A Phase 3 Study to Evaluate the Safety and Pharmacokinetics of Berotralstat Prophylaxis in Children With Hereditary Angioedema Who Are 2 to < 12 Years of Age
Phase: PHASE3
Conditions: Hereditary Angioedema, Pediatric
Sponsor: BioCryst Pharmaceuticals

TITLE PAGE 
BIOCRYST 
PHARMACEUTICALS, INC. 
Protocol No. BCX7353-304 
A PHASE 3 STUDY TO EVALUATE THE SAFETY AND 
PHARMACOKINETICS OF BEROTRALSTAT PROPHYLAXIS 
IN CHILDREN WITH HEREDITARY ANGIOEDEMA WHO 
ARE 2 TO < 12 YEARS OF AGE  
Version 7.0: 05 November 2024 
EU Clinical Trial No. 2024-511257-22-00 
 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Blvd., Suite 200 
Durham, NC 27703 
Phone: (919) 859-1302 
Fax: (919) 851-1416 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
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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INVESTIGATOR’S AGREEMENT 
 
Protocol No: 
BCX7353-304 
Protocol Title: 
A Phase 3 Study to Evaluate the Safety and Pharmacokinetics of Berotralstat 
Prophylaxis in Children with Hereditary Angioedema Who Are 2 to 
< 12 Years of Age 
 
Date: 
 
Version 7.0: 05 November 2024  
 
 
I have received and read the Investigator’s Brochure for berotralstat. I have read the 
Study BCX7353-304 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol: 
Study BCX7353-304.  
 
 
 
_____________________________________________________________________ 
Investigator’s Signature                                                                      Date 
 
 
_________________________________ 
Name (Print) 
 
 

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1. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc.  
Name of Investigational Product: 
Berotralstat, BCX7353 
Name of Active Ingredient: 
(R)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-
fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide  
Protocol Number: 
BCX7353-304 
Phase: 3 
Countries: Multiple study centers in North 
America, Israel, and Europe 
Title of Study:  
A Phase 3 study to evaluate the safety and pharmacokinetics of berotralstat prophylaxis in children with 
hereditary angioedema (HAE) who are 2 to < 12 years of age 
Principal Investigator: Jolanta Bernatoniene, MD 
Consultant in Paediatrics, Paediatric Infectious Disease and Immunology, Bristol Royal Hospital for 
Children, Bristol, United Kingdom 
Enrollment period (months): Approximately 24 months 
Phase of development: 3 
Primary Objective: 
• 
To describe the pharmacokinetic (PK) parameters of berotralstat administered orally to 
pediatric subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
Secondary Objectives: 
• 
To assess the safety and tolerability of berotralstat administered orally to pediatric subjects 
with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
• 
To summarize the effectiveness of berotralstat in pediatric subjects with HAE aged 2 to 
< 12 years old and weighing ≥ 12 kg. 
Exploratory Objective: 
• 
To assess the palatability/acceptability of berotralstat oral granules in pediatric subjects with 
HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
Primary Endpoint: 
• 
PK: The primary endpoint is the characterization of the PK profile of berotralstat in subjects 
aged 2 to < 12 years. 
Secondary Endpoints: 
• 
Safety: The frequency and severity of adverse events (AEs) and serious adverse events 
(SAEs), laboratory analyses (clinical chemistry, hematology, coagulation), height, weight, 
vital signs, electrocardiograms (ECGs), and physical examination findings 
• 
Effectiveness: the frequency of attacks, duration of symptoms, anatomical location of attack, 
on-demand treatment, number of days with angioedema symptoms, assessment of attack 
severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic 
visits from Week 1 through Weeks 12 and 48. 

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Exploratory Endpoint: 
• 
Age-appropriate questionnaire for palatability/acceptability of berotralstat oral granules as 
assessed by the site following the first dose  
Methodology:  
This is a single-arm, open-label study designed to evaluate the PK of berotralstat; plasma concentrations of 
berotralstat will be measured and used in population PK analyses, allowing for determination of the 
appropriate weight-based dose for pediatric patients 2 to < 12 years old. In addition, the safety and 
tolerability of berotralstat will be assessed when given to pediatric subjects who are 2 to < 12 years old as 
a prophylactic treatment to prevent attacks of HAE. The effectiveness of berotralstat in this population will 
be summarized using descriptive statistical methods. Subjects will be enrolled into 4 or more dose cohorts; 
subject weight will be used to determine assignment to each cohort with the higher weight cohorts 
(Cohorts 1 and 2) enrolling first and in parallel. Cohort 3 will open for enrollment and initiate the 12-week 
standard-of-care (SOC) phase after ≥ 4 subjects from Cohorts 1 and 2, with ≥ 2 of the subjects from 
Cohort 2, have reached Week 2. Cohort 4 will open for enrollment and initiate the 12-week SOC phase 
after ≥ 4 subjects in Cohort 3 have reached Week 2. BioCryst will notify sites when Cohorts 3 and 4 are 
open for enrollment. Safety assessments by the Data Monitoring Committee (DMC) and PK modelling 
from all available PK data to confirm the weight band for the cohort will occur prior to dosing subjects in 
Cohorts 3 and 4 with berotralstat. Additional dose cohort(s) may be enrolled if indicated based on safety 
and/or population PK analyses with DMC endorsement.  
This study will consist of 2 treatment periods: a 12-week SOC treatment period followed by an open-label 
berotralstat treatment period lasting up to 144 weeks. The berotralstat treatment period is divided into 
3 parts as defined below. Throughout the study, site personnel will monitor subject safety through a 
combination of in-person clinic visits and tele-communication with the parent/caregiver(s) (P/C). The tele-
contact may be either a telephone call or telemedicine visit conducted over the internet. 
The study schema is as follows: 
 
Abbreviations: BSLN = Baseline; DC = discontinue; Enr = enrollment; P/C = parents and/or caregivers; PK = pharmacokinetic; 
QD = once daily; SOC = Standard of Care; Wk = Week. 
a Subjects will be enrolled at the screening visit. If, after the screening visit, laboratory results are returned that indicate the 
subject no longer meets the inclusion and exclusion criteria, the subject will be considered a screen failure.  
b Indicates visits where a single, random, plasma sample is collected for PK. 
Pediatric patients who are considered good candidates for the study will report to the site for a screening 
visit. After P/C have provided informed consent, and, where appropriate, children have provided assent, 
screening assessments may be initiated. Screening assessments will be conducted at the screening visit 

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although, if necessary, the assessments may take place over a screening period not to exceed 14 days 
without prior consent of the sponsor. Subjects will be considered enrolled into the study as of the date of 
the screening visit if all available results satisfy the inclusion and exclusion criteria as of that date. If, after 
the screening visit, screening results are returned that indicate the subject no longer meets the inclusion 
and exclusion criteria, the subject will be considered a screen failure. The investigator will provide the P/C 
with study materials (eg, subject’s diary) at the end of the screening visit and request the P/C to record 
diary data starting at the date of the screening visit and for the next 12 weeks (ie, the SOC treatment 
period).  
To monitor effectiveness, the P/C must begin recording HAE attacks in the subject’s diary at the time of 
subject enrollment, and continue recording through Week 48 (ie, end of Part 2). 
SOC Treatment Period: Subjects will continue taking their SOC therapy for HAE (either short-term or 
long-term prophylaxis, or acute treatment for HAE attacks) for 12 weeks from the screening visit. No 
additional in-person visits are required during the SOC treatment period; however, at approximately 4 and 
8 weeks following screening, site personnel will contact the P/C to assess AEs and the overall status of the 
subject. 
Part 1: After 12 weeks on SOC, subjects will return to the site for the Day 1 (baseline) visit. Prior to the 
Day 1 visit, subjects must discontinue all prophylaxis for prevention of HAE attacks; use of on-demand 
medication to manage acute HAE attacks may continue throughout the study. At the Day 1 visit, the site 
will confirm concomitant medications, review subject diary entries, and discuss any AEs that occurred 
during the SOC treatment period. If study activities were not completed satisfactorily during this time 
(eg, diary entries were incomplete or the P/C was not reachable to assess AEs at the prescribed intervals), 
the subject may be discontinued from the study prior to the berotralstat treatment period at the sole 
discretion of the investigator. Beginning on Day 1, subjects will take berotralstat orally once each day, 
with food, for 12 weeks. Additional study visits in Part 1 will occur at Weeks 2, 6, and 12. All safety 
assessments will be assessed at each visit. In addition to the clinic visits, the site will contact the P/C at 
Week 9 to assess safety and subject status. 
Part 2: Beginning at the Week 12 visit, all subjects will be provided continued access to open-label 
berotralstat through Week 48 (a total of 36 weeks). Study visits in Part 2 will occur every 12 weeks 
(Weeks 24, 36, and 48). Also during Part 2, sites will contact the P/C at 4-week intervals between study 
visits (ie, at Weeks 16, 20, 28, 32, 40, and 44) to assess the subjects’ overall wellbeing. The contact should 
be an arranged tele-contact; however, it may become an on-site visit if the investigator or P/C considers an 
in-person visit necessary for medical management of the subject. At the Week 48 visit, the site will collect 
all subject diaries.  
Part 3: After Week 48, subjects may continue to receive open-label berotralstat in Part 3 (Weeks 48 
through 144; a total of 96 weeks). Visits in Part 3 will occur every 24 weeks: Weeks 72, 96, 120, and 144. 
Also during Part 3, sites will contact the P/C at 12-week intervals between study visits (ie, at Weeks 60, 
84, 108, and 132) to assess the subjects’ overall wellbeing. The contact should be an arranged tele-contact; 
however, it may become an on-site visit if the investigator or P/C considers an in-person visit necessary 
for medical management of the subject. Berotralstat will be provided in Part 3 through Study Week 144 or 
until another mechanism is available to provide drug to the subject (eg, market access, separate study) or 
the sponsor discontinues development of the product for the prevention of angioedema attacks in children 
< 12 years of age.  
Subjects who discontinue berotralstat at Week 144 or earlier will be required to attend an end-of-study 
(EOS) follow-up visit 3 weeks after study drug discontinuation. Subjects who discontinue the study but 

