. Relan, S. Visscher, G. Haase, L. Kaufman 
and C. E. Hack (2010). "Recombinant human C1-inhibitor for the treatment of acute angioedema 
attacks in patients with hereditary angioedema." J Allergy Clin Immunol 126(4): 821-827 e814. 
Zuraw, B. L., P. J. Busse, M. White, J. Jacobs, W. Lumry, J. Baker, T. Craig, J. A. Grant, D. 
Hurewitz, L. Bielory, W. E. Cartwright, M. Koleilat, W. Ryan, O. Schaefer, M. Manning, P. 
Patel, J. A. Bernstein, R. A. Friedman, R. Wilkinson, D. Tanner, G. Kohler, G. Gunther, R. 
Levy, J. McClellan, J. Redhead, D. Guss, E. Heyman, B. A. Blumenstein, I. Kalfus and M. M. 
Frank (2010). "Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema." N 
Engl J Med 363(6): 513-522. 
Zuraw, B. L. and S. C. Christiansen (2011). "Pathophysiology of hereditary angioedema." Am J 
Rhinol Allergy 25(6): 373-378. 
 


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APPENDICES 
15.1. 
DMID Adult Toxicity Table (Publish Date: Draft November 2007) 
 
https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf 
 
Copies of the DMID Toxicity 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_000.pdf: 
BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
1 
 
 
CONFIDENTIAL 
 
 
BIOCRYST PHARMACEUTICALS INC. 
STATISTICAL ANALYSIS PLAN 
PHASE III 
 
VERSION: 1.0  
DATE OF PLAN: 
29 January 2019 
 
BASED ON: 
Protocol Version 2.0: 11 October 2018 
CRF Version 22.0, 9 January 2019 
 
STUDY DRUG: 
BCX7353 
PROTOCOL NUMBER: 
BCX7353-302 
IND No. 135,058 
EudraCT No. 2017-003966-29 
 
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   
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. 


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	


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 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 Finished 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 dihydrochloride  
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 BCX7353-302) 
Investigators: 
Study Centers: Multiple study centers in North America and Europe 
Studied Period (years): 
Approximately 2 years 11 months 
(approximately a 9-month 
enrollment period plus 
approximately 2 months of 
screening and 2 years of treatment) 
 
Objectives: 
Part 1 Primary Objective 
• 
To determine the efficacy of prophylactic BCX7353 110 mg and 150 mg administered once daily (QD) 
for 24 weeks compared to placebo in subjects with hereditary angioedema (HAE) 
Part 1 Secondary Objectives 
• 
To assess the safety and tolerability of BCX7353 110 mg and 150 mg administered QD for 24 weeks  
• 
To assess the effects of BCX7353 on HAE disease activity and HAE attack characteristics 
• 
To evaluate the effects of BCX7353 on quality of life (QoL) 
• 
To characterize the pharmacodynamic effects of BCX7353 
Part 2 Primary Objective 
• 
To evaluate the long-term safety and tolerability of BCX7353 110 mg and 150 mg administered QD 
over a 24- to 48-week administration period in subjects with HAE 
Part 2 Secondary Objectives 
• 
To assess the effectiveness (ie, HAE attack frequency over time) of BCX7353 over a 24- to 48-week 
administration period 
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 48-week administration period 
• 
To evaluate subject satisfaction with BCX7353 over a 24- to 48-week administration period 
Part 3 Primary Objectives 
• 
To evaluate the long-term safety and tolerability of BCX7353 administered QD over a 48- to 96-week 
administration period in subjects with HAE 
Part 3 Secondary Objectives 
• 
To assess the effectiveness (ie, HAE attack frequency over time) of BCX7353 over a 48- to 96-week 
administration period 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
4 
 
 
CONFIDENTIAL 
 
• 
To evaluate QoL and HAE disease activity of BCX7353 over a 48- to 96-week administration period 
• 
To evaluate subject satisfaction with BCX7353 over a 48- to 96-week administration period 
Methodology: 
This is a randomized, placebo-controlled, double-blind, parallel-group, 3-part study. Part 1 is designed to test the 
hypothesis that the HAE attack rate during 24 weeks of prophylactic BCX7353 treatment at each of 2 dosage 
levels will be less than that observed during 24 weeks of placebo. 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, with Parts 2 and 3 conducted as continuous 
rollovers 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. 
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 attacks documented during a prospective 
run-in period of 2 to 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 administered orally QD for 24 weeks 
• 
Group 2:  BCX7353 150 mg administered orally QD for 24 weeks 
• 
Group 3:  Placebo administered orally QD for 24 weeks 
Enrollment into treatment groups will be stratified by the baseline HAE attack rate (≥ 2 attacks/month vs. 
< 2 attacks/month).  
Details of acute attacks of angioedema will be recorded in an electronic diary (e-diary). Attacks will be treated in 
accordance with the subject’s normal standard of care. Treatment medications for angioedema attacks will not be 
provided by the Sponsor. 
Within approximately 2 business days of the end of each attack that occurs beginning at the screening visit 
through the follow-up visit after Part 2, subjects will be contacted by the Investigator to discuss the clinical 
characteristics of the attack, any questions the Investigator has on the entered data or to gain additional attack 
details not included in the e-diary that the Investigator deems important to clinically evaluate the event, as 
applicable. This information, in conjunction with the e-diary record, will be used by the Investigator to verify or 
reject the event recorded in the diary as an HAE attack. All Investigator-confirmed attacks of HAE must include 
symptoms of swelling; prodromal symptoms in the absence of swelling are not considered HAE attacks, 
regardless of treatment. 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 main study will be comprised of adult subjects (≥ 18 years of age); a substudy in participating regions will 
allow adolescent subjects ≥ 12 to 17 years of age to participate. Main study and substudy subjects will be 
randomized via a separate randomization scheme; however, study-mandated procedures will be identical, and 
analyses will include all subjects who participate in the study.  
Safety and tolerability will be evaluated through assessments of treatment-adverse events (TEAEs), laboratory 
analyses (clinical chemistry, hematology, and urinalysis), vital signs, electrocardiograms, 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 who interact with sites during Part 2.  
Part 2 (24-week 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 mg or 150 mg dose in a blinded manner beginning at the Week 24 visit (see figure below). 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
5 
 
 
CONFIDENTIAL 
 
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, and 48 with telephone contacts at Weeks 40 
and 44. Subjects will continue to document all angioedema attacks that occur while on study drug in their e-diary 
and will have regular visits to assess safety and tolerability; Investigator confirmation of angioedema attacks will 
continue to be required for Part 2. Interim safety analyses will be conducted while Part 2 is ongoing to support 
regulatory filings. 
Part 3 (48-week evaluation of safety of open-label BCX7353) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 48 visit. Subjects 
will continue to receive the same BCX7353 dose in Part 3 as received in Part 2 but in an open-label manner. 
Once results from the Part 1 analysis, are available, all subjects in Part 3 may be moved to a single dose level of 
BCX7353, based on the data from Part 1, if appropriate. 
Study visits during Part 3 will occur during Weeks 60, 72, 84, and 96, with telephone contact at Weeks 52, 56, 
64, 68, 76, 80, 88, and 92. A final study follow-up visit will be scheduled approximately 3 weeks following the 
last administration of study drug (Week 99). Investigator confirmation of attacks will not be required in Part 3. 
All attacks 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 are outlined in this Statistical Analysis Plan. 
Number of Subjects (planned and analyzed): 
Approximately 120 subjects will be enrolled in this study (n = 40 per Part 1 dose group). This includes any 
adolescent subjects enrolled in the substudy.   
Diagnosis and main criteria for inclusion: 
See Protocol Section 8.2. 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
6 
 
 
CONFIDENTIAL 
 
Test product, dose and mode of administration: 
BCX7353 capsules, to be administered orally.  
BCX7353 capsules contain 55 and 75 mg of the active ingredient (free base equivalents). Subjects will take the 
following orally QD 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 in both Parts 1 and 2, for a total 
duration of 48 weeks of treatment during Parts 1 and 2 (24 weeks of treatment in each study part for Parts 1 and 
2).  
Subjects randomized to Treatment Group 3 (placebo) in Part 1 will be re-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 110 and 150 mg of the active ingredient (free base equivalents). 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. 
Treatment Groups 1 and 3a (110 mg QD) Part 3: one 110-mg capsule of BCX7353 
Treatment Groups 2 and 3b (150 mg QD) Part 3: one 150-mg capsule of BCX7353 
Subjects randomized to Treatment Groups 1 and 2 will receive a total of up to 96 weeks of active BCX7353 
treatment. Subjects randomized to Treatment Group 3 will receive a total of up to 72 weeks of active BCX7353 
treatment. 
Duration of treatment: 
Subjects will take capsules of BCX7353 or placebo orally for 24 weeks in Part 1 and capsule(s) of BCX7353 in 
Parts 2 and 3 orally for 72 weeks (24 weeks in Part 2 and 48 weeks in Part 3), for a total duration of study drug 
treatment of 96 weeks. 
Reference therapy, dose 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. 
Criteria for evaluation (see protocol section 7.1): 
Part 1 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is as follows: 
• 
The rate of investigator-confirmed HAE attacks during dosing in the entire 24-week treatment period 
(Day 1 to Day 168) 
Part 1 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows:  
• 
Change from baseline in Angioedema Quality of Life (AE-QoL) questionnaire at Week 24 (total score) 
• 
Number and proportion of days with angioedema symptoms through 24 weeks 
• 
Rate of investigator-confirmed HAE attacks 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 attacks over 24 weeks 
• 
Use of HAE attack medications over 24 weeks 
• 
The proportion of responders to study drug, defined as at least a 50% relative reduction in the rate of 
investigator-confirmed HAE attacks during treatment compared with the baseline attack rate 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
7 
 
 
CONFIDENTIAL 
 
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 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 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 consistent with a 
drug rash 
Part 2 Secondary Endpoints 
• 
Number and rate of HAE attacks 
• 
Durability of response (attack rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 
• 
Use of HAE attack medications 
• 
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 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 HAE attacks 
• 
Durability of response (attack rate trend over time) 
• 
Number and proportion of days with angioedema symptoms 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
8 
 
 
CONFIDENTIAL 
 
• 
Use of HAE attack medications 
• 
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 
Statistical methods: 
The primary endpoint is the rate of investigator-confirmed HAE attacks during dosing in the entire treatment 
period of Part 1, expressed as attacks per month where 1 month is defined as 28 days. Comparisons of the rate of 
investigator-confirmed HAE attacks between each BCX7353 dose and placebo during the entire dosing period for 
Part 1 will be conducted using a Poisson regression model. The number of investigator-confirmed attacks will be 
included as the dependent variable, the treatment will be included as a fixed effect, baseline attack rate will be 
included as a covariate and the logarithm of duration on treatment will be included as an offset variable. The 
estimated monthly rate of attacks for each treatment group, the treatment differences expressed as the attack rate 
ratio (BCX7353 over placebo rate ratio) and their associated 95% confidence intervals (CIs) will be provided 
from the Poisson regression model. 
Missing data sensitivity will be conducted for the analysis of the primary endpoint using data collected post 
treatment discontinuation and using multiple imputation for missing data, In addition, a  a tipping point analysis 
will be conducted. A separate analysis using only data from subjects who completed Part 1 will also be 
conducted. 
Analysis of secondary endpoints for Part 1 will be as follows: 
Treatment comparisons in the AE-QoL total score change from baseline will be analyzed using a mixed model 
for repeated measures (MMRM) with fixed effects for treatment, baseline attack rate, baseline AE-QoL, visit, a 
visit by treatment interaction, and a random effect for subject. An unstructured covariance structure will be used. 
The estimated treatment difference for each BCX7353 dose vs. 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 at Week 24. The change from baseline in the AE-QoL 
domain scores (function, fatigue, nutrition, and fear/shame) will also be analyzed using the MMRM model. 
The number and proportion of days with angioedema symptoms through Week 24 will be computed. The 
proportion of days with angioedema symptoms through Week 24 will be analyzed using an analysis of covariance 
model with baseline attack 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. Least squares means (LSM) will be presented with the standard error and the number of 
subjects who contribute to the LSM.  
For the Investigator-confirmed HAE attacks during the effective treatment period, between-treatment 
comparisons will be performed using a Poisson regression model similar to that used for the primary endpoint 
analysis. 
A combination of hierarchical testing and the Hochberg step-up procedure will be used to control the Type I error 
rate for testing of primary and secondary endpoints in Part 1. 
Analysis of safety data for Parts 1, 2, and 3 and of effectiveness data for Parts 2 and 3 will primarily be 
descriptive. 


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TABLE OF CONTENTS 
TECHNICAL SUMMARY REPORT (TSR) ..................................................................................3 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
1. 
LIST OF ABBREVIATIONS.....................................................................................15 
2. 
INTRODUCTION ......................................................................................................17 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................17 
3.1. 
Study Objectives .........................................................................................................17 
3.1.1. 
Part 1 Primary Objective ............................................................................................17 
3.1.2. 
Part 1 Secondary Objectives .......................................................................................17 
3.1.3. 
Part 2 Primary Objective ............................................................................................17 
3.1.4. 
Part 2 Secondary Objectives .......................................................................................17 
3.1.5. 
Part 3 Primary Objectives ...........................................................................................18 
3.1.6. 
Part 3 Secondary Objectives .......................................................................................18 
3.2. 
Study Endpoints ..........................................................................................................18 
3.2.1. 
Part 1 Primary Efficacy Endpoint ...............................................................................18 
3.2.2. 
Part 1 Secondary Efficacy Endpoints .........................................................................18 
3.2.3. 
Part 1 Exploratory Efficacy Endpoints .......................................................................18 
3.2.4. 
Part 1 Safety Endpoints ..............................................................................................19 
3.2.5. 
Part 1 Health Outcome Endpoints ..............................................................................19 
3.2.6. 
Part 2 Primary Endpoints ............................................................................................19 
3.2.7. 
Part 2 Secondary Endpoints ........................................................................................19 
3.2.8. 
Part 3 Primary Endpoints ............................................................................................20 
3.2.9. 
Part 3 Secondary Endpoints ........................................................................................20 
4. 
STUDY DESIGN .......................................................................................................20 
4.1. 
Summary of Study Design ..........................................................................................20 
4.2. 
Definition of Study Drugs ..........................................................................................24 
4.3. 
Sample Size Considerations .......................................................................................24 
4.3.1. 
Sample Size Justifications ..........................................................................................24 
4.3.2. 
Sample Size Re-estimation .........................................................................................24 
4.4. 
Randomization ............................................................................................................24 


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4.4.1. 
Part 1 Randomization .................................................................................................25 
4.4.2. 
Part 2 Randomization .................................................................................................25 
4.5. 
Clinical Assessments ..................................................................................................26 
5.
PLANNED ANALYSES ............................................................................................35 
5.1. 
Interim Analyses .........................................................................................................35 
5.2. 
Primary Efficacy Analysis at the End of Part 1 ..........................................................35 
5.3. 
Final Analysis .............................................................................................................35 
5.4. 
Other Analyses to Support Safety Review and Regulatory Submissions...................35 
6.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING ...............................................................................................................36 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........36 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................39 
6.3. 
Data Management .......................................................................................................40 
6.4. 
Data Presentation Conventions ...................................................................................40 
6.5. 
Analysis Populations ..................................................................................................41 
6.5.1. 
Screen Failures ............................................................................................................41 
6.5.2. 
Safety Population ........................................................................................................41 
6.5.3. 
Intent to Treat Population ...........................................................................................41 
6.5.4. 
Per-Protocol Population ..............................................................................................41 
6.5.5. 
Completers ..................................................................................................................41 
6.5.6. 
Pharmacodynamic Population ....................................................................................41 
6.5.7. 
Pharmacokinetic/Pharmacodynamic Population ........................................................41 
6.6. 
Baseline Definition .....................................................................................................42 
6.6.1. 
Baseline Attack Rate ...................................................................................................42 
6.6.2. 
Categorized Baseline Attack Rate ..............................................................................42 
6.6.3. 
Baseline Age ...............................................................................................................42 
6.7. 
Derived and Transformed Data ..................................................................................42 
6.7.1. 
Study Day ...................................................................................................................42 
6.7.2. 
Change from Baseline .................................................................................................43 
6.7.3. 
Visit Windows ............................................................................................................43 
6.7.4. 
Multiple Assessments .................................................................................................44 
6.7.5. 
Derived Efficacy Endpoints ........................................................................................44 