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will continue to receive berotralstat via another mechanism will have EOS assessments performed at their 
last regularly scheduled visit.  
PK Assessments: At Week 2 in Part 1, plasma samples for PK analysis will be collected immediately prior 
to dosing and at designated timepoints post dose. Based on the PK results, the dose regimen of berotralstat 
may be adjusted for an individual subject or for all subjects in the cohort to ensure exposures fall within 
the acceptable safety range; the dose of berotralstat will not be adjusted based on changes to the subject’s 
weight during Part 1. In Part 2, one random sample for PK analysis will be drawn at Weeks 12, 24, 36, and 
48. Reduced PK sampling may be performed in smaller subjects, especially subjects in Cohort 4, to 
maintain blood sample volumes within acceptable ranges.  
Additional PK samples should be drawn if the berotralstat dose is adjusted. 
 
Number of subjects (planned):  
Approximately 30 subjects are planned to be enrolled. 
Main criteria for inclusion:  
• Age 2 to < 12 years of age and weighing ≥ 12 kg  
• Parent/caregiver willing and able to provide written, informed consent (with assent from the child 
where appropriate).  
• Subjects with a clinical diagnosis of HAE. A clinical diagnosis of HAE is defined as:  
a. Screening results that document immunogenic C1 esterase inhibitor (C1-INH) antigenic level 
below the lower limit of normal (LLN) reference range or C1-INH function < 50%, and a 
complement 4 (C4) level below the LLN reference range. 
OR 
b. Laboratory documentation of historical C1-INH functional level below the assay lower limit 
of normal.  
OR 
c. 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, as assessed during the 
screening period OR a repeat C1-INH functional level < 50% will be considered acceptable 
for enrollment. 
OR 
d. Historical or new laboratory documentation of a SERPING-1 mutation known or likely to be 
associated with HAE.  
OR 
e. For subjects who currently use plasma-derived or recombinant C1-INH-based prophylactic 
therapies, a confirmed family history of C1-INH deficiency. 
• For subjects who are not currently receiving prophylaxis for HAE, documented history of ≥ 2 HAE 
attacks in the 6 months prior to the enrollment visit. 
• Access to and ability to use one or more acute medications approved by the relevant competent 
authority for the treatment of acute attacks of HAE. 

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• In the opinion of the investigator, the subject would benefit from long-term oral prophylaxis.  
• If sexually active, or become sexually active during the study, must agree to the use of effective 
contraception. 
Main criteria for exclusion: 
1. Concurrent diagnosis of any other type of recurrent angioedema. 
2. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant 
cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, myocarditis, pericarditis, 
congenital heart defects, or any other clinically significant cardiovascular abnormality such as 
poorly controlled hypertension. 
3. Known family history of sudden cardiac death at a young age (ie, < 40 years of age). Family history 
of sudden death from HAE is not exclusionary. 
4. History of or current implanted defibrillator or pacemaker. 
5. Moderate to severe hepatic impairment (Child-Pugh B or C). 
6. A calculated creatinine clearance using the Modified Schwartz formula of ≤ 30 mL/min/1.73 m2 or 
aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the 
age-appropriate normal reference range value. 
7. History of severe hypersensitivity to multiple medicinal products or severe 
hypersensitivity/anaphylaxis with unclear etiology. 
8. Current participation in any other investigational drug study or received another investigational drug 
within 30 days of enrollment; not willing to refrain from participation in another clinical study after 
enrollment and for the duration of the study. [Note: drugs/vaccines approved under FDA emergency 
use authorization (or country-specific analogous regulations) are not considered excluded or 
prohibited under this criterion.] 
9. An immediate family relationship to either sponsor employees, the investigator, or employees of the 
study site named on the delegation log. 
10. Any result at screening that, in the opinion of the investigator, is clinically significant and relevant 
for this study. 
11. Any clinically significant medical condition or medical history (including altered mental status) 
that, in the opinion of the investigator or sponsor, would interfere with the subject’s safety or ability 
to participate in the study. Examples include but are not limited to active malignancy under 
treatment, uncontrolled cardiovascular disease, organ dysfunction requiring supportive care.  
12. Clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated 
using Fridericia’s correction (QTcF = QT/RR0.33) > 450 msec, or ventricular and/or atrial premature 
contractions that are more frequent than occasional, and/or as couplets or higher in grouping. 
13. Known hypersensitivity to berotralstat or any of its formulation excipients. 

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Investigational product, dosage, and mode of administration:  
Berotralstat 150 mg capsules in multidose bottles and granules for oral administration packaged in 
unit-dose packets will be taken orally, once daily, with food. The doses for Cohorts 1, 2, 3, and 4 are 
shown in the table. Based on safety assessments and available PK data, the weight bands for Cohorts 3 and 
4 may be adjusted if needed. 
The berotralstat dose for Part 1 will be determined based on subject weight on Day 1; this dose will be 
changed for an individual subject or for all subjects in the cohort if indicated by safety and/or PK 
parameters. In Parts 2 and 3, subjects will continue open-label berotralstat for a total of up to an additional 
132 weeks. The dose in Parts 2 and 3 will be based on subject weight and may be adjusted throughout the 
132-week treatment period as indicated based on changes in the subject’s weight, safety, and/or PK 
parameters.  
 
Cohort 
Dose 
Minimum Target Enrollmenta 
Weight Band 
(from PK modelling) 
1 
150 mg capsule 
n = 4 
≥ 40 kg 
2 
108 mg granules 
n = 4 
32 to < 40 kg 
3 
96 mg granules 
n = 4 
24 to < 32 kg 
4 
78 mg granules 
n = 3 
12 to < 24 kg 
Note: Additional dose strengths ranging from 60 to < 150 mg and/or cohorts may be utilized as indicated 
based on safety and/or PK results.  
a The n represents the minimum number that will be enrolled into each cohort. Since the total target 
enrollment is approximately 30 subjects, additional subjects will be enrolled into one or more of the cohorts 
or additional dose cohort(s) may be added. Subject enrollment in any one or more cohorts may be suspended 
to ensure sufficient enrollment of subjects in each cohort. 
 
 
Reference therapy, dosage, and mode of administration:  
This is an open-label trial, and there is no reference therapy. Subjects will remain on their SOC regimen 
for the 12 weeks comprising the SOC treatment period. SOC may include short-term prophylaxis, 
long-term prophylaxis, and/or on-demand treatment for acute attacks. Data on AEs and HAE attacks will 
be collected during this period. 
Duration of treatment:  
Subjects will continue to take their SOC for 12 weeks following screening. Subjects who continue in the 
study will take berotralstat capsules (150 mg) or granules for oral administration (in unit-dose packets) for 
12 weeks (Part 1) beginning on Day 1. For Parts 2 and 3, subjects will take berotralstat through Weeks 48 
(Part 2) and 144 (Part 3), respectively. 

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Criteria for evaluation: 
Pharmacokinetics (PK): 
Plasma PK concentrations will be used in the population PK analysis.  
Safety: 
Frequency and severity of AEs/SAEs, laboratory analyses (clinical chemistry, hematology, coagulation), 
height, weight, vital signs, ECGs, and physical examinations.  
Effectiveness: 
Number of angioedema attacks (timing, duration of symptoms, anatomical location, treatment), number of 
days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, 
and number of hospitalizations and clinic visits through Week 48.  
Statistical methods: Descriptive statistics will be generated for PK, safety, and effectiveness endpoints. 
Summaries will include sample size (n), mean, standard deviation (SD) or standard error of the mean 
(SEM), median, minimum, and maximum for continuous data, and frequency and percentages for 
categorical data. Results will be presented by weight cohort and study visit where applicable. Interim 
analyses may be conducted after at least 15 subjects complete 48 weeks of treatment (Part 2) and/or after 
all subjects complete 48 weeks of treatment. Additional interim analyses may be performed during the 
course of the study as needed to support regulatory filings, safety updates, and publications. No inferential 
analyses are planned. The final analysis will be conducted following the last study visit and after database 
lock has occurred. 
Pharmacokinetics (PK):  
Plasma PK data from Cohorts 1 and 2 will be used to confirm/determine weight bands for any subsequent 
cohorts using population PK modeling. The results of the PK analyses will be reported in a separate 
pharmacometric report. 
Safety: 
Analysis of safety and tolerability will be descriptive. For treatment-emergent adverse event (TEAE) data, 
both the number of subjects and total number of events will be reported. An independent DMC will 
periodically review safety data in accordance with a DMC Charter. 
Effectiveness: 
Descriptive analysis of secondary effectiveness endpoints will be provided for Part 1 (Weeks 1 to 12) and 
Parts 1 and 2 combined (Weeks 1 to 48). No effectiveness data will be collected after Week 48.   
 