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6.7.6. 
Derived Health Outcomes Endpoints .........................................................................50 
6.8. 
Handling of Missing Data ...........................................................................................54 
6.8.1. 
Imputation of Missing Efficacy Endpoints Post Study Treatment 
Discontinuation ...........................................................................................................54 
6.8.2. 
Other Sensitivity Analyses for Missing Data .............................................................56 
6.8.3. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................56 
6.8.4. 
Missing Start Date, Stop Date, Severity, or Relationship for Adverse Event ............57 
6.8.5. 
Missing Time of First Dose or Time of Last Dose .....................................................57 
6.8.6. 
Incomplete Date and Time for a Subject-Reported Attack ........................................57 
7. 
STUDY POPULATION .............................................................................................57 
7.1. 
Subject Disposition .....................................................................................................57 
7.2. 
Screen Failures ............................................................................................................58 
7.3. 
Protocol Deviations and Listing of Subject Inclusion and Exclusion Criteria ...........58 
7.4. 
Demographic and Baseline Characteristics ................................................................59 
7.5. 
HAE Medical and Medication History .......................................................................59 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................59 
7.7. 
Prior and Concomitant Non-HAE and HAE Medications ..........................................59 
7.8. 
Baseline Physical Examination ...................................................................................60 
7.9. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................60 
8. 
EFFICACY .................................................................................................................60 
8.1. 
General Considerations ...............................................................................................60 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................61 
8.3. 
Statement of the Null and Alternate Hypotheses ........................................................61 
8.4. 
Subgroup Analyses .....................................................................................................62 
8.5. 
Multiple Comparisons and Multiplicity......................................................................62 
8.6. 
Analysis of the Primary Efficacy Endpoint ................................................................63 
8.6.1. 
Primary Efficacy Analysis ..........................................................................................63 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Results ................................................64 
8.7. 
Analysis of the Secondary Efficacy Endpoints ..........................................................65 
8.7.1. 
Angioedema Quality of Life (Total and Domain Scores) ..........................................65 
8.7.2. 
Number and Proportion of Days with Angioedema Symptoms .................................65 
8.7.3. 
Rate of Investigator-Confirmed HAE Attacks during Dosing in the Effective 
Treatment Period ........................................................................................................66 


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8.7.4. 
Use of HAE Attack Medications ................................................................................66 
8.7.5. 
Discontinuations due to Lack of Efficacy ..................................................................66 
8.8. 
Analysis of Additional Exploratory Efficacy Endpoints ............................................67 
8.8.1. 
Number and Proportion of Subjects with No Attacks ................................................67 
8.8.2. 
Proportion of Responders to Study Drug....................................................................67 
8.8.3. 
Attack Characteristics .................................................................................................67 
8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................68 
9. 
HEALTH OUTCOMES .............................................................................................68 
9.1. 
EQ-5D-5L ...................................................................................................................68 
9.2. 
Treatment Satisfaction Questionnaire for Medication ................................................68 
9.3. 
Work Productivity and Activity Impairment ..............................................................69 
10. 
SAFETY AND TOLERABILITY ..............................................................................69 
10.1. 
Adverse Event Preferred Term and System Organ Class Summary Tables ...............69 
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 ..................................................................................................................70 
10.1.2. 
Investigator-Identified Rash Events of Special Interest and Gastrointestinal 
Abdominal-Related Adverse Events ...........................................................................71 
10.1.3. 
Missing and Partial Adverse Event Onset Dates ........................................................72 
10.1.4. 
Summaries of Adverse Event Incidence Rates per 100 Person-Years of 
Exposure to Study Treatment .....................................................................................72 
10.2. 
Exposure to Study Treatment and Treatment Compliance .........................................73 
10.3. 
Concomitant and Other Medications ..........................................................................74 
10.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........74 
10.4. 
Laboratory Data ..........................................................................................................74 
10.4.1. 
Prior Androgen Use and Liver Function Test Abnormalities .....................................75 
10.4.2. 
Complement Factors and HAE Diagnosis ..................................................................76 
10.4.3. 
Laboratory Assessments for Rash ..............................................................................76 
10.5. 
Pregnancy ...................................................................................................................76 
10.6. 
Vital Signs ..................................................................................................................76 
10.7. 
12-lead Electrocardiograms ........................................................................................76 
10.8. 
Physical Examination .................................................................................................77 
10.9. 
Study Termination Status ...........................................................................................77 


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11. 
PHARMACOKINETICS ...........................................................................................77 
12. 
PHARMACODYNAMICS ........................................................................................77 
13. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................78 
14. 
PHARMACOGENETICS ..........................................................................................78 
15. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ....................................78 
16. 
REFERENCES ...........................................................................................................80 
17. 
APPENDIX.................................................................................................................81 
17.1. 
Table of Contents for Data Display Specifications ....................................................81 
Tables 
 ....................................................................................................................................81 
Listings 
 ....................................................................................................................................89 
Figures 
 ....................................................................................................................................92 
Data Display Specifications ...........................................................................................................95 
List of Preferred Terms, High Level Terms, and High-Level Group Terms for 
Gastrointestinal Abdominal-Related Treatment-Emergent Adverse Events ..............95 
 
 
 


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LIST OF TABLES 
 Table 1:        List of Abbreviations and Definitions of 
Terms ..........................................................................................................................15 
Table 2. 
Schedule of Assessments: Part 1 of Study BCX7353-302 .........................................27 
Table 3. 
Schedule of Assessments: Part 2 of Study BCX7353-302 .........................................31 
Table 4. 
Schedule of Assessments: Part 3 of Study BCX7353-302 .........................................33 
Table 5: 
Treatment Descriptors for Part 1 Only Displays ........................................................36 
Table 6: 
Treatment Descriptors for Displays using only Part 2 or Part 3 .................................37 
Table 7: 
Treatment Descriptors for Displays for Entire Study .................................................38 
Table 8: 
Adjusted Visit for Active Treatment for Subjects Originally Assigned to 
Placebo ........................................................................................................................39 
Table 9: 
Visit Windows (Days) ................................................................................................43 
Table 10: Determination of Attack Location Using Symptoms Collected in the e-Diary ..........48 
Table 11: EQ-5D-5L Dimensions (UK English Sample Version) ..............................................51 
Table 12: List of Questions for TSQM .......................................................................................52 
Table 13: Reason for Study Treatment Discontinuation and Whether Data are 
Considered Missing at Random or Not ......................................................................55 
Table 14: Definition of Compliance Categories .........................................................................74 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................23 
Figure 2: 
Study Randomization ..................................................................................................26 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations and Definitions of Terms 
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 
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  
ECG 
Electrocardiogram 
EC50 
Half-Maximal Effective Concentration  
eCRF 
Electronic Case Report Form 
e-diary 
Electronic Diary 
EQ-5D-5L 
EuroQoL 5-dimensional, 5-level questionnaire  
EQ VAS 
EuroQoL Visual Analogue Scale 
GI 
Gastrointestinal  
HAE 
Hereditary Angioedema 
HLGT 
High-Level Group Term 
ICH 
International Council for Harmonization  
ITT 
Intent-to-Treat Population 
IXRS 
Interactive Response System  
%KKI 
Percent Kallikrein Inhibition  
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 


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PBMC 
Peripheral Blood Mononuclear Count 
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 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SAS 
Statistical Analysis System  
SD 
Standard Deviation 
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  
TTO 
Time Trade-Off 
ULN 
Upper Limit of Normal 
US 
United States  
VAS 
Visual Analogue Scale 
WHO 
World Health Organization  
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 BCX7353-302. 
Protocol Revision Chronology: 
Protocol 
21 November 2017 
Version 1 
Protocol 
11 October 2018 
Version 2 – added Part 3 to extend the study to 
96 weeks to allow for collection of long-term 
safety and effectiveness data. 
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 BCX7353-302. 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 final analysis will be made, the SAP will be finalized, approved by the 
Sponsor, and placed on file before the database is locked for interim analysis. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Part 1 Primary Objective 
• To determine the efficacy of prophylactic BCX7353 110 mg and 150 mg 
administered once daily (QD) for 24 weeks compared to placebo 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 administered 
QD for 24 weeks  
• To assess the effects of BCX7353 on HAE disease activity and HAE attack 
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 mg and 150 mg 
administered QD over a 24- to 48-week administration period in subjects with HAE 
3.1.4. 
Part 2 Secondary Objectives 
• To assess the effectiveness (ie, HAE attack frequency over time) of BCX7353 over a 
24- to 48-week administration period 


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• To evaluate QoL and HAE disease activity of BCX7353 over a 24- to 48-week 
administration period 
• To evaluate subject’s satisfaction with BCX7353 over a 24- to 48-week 
administration period 
3.1.5. 
Part 3 Primary Objectives 
• To evaluate the long-term safety and tolerability of BCX7353 administered QD over 
a 48- to 96-week administration period in subjects with HAE 
3.1.6. 
Part 3 Secondary Objectives 
• To assess the effectiveness (ie, HAE attack frequency over time) of BCX7353 over a 
48- to 96-week administration period 
• To evaluate QoL and HAE disease activity of BCX7353 over a 48- to 96-week 
administration period 
• To evaluate subject satisfaction with BCX7353 over a 48- to 96-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 investigator-confirmed HAE attacks during dosing in the entire 24-week 
treatment period (Day 1 to Day 168) 
3.2.2. 
Part 1 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are as follows:  
• 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 
• Rate of investigator-confirmed HAE attacks 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 attacks over 24 weeks 
• Use of HAE attack medications over 24 weeks 
• The proportion of responders to study drug, defined as at least a 50% relative 
reduction in the rate of investigator-confirmed HAE attacks during treatment, 
compared with the baseline attack rate 


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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 questionnaire (EQ-5D-5L) scores 
• Treatment Satisfaction Questionnaire for Medication (TSQM) scores 
• Work productivity and activity impairment questionnaire (WPAI) 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 HAE attacks 
• Durability of response (attack rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Use of HAE attack medications 
• Discontinuations due to lack of efficacy 
• Durability in angioedema QoL questionnaire scores 
• Durability in EQ-5D-5L scores 
• Durability in TSQM scores 
• Durability in WPAI scores 


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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 HAE attacks 
• Durability of response (attack rate trend over time) 
• Number and proportion of days with angioedema symptoms 
• Use of HAE attack medications 
• 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 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part study. 
Part 1 is designed to test the hypothesis that the HAE attack rate during 24 weeks of prophylactic 
BCX7353 will be less than that observed during 24 weeks of placebo. 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, 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. 
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 attacks 


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documented during a prospective run-in period of 2 to 8 weeks from the date of the screening 
visit.  
Approximately 96 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 (N = 32): BCX7353 110 mg administered orally QD for 24 weeks 
Group 2 (N = 32): BCX7353 150 mg administered orally QD for 24 weeks 
Group 3 (N = 32): Placebo administered orally QD for 24 weeks 
Enrollment into treatment groups will be stratified by the baseline HAE attack rate 
(≥ 2 attacks/month vs. < 2 attacks/month).  
Qualifying attacks for eligibility determination are characterized as follows: 
• The attacks must occur during the run-in period of 56 consecutive days, starting on 
the day of the screening visit  
• The attacks are unique, defined as an attack that does not begin within 48 hours of the 
end of a previous attack. 
• The attacks must have either been treated, required medical attention, or be 
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 the HAE attack). 
• The attacks must include symptoms of swelling. Symptoms of swelling, in addition to 
visible swelling, may also include symptoms in the oropharyngeal or abdominal 
regions, which are indicative of internal swelling. 
• The attacks are otherwise confirmed by the Investigator to be HAE attacks.  
Once the subject records 2 such attacks, he or she may be randomized to study drug beginning on 
or after Day 28 of the run-in period; subjects who have at least 3 such attacks may be 
randomized to study drug beginning on or after Day 14 of the run-in period. A study schematic 
can be found in Figure 1. 
Beginning at screening and through the Week 48 visit, details of acute attacks of angioedema 
will be recorded in an electronic diary (e-diary). Attacks will be treated in accordance with the 
subject’s normal standard of care. Within approximately 2 business days of the end of each 
attack that occurs from the screening visit through the Week 48 visit, subjects will be contacted 
by the Investigator (or appropriately trained designee) to discuss the clinical characteristics of the 
attack, any questions on the entered data or to gain additional attack details not included in the 
e-diary that the Investigator deems important to clinically evaluate the event, as applicable. This 
information, in conjunction with the e-diary record, will be used by the Investigator to verify or 
reject the event recorded in the diary as an HAE attack. All Investigator-confirmed attacks of 
HAE must include symptoms of swelling; prodromal symptoms in the absence of swelling are 
not considered HAE attacks, regardless of treatment. Symptoms of swelling, in addition to 
visible swelling, may also include symptoms in the oropharyngeal or abdominal regions, which 
are indicative of internal swelling.  


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The main study will be comprised of adult subjects (≥ 18 years of age); a substudy in 
participating regions will allow adolescent subjects (≥ 12 to 17 years of age) to enroll. Main 
study and substudy subjects will be randomized via a separate randomization scheme; however, 
study-mandated procedures will be identical, and the analyses will include all subjects who 
participate in the study. 
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 subjects, site 
staff, and Sponsor staff who interact with sites on a regular basis during Part 2. 
Part 2 (24-week 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 mg QD dose 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, and 48 with telephone contact at 
Weeks 40 and 44. Subjects will continue to document all angioedema attacks that occur while on 
study drug in their e-diary. Investigator confirmation of attacks will continue to be required for 
Part 2. Interim safety analyses will be conducted while Part 2 is ongoing to support regulatory 
filings. 
Part 3 (48-week evaluation of safety of open-label BCX7353) 
Part 3 of the study will start with the administration of the study drug dispensed at the Week 48 
visit.  Subjects will continue to receive the same BCX7353 dose in Part 3 to which they were 
randomized in Part 2 of the study in an open-label manner. Once Part 1 results are available, all 
subjects in Part 3 may be moved to a single dose level of BCX7353, based on the data from 
Part 1, if appropriate.  
Study visits in Part 3 will occur during Weeks 60, 72, 84, and 96, with telephone contact at 
Weeks 52, 56, 64, 68, 76, 80, 88, and 92.  
Subjects will continue to document all angioedema attacks that occur in a paper diary throughout 
Part 3 and will have regular visits to assess safety and tolerability. Investigator confirmation of 
attacks will not be required for Part 3. All attacks 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, which were constructed in concert with HAE-treating physicians, will be 
outlined in this SAP.  
A final study follow-up visit will be scheduled approximately 3 weeks following the last 
administration of study drug (Week 99). 


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Figure 1: 
Study Schema 
 
Abbreviations: QD = once daily. 
 


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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 
and as one 110-mg capsule of BCX7353 per dose for Part 3. 
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 of BCX7353 per dose for Part 3. 
Placebo QD is supplied as 2 capsules of matching placebo per dose. 
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
The pooled standard deviation (SD) of the attack rate during effective dosing period (Days 8 to 
28) in Study BCX7353-203 was 0.55. The observed treatment difference between the BCX7353 
125 mg dose with dihydrochloride salt (equivalent to the 110 mg free base dose for the current 
study) and placebo for the effective dosing period using the full analysis population was 
0.70 attacks/week, which represented a 73.8% reduction in attack rate from the placebo group.  
Assuming a normalized placebo attack rate of 1 unit and a common SD of 0.55 units for 
BCX7353 and placebo attack rates, a sample size of 32 subjects will have 94% power to detect a 
50% attack rate reduction (a treatment difference of 0.5 units) between BCX7353 and placebo, 
based on a 2-sided test at significance level of 0.05. 
Sample sizes were increased to approximately 40 subjects for each active treatment group and 
placebo, to conservatively account for a potential dropout rate of 20%.  Initial sample size 
calculations at the time the protocol was written did not allow for dropout. 
4.3.2. 
Sample Size Re-estimation 
A blinded sample size re-estimation was originally planned to address uncertainty of the 
variability in the SD of the HAE attack rate. An interim analysis may have been performed after 
50% subjects completed 24 weeks to provide the SD of the attack rate based on pooled data. 
Based on the pooled SD, the sample size may have been re-estimated to maintain at least 90% 
power to detect a 50% attack rate reduction. The study would have remained blinded, and the 
interim analysis would have been based on pooled data for sample size re-estimation. The final 
sample size was to be the maximum of either the initial sample size or the re-estimated sample 
size. 
Due to rapid enrollment of study subjects, the sample size re-estimation was not performed. 
4.4. 
Randomization 
Subjects will be randomized via the interactive response system (IXRS). Details on the processes 
followed for randomization are provided in a separate manual. 


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4.4.1. 
Part 1 Randomization 
Approximately 96 subjects will be randomized in a 1:1:1 (active:active:placebo) ratio to 1 of the 
following treatments in Part 1:  
• Group 1: BCX7353 110 mg administered orally QD for 24 weeks  
• Group 2: BCX7353 150 mg administered orally QD for 24 weeks 
• Group 3: Placebo administered orally QD for 24 weeks 
Enrollment into treatment groups will be stratified by the site-calculated baseline HAE attack 
rate (≥ 2 attacks/month vs. < 2 attacks/month). The site-calculated baseline attack rate must have 
been provided during randomization and was to be calculated as: 
Number of HAE attacks meeting baseline criteria from Screening to Randomization × 28
Randomization Date −Screening Date + 1
 
 
HAE attacks to be utilized in calculation of the baseline attack rate must meet the following 
criteria: 
• The attacks must be unique, which is defined as an attack that does not begin within 
48 hours of the end of the previous attack. 
• The attacks must have either been treated, required medical attention, or have been 
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/she is at least slightly 
restricted in daily activities during the HAE attack). 
• The attacks must include symptoms of swelling. Symptoms of swelling, in addition to 
visible swelling, may also include symptoms in the oropharyngeal or abdominal 
regions, which are indicative of internal swelling. 
• The attacks must be confirmed by the Investigator to be HAE attacks. Subjects will 
be contacted within 2 business days of the attack to discuss the attack and to resolve 
any Investigator queries on the entered data in the e-diary, as applicable. 
4.4.2. 
Part 2 Randomization 
At the Week 24 visit, subjects originally randomized to placebo in Part 1 will be randomized in a 
1:1 (active:active) ratio to receive a 110 mg QD or 150 mg QD dose of BCX7353 in Part 2 (see 
Figure 2).  Subjects will continue to receive the same dosing regimen received in Part 2 during 
Part 3. Once Part 1 results are available, all subjects in Part 3 may be moved to a single dose 
level of BCX7353, based on the data from Part 1, if appropriate. 