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2. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
TABLE OF CONTENTS ...........................................................................................10 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
4. 
INTRODUCTION ......................................................................................................17 
4.1. 
Background .................................................................................................................17 
4.2. 
Nonclinical Findings for Berotralstat .........................................................................17 
4.3. 
Clinical Findings for Berotralstat ...............................................................................17 
4.3.1. 
Pivotal Studies ............................................................................................................17 
4.3.2. 
Data from Adolescent Patients Enrolled in Berotralstat Clinical Trials .....................18 
4.4. 
Rationale for Study .....................................................................................................18 
4.4.1. 
Rationale for Study Design .........................................................................................18 
4.4.2. 
Rationale for Berotralstat Doses .................................................................................19 
4.4.3. 
Rationale for Age and Weight Range .........................................................................19 
4.4.4. 
Rationale for Open-label Design ................................................................................20 
4.4.5. 
Berotralstat Risk Analysis ..........................................................................................20 
4.4.6. 
Benefits of Trial Participation ....................................................................................20 
4.4.7. 
Overall Benefit-Risk Assessment ...............................................................................20 
5. 
TRIAL OBJECTIVES AND OUTCOME MEASURES ...........................................21 
5.1. 
Objectives ...................................................................................................................21 
5.1.1. 
Primary Objective .......................................................................................................21 
5.1.2. 
Secondary Objectives .................................................................................................21 
5.1.3. 
Exploratory Objective .................................................................................................21 
5.2. 
Endpoints ....................................................................................................................21 
5.2.1. 
Primary Endpoints ......................................................................................................21 
5.2.2. 
Secondary Endpoints ..................................................................................................21 
5.2.3. 
Exploratory Endpoints ................................................................................................21 
6. 
OVERALL STUDY DESIGN AND PLAN ...............................................................22 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................23 
7.1. 
Number of Subjects ....................................................................................................23 
7.2. 
Subject Selection ........................................................................................................23 
7.2.1. 
Inclusion Criteria ........................................................................................................23 
7.2.2. 
Exclusion Criteria .......................................................................................................25 
7.3. 
Subject Withdrawal from the Study and from Study Drug ........................................26 
7.3.1. 
Subject Withdrawal from the Study ...........................................................................26 
7.3.2. 
Subject Discontinuation from Study Drug .................................................................26 
7.3.3. 
Criteria for Study Termination ...................................................................................27 
7.4. 
End of Study Definition ..............................................................................................27 
8. 
TREATMENT OF SUBJECTS ..................................................................................27 
8.1. 
Berotralstat Formulation .............................................................................................28 
8.2. 
Berotralstat Packaging, Labeling, and Storage ...........................................................28 
8.3. 
Dose and Administration of Berotralstat ....................................................................28 
8.3.1. 
Berotralstat Dose ........................................................................................................28 
8.3.2. 
Administration of Berotralstat ....................................................................................29 
8.4. 
Study Drug Dose Modification ...................................................................................30 
8.5. 
Accountability of Berotralstat .....................................................................................30 
8.6. 
Concomitant Medications ...........................................................................................31 
8.7. 
Prohibited Medications ...............................................................................................31 
9. 
STUDY CONDUCT ...................................................................................................33 
9.1. 
Schedule of Assessments ............................................................................................33 
9.2. 
Study Visits – Standard of Care Treatment Period .....................................................38 
9.2.1. 
Screening and Enrollment ...........................................................................................38 
9.2.2. 
Weeks 4 and 8 after Enrollment .................................................................................39 
9.3. 
Study Visits – Berotralstat Treatment Period: Part 1 ..................................................39 
9.3.1. 
Baseline Visit (Day 1) ................................................................................................39 
9.3.2. 
Weeks 2, 6, 9, and 12 ..................................................................................................39 
9.4. 
Study Visits – Berotralstat Treatment Period: Part 2 ..................................................40 
9.4.1. 
Week 16, 20, 28, 32, 40, and 44 Contacts ..................................................................40 
9.4.2. 
Week 24, 36, and 48 Visits .........................................................................................40 
9.5. 
Study Visits – Berotralstat Treatment Period: Part 3 ..................................................40 
9.5.1. 
Week 60, 84, 108, and 132 Contacts ..........................................................................40 

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9.5.2. 
Week 72, 96, and 120 Visits .......................................................................................40 
9.5.3. 
Week 144 / End of Treatment (EOT) .........................................................................40 
9.6. 
End-of-Study (EOS) Follow-up Visit .........................................................................41 
10. 
ASSESSMENTS.........................................................................................................41 
10.1. 
Demographics .............................................................................................................41 
10.2. 
HAE Medical and Medication History .......................................................................41 
10.3. 
Physical Examination .................................................................................................41 
10.4. 
Weight/Height/Body Mass Index ...............................................................................42 
10.5. 
12-lead Electrocardiograms ........................................................................................42 
10.6. 
Vital Signs ..................................................................................................................42 
10.7. 
Clinical Laboratory Evaluations .................................................................................43 
10.8. 
Confirmation of HAE Diagnosis ................................................................................45 
10.9. 
Pharmacokinetics ........................................................................................................45 
10.9.1. 
Plasma Pharmacokinetic Samples for Dose Modifications ........................................46 
10.10. 
Adverse Events ...........................................................................................................47 
10.11. 
HAE Attack Diary ......................................................................................................47 
11. 
ADVERSE EVENT MANAGEMENT AND REPORTING .....................................47 
11.1. 
Adverse Events ...........................................................................................................47 
11.1.1. 
Definitions ..................................................................................................................47 
11.1.2. 
Recording Adverse Events .........................................................................................51 
11.1.3. 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................51 
11.1.4. 
Unanticipated Problems ..............................................................................................53 
11.2. 
Toxicity Management .................................................................................................53 
11.2.1. 
Treatment Interruptions ..............................................................................................54 
11.2.2. 
Dose Reductions .........................................................................................................54 
11.2.3. 
Overdose .....................................................................................................................54 
11.3. 
Data Monitoring Committee .......................................................................................55 
11.4. 
COVID-19 ..................................................................................................................55 
12. 
STATISTICS ..............................................................................................................55 
12.1. 
Sample Size Considerations .......................................................................................55 
12.2. 
Statistical Methods ......................................................................................................56 
12.2.1. 
Analysis Populations ..................................................................................................56 

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12.2.2. 
General Considerations for Data Analysis .................................................................56 
12.2.3. 
Subject Demographic and Disposition Data ...............................................................57 
12.2.4. 
Pharmacokinetic Analyses ..........................................................................................57 
12.2.5. 
Analysis of Safety Variables ......................................................................................57 
12.2.6. 
Analysis of Effectiveness Variables ...........................................................................58 
12.2.7. 
Analysis of Exploratory Variables ..............................................................................58 
13. 
STUDY ADMINISTRATION ...................................................................................59 
13.1. 
Direct Access to Source Data/Documents ..................................................................59 
13.1.1. 
Study Monitoring ........................................................................................................59 
13.1.2. 
Audits and Inspections ................................................................................................59 
13.1.3. 
Ethics Committee ........................................................................................................60 
13.1.4. 
Serious Breaches of GCP ............................................................................................60 
13.2. 
Quality Control and Quality Assurance ......................................................................60 
13.3. 
Regulatory and Ethical Considerations ......................................................................60 
13.3.1. 
Ethics Review .............................................................................................................60 
13.3.2. 
Ethical Conduct of the Study ......................................................................................61 
13.3.3. 
Written Informed Consent and Assent .......................................................................61 
13.4. 
Data Handling and Recordkeeping .............................................................................62 
13.4.1. 
Inspection of Records .................................................................................................62 
13.4.2. 
Records Retention .......................................................................................................62 
13.5. 
Confidentiality of Information and Data ....................................................................62 
13.6. 
Study Publication ........................................................................................................63 
14. 
REFERENCES ...........................................................................................................64 
15. 
APPENDICES ............................................................................................................65 
15.1. 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events – July 2017 ........................................................................65 
 

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LIST OF TABLES 
Table 1: 
Cohort Dose and Weight Bands .................................................................................29 
Table 2: 
Schedule of Assessments ............................................................................................34 
Table 3: 
Clinical Laboratory Evaluations .................................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................22 
Figure 2: 
Cohort Enrollment Scheme .........................................................................................23 
 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BK 
bradykinin 
BMI 
body mass index 
C1-INH 
C1 esterase inhibitor 
C4 
complement component 4 
CDC 
Centers for Disease Control and Prevention 
CL 
clearance 
CLCR 
creatinine clearance 
Cmax 
maximum plasma concentration  
Ctrough 
concentration at the end of the dosing interval 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRF 
case report form 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
end-of-study 
EOT 
end-of-treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltranspeptidase 
GI 
gastrointestinal 
HAE 
hereditary angioedema 
HIPAA 
Health Insurance Portability and Accountability Act 