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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 2, Table 3, and Table 4, 
respectively. 


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Table 2. 
Schedule of Assessments: Part 1 of Study BCX7353-302 
Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
 
Week 24  
Day 169d 
 
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 
Informed consentb 
X 
 
 
 
 
 
 
 
 
In-clinic evaluations 
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 
 
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 
 
 
 
 
 
 
 
Attack qualification confirmationn 
 
X 
 
 
 
 
 
 
 
Safety laboratory evaluationsh 
X 
 
X 
Xc 
X 
X 
X 
X 
X 
Troponin I, Troponin T 
 
 
X 
 
X 
X 
X 
X 
X 
C3 and C1-INH antigenic level 
 
 
X 
 
 
 
 
 
 
HLA typingo 
 
 
X 
 
 
 
 
 
 
Optional sample for possible 
exploratory PG 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 
EQ-5D-5Lr,s 
 
 
X 
 
X 
X 
X 
X 
X 
AE-QoL, TSQM, WPAIs 
 
 
X 
 
X 
X 
X 
X 
X 


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Assessment 
Screening Period 
Baseline 
Part 1 
Double-Blind, Placebo-Controlled Study Drug Administration 
 
Week 24  
Day 169d 
 
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 
Concomitant medications 
 
AEs 
 
Randomizationt 
 
 
X 
 
 
 
 
 
X 
e-diary instruction/review/ 
set-upu 
X 
X 
X 
 
X 
X 
X 
X 
X 
e-diary daily completionv 
 
Study drug dosingw 
 
 
 
 
Investigator confirmation of 
attacksx 
 
Study drug accountability/ 
dispensing 
 
 
X 
 
X 
X 
X 
X 
X 
Plasma for PK analysisy 
 
 
X 
 
X 
X 
X 
X 
X 
Plasma for kallikrein inhibitiony 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; AE-QoL = Angioedema Quality of Life; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BMI = body mass index; C1-INH = C1 esterase inhibitor; C3 = complement 3; C4 = complement 4; CK-MB = creatine kinase MB isoenzyme; 
CRF = case report form; ECG = electrocardiogram; e-diary = electronic diary; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; FSH = follicle 
stimulating hormone; GGT = gamma glutamyl transferase; 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; LLN = lower limit of normal; NGAL = neutrophil 
gelatinase-associated lipocalin; PD = pharmacodynamic; PG = pharmacogenomic; PK = pharmacokinetic; QTcF = QT interval corrected using Fridericia’s 
method; TSQM = Treatment Satisfaction Questionnaire for Medication; WPAI = Work Productivity and Activity Index.  
a 
 The baseline visit must be held within 10 weeks (70 days) of the Screening visit, accommodating a run-in period of 14 days (minimum) to up to 56 days 
(maximum). 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 HAE attack 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 
may be required to accommodate possible reflex testing for abnormal GGT, AST or ALT. If preferred by the subject and clinical site, laboratory values may 
be drawn and resulted locally, with results entered into the CRF. 
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 during through 
Week 24; alternative forms of interactive communication such as returned email and cellular text correspondence are acceptable. During all calls, the 


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investigator (or designee) will assess the subject’s overall wellbeing, discuss compliance (if applicable), proper recording of attack details (if applicable), or 
any usability issues with the e-diary. A weekly phone call may be omitted if the subject records an attack as the Investigator must call and confirm or reject 
the attack (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 
The protocol 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 post-baseline visits except for Week 2. 
j  
For women of childbearing potential (including adolescents), regardless of contraception or lifestyle, a serum pregnancy test will be administered at 
screening, urinary 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. In addition to urine pregnancy tests at study visits, women of childbearing potential who enroll at 
sites in Europe will be dispensed urinary pregnancy tests to be completed at home at Weeks 16 and 22. Sites will confirm negative test results by telephone 
and record the results in source documents. 
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 I or II, defined as having a C1-INH functional level below 50% and a C4 level below the lower LLN reference range, as 
assessed during the screening period. In the absence of a low C4 value drawn during the intercritical period, 1 of the following is acceptable to confirm the 
diagnosis of HAE assessed during the Screening period: 1) a SERPING-1 gene mutation known or likely to be associated with HAE Type 1 or 2; 2) a 
confirmed family history of C1-INH deficiency; 3) a C4 redrawn and retested during an attack with the results below the LLN reference range. For subjects 
with C1-INH function ≥ 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II assessed 
during the screening period or a repeat C1-INH functional level < 50% will be considered acceptable for enrollment. 
n 
The subject will be determined as eligible for the study based upon screening evaluations and the prospective recording of HAE attacks during the run-in 
period. The subject must have at least 2 HAE attacks during the run-in period which meet all of the following requirements: 1) the attacks must occur during 
the run-in period (period between Screening and Baseline; minimum of 14 days and maximum of 56 days); 2) the attacks are unique, which is defined as an 
attack that does not begin within 48 hours of the end of a previous attack; 3) the attacks must have either been treated, required medical attention or be 
documented to cause functional impairment based on subject entry in the diary; 4) the attacks must include symptoms of swelling. Symptoms of swelling, in 
addition to visible swelling, may also include symptoms in the oropharyngeal or abdominal regions which are indicative of internal swelling and; 5) the 
attacks are otherwise confirmed by the Investigator to be HAE attacks (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 PG 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 this 
visit 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 the Week 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 


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a recollection of their health state during an average attack that they experienced since the last study visit. If the subject has not had an attack since their last 
study visit, the subject is not required to fill out the second, attack-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 for Part 1 and at the Week 24 visit for Part 2 study drug. At Baseline, it is preferred that 
randomization occur preferably after all Baseline assessments have been completed. Sites using a centralized pharmacy may randomize the subject the day 
prior to the baseline and Week 24 visits. 
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, up to the Week 48 visit, they will enter HAE attacks 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  
The Investigator (or designee) will review the e-diary record of all HAE attacks that occur from Screening through Week 48 and either confirm or reject the 
attack as an HAE attack. At least 2 attacks 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 attacks that occur, subjects will be contacted within approximately 2 business days of the end of the attack to 
discuss the clinical characteristics of the attack, any questions the Investigator has on the entered data or to gain additional attack details not included in the 
e-diary that the Investigator deems important to clinically evaluate the event, as applicable. This information, in conjunction with the e-diary record, will be 
used by the Investigator to verify or reject the event recorded in the diary as an HAE attack. The e-diary data review, subject contact summary, and 
Investigator verification of the attack will be documented in the source records; the Investigator attack verification (confirmed or rejected) will also be 
recorded.  
y  
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 CRF).  
 
 


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Table 3. 
Schedule of Assessments: Part 2 of Study BCX7353-302 
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 
In-clinic evaluations 
X 
X 
X 
X 
 
 
X 
Telephone contactc 
 
 
 
 
X 
X 
 
Subject weight 
 
X 
X 
X 
 
 
Xq 
Physical examinationd 
 
X 
X 
X 
 
 
X 
Urine pregnancy testp 
 
X 
X 
X 
 
 
X 
Vital signse 
 
X 
X 
X 
 
 
X 
Safety laboratory evaluationsf 
Xb 
X 
X 
X 
 
 
X 
Troponin I and Troponin T 
 
X 
X 
X 
 
 
X 
NGAL 
 
X 
X 
X 
 
 
X 
CK-MB 
 
X 
X 
X 
 
 
X 
Urinalysisf 
Xb 
X 
X 
X 
 
 
X 
12-lead ECGg 
 
X 
X 
X 
 
 
X 
EQ-5D-5Lh,i 
 
X 
X 
X 
 
 
X 
AE-QoL, TSQM, WPAIi 
 
X 
X 
X 
 
 
X 
Concomitant medications 
 
AEs 
 
e-diary instruction/reviewj 
 
X 
X 
X 
X 
X 
X 
e-diary daily completionk 
 
Study drug dosing1 
 
Investigator confirmation of attacksm 
 
Study drug accountability/ dispensing 
 
X 
X 
X 
 
 
X 
Plasma for PK analysiso 
 
X 
X 
X 
 
 
X 
Plasma for kallikrein inhibitiono 
 
X 
X 
X 
 
 
X 
Abbreviations: AE = adverse event; AE-QoL = Angioedema Quality of Life; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; CK-MB = creatine kinase MB isoenzyme; CRF = case report form; 
ECG = electrocardiogram; e-diary = electronic diary; GGT = gamma glutamyl transferase; HAE = hereditary angioedema ; NGAL = neutrophil 
gelatinase-associated lipocalin; PD = pharmacodynamic; PK = pharmacokinetic; QoL = quality of life; QTcF = QT interval corrected using Fridericia’s method; 
TSQM = Treatment Satisfaction Questionnaire for Medication; WPAI = Work Productivity and Activity Index.  
a 
Period 2 study drug is to be initiated upon administration of study drug dispensed at the Week 24 visit. 
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 may be required to accommodate possible reflex testing for abnormal GGT, AST or ALT. If preferred by the subject and clinical site, laboratory 
values may be drawn and resulted locally, with results entered into the CRF. 


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c      The Investigator (or designee) must call and talk to the subject during Week 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 attack details (if applicable), or any usability issues with the e-diary. The phone call may be omitted if the 
subject records an attack as the Investigator must call and confirm or reject the attack (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       The protocol 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 once at baseline and 1 to 2 × at Weeks 28, 32, 36, and 48. 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 attack that they experienced since the last study visit. If the subject has not had an attack since their last study visit, the 
subject is not required to fill out the second, attack-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 up to the Week 48 visit, they will enter HAE attacks 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  
The Investigator (or designee) will review the e-diary record of all HAE attacks that occur from Screening through Week 48 and either confirm or reject the 
attack as an HAE attack. For all attacks that occur, subjects will be contacted within approximately 2 business days of the end of the attack to discuss the 
clinical characteristics of the attack, any questions the Investigator has on the entered data or to gain additional attack details not included in the e-diary that 
the Investigator deems important to clinically evaluate the event, as applicable. This information, in conjunction with the e-diary record, will be used by the 
Investigator to verify or reject the event recorded in the diary as an HAE attack. The e-diary data review, subject contact summary, and Investigator 
verification of the attack will be documented in the source records; the Investigator attack verification (confirmed or rejected) will also be recorded.  
n  
Early termination visit only (if occurring during dosing phase) 
o         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 CRF).  
p 
In addition to urine pregnancy tests at study visits, women of childbearing potential who enroll at sites in Europe will be dispensed urinary pregnancy tests to 
be completed at home at Weeks 40 and 44. Sites will confirm negative test results by telephone and record in source documents. 
q  
Adolescent subjects will also have height measured at Week 48. 
 
 


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Table 4. 
Schedule of Assessments: Part 3 of Study BCX7353-302  
Assessment 
Part 3 
Open-Label, Active Study Drug Administrationa 
 
Follow-up/  
Early Termination Visit  
Week 99 + 1 week 
 
Week 60 
Day 421 ± 6 days  
Week 72 
Day 505 ± 6 days 
Week 84 
Day 589 ± 6 days 
Week 96 
Day 673 + 7 days 
In-clinic evaluations 
X 
X 
X 
X 
X 
Telephone contactb 
 
 
 
 
 
Subject weight 
X 
X 
X 
X 
X 
Physical examinationc 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
Xd 
Xd 
X 
X 
Vital signse 
X 
X 
X 
X 
X 
Safety laboratory evaluationsf 
X 
X 
X 
X 
X 
Troponin I and Troponin T 
X 
X 
X 
X 
X 
NGAL 
X 
X 
X 
X 
X 
CK-MB 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
X 
X 
X 
12-lead ECGg 
X 
X 
X 
X 
X 
EQ-5D-5Lh,i 
X 
X 
X 
X 
 
AE-QoL, TSQM, WPAIi 
X 
X 
X 
X 
 
Concomitant medications 
 
AEs 
 
Diary instruction/reviewj 
X 
X 
X 
X 
X 
Diary daily completionk  
 
 
Study drug dosingl 
 
 
Study drug accountability/ 
dispensing 
X 
X 
X 
X 
Xm 
Plasma for PK analysisn 
 
 
 
 
Xm 
Plasma for kallikrein inhibitionn 
 
 
 
 
Xm 
Abbreviations: AE = adverse event; AE-QoL = Angioedema Quality of Life; CK-MB = creatine kinase MB isoenzyme; CRF = case report form; 
ECG = electrocardiogram; EQ-5D-5L = EuroQoL 5-dimensional, 5-level questionnaire; NGAL = neutrophil gelatinase-associated lipocalin; 
PD = pharmacodynamic; PK = pharmacokinetic; QoL = quality of life; QTcF = QT interval corrected using Fridericia’s method; TSQM = Treatment Satisfaction 
Questionnaire for Medication; WPAI = Work Productivity and Activity Index.  
a 
Period 3 study drug is to be initiated on Day 337, the day of the Week 48 visit. 
b  
The Investigator (or designee) must call and talk to the subject during Weeks 52, 56, 64, 68, 76, 80, 88, and 92; 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 attack details (if applicable).  


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c 
Abbreviated physical examinations targeted to signs and symptoms will be performed at post-baseline visits.  
d 
At the Week 60, 72, and 84 visits, sites in Europe will dispense urinary pregnancy tests to subjects who are women of childbearing potential. These will be 
performed by the subject at home at Weeks 64, 68, 76, 80, 88, and 92. 
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 
The protocol 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. An ECG should be 
repeated for a change from baseline in QTcF > 60 msec or a QTcF interval > 500 msec. 
h  
Two EQ-5D-5L assessments will be administered at Weeks 60, 72, 84, and 96. The subject will fill out the first EQ-5D-5L 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 
attack that they experienced since the last study visit. If the subject has not had an attack since their last study visit, the subject is not required to fill out the 
second, attack-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 diary re-education should occur on an as-needed basis. 
k 
Any time the diary is in the subject's possession after Week 48 the subject will enter HAE attacks and relevant details at least once per day. No dosing 
information will be collected in in subject diaries in Part 3.  
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. 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 diary (this may also be captured in the CRF).  
 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
A blinded interim analysis for the purpose of sample size re-estimation after 50% of subjects 
(48 subjects) complete 24 weeks (See Section 4.3.2) may be conducted. A primary analysis is 
planned at the end of Part 1 when all subjects have completed Part 1 of the study.  
An additional interim cut of the data may be required for purposes of regulatory filings when a 
total of 100 subjects have completed 48 weeks of dosing at 150 mg in either the current study or 
Study BCX7353-204, an open-label study of safety of 2 active doses, 110 and 150 mg. At the 
time of this data cut, an analysis of integrated safety data from Studies BCX7353-204 and 
BCX7353-302 may be performed. The integrated analysis will be the subject of a separate SAP. 
Additionally, summaries of attack rates over time by month and AE-QoL by visit, including all 
available data post Week 24, may be produced for the current study at the time of the integrated 
analysis. 
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. This analysis will include all data through the end of Part 1 (24-week assessment). 
This is a double-blind study throughout both Parts 1 and 2. As such, study drug assignment for 
each subject will be blinded to the Investigator, site staff, study subjects, and clinical research 
organization (CRO) staff involved with study operations.  Part 3 is open-label and will unblind 
the subject, Investigator, and site staff to Part 2 treatment assignment (but not Part 1 treatment) at 
the time that the subject transitions to Part 3 as Part 3 involves a continuation of the treatment 
received in Part 2. 
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 locked for the primary analysis at the end of 
Part 1. 
5.3. 
Final Analysis   
Final analysis for the study will occur when the last subject completes the study, the data are 
cleaned, and the database is locked for analysis.  
5.4. 
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. 
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 (ICH 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 
• Statistical Analysis System (SAS®) program name, including the path where the 
program is stored 
• Any other output specific details that require further elaboration 
Version 9.4 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 subject ID, and visit, if applicable. Listings for the entire study period will 
include will generally be sorted by subject ID, treatment, and visit, if applicable.  
Adjusted visit (as described in Table 8) 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 first dose of Part 2 treatment, if applicable. 
One exception to the sort order is that laboratory listings will be sorted by laboratory parameter 
first and then by the other variables. 
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 5). 
Table 5: 
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 
 


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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 6. The descriptors shown in Table 6  also apply 
to any displays specific to Part 3. 
Table 6: 
Treatment Descriptors for Displays using only Part 2 or Part 3  
Sort 
order 
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 Parts 2 with continuation of 
treatment in Part 3. 
4 
150 mg after placebo 
For subjects who were originally randomized to placebo and 
were randomized to 150 mg for Parts 2 with continuation of 
treatment in Part 3. 
 
For tables that cover the entire study period, 110 and 150 mg data 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 and 3 only or during the entire study. Treatment 
descriptors are provided in Table 7.   


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Table 7: 
Treatment Descriptors for Displays for Entire Study  
Sort order 
Treatment Descriptor 
Notes 
1 
110 mg 
110 mg (originally randomized) 
2 
110 mg after placebo  
Active treatment data from subjects who were originally 
randomized to placebo and were randomized to 110 mg for 
Parts 2 and 3 
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 
Active treatment data from subjects who were originally 
randomized to placebo and were randomized to 150 mg for 
Parts 2 and 3 
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 8). This will allow for 
combining data from active treatments in Part 1 (either 110 or 150 mg) with active treatment in 
Parts 2 and 3 that follows 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).  


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Table 8: 
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 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 visit in Part 1.  Likewise, there are no Part 3 
adjusted visits corresponding with original visits of Weeks 26, 28, and 32 
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 (WHO) Drug Dictionary from March 2017. AE 
preferred terms (PT) and body/organ systems are coded using Medical Dictionary for Regulatory 
Affairs (MedDRA) version 19.1.  
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 pharmacokinetics (PK), and 
6 for PD. The third level of numbering represents the type of endpoint within the data type, the 
fourth 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 


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included on listings. For listings produced for the entire study that include visit, displays should 
include visit, adjusted visit, visit date, study day, and adjusted study day.  
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 version 9.4 or above 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, race) 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 written 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. 
Safety Population 
The safety population will include all subjects who receive at least 1 capsule of study treatment. 
This population will be used in the assessment and reporting of demographic information, 
BCX7353 drug concentrations, accountability, baseline disease characteristics, and safety data. 
Data will be analyzed according to the actual treatment received at first dose for all subjects or at 
first dose of Part 2 for subjects originally randomized to placebo.  
6.5.3. 
Intent to Treat Population 
The intent to treat (ITT) population will include all randomized subjects, regardless of whether 
study treatment was administered. This population is the primary population for the analysis of 
the efficacy and health outcomes data. Data will be analyzed according to randomized treatment. 
6.5.4. 
Per-Protocol Population 
The per protocol (PP) population will include subjects in the safety population who complete 
Part 1. In addition, 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. The PP population may be used 
as a secondary population for efficacy analyses. 
6.5.5. 
Completers 
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. 
6.5.6. 
Pharmacodynamic Population 
The PD population 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 the listings and summaries of PD data. 
6.5.7. 
Pharmacokinetic/Pharmacodynamic Population   
The PK/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 plots comparing 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. The date and time of first dose of treatment in Part 2 is recorded in the eCRF at the 
Week 24 assessment. 
6.6.1. 
Baseline Attack Rate 
Enrollment into treatment groups is stratified by the baseline HAE attack rate as determined by 
the IXRS system based on the number of attacks and duration of screening as input by the sites 
(≥ 2 attacks/month vs. < 2 attacks/month). For analysis purposes, the baseline attack rate will be 
calculated from the diary data and expressed as attacks per month where 1 month = 28 days as 
follows: 
Number of HAE attacks meeting baseline criteria from Screening to First Dose Date/time × 28
 Date of First Dose −Screening Date + 1
 
Criteria that must be met for attacks to qualify for confirmation by the Investigator during the 
baseline period are provided in Section 4.1.  
Baseline attack rate will be included in statistical models as appropriate. 
6.6.2. 
Categorized Baseline Attack Rate 
Categorized baseline attack rate refers to the categorization of the calculated baseline attack rate 
into strata (≥ 2 attacks/month vs < 2 attacks/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: 
(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 −𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) + 1 
If the date of measurement occurs prior to the first dose date then study day will be calculated as: 
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 −𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 
 There is no Day 0.  


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6.7.2. 
Change from Baseline 
Change from baseline is calculated as: 
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 
Percent change from baseline is calculated as: 
(𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏÷ 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟) × 100 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline 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 9. All information collected at an unscheduled visit will be identified as such in the 
listings. 
Table 9: 
Visit Windows (Days) 
Visit 
Relative Target Day 
Protocol-Specified 
Visit Window 
Analysis Visit 
Window 
Screening visit 
-14 to -56 
-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 373 
Week 60 
421 
415 to 427 
374 to 463 
Week 72 
505 
499 to 511 
463 to 547 
Week 84 
589 
583 to 595 
548 to 631 
Week 96 
673 
664 to 680 
≥632 
 


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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 
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. 
Attack Rate 
General Formula for Attack Rate 
In general, the formula for computing an attack rate is the number of attacks meeting the attack 
criteria divided by the duration of treatment during the reporting period of interest.   
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑜𝑜𝑜𝑜 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖
= 𝑡𝑡ℎ𝑒𝑒 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
−𝑡𝑡ℎ𝑒𝑒 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝+ 1 
 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 ൬𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ൰ 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 
=
 Number of Attacks ∗28
 Duration of Treatment During Reporting Period in Days 
If the subject discontinues treatment early, any attacks that occur within 24 hours after last dose 
will be counted in the calculation of attack rate and the additional 24 hour period will be 
included in the duration of the reporting period. 
 
Subject-Reported Attack Rate 
Diary entries for attacks are considered subject-reported attacks. The count of subject-reported 
attacks can differ from the count of confirmed attacks. In Parts 1 and 2, the investigator reviews 
each attack and either confirms it as an attack or rejects it as an attack. For Part 3, there is no 
investigator review of attacks, but an adjusted subject-reported attack rate will be computed 
based on a list of programmable requirements.     
Subject-reported attack rates will be computed for Parts 1, 2, and 3. 


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Adjusted Subject-Reported Attack Rate for Part 3 
 
Because there is no investigator-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” 
• 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 Attack Rate 
Confirmed attack rates will be computed based on the number of confirmed attacks that occur 
during the reporting period of interest.   
Confirmed attack rates will be computed for the following reporting periods and expressed in 
units of attacks/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 attack rates will be computed for Part 1 and at the end of Part 2. For confirmed attack 
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 
first dose for Part 3. Investigator confirmation is not done in Part 3 and so confirmed attack rate 


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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 attacks that occur within 24 hours after last 
dose will be counted in the calculation of attack rate.  If there are confirmed attacks in the eCRF 
without corresponding diary information, as may happen if a subject verbally reports an attack to 
an investigator but does not enter it into the ediary, the attack will be counted. 
For sensitivity analyses for missing data for the Part 1 primary analysis, confirmed attack 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 attack rate and an imputed 
attack rate for periods of missing data post-treatment discontinuation. Details are provided in 
Section 6.8.1.  
Confirmed Attack Rate by Location 
Confirmed abdominal-only, peripheral, and mixed attack rates will be computed using the 
location definitions provided in Section 6.7.5.9. 
Adjusted Confirmed Attack Rate 
An adjusted confirmed attack rate will be computed for use in the determination of the 50% 
responder endpoint comparing post-baseline attack rates to baseline attack rates. For the adjusted 
confirmed attack rate, the 2 additional requirements for confirmation of attack rates used during 
screening will be applied to post-baseline confirmed attacks to determine the number of 
confirmed attacks meeting the additional requirements. The additional requirements are: 
• The attacks are unique, which is defined as an attack that does not begin within 
48 hours of the end of a previous attack. 
• The attacks 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 attack). 
6.7.5.2. 
Number and Percentage of Subjects Who Are Attack Free over Entire Dosing 
Period and Effective Dosing Period 
The following attack-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 attacks during the period 
of interest. Subjects with no confirmed attacks who discontinue before the end of the 
planned treatment period are not considered attack-free.  
The attack-free rate for active treatment for subjects originally randomized to placebo will be 
based on the 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 reporting 
period for which at least 1 symptom is reported during an investigator-confirmed HAE attack. 


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This endpoint will be determined for Parts 1 and 2 as investigator-confirmation will not be 
calculated for Part 3.  As with the calculation of attack 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.   
6.7.5.4. 
Responder Endpoint 
A subject is defined as being a responder to study treatment if the rate of adjusted confirmed 
attacks during study treatment represents at least a 50% relative reduction compared with the 
baseline attack rate as defined in Section 6.6.1. 
The relative reduction is calculated for Part 1 as:  
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 
= Baseline attack rate − Adjusted Confirmed attack rate on treatment
Baseline attack rate
 × 100% 
where the adjusted confirmed attack 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 attack rate for Part 1 is 
≥ 50%. Otherwise, the subject is classified as a non-responder.  
Responder analysis will be conducted for Part 1 only. 
6.7.5.5. 
Attack Duration 
The duration of each confirmed on-treatment attack will be calculated in hours, based on the start 
and stop date and time of the confirmed attack (time the attack finished). Investigators have the 
option to count more than 1 subject-reported attack as a single confirmed attack. For a confirmed 
attack that includes more than 1 subject-reported attack, the duration is calculated from the start 
of the first subject-reported attack to the end of the last subject-reported attack that has been 
combined into 1 attack.  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 attack from start of the attack to time that the worst was over will also be 
calculated and summarized. 
6.7.5.6. 
Attack Onset Relative to Prior Dose of Study Drug 
For each confirmed on-treatment attack, the time to attack 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 attack, the attack onset time relative to prior dose will be 
missing. The attack onset time relative to prior dose of study drug is information is used in the 
listing of attack data only. 


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6.7.5.7. 
 Medications to Treat HAE Attacks 
The following medications reported as taken as acute treatment in the subject diary or androgens 
listed as acute treatment in the concomitant medications log will be classified in the analyses as 
targeted medications to treat subject-reported HAE attacks: Androgens, Berinert, Cinrzye, 
Kalbitor, Firazyr, Ruconest, fresh frozen plasma.  Other medications listed in the diary for 
treatment of HAE attacks will be considered non-targeted medications to treat subject-reported 
HAE attacks. 
6.7.5.8. 
Attack Symptoms 
Symptoms reported for confirmed on-treatment attacks will be included in summaries of attack 
characteristics. In addition, listings of diary data will show symptoms for all attacks, whether 
subject-reported or investigator-confirmed. 
6.7.5.9. 
Attack Location 
The location of each subject-reported and confirmed on-treatment attack will be determined 
based on the symptoms indicated in the e-diary as shown in Table 10. 
Table 10: 
Determination of Attack Location Using Symptoms Collected in the e-Diary 
Abdominal-Only Attack 
Mixed Attack 
Peripheral Attack  
(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 
• 
Diarrhea a 
Must have at least 1 symptom 
from left and right box (from 
abdominal and peripheral 
attack 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 attack 


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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 attack. 
 
6.7.5.10. Attack Triggers 
All attack triggers for each subject-reported attack will be included in listings of attack data.   
6.7.5.11. AE-QoL 
The AE-QoL (Weller, Groffik 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: 
(𝛴𝛴 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) ÷ (max 𝛴𝛴 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) × 100 
where 
Σ items = Sum of reported item scores per CRF 
Max Σ items = Sum of the maximum possible score for each domain 
The calculated AE-QoL ranges from 0 (best) to 100 (worst).  


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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. 
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 five dimensions; mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression as shown in Table 11. 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 attack since their last visit, starting at Week 4, they 
complete it a second time to reflect on their health status during a “usual attack”. On summary 
tables, the “today” and “usual attack” questionnaire results should appear in different rows. 


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Table 11: 
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 analogue 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’. 


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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 US value set (van Hout, Janssen et 
al. 2012).   
A manual for EQ-5D is available (van Reenen and Janssen 2015).  
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, 1 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 12. 
Table 12: 
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 
clearning, 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 7-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) 
 
 


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The scale scores, also with higher numbers indicating higher satisfaction, are calculated as: 
Effectiveness 
([(𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 1 + 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 2 + 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 3) −3] ÷ 18) × 100 
If 1 item is missing:  
([𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) −2] ÷ 12) × 100 
Side Effects 
If Item 4 answer is “No” then score = 100. 
Else: 
([𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 5 𝑡𝑡𝑡𝑡 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 8) −4] ÷ 16) × 100 
If 1 item is missing:  
([(𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) −3] ÷ 12) × 100 
Convenience 
([𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 9 𝑡𝑡𝑡𝑡 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 11) −3] ÷ 18) × 100 
If 1 item is missing:  
([(𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) −2] ÷ 12] × 100) 
Global Satisfaction 
 ([𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 12 𝑡𝑡𝑡𝑡 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 14) −3] ÷ 14) × 100 
If Item 12 or Item 13 is missing: 
([(𝐼𝐼𝐼𝐼 𝑆𝑆𝑆𝑆𝑆𝑆 (𝑡𝑡ℎ𝑒𝑒 2 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) −2] ÷ 10) × 100 
If Item 14 is missing:  
([𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) −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 × [𝑄𝑄2 ÷ (𝑄𝑄2 +Q4)] 
2. Presenteeism: Percent impairment while working due to health:  
100 × [𝑄𝑄5 ÷ 10] 
3. Work productivity loss: Percent overall work impairment due to problem: 
100 × {𝑄𝑄2 ÷ (𝑄𝑄2 + 𝑄𝑄4) + [(1 −𝑄𝑄2 ÷ (𝑄𝑄2 + 𝑄𝑄4) × (𝑄𝑄5 ÷ 𝑄𝑄10)]} 
4. Activity impairment: Percent activity impairment due to health:  


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100 × (𝑄𝑄6 ÷ 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. 
6.8. 
Handling of Missing Data 
6.8.1. 
Imputation of Missing Efficacy Endpoints Post Study Treatment 
Discontinuation 
The attack rate used in the Part 1 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 three ways: 
1. Using observed post-treatment discontinuation data where available without imputation 
for missing data. For this analysis, the attack 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 attack 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 attack 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 attack 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: 


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𝑓𝑓= 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑜𝑜𝑜𝑜 𝑁𝑁𝑁𝑁𝑁𝑁-𝑚𝑚𝑚𝑚𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 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 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
=
 Number of Attacks ∗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 𝑃𝑃𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 
 
= ൜
𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔                                                                                                
𝑖𝑖𝑖𝑖 𝑛𝑛𝑛𝑛𝑛𝑛 𝑚𝑚𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑜𝑜𝑜𝑜 ℎ𝑖𝑖𝑖𝑖ℎ𝑒𝑒𝑒𝑒𝑒𝑒 (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤) 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟, 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤  
 
𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎=  𝑓𝑓∗𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑟𝑟𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣+ (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 13. Data missing at random will 
be imputed using multiple imputation with 10 separate founds of imputations, randomly 
selecting from observed confirmed attack 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 attack rate of subjects in the worst quartile of performance (ie, highest 
attack 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 13: 
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. 


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1. A tipping point analysis will be conducted using the observed data post treatment-
discontinuation combined with imputed data for missing time periods. However, for 
tipping point analysis, rimputed will be multiplied by a factor, δ, for the active treatment 
group in the determination of the analyzed rate, as shown below. For the placebo group, 
there will be no such multiplicative factor. The tipping point is the value of δ that leads to 
a reversal of a significant p-value. It shows how much larger than expected the attack rate 
would need to be for the time period of missing data for the active group in order to “tip” 
the significance level to non-significant. For tipping point analysis, the analyzed rate for 
the active treatment group is:  
𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎=  𝑓𝑓∗𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜+ (1 −𝑓𝑓) ∗𝛿𝛿∗𝑟𝑟𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
For the placebo group, the analyzed rate would remain as: 
𝑟𝑟𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎=  𝑓𝑓∗𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜+ (1 −𝑓𝑓) ∗𝑟𝑟𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 
   
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 attack 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 to identify medication as 
occurring during treatment or not. For the purposes of handling partially reported start and stop 
dates for medication the following algorithm will be applied: 
• Missing start day, but month and year present: 
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. 
• 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. 


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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. 
• For paper diaries where the date of an acute concomitant medication is missing, the 
date will be imputed as the date of the attack. 
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 Attack 
For HAE attacks reported with a missing stop date and or time, the following algorithm will be 
applied: 
• 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 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 attack 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 


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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 of 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 CSR, starting with 
the number of subjects screened. 
A summary of enrollment by country and 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.  
Confirmation of clinical diagnosis of HAE will be summarized based on the protocol inclusion 
criterion: C1 esterase inhibitor (C1-INH) functional levels, 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 Parts 2 and 3 will be conducted prior to database lock for the 
final CSR after the last subject has completed the last study visit. Protocol deviations for Parts 2 
and 3 will be summarized by Part 2/3 treatment (Table 6) and category of deviation and will be 
listed but will not result in exclusion from the PP population.  