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Abbreviation  
Explanation 
HK 
high-molecular-weight kininogen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product (study drug) 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent to treat 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
P/C 
parents and/or caregivers 
P-gp 
P-glycoprotein efflux pump 
PIP  
Paediatric Investigation Plan 
PK 
pharmacokinetic(s) 
PKK 
prekallikrein 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
corrected QT interval using Fridericia’s correction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEM 
standard error of the mean 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 

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4. 
INTRODUCTION 
4.1. 
Background 
Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is an autosomal 
dominant disorder characterized by recurrent episodes of swelling of the skin, pharynx, larynx, 
gastrointestinal (GI) 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 (QoL) (Lumry, Castaldo et al. 2010). Although mortality risk 
from asphyxiation is much higher in undiagnosed patients with HAE, deaths still occur in 
diagnosed patients with access to care at centers of excellence (Bork, Hardt et al. 2012). 
Extensive evidence from animal models and clinical studies supports the role of bradykinin (BK) 
as the principal mediator of the signs and symptoms that characterize attacks of HAE (Han, 
MacFarlane et al. 2002, Kaplan 2010, Zuraw and Christiansen 2011). Plasma kallikrein is a 
serine protease integral to the contact activation pathway (Saxena, Thompson et al. 2011). 
Kallikrein circulates in plasma as a zymogen, prekallikrein (PKK), bound to one of its main 
substrates, high-molecular-weight kininogen (HK). During contact activation, PKK is cleaved by 
activated factor XII, forming the active protease kallikrein. Kallikrein in turn cleaves HK, 
producing BK (Kaplan and Ghebrehiwet 2010). The activation of the 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).  
Berotralstat (also known as BCX7353 and Orladeyo®) is a potent, synthetic, small-molecule 
inhibitor of plasma kallikrein that has been approved in the United States (US), European Union 
(EU), United Kingdom (UK), Japan, and other markets. Berotralstat is indicated for prophylaxis 
to prevent attacks of HAE in adults and pediatric patients 12 years and older. In contrast to 
parenterally administered options commercially available for prophylaxis against HAE attacks, 
inhibition of kallikrein with an orally bioavailable small molecule such as berotralstat offers the 
advantage of oral administration.  
4.2. 
Nonclinical Findings for Berotralstat 
The principal findings of nonclinical pharmacology, pharmacokinetic (PK), and toxicology 
studies of berotralstat are described in the berotralstat Investigator’s Brochure (IB) and approved 
product labeling for Orladeyo. 
4.3. 
Clinical Findings for Berotralstat 
4.3.1. 
Pivotal Studies 
The principal results of clinical pharmacology, PK, and clinical safety and efficacy studies of 
berotralstat are described in the berotralstat IB and approved product labelling for Orladeyo. 

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4.3.2. 
Data from Adolescent Patients Enrolled in Berotralstat Clinical Trials 
Orladeyo has been approved in the US, EU, UK, Japan, and other countries for prophylaxis to 
prevent attacks of HAE in adult and pediatric patients 12 years of age and older. To support 
expanding the Orladeyo label to include patients aged ≥ 2 years, BioCryst is conducting this 
study in pediatric patients aged 2 to < 12 years and weighing ≥ 12 kg.  
A detailed overview of data obtained as part of the berotralstat clinical development program in 
adolescent subjects is presented in the berotralstat IB. A total of 28 adolescent subjects 
≥ 12 years of age who weighed at least 40 kg were enrolled in 2 studies: 6 adolescent subjects 
enrolled in Study 302, and 22 adolescent subjects enrolled in Study 204. The safety and 
efficacy/effectiveness data generated from these studies was part of the submissions for 
marketing authorization and supported the approval in pediatric subjects aged 12 and older. 
4.4. 
Rationale for Study 
HAE is an autosomal dominant disorder; thus, the disease is inherited in an autosomal dominant 
pattern with nearly 100% penetrance. Family history is negative in about 25% of cases, 
suggestive of de novo mutations (Agostoni and Cicardi 1992). HAE attacks can be painful, 
disabling, and disfiguring, and have a significant impact on functionality and QoL (Lumry, 
Castaldo et al. 2010). Upper airway attacks are potentially fatal.  
The mean age of HAE diagnosis varies greatly and is significantly affected by family history and 
symptoms. The age of symptom onset ranges from 1 to 20 years with increases around 3 to 
6 years of age and puberty (Farkas 2010). However, only 2 therapies are currently approved for 
prophylaxis in children < 12 years, both of which are administered by injection (intravenous or 
subcutaneous) and both of which are approved only for children aged 6 years and older. Given 
the advantage of an orally administered drug in this pediatric population, BioCryst is conducting 
this study to define the safety, tolerability, and PK of berotralstat in pediatric patients aged 
2 years and older in order to expand the label and provide an oral therapeutic option for young 
children who suffer from this debilitating rare disease. 
4.4.1. 
Rationale for Study Design  
The European Medicines Agency (EMA) (European Medicines Agency 2006), US Food and 
Drug Administration (FDA) (FDA 2022), and International Council for Harmonisation (ICH) 
(ICH 2018) (ICH E11(R1), 2018) provide guidelines for development of therapeutics in the 
pediatric population. Use of berotralstat in the treatment of type 1 and 2 HAE meets the criteria 
specified in the FDA guidance for a PK and safety approach to extrapolation for development of 
drugs in the pediatric population (FDA 2022). The criteria include a sufficiently similar disease 
course and response to intervention compared to adult and adolescent patients to allow for 
exposure matching to establish efficacy. The extrapolation approach also takes into consideration 
safety and efficacy data obtained in studies conducted as part of the berotralstat clinical program. 
Therefore, Study 304 is a PK and safety study designed to satisfy the clinical study requirements 
for the extrapolation approach as set forth in the guidance documents.  
The Paediatric Committee of the EMA formulated a positive opinion on a Paediatric 
Investigation Plan (PIP) for berotralstat in accordance with Regulation (EC) No 1901/2006; 
Study 304 is defined as a measure in the agreed PIP.  

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4.4.2. 
Rationale for Berotralstat Doses  
The doses for berotralstat were determined using a population PK modelling and simulation 
approach. A population PK model was based on 13 berotralstat studies conducted in 771 adult 
and adolescent subjects. Thirteen Phase 1 to 3 studies were used to generate exposures in 
pediatric subjects. The weights of the simulated pediatric subjects were randomly selected from 
the uniform distribution with the four proposed weight ranges. For the weight group 40 kg and 
above, the maximum weight was 62 kg which was in the 97th percentile of body weight in 
pediatric subjects 12 years of age in the Centers for Disease Control and Prevention (CDC) 
growth charts.   
Steady-state PK profiles of simulated pediatric subjects were generated for proposed weight 
groups of 12 to < 24 kg, 24 to < 32 kg, 32 to < 40 kg, and ≥ 40 kg. The doses for each weight 
group were then selected to match exposures (steady-state maximum plasma concentration 
[Cmax] and concentration at the end of the dosing interval [Ctrough] in adults).  
4.4.3. 
Rationale for Age and Weight Range 
Orladeyo is approved for patients aged 12 years and above in the US, EU, UK, Japan, and other 
markets. It has been noted in the EU, UK, Canada, and Switzerland labels that no subjects 
weighing < 40 kg were enrolled into the pivotal studies. The age and weight range for the 
population enrolled into this study is proposed to be 2 to < 12 years and weighing ≥ 12 kg, 
respectively.  
Since the dose of berotralstat will be weight-based, it was necessary to select a minimum weight 
for study participants. The lower weight limit of 12 kg was selected based on PK modelling of 
the berotralstat dose in conjunction with estimated age ranges for the selected weight. 
Specifically, using the pediatric growth charts published by the CDC, it is expected that the 
target weight range (≥ 12 kg) will include pediatric patients across the target age range of 2 to 
< 12 years, including down to approximately 2 years (50th percentile for boys 12 kg; for girls 
11 kg). It should be noted that 40 kg is approximately the 50th percentile for girls at 12 years of 
age; thus, it is anticipated that the number of enrolled children who weigh ≥ 40 kg will be small. 
The upper age limit of < 12 years was chosen based on currently approved ages, ie, pediatric 
subjects who do not qualify for commercial product are eligible to participate in this study. The 
lower age limit was selected based on appearance of first HAE symptoms (Bork, Meng et al. 
2006, Farkas 2010, Christiansen, Davis et al. 2016). Importantly, no other prophylactic therapy is 
approved for children from 2 to < 6 years of age. The only therapies approved for pediatric 
patients aged 6 to < 12 years are injectables, so having an oral prophylactic therapy available as 
an option for young children would represent a needed advancement in the treatment of HAE 
patients. While HAE attacks are rarer in young children, an increase in the number of attacks is 
often seen around the ages of 3 to 6 years and at puberty (Farkas 2010). Including children as 
young as 2 years old such that the label would include patients at that age allows for treatment to 
be available for young children at an age where the attack frequency and severity may increase. 
Of note, enrolling subjects from birth to < 2 years old is not feasible nor justifiable given that the 
earliest possible HAE diagnosis is at 1 year of age and patient recruitment difficulties due to the 
extremely low prevalence of HAE and HAE symptoms in this age group. Nevertheless, the 
therapeutic need is recognized for the targeted indication and therefore all other pediatric subsets 
(2 to < 12 years of age) will be included. 