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7.4. 
Demographic and Baseline Characteristics 
Demographic summary tables will be provided separately for Part 1 and the end of study 
(Table 6). 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.  
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), Ecallentide (brand name = 
Kalbitor), fresh frozen plasma, and lanadelumab (brand name = Takhzyro).  The summary of 
androgens will include androgens (unspecified), oxandrolone, danazol (brand name = 
Danocrine), and stanozolol. 
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 


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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 or 3 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. 
Medication verbatim text will be coded using the WHO Drug Dictionary, 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 5 and Table 7, 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 attack-level summary will also be provided showing the number of attacks for which the 
various HAE-related medications were taken based on the subject diary and the concomitant 
medication form (androgens) in the eCRF. 
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 attacks will be listed. The baseline attack rate and the categorized baseline attack rate will be 
summarized by Part 1 treatment using descriptive statistics for baseline attack rate and n [%] for 
the categorized baseline attack rate. The proportion of days with HAE symptoms 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. Analyses of Part 2 data will be descriptive. No hypotheses will 


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be tested for Parts 2 and 3 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 subgroups will be provided by Part 1 treatment. In addition, the duration of 
baseline period, baseline attack rate, categorized baseline attack rate (≥ 2 attacks/month vs. 
< 2 attacks/month), and baseline AE-QoL will be summarized by Part 1 treatment. 
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 
investigator-confirmed HAE attacks 
• HA: RA ≠ RP; active treatment does have a differential effect on the rate of 
investigator-confirmed HAE attacks 
where RA is the monthly attack rate for active treatment and RP is the monthly attack rate 
for placebo treatment. 
Secondary hypotheses are (in order of hierarchical testing): 
1. 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). 
2. 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. 
3. Rate of investigator-confirmed HAE attacks 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 
investigator-confirmed HAE attacks during the effective treatment period 
• HA: RA ≠ RP; active treatment does have a differential effect on the rate of 
investigator-confirmed HAE attacks during the effective treatment period 


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where RA is the monthly attack rate for active treatment and RP is the monthly attack rate 
for placebo treatment during the effective treatment period. 
8.4. 
Subgroup Analyses 
Subgroup analyses for the primary endpoint of investigator-confirmed attack rate during the 
entire 24-week dosing period and the secondary endpoint of Week 24 change from baseline AE-
QoL (total score) will be provided by: 
1. Region (North America vs. Europe) 
2. Sex 
3. Race (white vs. other) 
4. Baseline attack rate (≥ 2 attacks/month vs. < 2 attacks/month)  
5. Age group (< 18, 18 to 65, > 65 years) 
Forest plots showing the original results and the results by subgroups will be provided. 
A summary of TEAEs by age group will also be provided. 
8.5. 
Multiple Comparisons and Multiplicity 
There are 4 endpoints being tested. For each endpoint, there are 2 potential doses to be tested 
against placebo. 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 investigator-confirmed HAE 
attacks 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 attacks 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 next endpoint in the 
hierarchy cannot be tested. 
The first, second, third, and fourth endpoints in the hierarchy are: 
1. The rate of investigator-confirmed HAE attacks during dosing in the entire 24-week 
treatment period (Day 1 to Day 168) 
2. Change from baseline in AE-QoL at Week 24 (total score) 
3. Number and proportion of days with angioedema symptoms through 24 weeks 
4. Rate of investigator-confirmed HAE attacks during dosing in the effective treatment 
period (beginning on Day 8 through 24 weeks) 


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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. 
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 investigator-confirmed HAE 
attacks during dosing in the entire 24-week treatment 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 investigator-confirmed HAE attacks for Part 1 will be analyzed by treatment 
group using appropriate descriptive statistics for the confirmed attack rate (expressed as 
attacks/month) based on the 24-week dosing period or until study treatment discontinuation, if 
applicable. An additional summary of confirmed attack rate by month, including change from 
baseline attack rate and percentage change from baseline attack 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 attack rate and the treatment comparisons between each BCX7353 dose and placebo in the 
rate of investigator-confirmed HAE attacks during the Part 1 dosing period will be analyzed 
using a Poisson regression model. The number of investigator-confirmed attacks will be included 
as the dependent variable, the treatment will be included as a fixed effect, the stratification 
variable (baseline attack 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 attack for each treatment 
group, the treatment differences expressed as the attack rate ratio (BCX7353 over placebo rate 
ratio) and their associated 95% confidence intervals (CIs) will be provided from the Poisson 
regression model. The percentage reduction from placebo will be calculated for each dose as:  
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑟𝑟𝑟𝑟𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑=  1 −𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟= 1 −RA
RP
 
Where RP is the estimated attack rate for Placebo treatment and RA is the estimated attack rate for 
Active treatment. 
Example SAS pseudo-code for the Poisson regression analysis is as follows: 
proc genmod data = datasetname; 
   class trt01p catblatk/param=glm; 
   model icattacks = trt01p catblatk /dist=poisson link=log offset=logdurtrt; 
run; 
All statistical tests will be 2-sided. Multiplicity adjustments for Part 1 analyses for the 2 dose 
groups are discussed in Section 8.5 along with handling of testing of multiple endpoints. 


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The Poisson model assumes that the mean and variance are equal. When the variance in the data 
is larger than the mean, the model is said to be over-dispersed. Over-dispersion is more likely to 
be a problem if a significant number of subjects have no attacks during the 24-week treatment 
period. As a sensitivity analysis to examine the appropriateness of the Poisson model, a negative 
binomial model will be used in place of the Poisson regression model. When the negative 
binomial dispersion parameter is equal to zero, the negative binomial and Poisson models are 
equivalent. If the results of the model obtained using the negative binomial distribution are 
similar to that of the model that assumes the Poisson distribution and a statistical test of the 
dispersion parameter does not show that it is significantly greater than zero, the Poisson model 
will remain as the primary model for analysis. 
Plots of mean confirmed attack rate by month and scatter plots of baseline attack rate vs. 
24-week attack rate will be produced with a different color for each treatment. Plots of mean 
attack rate per month will be updated to include the Part 2 data at the end of the study. Adjusted 
subject-reported attack rate data per month will be plotted separately for Part 3, as Part 3 does 
not include investigator confirmation of attacks. 
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 investigator-confirmed attacks will also be 
conducted. 
In addition, there will be 3 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 attack rate determination. The estimand for this 
analysis is referred to as the de facto estimand. Details on the determination of the attack 
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 
attack 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. 
 
3. A tipping point analysis will be conducted in which observed data post study drug 
discontinuation are combined with imputed data for subjects who discontinue study 
treatment prior to the end of Part 1 and do not continue to provide attack information. 
However, for this analysis the imputed attack rates will be multiplied by a factor, δ, for 
subjects on active treatment. No such factor will be used for subjects on placebo 
treatment. The tipping point will be estimated as the value of δ that tips the analysis to 
non-significant. It shows how much greater than expected the attack rate on active 
treatment would need to be for the missing data to alter the result of the analysis. Details 
are provided in Section 6.8.1.  


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A forest plot will be provided to visually compare the results obtained using first 2 methods of 
sensitivity analyses to the primary efficacy result.   
8.7. 
Analysis of the Secondary Efficacy Endpoints 
8.7.1. 
Angioedema Quality of Life (Total and Domain Scores) 
Change from baseline 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 Parts 2 and 3. 
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 attack 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 1 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 study will also include data from visits at Weeks 28, 32, 36, 48, 60, 
72, 84, 96, and follow-up. Summaries will be updated to include the additional information. An 
additional descriptive summary of change from Week 24 will be provided for Part 2 and 3 visits 
for subjects originally randomized to placebo treatment. 
A summary and analysis of the number and percent of subjects with at least a 6-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 the study. The analysis for Part 1 will 
be based on a logistic model with response of achievement of the MCID (yes/no), baseline attack 
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 Parts 2 and 3. 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 attack 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 


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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. 
Final analyses at the end of the study will include a summary of the number and proportion of 
days with angioedema symptoms through Week 48 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 1 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 Week 48. 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 Investigator-Confirmed HAE Attacks during Dosing in the Effective 
Treatment Period 
The rate of investigator-confirmed HAE attacks during dosing in the effective treatment period is 
a secondary endpoint for Part 1. 
Summaries and analysis of the investigator-confirmed attack rate using the ITT population for 
the effective treatment period (Day 8 through Week 24, inclusive) will be conducted using 
Poisson 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 Attack Medications 
The use of HAE attack medications over 24 weeks is an exploratory efficacy endpoint for Part 1 
and a secondary endpoint for Parts 2 and 3. Use of HAE medications based on diary data will be 
summarized separately from concomitant medications. In addition, summaries and analyses of 
the rate of investigator-confirmed HAE attacks requiring treatment will be provided for Part 1 
and for the study period from Day 1 to the end of Part 2. The analysis will be performed 
similarly to the analysis of rate of confirmed HAE attacks. For a list of medications that qualify 
as targeted and non-targeted HAE attack medications, see Section 6.7.5.7. Separate summaries of 
HAE attack medication use for Part 3 will be produced based on adjusted subject-reported 
attacks. 
A Kaplan-Meier plot of time to first use of a targeted HAE rescue medication to treat an 
investigator-confirmed attack and corresponding summary table will be produced for Part 1. 
8.7.5. 
Discontinuations due to Lack of Efficacy 
Discontinuation due to lack of efficacy is a secondary endpoint for Parts 2 and 3. 
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, 2 and 3 as well as overall. 


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8.8. 
Analysis of Additional Exploratory Efficacy Endpoints 
8.8.1. 
Number and Proportion of Subjects with No Attacks  
The number and proportion of subjects with no attacks 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 attacks over the 
entire dosing period of 48 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 attacks 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 attack-free.  A separate summary of the 
number and proportion of subjects with no adjusted subject-reported attacks 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 attacks 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 Kaplan-Meier plot and corresponding summary of time to first attack 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 investigator-confirmed HAE attacks meeting the stricter screening criteria during 
treatment compared with the baseline attack 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 attack 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.  
8.8.3. 
Attack Characteristics 
Characteristics of attacks including location of attack, duration of attacks from start to finish and 
from start to the time the worst symptoms of the attack were over, time since last dose, triggers, 
swelling, other symptoms, whether the attack was treated, severity as assessed by the subject 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 attack for abdominal, peripheral and mixed attacks will also be 
provided. 


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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 Parts 2 and 3. 
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 attack 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 
attack”. On summary tables, the “today” and “usual attack” 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 change from baseline 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 attack 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.   
Analyses at the end of the study 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 attack” will be provided. 
Plots of VAS and EQ-5D-5L index mean scores over time and change from baseline mean scores 
will be provided for Part 1 analysis and for the analysis at end of the study using the health status 
“today”. For Parts 2 and 3, 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 Parts 2 and 3. 
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 change from baseline score of interest will be included as the dependent 
variable in the model with fixed effects for treatment, baseline attack value, baseline TSQM 


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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 1 line per treatment group will be provided. There will be 1 set of figures 
for Part 1 and another for the entire study period. For the analysis at the end of the study, 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 Parts 2 and 3. 
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 change from baseline 
WPAI score of interest will be included as the dependent variable in the model with fixed effects 
for treatment, baseline attack 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 change from baseline mean scores over 
time with 1 line per treatment group will be provided. There will be 1 set of figures for Part 1 
and another for the entire study period. For the plots produced at the end of the study, the figure 
will have separate lines for active treatment for subjects originally randomized to placebo. 
10. 
SAFETY AND TOLERABILITY 
Analyses of safety and tolerability will be conducted at the end of Part 1 of the study and 
repeated for the entire study period. 
10.1. 
Adverse Event Preferred Term and System Organ Class Summary 
Tables 
The following are Part 1 secondary endpoints and Part 2 and 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 


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AEs will be mapped to the MedDRA version 19.1 PT and system organ class (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, 2 or 3, and will be assigned to the relevant treatment depending on when the TEAE began 
(Part 1 or Part 2 and 3 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 or 3 will be 
considered as TEAEs and will be associated with Part 1, 2 or 3 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. 
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 an TEAE, 4) had any serious adverse event (SAE), 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, 8) had a drug-related SAE, or 9) had a fatal SAE.   
TEAEs 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 


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• 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 TEAEs will be provided by PT (not by SOC and PT), in 
decreasing order of frequency. Frequent TEAEs will be defined as events that occur in at least 
5% of the total number of subjects in the clinical trial. 
A summary of TEAEs by age group will also be provided 
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 
• SAEs (fatal and non-fatal) 
A forest plot of most-frequent treatment-emergent AEs sorted by relative risk 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 format of the plot to be 
used is the example plot of most-frequent on-therapy AEs sorted by risk difference. However, 
the relative risk (aka risk ratio) will be displayed rather than the risk difference.  The 95% 
confidence interval for the relative risk will be derived using the assumption of normality of the 
log of the relative risk. 
10.1.2. 
Investigator-Identified Rash Events of Special Interest and Gastrointestinal 
Abdominal-Related Adverse Events 
The following is a primary endpoint for Parts 2 and 3: 
• 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 
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 
TEAEs of special interest for investigator reporting purposes. There are no appropriate 
standardized MedDRA queries in MedDRA to evaluate abdominal-related AEs that are 
appropriate to assess potential adverse events 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 19.1 hierarchy under the High-Level Group Terms (HLGTs) of 1) GI signs 
and symptoms; and 2) GI motility and defecation conditions. See Section 17 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.  


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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 
• An TEAE that was considered a drug-related TESAE 
• A TEAE that required use of concomitant medication 
For treatment-emergent investigator-identified rashes and GI abdominal-related AEs, time to 
development of the TEAE will be estimated using the Kaplan-Meier method. The results will be 
displayed in summary tables as well as in a Kaplan-Meier 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 TEAE. 
A Kaplan-Meier plot and summary of duration of event will be provided for the 
investigator-identified rashes and GI abdominal-related 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 attack 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 100 Person-Years 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 TEAE 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 person-year of exposure, the duration of treatment exposure 
will be computed for each subject and treatment.  The rate of TEAEs per person-year will then 


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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-year of exposure 
• Summary of drug-related, TEAE rate per 100 person-year of exposure 
• Summary of TESAEs per 100 person-year of exposure 
A listing of exposure to study treatment in 100 person-years will be provided by subject and 
treatment. 
10.2. 
Exposure to Study Treatment and Treatment Compliance 
The number of subjects exposed to study treatment and the number of subjects who discontinue 
treatment early 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 100 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. Kaplan-Meier 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: 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
= 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 
 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
= 2 × (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷+ 1) 
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 and overall for the entire study 
period at the time of the end of study analysis. For subjects initially assigned to placebo, 
treatment compliance will be computed for placebo treatment and separately for the active 
treatment received in Parts 2 and 3.  
A categorical summary of treatment compliance will be produced with the following categories 
shown in Table 14. 


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Table 14: 
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 change from baseline attack rate by % compliance will be produced for Part 1, with 
treatment groups overlaid. 
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 a primary endpoint for Parts 2 and 3: 
• 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 1-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.  


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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 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 
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 
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 versus 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 Kaplan-Meier plots of time to event for a Grade 3 or higher ALT, AST, or bilirubin will 
be produced.   
A listing of adverse events of nausea, vomiting, anorexia, abdominal pain, or fatigue occurring 
within 24 hours of an elevation of >3xULN for 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. 


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10.4.2. 
Complement Factors and HAE Diagnosis 
Laboratory results related to HAE diagnosis, including complement factors C1-INHAg, 
C1-INHf, 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. 
10.4.3. 
Laboratory Assessments for Rash 
For subjects with rash, peripheral blood mononuclear cells (PBMCs) will be collected for 
analysis of possible drug-specific immune responses and possible drug-responsive T-cells. The 
data from PBMC analysis, if collected, will be listed. 
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. 
10.7. 
12-lead Electrocardiograms  
Baseline (predose) and Week 24 ECGs will be obtained in triplicate (ie, 3 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 change from baseline in corrected QT interval using 
Fridericia’s method (QTcF) > 60 msec or a QTcF interval > 500 msec. 
ECGs and corresponding changes from baseline will be summarized by treatment group and visit 
using descriptive statistics.  
ECG findings will be summarized. 
The change from baseline in QTcF will be determined by routine ECGs. At each time point 
where ECGs are analyzed, an individual subject’s change from baseline will be calculated as: 
∆𝑖𝑖𝑖𝑖= (𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄 𝑓𝑓𝑓𝑓𝑓𝑓 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑖𝑖 𝑎𝑎𝑎𝑎 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑘𝑘−𝐵𝐵𝐵𝐵𝐵𝐵𝑒𝑒𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄) 
QTcF measurements will be the average of triplicate ECGs at baseline and Week 24 and single 
values at all other time points.  


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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. 
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 this will be repeated for the 
entire study period for the analysis at the end of the study. Note that PK concentration data 
collected at each visit will not be summarized by visit as the timings 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 PD data will be performed using the PD population.  Plasma kallikrein inhibition 
data will be expressed as percent inhibition compared to subject baseline activity (%KKI). The 
formula for percent inhibition is: 
%𝐾𝐾𝐾𝐾𝐾𝐾= −𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
 
where the values are the amidolytic activity (%) at each time point. 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 for the analysis at the end of the study. 
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 at the time of the analysis at the end of the 
study, using the PK/PD population.  Note the division by 4 of the concentration corrects for the 
dilution of the plasma required for the PD assay. 
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 will be evaluated in a separate cross-study analysis. 
15. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
Changes from protocol-specified analyses include:  
• For Part 1 analyses, the protocol says efficacy displays will be generally be performed 
over the entire dosing period beginning on Day 1 and effective dosing period 
beginning on Day 8. In the SAP, a reduced number of displays have been selected for 
analysis over the effective dosing period. 
• In the protocol, the PP population was originally defined as a subset of the ITT 
population. It has been redefined in the SAP as a subset of the safety population. 
• Due to an error in the IXRS equation, the baseline attack rate for screening for 
purposes of stratification was slightly larger than it should have been because the 
denominator did not include the “+1”; ie, the number of days in screening was 
underestimated by 1 day. For analysis purposes, the baseline attack rate is 
recalculated using the intended equation for baseline attack rate as shown in 
Section 6.6.1.  
• Clarified that Part 1 ends at the time of first dose for Part 2.   
• Increased the sample size per group from 32 to 40 to account for potential dropout.  
Initial sample size estimates did not allow for any subject dropout. 


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• Due to rapid enrollment and the timing of planned sample size re-estimation when 
50% of subjects reach Week 24, the planned sample size re-estimation was not 
conducted. 


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16. 
REFERENCES 
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, using a national panel study of chronic disease." Health Quality 
Life Outcomes 2. 
DHHS (2009). "Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation." 
ICH (1995). "ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study 
Reports E3." 
Reilly Associates (2002). "WPAI Scoring ". 
van Hout, B., M. F. Janssen, Y. S. Feng, T. Kohlmann, J. Busschbach, D. Golicki, A. Lloyd, L. 
Scalone, P. Kind and A. S. Pickard (2012). "Interim scoring for the EQ-5D-5L: mapping the EQ-
5D-5L to EQ-5D-3L value sets." Value Health 15(5): 708-715. 
van Reenen, M. and B. Janssen (2015). "EQ-5D-5L User Guide Version 2.1." 
Weller, K., A. Groffik, M. Magerl, N. Tohme, P. Martus, K. Krause, M. Metz, P. Staubach and 
M. Maurer (2012). "Development and construct validation of the angioedema quality of life 
questionnaire." Allergy 67: 1289-1298. 
 