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4.4.4. 
Rationale for Open-label Design 
Several options for control groups were considered in the design of Study 304. A placebo control 
was not considered appropriate for this PK study, which is designed to fulfill the obligations of 
the full extrapolation model. An active control was also considered and was included as a 
question in a feasibility assessment conducted by BioCryst. In addition, BioCryst sought expert 
advice from Key Opinion Leaders (KOLs) to define current use of prophylaxis medications in 
this HAE pediatric population. Those investigations found that the use of prophylaxis in the 
proposed study population was extremely limited due to numerous factors, one of which was 
lack of an orally administered option. That is, all approved options for the prophylaxis of HAE 
are injectables, which are more difficult and stressful to administer to children and none of which 
are approved for children below the age of 6 years. As a result, use of an active control group in 
this study was not considered feasible. Therefore, this study is designed as an open-label study 
with a 12-week standard-of-care (SOC) treatment period followed by a 12-week treatment period 
with berotralstat (Part 1). The SOC treatment period will serve as a control for safety 
assessments as well as provide additional data regarding baseline attack rates in this population.  
4.4.5. 
Berotralstat Risk Analysis 
Potential risks and findings from nonclinical and clinical studies of berotralstat are discussed in 
Section 6 of the IB (Summary of Data and Guidance for the Investigators). Adverse reactions 
seen during clinical trials with berotralstat at 150 mg once daily (QD) include abdominal pain, 
vomiting, diarrhea, and gastroesophageal reflux disease. In the prescribing information, a 
warning and precaution is noted for an increase in QT prolongation which can occur at dosages 
higher than the recommended adolescent and adult dose of 150 mg QD. 
4.4.6. 
Benefits of Trial Participation 
Orladeyo has been approved for prophylaxis of HAE attacks in adult and pediatric patients aged 
12 years and older. Therefore, subjects in this study may benefit by experiencing a reduction in 
the number of HAE attacks. In addition, study subjects will receive regular medical care for the 
duration of the study.  
4.4.7. 
Overall Benefit-Risk Assessment 
The risks from daily oral administration of berotralstat seen to date in both nonclinical and 
clinical studies were primarily mild, monitorable, and reversible. Based on the utility of other 
kallikrein inhibitors such as C1-INH and the pharmacology of berotralstat, there is an 
expectation of benefit to the individual subject. The information obtained from this study will 
support expanding the approved indication for Orladeyo down to patients aged 2 years and 
weighing a minimum of 12 kg. The overall benefit-risk balance is therefore considered to be 
acceptable. 

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5. 
TRIAL OBJECTIVES AND OUTCOME MEASURES 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
• To describe the PK parameters of berotralstat administered orally to pediatric subjects 
with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
5.1.2. 
Secondary Objectives 
• To assess the safety and tolerability of berotralstat administered orally to pediatric 
subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
• To summarize the effectiveness of berotralstat in pediatric subjects with HAE aged 2 
to < 12 years old and weighing ≥ 12 kg. 
5.1.3. 
Exploratory Objective 
• To assess the palatability/acceptability of berotralstat oral granules in pediatric 
subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. 
5.2. 
Endpoints 
5.2.1. 
Primary Endpoints 
The primary endpoint is the characterization of the PK profile of berotralstat in subjects aged 2 to 
< 12 years. 
5.2.2. 
Secondary Endpoints 
The secondary endpoint of safety will be measured by frequency and severity of adverse events 
(AEs) and serious adverse events (SAEs), laboratory analyses (clinical chemistry, hematology, 
coagulation), height, weight, vital signs, electrocardiograms (ECGs), and findings from physical 
examinations.  
Safety endpoints will be assessed at the end of each Part (ie, Weeks 12, 48, and 144/end of study 
[EOS]).  
The other secondary endpoint of effectiveness will be measured by assessing the frequency of 
attacks, duration of symptoms, anatomical location, on-demand treatment required, number of 
days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of 
efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48. 
5.2.3. 
Exploratory Endpoints 
Acceptability/palatability of the berotralstat oral granules will be assessed in children receiving 
the granules using an age-appropriate scale. Acceptability/palatability of the berotralstat granules 
will be assessed by site personnel at the time of first dose (Day 1).  

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6. 
OVERALL STUDY DESIGN AND PLAN 
This is a sequential, three-part, open-label study. A subject’s participation in this study is 
expected to be a minimum of 24 weeks in the SOC treatment period through Part 1 of the study 
and up to an additional 132 weeks in Parts 2 and 3. A schematic of study visits is shown in 
Figure 1. 
Figure 1: 
Study Schema 
 
Abbreviations: BSLN = Baseline; DC = discontinue; Enr = enrollment; P/C = parents and/or caregivers; 
PK = pharmacokinetic; QD = once daily; SOC = Standard of Care; Wk = Week. 
a Subjects will be enrolled at the screening visit. If, after the screening visit, laboratory results are returned that 
indicate the subject no longer meets the inclusion and exclusion criteria, the subject will be considered a screen 
failure. 
b Indicates visits where single, random, plasma sample is collected for PK. 
The study will enroll subjects into 4 or more dose cohorts. Subjects will be assigned into each 
cohort based on subject weight on Day 1/baseline. The subject weight bands for each cohort 
were determined based on PK modelling and simulation as discussed in Section 4.4.2 and 
presented in Table 1.  
As shown in Figure 2, Cohorts 1 and 2 will enroll in parallel. Subjects will be dosed based on 
their weight at the Day 1 visit. After 4 subjects from either Cohort 1 and/or 2 have completed the 
Week 2 visit, population PK modeling will be used to verify doses for subsequent cohorts.  
Cohort 3 will open for enrollment and initiate the 12-week SOC phase after ≥ 4 subjects from 
Cohorts 1 and 2, with ≥ 2 of the subjects from Cohort 2, have reached Week 2. Cohort 4 will 
open for enrollment and initiate the 12-week SOC phase after ≥ 4 subjects in Cohort 3 have 
reached Week 2. BioCryst will notify sites when Cohorts 3 and 4 (or any subsequent cohorts) are 
open for enrollment. Safety assessments by the Data Monitoring Committee (DMC) and PK 
modelling from all available PK data to confirm the weight band for the cohort will occur prior 
to dosing subjects in Cohorts 3 and 4 (or any subsequent cohorts) with berotralstat.  
Based on emerging safety data and analysis of PK, additional cohorts with doses ranging from 
60 mg to < 150 mg may be added with DMC endorsement.  

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Figure 2: 
Cohort Enrollment Scheme 
 
Abbreviations: DMC = Data Monitoring Committee; PK = pharmacokinetic; SOC = standard of care. 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Number of Subjects 
Approximately 30 subjects are planned to be enrolled in the study with a minimum of 15 subjects 
who complete the study through Week 48 and are evaluable for the PK and safety endpoints.  
7.2. 
Subject Selection 
7.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1. Male and non-pregnant, non-lactating females 2 to < 12 years of age and weighing 
≥ 12 kg.   
2. Parent/caregiver (P/C) willing and able to provide written, informed consent (with assent 
from the child where appropriate).  
3. Subjects with a clinical diagnosis of HAE. A clinical diagnosis of HAE is defined as:  
a. Screening results that document immunogenic C1-INH antigenic level below the 
lower limit of normal (LLN) reference range or C1-INH function < 50%, and a 
complement 4 (C4) level below the LLN reference range. 

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OR 
b. Laboratory documentation of historical C1-INH functional level below the assay 
lower limit of normal.  
OR 
c. 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, as assessed 
during the screening period OR a repeat C1-INH functional level < 50% will be 
considered acceptable for enrollment. 
OR 
d. Historical or new laboratory documentation of a SERPING-1 mutation known or 
likely to be associated with HAE.  
OR 
e. For subjects who currently use plasma-derived or recombinant C1-INH based 
prophylactic therapies, a confirmed family history of C1-INH deficiency. 
4. For subjects who are not currently receiving prophylaxis for HAE, documented history of 
≥ 2 HAE attacks in the 6 months prior to the enrollment visit. 
5. Access to and ability to use one or more acute medications approved by the relevant 
competent authority for the treatment of acute attacks of HAE. 
6. In the opinion of the investigator, the subject would benefit from long term oral HAE 
prophylaxis. 
7. Females who had started their menses and males must either: 
a. Be sexually abstinent. Abstinence in this study is defined as true abstinence: when 
this is in line with the preferred and usual lifestyle of the subject. 
b. Use contraception. The following represents the minimum contraception that should 
be used by subjects who could be sexually active. Additional contraceptive 
requirements, such as highly effective methods, may be required by local site practice 
and/or governing institutional review board/ethics committee. It is anticipated that not 
all contraceptive methods may be available in all countries/regions, so the list should 
be modified accordingly. 
 
Male subjects should use condoms while enrolled in the study. 
 
Female subjects should use one or more of the following methods during the study 
and 30 days after the last dose of berotralstat: 
− Intrauterine device (IUD) or intrauterine hormone releasing system (IUS) 
− Progesterone-only (implantable or injectable only) or oral (norethindrone based 
only) hormonal contraception 
− Combined (estrogen and progestogen containing) oral, intravaginal, or 
transdermal hormonal contraception associated with inhibition of ovulation 
Note: Angioedema attacks may be precipitated by estrogen. 

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− 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)  
7.2.2. 
Exclusion Criteria 
Subjects must meet none of the numbered exclusion criteria below to be eligible for participation 
in this study. Medications prohibited for use during the study are addressed in Section 8.7. 
1. Concurrent diagnosis of any other type of recurrent angioedema. 
2. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, 
myocarditis, pericarditis, congenital heart defects, or any other clinically significant 
cardiovascular abnormality such as poorly controlled hypertension. 
3. Known family history of sudden cardiac death at a young age (ie, < 40 years of age). 
Family history of sudden death from HAE is not exclusionary. 
4. History of or current implanted defibrillator or pacemaker. 
5. Moderate to severe hepatic impairment (Child-Pugh B or C). 
6. A calculated creatinine clearance (CLCR) using the Modified Schwartz formula of 
≤ 30 mL/min/1.73 m2 or aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) value ≥ 3 × the upper limit of the age-appropriate normal reference range value. 
7. History of severe hypersensitivity to multiple medicinal products or severe 
hypersensitivity/anaphylaxis with unclear etiology. 
8. Current participation in any other investigational drug study or received another 
investigational drug within 30 days of enrollment; not willing to refrain from 
participation in another clinical study after enrollment and for the duration of the study. 
(Note: drugs/vaccines approved under FDA emergency use authorization [or country-
specific analogous regulations] are not considered excluded or prohibited under this 
criterion). 
9. An immediate family relationship to either sponsor employees, the investigator, or 
employees of the study site named on the delegation log. 
10. Any result at screening that, in the opinion of the investigator, is clinically significant and 
relevant for this study.  
11. Any clinically significant medical condition or medical history (including altered mental 
status) that, in the opinion of the investigator or sponsor, would interfere with the 
subject’s safety or ability to participate in the study. Examples include but are not limited 
to active malignancy under treatment, uncontrolled cardiovascular disease, organ 
dysfunction requiring supportive care.   
12. Clinically significant abnormal ECG including but not limited to, a corrected QT interval 
calculated using Fridericia’s correction (QTcF = QT/RR0.33) > 450 msec, or ventricular 
and/or atrial premature contractions that are more frequent than occasional, and/or as 
couplets or higher in grouping.  

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13. Known hypersensitivity to berotralstat or any of its formulation excipients. 
7.3. 
Subject Withdrawal from the Study and from Study Drug 
7.3.1. 
Subject Withdrawal from the Study 
Participation in the study is strictly voluntary; the parents and/or caregivers (P/C) may withdraw 
consent for their child or, where appropriate, the child may withdraw assent to contribute 
additional study information at any point. A subject who has had consent withdrawn by the P/C 
or assent withdrawn will be requested to attend an early termination visit to complete all 
end-of-study evaluations as appropriate for the study part. Although a subject may be withdrawn 
from the study at any time without specifying a reason for withdrawal, if known, the reason for 
withdrawal will be recorded in the subject’s medical records (source documents) and in the case 
report form (CRF). 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 11. If at any point in the study the clinic is 
unable to contact the P/C after appropriate attempts have been made, the subject will be 
considered lost to follow-up.  
Once subjects have withdrawn from the study, the sponsor will no longer provide treatment 
through the study. Following withdrawal from the study, a subject will be able to receive further 
treatment as recommended by their treating physician and according to the accepted SOC. 
7.3.2. 
Subject Discontinuation from Study Drug 
A subject will be permanently discontinued from study drug for any of the following reasons, 
which will be recorded in the source documents and CRF:  
• Emergence of any laboratory abnormality or AE that in the judgment of the 
investigator compromises the ability of the subject to continue study-specific 
procedures or it is considered not to be in the subject’s best interest to continue in the 
study due to an altered benefit-risk profile. 
• Subsequent determination that inclusion/exclusion criteria were not met.  
• Intercurrent illness or emergence of a new illness/medical condition that would, in the 
judgment of the investigator, affect assessments of clinical status to a significant 
degree. 
• Subject noncompliance with study drug or to the protocol. 
• The subject has a confirmed QTcF > 500 msec (if there is an associated Cmax 
exceeding the adult range, the dose may first be interrupted and/or reduced; see 
Sections 11.2.1 and 11.2.2). 
• The subject has a confirmed QTcF increase of more than 60 msec from the mean 
QTcF value calculated from triplicate ECGs recorded at the Baseline visit and a 
simultaneous absolute QTcF > 460 msec (if there is an associated Cmax exceeding the 
adult range, the dose may first be interrupted and/or reduced; see Sections 11.2.1 and 
11.2.2).  

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• Pregnancy in a female subject. 
Discontinuation of study drug should be considered for a subject if any of the following 
thresholds are met and confirmed by repeat measure 
• ALT or AST > 8× upper limit of normal (ULN) 
• ALT or AST > 5× ULN for more than 2 weeks 
• ALT or AST > 3× ULN and (total bilirubin > 2× ULN or international normalized 
ratio [INR] > 1.5) 
• ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Subjects are not eligible to receive berotralstat in Parts 2 or 3 if they discontinue prior to 
completing Parts 1 or 2, respectively.  
7.3.3. 
Criteria for Study Termination 
The following study rules will be used to stop the study (permanent termination or suspension of 
enrollment/treatment) or the participation of a particular site: 
• Emergence of unacceptable risk, toxicity, or negative change in the benefit-risk 
assessment 
• Request of the relevant competent authority/ethics committee/institutional review 
board 
• Non-compliance with the study protocol, including inaccurate or incomplete 
recordkeeping, that jeopardizes the scientific integrity of the study or subject safety 
BioCryst reserves the right to discontinue the study prior to inclusion of the planned number of 
subjects but intends to exercise this right only for valid scientific or administrative reasons. If 
BioCryst does discontinue the study, the investigator must contact all participating subjects 
immediately after notification of study termination. 
7.4. 
End of Study Definition 
The end of study will be defined as when the last subject completes the last protocol-scheduled 
visit or sponsor-defined last visit should study be terminated early.  
Berotralstat will be provided in Part 3 through Study Week 144 or until another mechanism is 
available to provide drug to the subject (eg, market access, separate study) or the sponsor 
discontinues development of the product for the prevention of angioedema attacks in children 
< 12 years of age. 
8. 
TREATMENT OF SUBJECTS 
Subjects in will remain on their SOC regimen for the first 12 weeks of the study (SOC treatment 
period). These SOC medications, including on-demand therapy for attacks, must be obtained by 
the subject’s P/C, presumably via the normal method. BioCryst will not supply SOC medications 

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(prophylaxis during the SOC treatment period or acute medications for use throughout the 
study). All SOC medications taken during the study must be recorded on the CRF. 
Beginning on Day 1/Baseline, subjects will take open-label berotralstat for 12 weeks in Part 1, 
for 36 weeks in Part 2 (Weeks 12 to 48), and for up to an additional 96 weeks in Part 3 
(ie, through study Week 144). 
8.1. 
Berotralstat Formulation 
Berotralstat (BCX7353) is an oral small-molecule inhibitor of plasma kallikrein.  
The investigational active pharmaceutical ingredient (API) is BCX7353 and is supplied as either 
150 mg capsules (identical to commercial product) or granules for oral administration. All 
ingredients are considered safe for use in the targeted pediatric population. 
Additional details for the chemical and physical characteristics of berotralstat may be found in 
the IB. 
8.2. 
Berotralstat Packaging, Labeling, and Storage 
Berotralstat capsules will be packaged in bottles while granules will be packaged in unit-dose 
packets as described in the investigational medicinal product (IMP) manual. Subjects will be 
dispensed a sufficient amount of berotralstat to cover the dosing period until the next study visit.  
Each container of berotralstat will be labeled with the information required per 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 kit number. 
Berotralstat must be stored between 15°C and 25°C (controlled room temperature). 
Details on packaging, labeling, shipment, storage, and dispensing of berotralstat will be provided 
in the IMP manual. 
8.3. 
Dose and Administration of Berotralstat  
8.3.1. 
Berotralstat Dose 
Subjects will be enrolled into 4 or more cohorts of decreasing dose of berotralstat as shown in 
Table 1.  