 


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17. 
APPENDIX 
17.1. 
Table of Contents for Data Display Specifications 
Tables 
Output # 
Population 
Output Title 
14.1.1.1 
ITT 
Summary of Subject Disposition by Country and Site, Part 1 
14.1.1.1.ES 
ITT  
Summary of Subject Disposition by Country and Site, Entire Study 
14.1.2.1 
ITT  
Summary of Analysis Populations 
14.1.2.2 
ITT  
Summary of Subgroups 
14.1.2.3.1 
ITT  
Summary of Inclusion/Exclusion Criteria Deviations 
14.1.2.3.2 
Screen Failures 
Summary of Inclusion/Exclusion Criteria Deviations 
14.1.2.4 
ITT  
Summary of Protocol Deviations, Part 1 
14.1.2.4.ES 
ITT  
Summary of Protocol Deviations that Occurred During Part 2 
14.1.2.5 
ITT  
Summary of Confirmation of Diagnosis of HAE Type I or II 
14.1.3.1.1 
ITT  
Summary of Demographic Characteristics 
14.1.3.1.1.ES 
ITT  
Summary of Demographic Characteristics - Subjects Who Transitioned to Part 2  
14.1.3.1.2 
PP  
Summary of Demographic Characteristics 
14.1.3.1.3 
Screen Failures 
Summary of Demographic Characteristics 
14.1.3.2 
ITT  
Summary of Subject-Reported HAE Baseline Characteristics – HAE Medical History 
14.1.3.3 
ITT  
Summary of Past Prophylactic Treatments of HAE 
14.1.3.4 
ITT  
Summary of Current On-Demand Treatments of HAE  
14.1.3.5 
ITT  
Summary of Subject-Reported HAE Baseline Characteristics – Primary Acute Attack Treatment 
Information 
14.1.3.6 
ITT  
Summary of Pre-Treatment Investigator-Confirmed Attack Rates and Angioedema Symptoms 
14.1.4.1 
ITT  
Summary of Medications Taken within 30 Days of Screening and Discontinued Prior to Dosing 
14.1.4.2 
ITT  
Summary of Concomitant Medications, Part 1 
14.1.4.2.ES 
ITT  
Summary of Concomitant Medications – Entire Study 
14.1.4.3 
ITT  
Summary of Concomitant Medications for HAE, Part 1 
14.1.4.3.ES 
ITT  
Summary of Concomitant Medications for HAE, Entire Study 
14.1.4.3.P3 
ITT 
Summary of Concomitant Medications for HAE, Part 3 
14.1.4.4 
ITT  
Summary of Concomitant Medications for HAE – Attack Level, Part 1 
14.1.4.4.ES 
ITT  
Summary of Concomitant Medications for HAE – Attack Level, Entire Study 
14.1.4.4.P3 
ITT 
Summary of Concomitant Medications for HAE – Attack Level, Part 3 
14.1.5.1 
Safety  
Summary of Treatment Exposure and Treatment Compliance, Part 1 
14.1.5.1.ES 
Safety  
Summary of Treatment Exposure and Treatment Compliance, Entire Study 
14.2.1.1 
ITT  
Summary of Hierarchical Testing for Efficacy Endpoints 
14.2.1.2.1 
ITT  
Overall Attack Summary During Part 1 
14.2.1.2.1.ES 
ITT  
Overall Attack Summary During Entire Study 
14.2.1.2.2 
PP  
Overall Attack Summary During Part 1  


BioCryst Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
82 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.2.1.3.1 
ITT  
Overall Attack Summary During the Effective Dosing Period, Part 1 
14.2.1.3.1.ES 
ITT  
Overall Attack Summary During the Effective Dosing Period, Entire Study 
14.2.1.3.2 
PP  
Overall Attack Summary During the Effective Dosing Period, Part 1 
14.2.1.4.1 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Part 1 
14.2.1.4.1.ES 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Entire Study 
14.2.1.4.2 
PP  
Summary of Rate of Investigator-Confirmed Attacks During Part 1 
14.2.1.4.2.ES 
PP  
Summary of Rate of Investigator-Confirmed Attacks During Entire Study 
14.2.1.4.3 
Completers  
Summary of Rate of Investigator-Confirmed Attacks During Part 1 
14.2.1.4.4 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Part 1, Including Observed Data Post 
Treatment Discontinuation  
14.2.1.4.5 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Part 1, Including Observed Data Post 
Treatment Discontinuation and Missing Data Post Treatment Discontinuation are Imputed 
14.2.1.5 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Part 1, Tipping Point Analysis 
Results 
14.2.1.6 
ITT 
Summary of Rate of Investigator-Confirmed Attacks During Part 1 by Subgroups 
14.2.1.11.1 
ITT  
Summary of Rate of Investigator-Confirmed Attacks During Effective Dosing Period, Part 1 
14.2.1.11.1.ES 
ITT  
Summary of Rate of Investigator-Confirmed Attacks During Effective Dosing Period, Entire Study 
14.2.1.11.2 
PP  
Summary of Rate of Investigator-Confirmed Attacks During Effective Dosing Period, Part 1 
14.2.1.11.2.ES 
PP  
Summary of Rate of Investigator-Confirmed Attacks During Effective Dosing Period, Entire Study 
14.2.1.14 
ITT  
Summary of Rate of Investigator-Confirmed Attacks Requiring Treatment During Part 1 
14.2.1.14.ES 
ITT  
Summary of Rate of Investigator-Confirmed Attacks Requiring Treatment During Entire Study 
14.2.1.15 
ITT  
Summary of Rate of Investigator-Confirmed Abdominal-Only Attacks During Part 1 
14.2.1.15.ES 
ITT  
Summary of Rate of Investigator-Confirmed Abdominal-Only Attacks During Entire Study 
14.2.1.16 
ITT  
Summary of Rate of Investigator-Confirmed Peripheral-Only Attacks During Part 1 
14.2.1.16.ES 
ITT  
Summary of Rate of Investigator-Confirmed Peripheral-Only Attacks During Entire Study 
14.2.1.17 
ITT  
Summary of Rate of Investigator-Confirmed Mixed Location Attacks During Part 1 
14.2.1.17.ES 
ITT 
Summary of Rate of Investigator-Confirmed Mixed Location Attacks During Entire Study 
14.2.1.18 
ITT 
Summary of Rate of Subject-Reported Attacks During Part 1 
14.2.1.18.ES 
ITT 
Summary of Rate of Subject-Reported Attacks During Entire Study 
14.2.1.18.P3 
ITT 
Summary of Rate of Subject-Reported Attacks During Part 3 
14.2.1.19.P3 
ITT 
Summary of Rate of Subject-Reported Attacks Requiring Treatment During Part 3 
14.2.2.1 
ITT 
Summary of Rate of Investigator-Confirmed Attacks By Month During Part 1 
14.2.2.1.ES 
ITT 
Summary of Rate of Investigator-Confirmed Attacks By Month During Entire Study 
14.2.2.1.P3 
ITT 
Summary of Rate of Investigator-Confirmed Attacks By Month During Part 3 
14.2.3.1.1 
ITT 
Summary of AE-QoL Scores, Part 1 
14.2.3.1.1.ES 
ITT 
Summary of AE-QoL Scores, Entire Study 
14.2.3.1.2 
PP  
Summary of AE-QoL Scores, Part 1 
14.2.3.1.2.ES 
PP  
Summary of AE-QoL Scores, Entire Study 
14.2.3.2 
ITT 
Summary of AE-QoL Scores, Part 1 by Subgroups 
14.2.3.7 
ITT 
Number and Percent of Subjects Achieving the MCID (Decrease in Total AE-QoL Score), Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
83 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.2.3.7.ES 
ITT 
Number and Percent of Subjects Achieving the MCID (Decrease in Total AE-QoL Score), Entire 
Study 
14.2.4.1 
ITT 
Summary of Number and Proportion of Subjects Who are Investigator-Confirmed Attack-Free, 
Part 1 
14.2.4.1.ES 
ITT 
Summary of Number and Proportion of Subjects Who are Investigator-Confirmed Attack-Free, 
Entire Study 
14.2.4.2 
ITT 
Summary of Number and Proportion of Subjects Who are Subject-Reported Attack-Free, Part 3 
14.2.4.3 
ITT 
Summary of Number and Proportion of Subjects Who are Investigator-Confirmed Attack-Free in 
the Effective Dosing Period, Part 1 
14.2.4.3.ES 
ITT 
Summary of Number and Proportion of Subjects Who are Investigator-Confirmed Attack-Free in 
the Effective Dosing Period, Entire Study 
14.2.5.1.1 
ITT 
Summary of Number and Proportion of Days with Angioedema Symptoms from Investigator-
Confirmed Attacks, Part 1  
14.2.5.1.1.ES 
ITT 
Summary of Number and Proportion of Days with Angioedema Symptoms from Investigator-
Confirmed Attacks, Entire Study 
14.2.5.1.1.P3 
ITT 
Summary of Number and Proportion of Days with Angioedema Symptoms from Subject-Reported 
Attacks, Part 3 
14.2.5.1.2 
PP  
Summary of Number and Proportion of Days with Angioedema Symptoms from Investigator-
Confirmed Attacks, Part 1  
14.2.5.1.2.ES 
PP  
Summary of Number and Proportion of Days with Angioedema Symptoms from Investigator-
Confirmed Attacks, Entire Study 
14.2.5.1.2.P3 
PP  
Summary of Number and Proportion of Days with Angioedema Symptoms from Subject-Reported 
Attacks, Part 3 
14.2.6.1.1 
ITT 
Summary of Relative Reduction from Baseline in Adjusted Investigator-Confirmed Attack Rate, 
Part 1 
14.2.6.1.2 
PP  
Summary of Relative Reduction from Baseline in Adjusted Investigator-Confirmed Attack Rate, 
Part 1 
14.2.7.1 
ITT 
Attack-Level Duration of Investigator-Confirmed Attacks (hours) from Start of Attack to the Time 
the Attack Finished, Part 1 
14.2.7.1.ES 
ITT 
Attack-Level Duration of Investigator-Confirmed Attacks (hours) from Start of Attack to the Time 
the Attack Finished, Entire Study 
14.2.7.2 
ITT 
Attack-Level Duration of Investigator-Confirmed Attacks (hours) from Start of Attack Until Worst 
Was Over, Part 1 
14.2.7.2.ES 
ITT 
Attack-Level Duration of Investigator-Confirmed Attacks (hours) from Start of Attack Until Worst 
Was Over, Entire Study 
14.2.8.1 
ITT 
Summary of Time to First Investigator-Confirmed Attack (KM Estimates), Part 1 
14.2.9.1 
ITT 
Time to First Use of Targeted HAE Rescue Medication to Treat an Investigator-Confirmed Attack 
(KM Estimates), Part 1  
14.2.10.1 
ITT 
Summary of Attack Characteristics for Investigator-Confirmed Attacks, Part 1  
14.2.10.1.ES 
ITT 
Summary of Attack Characteristics for Investigator-Confirmed Attacks, Entire Study  
14.2.11.1 
ITT 
Summary of Attack Locations for Investigator-Confirmed Attacks, Part 1  
14.2.11.1.ES 
ITT 
Summary of Attack Locations for Investigator-Confirmed Attacks, Entire study 
14.3.1.1 
Safety 
Overall Summary of Treatment-Emergent Adverse Events, Part 1 
14.3.1.1.ES 
Safety 
Overall Summary of Treatment-Emergent Adverse Events, Entire Study 
14.3.1.2 
Safety 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, Part 1 
14.3.1.2.ES 
Safety 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
84 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.3.1.3 
Safety 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, 
Part 1 
14.3.1.3.ES 
Safety 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, 
Entire Study 
14.3.1.4 
Safety 
Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term, Part 1 
14.3.1.4.ES 
Safety 
Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term, Entire 
Study 
14.3.1.5 
Safety 
Drug-Related Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred 
Term, Part 1 
14.3.1.5.ES 
Safety 
Drug-Related Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred 
Term, Entire Study 
14.3.1.6 
Safety 
Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System Organ Class and Preferred 
Term, Part 1 
14.3.1.6.ES 
Safety 
Treatment-Emergent Grade 3 or Grade 4 Adverse Events by System Organ Class and Preferred 
Term, Entire Study 
14.3.1.7 
Safety 
Drug-Related Treatment-Emergent Grade 3 or 4 Adverse Events by System Organ Class and 
Preferred Term, Part 1 
14.3.1.7.ES 
Safety 
Drug-Related Treatment-Emergent Grade 3 or 4 Adverse Events by System Organ Class and 
Preferred Term, Entire Study 
14.3.1.8 
Safety  
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  
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  
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  
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  
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Severity, Part 1 
14.3.1.10.ES 
Safety  
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Severity, Entire Study 
14.3.1.11 
Safety 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Age Group, Part 1 
14.3.1.11.ES 
Safety 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Age Group, Entire Study 
14.3.1.12 
Safety  
Summary of Frequent Adverse Events, Part 1 
14.3.1.12.ES 
Safety  
Summary of Frequent Adverse Events, Entire Study 
14.3.1.14 
Safety  
Summary of Drug-related Frequent Adverse Events, Part 1 
14.3.1.14.ES 
Safety  
Summary of Drug-related Frequent Adverse Events, Entire Study 
14.3.1.15 
Safety  
Overall Summary of Treatment-Emergent Investigator-identified Rash, Part 1 
14.3.1.15.ES 
Safety  
Overall Summary of Treatment-Emergent Investigator-identified Rash, Entire Study 
14.3.1.16 
Safety   
Treatment-Emergent Investigator-identified Rash by System Organ Class and Preferred Term, Part 
1 
14.3.1.16.ES 
Safety   
Treatment-Emergent Investigator-identified Rash by System Organ Class and Preferred Term, 
Entire Study 
14.3.1.17 
Safety   
Drug-Related Treatment-Emergent Investigator-identified Rash by System Organ Class and 
Preferred Term, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
85 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.3.1.17.ES 
Safety   
Drug-Related Treatment-Emergent Investigator-identified Rash by System Organ Class and 
Preferred Term, Entire Study 
14.3.1.18 
Safety   
Treatment-Emergent Investigator-identified Rash Serious Adverse Events by System Organ Class 
and Preferred Term, Part 1 
14.3.1.18.ES 
Safety   
Treatment-Emergent Investigator-identified Rash Serious Adverse Events by System Organ Class 
and Preferred Term, Entire Study 
14.3.1.19 
Safety   
Drug-Related Treatment-Emergent Investigator-identified Rash Serious Adverse Events by 
System Organ Class and Preferred Term, Part 1 
14.3.1.19.ES 
Safety   
Drug-Related Treatment-Emergent Investigator-identified Rash Serious Adverse Events by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.20 
Safety   
Treatment-Emergent Grade 3 or Grade 4 Investigator-identified Rash by System Organ Class and 
Preferred Term, Part 1 
14.3.1.20.ES 
Safety   
Treatment-Emergent Grade 3 or Grade 4 Investigator-identified Rash by System Organ Class and 
Preferred Term, Entire Study 
14.3.1.21 
Safety   
Drug-Related Treatment-Emergent Grade 3 or 4 Investigator-identified Rash by System Organ 
Class and Preferred Term, Part 1 
14.3.1.21.ES 
Safety   
Drug-Related Treatment-Emergent Grade 3 or 4 Investigator-identified Rash by System Organ 
Class and Preferred Term, Entire Study 
14.3.1.22 
Safety   
Treatment-Emergent Investigator-identified Rash Leading to the Interruption of Study Drug by 
System Organ Class and Preferred Term, Part 1 
14.3.1.22.ES 
Safety   
Treatment-Emergent Investigator-identified Rash Leading to the Interruption of Study Drug by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.23 
Safety   
Treatment-Emergent Investigator-identified Rash Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term, Part 1 
14.3.1.23.ES 
Safety   
Treatment-Emergent Investigator-identified Rash Leading to the Discontinuation of Study Drug by 
System Organ Class and Preferred Term, Entire Study 
14.3.1.24 
Safety   
Treatment-Emergent Investigator-identified Rash Requiring the Use of Concomitant Medication 
by System Organ Class and Preferred Term, Part 1 
14.3.1.24.ES 
Safety   
Treatment-Emergent Investigator-identified Rash Requiring the Use of Concomitant Medication 
by System Organ Class and Preferred Term, Entire Study 
14.3.1.25 
Safety   
Summary of Time to Development of Investigator-identified Rash, Part 1 
14.3.1.25.ES 
Safety   
Summary of Time to Development of Investigator-identified Rash, Entire Study 
14.3.1.27 
Safety   
Duration of Investigator-identified Rash, Part 1 
14.3.1.27.ES 
Safety   
Duration of Investigator-identified Rash, Entire Study 
14.3.1.29 
Safety   
Overall Summary of Treatment-Emergent GI Abdominal-Related Adverse Events , Part 1 
14.3.1.29.ES 
Safety   
Overall Summary of Treatment-Emergent GI Abdominal-Related Adverse Events, Entire Study 
14.3.1.30 
Safety   
Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class and Preferred 
Term, Part 1 
14.3.1.30.ES 
Safety   
Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class and Preferred 
Term, Entire Study 
14.3.1.31 
Safety   
Drug-Related Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class 
and Preferred Term, Part 1 
14.3.1.31.ES 
Safety   
Drug-Related Treatment-Emergent GI Abdominal-Related Adverse Events by System Organ Class 
and Preferred Term, Entire Study 
14.3.1.32 
Safety   
Treatment-Emergent GI Abdominal-Related   Serious Adverse Events by System Organ Class and 
Preferred Term, Part 1 
14.3.1.32.ES 
Safety   
Treatment-Emergent GI Abdominal-Related   Serious Adverse Events by System Organ Class and 
Preferred Term, Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
86 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.3.1.33 
Safety   
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   
Drug-Related Treatment-Emergent GI Abdominal-Related Serious Adverse Events by System 
Organ Class and Preferred Term, Entire Study 
14.3.1.34 
Safety   
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   
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   
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   
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   
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   
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   
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   
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   
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   
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   
Summary of Time to Development of GI Abdominal-Related Adverse Events, Part 1  
14.3.1.39.ES 
Safety   
Summary of Time to Development of GI Abdominal-Related Adverse Events, Entire Study  
14.3.1.41 
Safety   
Duration of GI Abdominal-Related Adverse Events, Part 1 
14.3.1.41.ES 
Safety   
Duration of GI Abdominal-Related Adverse Events, Entire Study 
14.3.1.44 
Safety   
Summary of GI Abdominal-Related Adverse Events and Unconfirmed HAE Attacks with 
Abdominal-Only Symptoms, Part 1 
14.3.1.44.ES 
Safety   
Summary of GI Abdominal-Related Adverse Events and Unconfirmed HAE Attacks with 
Abdominal-Only Symptoms, Entire Study 
14.3.1.45.ES 
Safety   
Summary of Treatment-Emergent Adverse Event Rate Per 100 Person-Years of Exposure, Entire 
Study 
14.3.1.46.ES 
Safety   
Summary of Drug-Related Treatment-Emergent Adverse Event Rate Per 100 Person-Years of 
Exposure, Entire Study 
14.3.1.47.ES 
Safety   
Summary of Treatment-Emergent Serious Adverse Event Rate Per 100 Person-Years of Exposure, 
Entire Study 
14.3.5.1 
Safety   
Summary of Observed and Change from Baseline Laboratory Data: Clinical Chemistry, Part 1 
14.3.5.1.ES 
Safety   
Summary of Observed and Change from Baseline Laboratory Data: Clinical Chemistry, Entire 
Study 
14.3.5.2 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Hematology and Coagulation, 
Part 1 
14.3.5.2.ES 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Hematology and Coagulation, 
Entire Study 
14.3.5.3 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Complement Factors, Part 1 
14.3.5.3.ES 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Complement Factors, Entire 
Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
87 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.3.5.4 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Additional Tests, Part 1 
14.3.5.4.ES 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Additional Tests, Entire 
Study 
14.3.5.5 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Continuous Urinalysis 
Parameters, Part 1 
14.3.5.5.ES 
Safety   
Summary of Observed and Change from Baseline Laboratory Data:  Continuous Urinalysis 
Parameters, Entire Study 
14.3.5.6 
Safety   
Summary of Observed Laboratory Data: Categorical Urinalysis Parameters, Part 1 
14.3.5.6.ES 
Safety   
Summary of Observed Laboratory Data: Categorical Urinalysis Parameters, Entire Study 
14.3.5.7 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Clinical Chemistry, Part 1 
14.3.5.7.ES 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Clinical Chemistry, Entire Study 
14.3.5.8 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Hematology and Coagulation, Part 1 
14.3.5.8.ES 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Hematology and Coagulation, Entire Study 
14.3.5.9 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Urinalysis, Part 1 
14.3.5.9.ES 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Urinalysis, Entire Study 
14.3.5.10 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Additional Tests, Part 1 
14.3.5.10.ES 
Safety   
Shift from Baseline to Worst Postbaseline Assessment: Additional Tests, Entire Study 
14.3.5.11 
Safety   
Summary of Treatment-Emergent Graded Laboratory Abnormalities, Part 1 
14.3.5.11.ES 
Safety   
Summary of Treatment-Emergent Graded Laboratory Abnormalities, Entire Study 
14.3.5.12 
Safety   
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities, Part 1 
14.3.5.12.ES 
Safety   
Summary of Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities, Entire Study 
14.3.5.13 
Safety   
Summary of Treatment-Emergent Laboratory Toxicity Grade Increases from Baseline, Part 1 
14.3.5.13.ES 
Safety   
Summary of Treatment-Emergent Laboratory Toxicity Grade Increases from Baseline, Entire 
Study 
14.3.5.14 
Safety   
Summary of Fold x ULN for Liver Function Tests, Part 1 
14.3.5.14.ES 
Safety   
Summary of Fold x ULN for Liver Function Tests, Entire Study 
14.3.5.15 
Safety   
Summary of Fold Change from Baseline for Liver Function Tests, Part 1 
14.3.5.15.ES 
Safety   
Summary of Fold Change from Baseline for Liver Function Tests, Entire Study 
14.3.5.16 
Safety   
Summary of Elevations in Post-baseline Liver Function Tests, Part 1 
14.3.5.16.ES 
Safety   
Summary of Elevations in Post-baseline Liver Function Tests, Entire Study 
14.3.5.17 
Safety - Subjects 
with Prior 
Androgen Use 
Summary of Elevations in Post-baseline Liver Function Tests, Part 1 
14.3.5.17.ES 
Safety - Subjects 
with Prior 
Androgen Use 
Summary of Elevations in Post-baseline Liver Function Tests, Entire Study 
14.3.5.18 
Safety - Subjects 
with No Prior 
Androgen Use 
Summary of Elevations in Post-baseline Liver Function Tests, Part 1 
14.3.5.18.ES 
Safety - Subjects 
with No Prior 
Androgen Use 
Summary of Elevations in Post-baseline Liver Function Tests, Entire Study 
14.3.5.19 
Safety   
Summary of Treatment-Emergent Elevations in Post-baseline Liver Function Tests, Part 1 
14.3.5.19.ES 
Safety   
Summary of Treatment-Emergent Elevations in Post-baseline Liver Function Tests, Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
88 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.3.5.25 
Safety   
Time to First Occurrence of Grade 3 or 4 ALT, Part 1 
14.3.5.27 
Safety   
Time to First Occurrence of Grade 3 or 4 AST, Part 1 
14.3.5.29 
Safety   
Time to First Occurrence of Grade 3 or 4 Total Bilirubin, Part 1 
14.3.5.31.ES 
Safety   
Summary of Rate of Elevations in Post-baseline Liver Function Tests Per 100 Person-Years of 
Exposure, Entire Study 
14.3.6.1 
Safety   
Summary of Observed and Change from Baseline Vital Signs, Part 1 
14.3.6.1.ES 
Safety   
Summary of Observed and Change from Baseline Vital Signs, Entire Study 
14.3.7.1 
Safety   
Summary of Observed and Change from Baseline ECG Interval Values, Part 1 
14.3.7.1.ES 
Safety   
Summary of Observed and Change from Baseline ECG Interval Values, Entire Study  
14.3.7.2 
Safety   
Summary of ECG Findings, Part 1 
14.3.7.2.ES 
Safety   
Summary of ECG Findings, Entire Study 
14.3.7.3 
Safety   
Summary of QTcF Observed and Change from Baseline Categorical Findings, Part 1 
14.3.7.3.ES 
Safety   
Summary of QTcF Observed and Change from Baseline Categorical Findings, Entire Study 
14.4.1.1 
ITT   
Summary of WPAI Scores, Part 1 
14.4.1.1.ES 
ITT   
Summary of WPAI Scores, Entire Study 
14.4.1.4 
ITT   
Summary of Responses to WPAI Individual Questions, Part 1 
14.4.1.4.ES 
ITT   
Summary of Responses to WPAI Individual Questions, Entire study 
14.4.2.1 
ITT   
Summary of EQ-5D-5L VAS Scores, Part 1 
14.4.2.1.ES 
ITT   
Summary of EQ-5D-5L VAS Scores, Entire Study 
14.4.2.4 
ITT   
Summary of EQ-5D-5L VAS Scores from Usual Attack, Part 1 
14.4.2.4.ES 
ITT   
Summary of EQ-5D-5L VAS Scores from Usual Attack, Entire Study 
14.4.2.7 
ITT   
Summary of EQ-5D-5L Index Scores, Part 1 
14.4.2.7.ES 
ITT   
Summary of EQ-5D-5L Index Scores, Entire Study  
14.4.2.10 
ITT   
Summary of EQ-5D-5L Index Scores from Usual Attack, Part 1 
14.4.2.10.ES 
ITT   
Summary of EQ-5D-5L Index Scores from Usual Attack, Entire Study  
14.4.2.13 
ITT   
Summary of Responses to EQ-5D-5L Individual Questions, Part 1 
14.4.2.13.ES 
ITT   
Summary of Responses to EQ-5D-5L Individual Questions, Entire study 
14.4.3.1 
ITT   
Summary of TSQM Scores, Part 1 
14.4.3.1.ES 
ITT   
Summary of TSQM Scores, Entire Study  
14.4.3.4 
ITT   
Summary of Responses to TSQM Individual Questions, Part 1 
14.4.3.4.ES 
ITT   
Summary of Responses to TSQM Individual Questions, Entire study 
14.5.1.1 
Safety   
Summary of Plasma BCX7353 Concentration (ng/mL), Part 1 
14.5.1.1.ES 
Safety   
Summary of Plasma BCX7353 Concentration (ng/mL), Entire Study 
14.5.2.1 
Safety   
Plasma BCX7353 Concentration (ng/mL) Trough Samples above Kallikrein Inhibition EC50, Part 
1 
14.5.2.1.ES 
Safety   
Plasma BCX7353 Concentration (ng/mL) Trough Samples above Kallikrein Inhibition EC50, 
Entire Study 
14.6.1.1 
PD 
Summary of Plasma Kallikrein Inhibition (%), Part 1 
14.6.1.1.ES 
PD 
Summary of Plasma Kallikrein Inhibition (%), Entire Study 
14.6.2.1 
PD 
Plasma Kallikrein Inhibition Trough Samples above 50% and 80%, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
89 
 