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Table 1: 
Cohort Dose and Weight Bands 
Cohort 
Dose 
Minimum Target 
Enrollmenta 
Weight Band 
(from PK Modelling) 
1 
150 mg capsuleb 
n = 4 
≥ 40 kg 
2 
108 mg granules 
n = 4 
32 to < 40 kg 
3 
96 mg granules 
n = 4 
24 to < 32 kg 
4 
78 mg granules 
n = 3 
12 to < 24 kg 
Abbreviation: PK = pharmacokinetic.  
Note: Additional dose strength(s) ranging from 60 to < 150 mg (including 60 and/or 66 mg) and/or cohorts may be 
utilized as indicated based on safety and/or PK results.  
a The n represents the minimum number who will be enrolled into each cohort. Since the total target enrollment is 
planned to be approximately 30 subjects, additional subjects will be enrolled into one or more of the cohorts or 
additional dose cohort(s) may be added. Subject enrollment in any one or more cohorts may be suspended to 
ensure sufficient enrollment of subjects in each cohort.  
b The 150 mg capsule is identical to commercial product (Orladeyo) which is approved for adolescents and adults 
ages ≥ 12 years and weighing ≥ 40 kg. 
The weight bands for Cohorts 1 and 2 were determined based on PK modelling and simulation 
(Section 4.4.2). These dose cohorts will be enrolled in parallel.  
The weight bands for subsequent cohorts are extrapolated from previous study data and will be 
finalized based on available safety and/or PK data as discussed in Section 6.  
Cohort 3 will open for enrollment and initiate the 12-week SOC phase after ≥ 4 subjects from 
Cohorts 1 and 2, with ≥ 2 of the subjects from Cohort 2, have reached Week 2. Cohort 4 will 
open for enrollment and initiate the 12-week SOC phase after ≥ 4 subjects in Cohort 3 have 
reached Week 2. BioCryst will notify sites when Cohorts 3 and 4 (and any subsequent cohorts) 
are open for enrollment. Safety assessments by the DMC and PK modelling from all available 
PK data to confirm the weight band for the cohort will occur prior to dosing subjects in 
Cohorts 3 and 4 (and any subsequent cohorts) with berotralstat. 
8.3.2. 
Administration of Berotralstat 
Subjects should take berotralstat orally QD at approximately the same time each day with food 
as follows: 
• From Day 1 until the Week 2 Visit: Subjects will take their first dose on Day 1 in the 
clinic. This dose should be given with food. Beginning at Day 2 and up to the Week 2 
visit, subjects should take their daily dose of berotralstat at home in the morning with 
food, presumably breakfast. At the Week 2 visit, subjects should take their daily dose 
of berotralstat in the clinic with food. A series of blood draws for PK analysis will be 
collected at this visit (see Section 10.9 and the Schedule of Assessments). 
• After Week 2 to the End of Treatment (EOT): Subjects should take berotralstat at 
approximately the same time each day with whichever meal is typically the largest 
meal of the day, or up to 30 minutes after consuming that meal. No adjustment of 
dosing time is needed prior to or on clinic visit days, even those where a PK sample is 
planned to be collected unless the dose is modified (see Section 10.9.1). 

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It is recommended that berotralstat be administered with food to help minimize GI effects. If 
GI-related symptoms are noted as an AE, the site should query the subject and record whether 
the drug is being taken as instructed (ie, with a meal).  
Subjects taking the granule formulation must take all of the granules in the packet at the same 
time in accordance with instructions provided by the site.  
After each dose, the P/C should ensure that all of the granules were dispensed and that all of the 
granules were consumed by the subject.  
As much as possible, subjects should keep the same daily dosing interval between berotralstat 
doses. If a subject forgets to take berotralstat at the correct time, the dose may be taken later in 
the day; however, no more than 1 dose of berotralstat should be taken on any calendar day. The 
subject should resume their regular dosing schedule on the next day. Dosing may not be split 
across a day. 
8.4. 
Study Drug Dose Modification 
Emerging PK data will be incorporated into a population PK analysis on an ongoing basis, and 
simulations of pediatric exposure will be compared to those in adults. Adjustments to the 
berotralstat dose regimen and/or cohort weight bands may be made: to ensure that exposures fall 
into the acceptable safety range, due to a safety finding, or due to changes in subject weight; this 
may result in a dose increase or a dose reduction. If the dose is adjusted, additional plasma PK 
samples will be collected as described in Section 10.9.1.When dose modifications are made, the 
sponsor must be contacted prior to any dose adjustment to verify drug supply is readily available. 
Study drug interruptions and reductions are discussed in Section 11.2.1 and Section 11.2.2, 
respectively.  
8.5. 
Accountability of Berotralstat 
Accountability of the amount of berotralstat dispensed and returned (as applicable) will be 
performed starting at Day 1 and throughout Parts 1, 2, and 3 or until the subject withdraws from 
the study. Therefore, subjects should bring all bottles/kits, used and unused, with them to each 
study visit beginning in Part 1 through the Week 144 visit. Accountability and adherence will be 
reviewed at these visits. Returned bottles and/or kits must be retained by the site and will be 
reviewed during monitoring visits by the clinical research associate (CRA). 
The investigator/pharmacist must maintain accurate records of the disposition of berotralstat, 
issued to the subject (including date), and any drug accidentally destroyed. At the end of the 
study, information describing supplies of berotralstat (eg, kit numbers) and disposition of 
supplies for each subject must be provided, signed by the investigator or designee, and collected 
by the CRA. If any errors or irregularities in any shipment of berotralstat to the site are 
discovered at any time, the sponsor (and or designee) must be contacted immediately. 
At the end of the study or at other times as agreed by all involved parties, all berotralstat not 
dispensed or administered will either be collected under the supervision of the CRA and returned 
to the sponsor or destroyed on site as dictated by the appropriate Standard Operating Procedure 
at the participating institution. 

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8.6. 
Concomitant Medications 
All SOC prophylactic medication used in the SOC treatment period and all medication used for 
treatment of acute attacks throughout the study must be recorded in the CRF. 
Any regularly administered concomitant medication not listed as prohibited must be anticipated 
to be continued at a stable dose and regimen throughout SOC treatment and Part 1 of the study, 
and, preferably throughout Parts 2 and 3 of the study as well.  
Details of the use of all prior medications (taken within 30 days of screening) and all current 
concomitant medications (including herbal supplements) through the EOS visit, including all 
medications administered for the treatment of AEs, will be recorded in the source documentation 
and CRFs.  
Clinics will instruct the P/C to contact the site when starting any new concomitant medications. 
Note that berotralstat is a P-glycoprotein efflux pump (P-gp) inhibitor at a dose of 300 mg. 
Therefore, close monitoring with potential dose titration is recommended for P-gp substrates 
(eg, digoxin, loperamide) when co-administered with berotralstat during the course of the study.  
The sponsor will provide a spreadsheet outlining potential drugs with interactions with 
berotralstat to sites.  
8.7. 
Prohibited Medications 
All subjects in the study must refrain from taking prohibited medications throughout the entire 
course of the study. 
During the 12-week SOC treatment period, subjects will remain on their normal SOC regimen, 
either prophylaxis and/or treatment for acute attacks. Subjects will stop prophylaxis for HAE no 
later than the day before Day 1/baseline. At the Day 1/baseline visit (the beginning of Part 1), 
subjects will start open-label treatment with berotralstat. Any other long-term prophylaxis to 
prevent HAE attacks is prohibited during berotralstat treatment (Parts 1, 2, and 3 of the study).  
The following medications are excluded during the study (Section 7.2.2): 
• Angiotensin-converting enzyme inhibitors within 7 days of the baseline visit or 
planned initiation during the study (potential for exacerbation of HAE).  
• Another investigational drug within 30 days of the screening visit or initiation during 
the study. 
• Daily use of concomitant medications with a narrow therapeutic index that are 
metabolized by cytochrome P450 (CYP)2D6 (eg, thioridazine, pimozide) or CYP3A4 
(eg, cyclosporine, fentanyl) within 7 days of the baseline visit or planned initiation of 
such medications during the study. 
• Chronic administration of P-gp or breast cancer resistance protein (BCRP) inhibitors 
(eg, cyclosporine).  
• Any use of P-gp inducers (eg, rifampin, St. John’s wort).  
Androgens for prophylaxis of HAE attacks within the 28 days prior to the Day 1 (baseline) visit 
or initiation during the study. Androgens must not be used at all during Parts 1, 2, or 3 of the 

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study. Note: Use of testosterone replacement therapy is allowed. The following medications are 
excluded in the time frame specified prior to Day 1 and for the duration of the study: 
• Concurrent chronic administration of P-gp or BCRP inhibitors (eg, cyclosporine) 
within 7 days of the Day 1 visit.  
• Use of P-gp inducers (eg, rifampin, St. John’s wort) within 7 days of the Day 1 visit. 
• Use of oral androgens for treatment of HAE (prophylaxis or acute) within 28 days of 
the Day 1 visit or planned initiation during the berotralstat treatment period (Parts 1, 
2, and 3).  
• Daily use of concomitant medications with a narrow therapeutic index that are 
metabolized by CYP2D6 (eg, thioridazine, pimozide) or CYP3A4 (eg, cyclosporine, 
fentanyl) within 7 days of the baseline visit or planned initiation of such medications 
during the berotralstat treatment period (Parts 1, 2, and 3).  
• Use of an angiotensin-converting enzyme inhibitor within 7 days of the Day 1 visit or 
planned initiation during the berotralstat treatment period (Parts 1, 2, and 3). 
• Use of lanadelumab, where available, within 28 days prior to the Day 1 visit. 

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9. 
STUDY CONDUCT 
9.1. 
Schedule of Assessments 
The study schedule of assessments is shown in Table 2; study procedures are described in 
Section 10.