 
CONFIDENTIAL 
 
Output # 
Population 
Output Title 
14.6.2.1.ES 
PD 
Plasma Kallikrein Inhibition Trough Samples above 50% and 80%, Entire Study 
 
Listings 
Output # 
Population Title 
Output Title 
16.2.1.1 
All Subjects 
Informed Consent and Screen Failures 
16.2.1.2 
All Subjects 
Subject Randomization, Site, and Country 
16.2.1.3 
Safety   
Planned and Actual Treatment Assignments for Subjects with Incorrect Treatment, Part 1 
16.2.1.3.ES 
Safety   
Planned and Actual Treatment Assignments for Subjects with Incorrect Treatment, Entire Study 
16.2.1.4 
ITT   
Subject Disposition 
16.2.1.5 
All Subjects 
Confirmation of Clinical Diagnosis of HAE 
16.2.1.6 
ITT   
Analysis Populations 
16.2.1.7 
ITT   
Subgroups Based on Baseline Characteristics 
16.2.2.2 
ITT   
Protocol Deviations, Part 1 
16.2.2.2.ES 
ITT   
Protocol Deviations Occurring During Part 2 of the Study 
16.2.2.3 
Safety   
Subjects for Whom the Treatment Blind Was Broken, Part 1 
16.2.2.3.ES 
Safety   
Subjects for Whom the Treatment Blind Was Broken, Entire Study 
16.2.4.1 
ITT   
Inclusion/Exclusion Criteria Not Met 
16.2.4.2.1 
All Subjects 
Demography 
16.2.4.2.2 
All Subjects 
Demography - Contraception 
16.2.4.3.1 
ITT   
Medical History 
16.2.4.3.2 
ITT   
HAE Baseline Characteristics – HAE Medical History 
16.2.4.3.3 
Safety   
HAE Medication History: Past and Current On-Demand HAE Treatment 
16.2.4.3.4 
Safety   
HAE Medication History: Past Prophylactic HAE Treatment 
16.2.4.4.1 
Safety   
Medications Discontinued Within 30 Days of Screening 
16.2.4.4.2 
Safety   
Concomitant Medication Use, Part 1 
16.2.4.4.2.ES 
Safety   
Concomitant Medication Use, Entire Study 
16.2.4.4.3 
Safety   
Use of Concomitant Medications for HAE, Part 1 
16.2.4.4.3.ES 
Safety   
Use of Concomitant Medications for HAE, Entire Study 
16.2.4.5 
ITT   
Pre-Treatment Investigator-Confirmed Attack Rates and Angioedema Symptoms 
16.2.5.1 
Safety   
Drug Accountability, Part 1 
16.2.5.1.ES 
Safety   
Drug Accountability, Entire Study 
16.2.5.2 
Safety   
Dosing Diary, Part 1 
16.2.5.2.ES 
Safety   
Dosing Diary, Entire Study 
16.2.5.3 
Safety   
Person-Years of Exposure, Part 1 
16.2.5.3.ES 
Safety   
Person-Years of Exposure, Entire Study 
16.2.6.1.1 
ITT   
HAE Attack Diary and Investigator Confirmation for All Attacks, Part 1 
16.2.6.1.1.ES 
ITT   
HAE Attack Diary and Investigator Confirmation dor All Attacks, Entire Study 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
90 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
16.2.6.1.2 
ITT   
HAE Attack Diary and Investigator Confirmation (Investigator-Confirmed Attacks Only), Part 1 
16.2.6.1.2.ES 
ITT   
HAE Attack Diary and Investigator Confirmation (Investigator-Confirmed Confirmed Attacks 
Only), Entire Study 
16.2.6.1.3 
ITT   
HAE Attack Diary Detail - Subject-Reported Attacks, Part 1 
16.2.6.1.3.ES 
ITT   
HAE Attack Diary Detail - Subject-Reported Attacks, Entire Study 
16.2.6.1.4 
ITT   
HAE Attack Diary Detail - Investigator-Confirmed Attacks, Part 1 
16.2.6.1.4.ES 
ITT   
HAE Attack Diary Detail - Investigator-Confirmed Attacks, Entire Study 
16.2.6.1.5 
ITT   
HAE Attack Level Summary - Subject-Reported Attacks, Part 1 
16.2.6.1.5.ES 
ITT   
HAE Attack Level Summary - Subject-Reported Attacks, Entire Study 
16.2.6.1.6 
ITT   
HAE Attack Level Summary - Investigator-Confirmed Attacks, Part 1 
16.2.6.1.6.ES 
ITT   
HAE Attack Level Summary - Investigator-Confirmed Attacks, Entire Study 
16.2.6.1.7 
ITT   
Attack Rate, Part 1 
16.2.6.1.7.ES 
ITT   
Attack Rate, Entire Study 
16.2.6.1.8 
ITT   
Imputed Investigator-Confirmed Attack Rates for Subjects with Missing Data, Part 1 
16.2.6.1.9 
ITT   
Subjects Who Are Investigator-Confirmed Attack-Free During Entire Dosing Period and Effective 
Dosing Period, Part 1 
16.2.6.1.9.ES 
ITT   
Subjects Who Are Investigator-Confirmed Attack-Free During Entire Dosing Period and Effective 
Dosing Period, Entire Study 
16.2.6.1.10 
ITT   
Days with Angioedema Symptoms from Investigator-Confirmed Attacks, Part 1 
16.2.6.1.10.ES 
ITT   
Days with Angioedema Symptoms from Investigator-Confirmed Attacks, Entire Study 
16.2.6.1.11.1 
ITT   
Subject-Level Efficacy Endpoint Profile, Part 1 
16.2.6.1.11.2 
ITT   
Subject-Level Additional Derived Endpoint Profile , Part 1 
16.2.6.2.1 
ITT   
AE-QoL: Individual Question Responses and Days Missed, Part 1 
16.2.6.2.1.ES 
ITT   
AE-QoL: Individual Question Responses and Days Missed, Entire Study 
16.2.6.2.2 
ITT   
AE-QoL: Domain Scores, Part 1 
16.2.6.2.2.ES 
ITT   
AE-QoL: Domain Scores, Entire Study 
16.2.6.3.1 
ITT   
TSQM Global Satisfaction Individual Responses, Part 1 
16.2.6.3.1.ES 
ITT   
TSQM Global Satisfaction Individual Responses, Entire Study 
16.2.6.3.2 
ITT   
TSQM Effect, Side Effect, Convenience and Global Satisfaction Scores, Part 1 
16.2.6.3.2.ES 
ITT   
TSQM Effect, Side Effect, Convenience and Global Satisfaction Scores, Entire Study 
16.2.6.4.1 
ITT   
EQ-5D-5L Individual Question Responses, Part 1 
16.2.6.4.1.ES 
ITT   
EQ-5D-5L Individual Question Responses, Entire Study 
16.2.6.4.2 
ITT   
EQ-5D-5L Descriptive, VAS, and Index Scores, Part 1 
16.2.6.4.3 
ITT   
EQ-5D-5L for Usual Attack Individual Question Responses, Part 1 
16.2.6.4.3.ES 
ITT   
EQ-5D-5L for Usual Attack Individual Question Responses, Entire Study 
16.2.6.4.4 
ITT   
EQ-5D-5L for Usual Attack Descriptive, VAS, and Index Scores, Part 1 
16.2.6.4.4.ES 
ITT   
EQ-5D-5L for Usual Attack Descriptive, VAS, and Index Scores, Entire Study 
16.2.6.5.1 
ITT   
WPAI Individual Question Responses, Part 1 
16.2.6.5.1.ES 
ITT   
WPAI Individual Question Responses, Entire Study 
16.2.6.5.2 
ITT   
WPAI Absenteeism, Presenteeism, Word Productivity Loss, and Activity Impairment Scores, 
Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
91 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
16.2.6.5.2.ES 
ITT   
WPAI Absenteeism, Presenteeism, Word Productivity Loss, and Activity Impairment Scores, 
Entire Study 
16.2.7.1 
Safety   
Adverse Events, Part 1 
16.2.7.1.ES 
Safety   
Adverse Events, Entire Study 
16.2.7.2 
Safety   
Serious Adverse Events, Part 1 
16.2.7.2.ES 
Safety   
Serious Adverse Events, Entire Study 
16.2.7.3 
Safety   
Grade 3 or 4 Adverse Events, Part 1 
16.2.7.3.ES 
Safety   
Grade 3 or 4 Adverse Events, Entire Study 
16.2.7.4 
Safety   
Adverse Events Leading to Permanent Discontinuation of Study Drug, Part 1 
16.2.7.4.ES 
Safety   
Adverse Events Leading to Permanent Discontinuation of Study Drug, Entire Study 
16.2.7.5.1 
Safety   
Fatal Serious Adverse Events, Part 1 
16.2.7.5.2 
Safety   
Fatal Serious Adverse Events, Entire Study 
16.2.7.6 
Safety   
Adverse Events Leading to Interruption of Study Drug, Part 1 
16.2.7.6.ES 
Safety   
Adverse Events Leading to Interruption of Study Drug, Entire Study 
16.2.7.7 
Safety   
Investigator-identified Rash, Part 1 
16.2.7.7.ES 
Safety   
Investigator-identified Rash, Entire Study 
16.2.7.8 
Safety   
GI Abdominal-Related Adverse Events, Part 1 
16.2.7.8.ES 
Safety   
GI Abdominal-Related Adverse Events, Entire Study 
16.2.7.9 
Safety   
Adverse Events For Subjects with Elevated LFTs, Part 1 
16.2.7.9.ES 
Safety   
Adverse Events For Subjects with Elevated LFTs, Entire Study 
16.2.7.10 
ITT   
Listing of GI Abdominal-Related Adverse Events and Unconfirmed HAE Attacks with 
Abdominal-Only Symptoms, Part 1 
16.2.7.10.ES 
ITT   
Listing of GI Abdominal-Related Adverse Events and Unconfirmed HAE Attacks with 
Abdominal-Only Symptoms, Entire Study 
16.2.8.1 
Safety   
Clinical Chemistry, Part 1 
16.2.8.1.ES 
Safety   
Clinical Chemistry, Entire Study 
16.2.8.2 
Safety   
Hematology, Part 1 
16.2.8.2.ES 
Safety   
Hematology, Entire Study 
16.2.8.3 
Safety   
Coagulation, Part 1 
16.2.8.3.ES 
Safety   
Coagulation, Entire Study 
16.2.8.4 
Safety   
Urinalysis, Part 1 
16.2.8.4.ES 
Safety   
Urinalysis, Entire Study 
16.2.8.5 
Safety   
Other Laboratory Tests, Part 1 
16.2.8.5.ES 
Safety   
Other Laboratory Tests, Entire Study 
16.2.8.6 
Safety   
Complement Factors C3, C4, and C1-INH, Part 1 
16.2.8.6.ES 
Safety   
Complement Factors C3, C4, and C1-INH, Entire Study 
16.2.8.7 
ITT   
SERPING Results 
16.2.8.8 
ITT   
Pregnancy Tests, Part 1 
16.2.8.8.ES 
ITT   
Pregnancy Tests, Entire Study 
16.2.8.9 
Safety   
Laboratory Abnormalities, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
92 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
16.2.8.9.ES 
Safety   
Laboratory Abnormalities, Entire Study 
16.2.8.10 
Safety   
Grade 3 or Grade 4 Laboratory Abnormalities, Part 1 
16.2.8.10.ES 
Safety   
Grade 3 or Grade 4 Laboratory Abnormalities, Entire Study 
16.2.8.11 
Safety   
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   
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 
Safety   
Vital Signs, Part 1 
16.2.8.13.ES 
Safety   
Vital Signs, Part 1, Entire Study 
16.2.8.14 
Safety   
12-Lead Electrocardiogram, Part 1 
16.2.8.14.ES 
Safety   
12-Lead Electrocardiogram, Entire Study 
16.2.8.15 
Safety   
QTcF Values > 450 msec or QTF Change from Baseline Values > 30 msec, Part 1 
16.2.8.15.ES 
Safety   
QTcF Values > 450 msec or QTF Change from Baseline Values > 30 msec, Entire Study 
16.2.8.16 
Safety   
Physical Exam, Part 1 
16.2.8.16.ES 
Safety   
Physical Exam, Entire Study 
16.2.8.17 
Safety   
Pharmacokinetic Sample Collection, Part 1 
16.2.8.17.ES 
Safety   
Pharmacokinetic Sample Collection, Entire Study 
16.2.8.18 
PD   
Plasma Kallikrein Inhibition (%), Part 1 
16.2.8.18.ES 
PD   
Plasma Kallikrein Inhibition (%), Entire Study 
 
Figures 
Output # 
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 
14.1.5.2 
Safety   
Plot of Duration of Exposure to Study Drug, Part 1 
14.1.5.2.ES 
Safety   
Plot of Duration of Exposure to Study Drug, Entire Study 
14.2.1.7 
ITT   
Box Plot of Individual Investigator-Confirmed Attack Rate for Entire Dosing Period, Part 1 
14.2.1.7.ES 
ITT   
Box Plot of Individual Investigator-Confirmed Attack Rate for Entire Dosing Period, Entire 
Study 
14.2.1.8 
ITT   
Cumuative Distribution Plot of Individual Investigator-Confirmed Attack Rate for Entire Dosing 
Period, Part 1 
14.2.1.8.ES 
ITT   
Cumulative Distribution Plot of Individual Investigator-Confirmed Attack Rate for Entire Dosing 
Period, Entire Study 
14.2.1.9 
ITT 
Forest Plot of Results of Sensitivity Analyses of  Investigator-Confirmed Attack Rate for Entire 
Dosing Period, Part 1 
14.2.1.10 
ITT 
Forest Plot of Results of Subgroup Analyses of  Investigator-Confirmed Attack Rate for Entire 
Dosing Period, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
93 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
14.2.1.12 
ITT   
Box Plot of Individual Investigator-Confirmed Attack Rate for Effective Dosing Period, Part 1, 
14.2.1.12.ES 
ITT   
Box Plot of Individual Investigator-Confirmed Attack Rate for Effective Dosing Period, Entire 
Study 
14.2.1.13 
ITT   
Cumulative Distribution Plot of Individual Investigator-Confirmed Attack Rate for Effective 
Dosing Period, Part 1 
14.2.1.13.ES 
ITT   
Cumulative Distribution Plot of Individual Investigator-Confirmed Attack Rate for Effective 
Dosing Period, Entire Study 
14.2.2.2 
ITT   
Histogram Plot of Baseline Investigator-Confirmed Attack Rate, Part 1 
14.2.2.3 
ITT   
Plot of Mean Investigator-Confirmed Attack Rate by Month, Part 1 
14.2.2.3.ES 
ITT   
Plot of Mean Investigator-Confirmed Attack Rate by Month, Entire Study 
14.2.2.3.P3 
ITT   
Plot of Mean Subject-Reported Attack Rate by Month, Part 3 
14.2.2.4 
ITT   
Plot of On-Study Investigator-Confirmed Attack Rate vs Baseline Investigator-Confirmed Attack 
Rate, Part 1 
14.2.2.4.ES 
ITT   
Plot of On-Study Investigator-Confirmed Attack Rate vs Baseline Investigator-Confirmed Attack 
Rate, Entire Study 
14.2.2.5 
ITT   
Plot of Difference Between On-Study Investigator-Confirmed Attack Rate and Baseline 
Investigator-Confirmed Attack Rate vs Baseline Investigator-Confirmed Attack Rate, Part 1 
14.2.2.6 
ITT   
Plot of Change from Baseline Attack Rate Versus Percent Compliance, Part 1 
14.2.3.3 
ITT   
Plot of Mean AE-QoL Scores Over Time, Part 1 
14.2.3.3.ES 
ITT   
Plot of Mean AE-QoL Scores Over Time, Entire Study 
14.2.3.4 
ITT   
Plot of Mean Change from Baseline AE-QoL Scores Over Time, Part 1 
14.2.3.4.ES 
ITT   
Plot of Mean Change from Baseline AE-QoL Scores Over Time, Entire Study 
14.2.3.5 
ITT   
Cumulative Distribution of Total AE-QoL Change from Baseline at Week 24 
14.2.3.6 
ITT 
Forest Plot of Results of Subgroup Analyses of  Total AE-QOL Change from Baseline at Week 
24, Part 1 
14.2.8.2 
ITT   
Kaplan-Meier Plot of Time to First Investigator-Confirmed Attack, Part 1 
14.2.9.2 
ITT   
Kaplan-Meier Plot of Time to First Use of Targeted HAE Rescue Medication to Treat an 
Investigator-Confirmed Attack, Part 1 
14.3.1.13 
ITT 
Forest Plot of Treatment-Emergent Adverse Events Sorted by Relative Risk,  Part 1 
14.3.1.13.ES 
ITT 
Forest Plot of Treatment-Emergent Adverse Events Sorted by Relative Risk,  Entire Study 
14.3.1.26 
Safety   
Kaplan-Meier Plot of Time to Development of Investigator-identified Rash, Part 1 
14.3.1.26.ES 
Safety   
Kaplan-Meier Plot of Time to Development of Investigator-identified Rash, Entire Study 
14.3.1.28 
Safety   
Kaplan-Meier Plot of Duration of Investigator-identified Rash, Part 1 
14.3.1.28.ES 
Safety   
Kaplan-Meier Plot of Duration of Investigator-identified Rash, Entire Study 
14.3.1.40 
Safety   
Kaplan-Meier Plot of Time to First Occurrence of a GI Abdominal-related Adverse Event Part 1 
14.3.1.40.ES 
Safety   
Kaplan-Meier Plot of Time to First Occurrence of a GI Abdominal-related Adverse Event Entire 
Study 
14.3.1.42 
Safety   
Kaplan-Meier Plot of Duration of GI Abdominal-related Adverse Events Part 1 
14.3.1.42.ES 
Safety   
Kaplan-Meier Plot of Duration of GI Abdominal-related Adverse Events Entire Study 
14.3.1.43 
Safety   
Plot of Occurrence of Treatment-Emergent GI Abdominal-related Adverse Events, Part 1 
14.3.1.43.ES 
Safety   
Plot of Occurrence of Treatment-Emergent GI Abdominal-related Adverse Events, Entire Study 
14.3.5.20 
Safety   
Plot of Liver Function Test Profiles for Subjects with Grade 3 or 4 Liver Abnormalities, Part 1 
14.3.5.21 
Safety 
Hy’s Law Plot of Maximum Total Bilirubin vs. Maximum ALT, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
94 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
14.3.5.21.ES 
Safety 
Hy’s Law Plot of Maximum Total Bilirubin vs. Maximum ALT, Entire Study 
14.3.5.22 
Safety 
Liver Test Safety Panel Over Time, Baseline vs. On-Study, Part 1 
14.3.5.22.ES 
Safety 
Liver Test Safety Panel Over Time, Baseline vs. On-Study, Entire Study 
14.3.5.23 
Safety 
Distribution of Liver Tests Over Time: ALT, AST, ALP, and Bilirubin, Part 1 
14.3.5.23.ES 
Safety 
Distribution of Liver Tests Over Time: ALT, AST, ALP, and Bilirubin, Entire Study 
14.3.5.24 
Safety 
Distribution of Cholesterol and Triglycerides Over Time, Part 1 
14.3.5.24.ES 
Safety 
Distribution of Cholesterol and Triglycerides Over Time, Entire Study 
14.3.5.26 
Safety   
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 ALT Part 1 
14.3.5.28 
Safety   
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 AST Part 1 
14.3.5.30 
Safety   
Kaplan-Meier Plot of Time to First Occurrence of Grade 3 or 4 Total Bilirubin, Part 1 
14.3.6.2 
Safety 
Distribution of Diastolic and Systolic Blood Pressure Over Time, Part 1 
14.3.6.2.ES 
Safety 
Distribution of Diastolic and Systolic Blood Pressure Over Time, Entire Study 
14.3.7.4 
Safety 
Distribution of QTcF Over Time, Part 1 
14.3.7.4.ES 
Safety 
Distribution of QTcF Over Time, Entire Study 
14.4.1.2 
ITT   
Plot of Mean WPAI Scores Over Time, Part 1 
14.4.1.2.ES 
ITT   
Plot of Mean WPAI Scores Over Time, Entire Study 
14.4.1.3 
ITT   
Plot of Mean Change from Baseline WPAI Scores Over Time, Part 1 
14.4.1.3.ES 
ITT   
Plot of Mean Change from Baseline WPAI Scores Over Time, Entire Study 
14.4.2.2 
ITT   
Plot of Mean EQ-5D-5L VAS Scores Over Time, Part 1 
14.4.2.2.ES 
ITT   
Plot of Mean EQ-5D-5L VAS Scores Over Time, Entire Study 
14.4.2.3 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores Over Time, Part 1 
14.4.2.3.ES 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores Over Time, Entire Study 
14.4.2.5 
ITT   
Plot of Mean EQ-5D-5L VAS Scores from Usual Attack Over Time, Part 1 
14.4.2.5.ES 
ITT   
Plot of Mean EQ-5D-5L VAS Scores from Usual Attack Over Time, Entire Study 
14.4.2.6 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores from Usual Attack Over Time, Part 
1 
14.4.2.6.ES 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L VAS Scores Usual Attack Over Time, Entire 
Study 
14.4.2.8 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Part 1 
14.4.2.8.ES 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Entire Study 
14.4.2.9 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Part 1 
14.4.2.9.ES 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Over Time, Entire Study 
14.4.2.11 
ITT   
Plot of Mean EQ-5D-5L Index Scores from Usual Attack Over Time, Part 1 
14.4.2.11.ES 
ITT   
Plot of Mean EQ-5D-5L Index Scores from Usual Attack Over Time, Entire Study 
14.4.2.12 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores from Usual Attack Over Time, Part 
1 
14.4.2.12.ES 
ITT   
Plot of Mean Change from Baseline EQ-5D-5L Index Scores Usual Attack Over Time, Entire 
Study 
14.4.3.2 
ITT   
Plot of Mean TSQM Scores Over Time, Part 1 
14.4.3.2.ES 
ITT   
Plot of Mean TSQM Scores Over Time, Entire Study 
14.4.3.3 
ITT   
Plot of Mean Change from Baseline TSQM Scores Over Time, Part 1 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
95 
 
 
CONFIDENTIAL 
 
Output # 
Population Title 
Output Title 
14.4.3.3.ES 
ITT   
Plot of Mean Change from Baseline TSQM Scores Over Time, Entire Study 
14.6.1.2 
PK-PD   
Scatterplot of Kallekrein Inhibition (%) and BCX7353 Plasma Concentration/4by Study Visit, 
Part 1 
14.6.1.2.ES 
PK-PD   
Scatterplot of Kallekrein Inhibition (%) and BCX7353 Plasma Concentration/4by Study Visit, 
Entire Study 
 
Data Display Specifications 
Table, listing, and figure shells will be stored in a separate document. 
List of Preferred Terms, High Level Terms, and High-Level Group Terms for 
Gastrointestinal Abdominal-Related Treatment-Emergent Adverse 
Events 
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 
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 


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Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 


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Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 
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 
Gastrointestinal 
pain 
Gastrointestinal and 
abdominal pains (excl 
oral and throat) 
Gastrointestinal 
signs and 
symptoms 
Gastrointestinal 
disorders 
10067715 
Gastrointestinal 
sounds 
abnormal 
Abdominal findings 
abnormal 
Gastrointestinal 
signs and 
symptoms 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
10075724 
Gastrointestinal 
wall thickening 
Gastrointestinal signs 
and symptoms NEC 
Gastrointestinal 
signs and 
symptoms 
Gastrointestinal 
disorders 
10075726 
Gastrointestinal 
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 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
99 
 
 
CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 
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 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
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CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
defaecation 
conditions 
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 
10060865 
Duodenogastric 
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 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
101 
 
 
CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 
Gastrointestinal 
hypermotility 
Gastrointestinal spastic 
and hypermotility 
disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10052105 
Gastrointestinal 
hypomotility 
Gastrointestinal atonic 
and hypomotility 
disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10061173 
Gastrointestinal 
motility 
disorder 
Gastrointestinal 
dyskinetic disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10017885 
Gastrooesophag
eal reflux 
disease 
Gastrointestinal atonic 
and hypomotility 
disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10062879 
Gastrooesophag
eal 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 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
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CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 
10067752 
Oesophageal 
hypomotility 
Gastrointestinal atonic 
and hypomotility 
disorders NEC 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 


BioCryst Pharmaceuticals, Inc. 
 
BCX7353-302 
Statistical Analysis Plan Version 1.0 
 
 29 January 2019 
 
103 
 
 
CONFIDENTIAL 
 
Code 
Preferred 
Term (PT) 
High Level Term 
(HLT) 
High Level Group 
Term (HLGT) 
SOC 
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 
Presbyoesophag
us 
Gastrointestinal 
dyskinetic disorders 
Gastrointestinal 
motility and 
defaecation 
conditions 
Gastrointestinal 
disorders 
10075246 
Pseudoachalasia 
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