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Table 2: 
Schedule of Assessments 
Assessment 
Standard-of-Care 
Therapy 
Open-label Berotralstat Treatment 
Post 
Treatment 
Follow-Up  
Part 1  
Part 2 (Wks) 
Part 3 (Wks) 
Clinic Visits and Contact 
Site 
Contact 
Visits 
Site 
Contact 
Visits 
EOT 
EOS Visita 
Scr./ 
Enr.b 
Wks 4 
& 8 
± 1Wk 
Washout 
[prior to 
Day 1]  
Baseline 
(Day 1)c 
± 4 days 
Wk 
2 
+4 
days 
Wk 
6 
± 3 
days 
Wk 
9d 
± 1 
Wk 
Wk 
12 
± 3 
days 
16, 20, 
28, 32, 
40, 44 
±1 Wk 
24, 36, 
48 
± 1 
Wk 
60, 84, 
108, 132 
± 1  
Wk 
72, 96, 
120 
± 1  
Wk 
Wk 
144 
± 1 
Wk 
3 wks 
(± 3 days) 
after the last 
dose 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion-exclusion criteria 
(including confirmation of 
C1-INH HAE diagnosis) 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
Medical and medication 
history  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight/height/BMIg 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Physical examinationh 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signsi 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Clinical 
chemistry/hematologyj 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
Urinalysisk 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
Pregnancy testingl 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Discontinuation of therapym 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Oral androgenn 
 
 
≥ Day -28 
 
 
 
 
 
 
 
 
 
 
 
• CYP2D6 or CYP3A4 
substrates 
 
 
≥ Day -7 
 
 
 
 
 
 
 
 
 
 
 
• ACE-inhibitor 
• Lanadelumab 
 
 
≥ Day -7 
≥ Day -28 
 
 
 
 
 
 
 
 
 
 
 
• SOC prophylaxiso 
 
 
≥ Day -1 
 
 
 
 
 
 
 
 
 
 
 
ECGp,q 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
Telephone/telemedicine 
contactr 
 
Xs 
 
 
 
 
X 
 
Xt 
 
Xt 
 
 
 
PK: single, random plasma 
sampleu 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
PK: multiple samplesv 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Diary instructions and/or 
revieww 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 

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Assessment 
Standard-of-Care 
Therapy 
Open-label Berotralstat Treatment 
Post 
Treatment 
Follow-Up  
Part 1  
Part 2 (Wks) 
Part 3 (Wks) 
Clinic Visits and Contact 
Site 
Contact 
Visits 
Site 
Contact 
Visits 
EOT 
EOS Visita 
Scr./ 
Enr.b 
Wks 4 
& 8 
± 1Wk 
Washout 
[prior to 
Day 1]  
Baseline 
(Day 1)c 
± 4 days 
Wk 
2 
+4 
days 
Wk 
6 
± 3 
days 
Wk 
9d 
± 1 
Wk 
Wk 
12 
± 3 
days 
16, 20, 
28, 32, 
40, 44 
±1 Wk 
24, 36, 
48 
± 1 
Wk 
60, 84, 
108, 132 
± 1  
Wk 
72, 96, 
120 
± 1  
Wk 
Wk 
144 
± 1 
Wk 
3 wks 
(± 3 days) 
after the last 
dose 
HAE therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Standard of care (SOC)  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
• Berotralstat 
 
 
 
X 
X 
X 
X 
Xx 
X 
X 
X 
X 
X 
 
Palatability/acceptability 
assessmenty 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Xz 
Concomitant medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACE = angiotensin-converting enzyme; AE = adverse event; BMI = body mass index; C1-INH = C1 esterase inhibitor; CRF = case report form; 
ECG = electrocardiogram; Enr. = enrollment; EOS = end of study; EOT = end of treatment; HAE = hereditary angioedema; hr = hour; LLN = lower limit of 
normal; P/C = parent/caregiver; PK = pharmacokinetic(s); QTc = corrected QT interval; Scr. = screening; SOC = standard of care; Wk(s) = week(s) 
a Subjects who discontinue berotralstat either at the Week 144 visit or earlier will be required to attend an EOS follow-up visit 3 weeks (± 3 days) after study 
drug discontinuation. Subjects who discontinue the study but will continue to receive berotralstat via another mechanism will have EOS assessments performed 
at their last regularly scheduled visit. 
b Screening assessments will be conducted at the screening visit although, if necessary, the assessments may take place over a screening period not to exceed 
14 days without prior consent of the sponsor. Subjects will be considered enrolled into the study as of the date of the screening visit if all available results 
satisfy the inclusion and exclusion criteria as of that date. If, after the screening visit, screening results are returned that indicate the subject no longer meets the 
inclusion and exclusion criteria, the subject will be considered a screen failure. The investigator will provide the P/C with study materials (eg, subject’s diary) 
at the end of the screening visit and request the P/C to record diary data starting at the date of the screening visit and for the next 12 weeks (ie, the SOC 
treatment period). The P/C will be subsequently contacted via tele-contact once all screening results are available to confirm eligibility or screen failure.  
c The Day 1/baseline visit should occur 12 weeks ± 4 days after enrollment. If extenuating circumstances prevail, this timeframe may be extended with medical 
monitor approval (see Section 9.3.1).  
d At Week 9, the site should contact the P/C to assess subject status including AEs and concomitant medications. 
e The informed consent form must be signed by the parent or child’s legal representative prior to conducting any study-related procedures. Based on the child’s 
age and local regulatory requirements, subject assent will be collected as appropriate. 
f At the baseline visit, the site will review prohibited medications (Section 8.7), subject diary entries, and discuss any AEs that occurred during the SOC 
treatment period. If any activities were not completed satisfactorily (eg, diary entries were incomplete or the P/C could not be contacted to assess AEs at the 
prescribed intervals) or the use of prohibited medications is discovered, the subject may be discontinued from the study and not enrolled into Part 1 at the sole 
discretion of the investigator. If subjects are discontinued at Day 1, subject diaries should be collected, and subjects should be instructed to remain on their 
SOC therapy. No additional visits are required for subjects who discontinue after the SOC treatment period and never receive berotralstat. 

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g Weight will be recorded at each visit. Height will be recorded, and BMI calculated, at screening, baseline/Day 1, Weeks 12, 24, 36, 48, 72, 96, 120, 144, and 
the EOS visit. At 8 weeks after enrollment, where possible, the subject should assess their weight at home in light clothing with shoes and other heavier items 
removed. The site will obtain the results of the home weight assessment by telephone and record the results in source documents. 
h Full physical examinations will be performed at screening, Day 1/baseline, and Week 12; symptom-directed physical examinations will be performed only as 
necessary at all other visits. 
i Vital signs will include blood pressure, pulse rate, and body temperature. Respiratory rate will only be captured at screening, Day 1/baseline, and Week 12. 
j See Table 3 for a list of analytes to be assessed. 
k Urine samples will be collected from all children old enough to provide a reasonable clean-catch sample. If very young children are not able to provide a urine 
sample, the lack of a sample should be noted in the source documents; lack of sample collection in small children will not be considered a protocol deviation. 
l For all girls of childbearing potential, a serum pregnancy test will be administered at screening. Urine pregnancy tests will be assessed at all subsequent visits 
as indicated in the table. A serum pregnancy test should immediately be drawn and sent for analysis for any positive urine pregnancy test. In addition, girls of 
childbearing potential will be dispensed urine pregnancy tests to complete at home approximately every 4 weeks, where dictated by local requirements; 
participants will receive the appropriate number of pregnancy tests to complete testing at the intervals above during in-person clinic visits as needed. Sites will 
obtain the home test results during planned site contacts and record the results in source documents. 
m To qualify for entry into Part 1, subjects must discontinue use of listed medications at the times indicated. Note that the times are relative to the Day 1/baseline 
visit. Refer to exclusion criteria (Section 7.2.2) for further explanation. 
n Subjects should have alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-
glutamyl-transpeptidase (GGT), and total and direct bilirubin measured 2 weeks (+ 7 days) after androgen discontinuation. 
o The final dose of SOC prophylaxis must be administered no later than the day before the Day 1/baseline visit. Subjects may continue to take medication to treat 
acute attacks throughout the study.  
p All ECGs during the study will be single assessments with the exception of baseline, which will be obtained in triplicate. An ECG should be repeated for a 
change from baseline in QTc > 60 msec or a QTc interval > 500 msec. Prior to obtaining an ECG, subjects should rest quietly. When possible, ECGs should be 
obtained prior to any blood sampling. 
q If adverse events commonly associated with prolonged QTc interval (eg, unexplained intermittent or continuous lightheadedness, syncope, palpitation, chest 
pain) are reported or the dose is modified, additional ECGs should be recorded. 
r The site should contact the P/C by the method agreed upon at the screening visit; the contact may be by telephone or may be a telemedicine visit.  
s The contact should occur at 4 ± 1 and 8 ± 1 weeks following the enrollment visit and should be as evenly spaced out over the SOC therapy period as is 
reasonable. The tele-contact must be interactive, eg, a telephone call or telemedicine visit. An in-person clinic visit would also satisfy this requirement (see 
Section 9.2.2 for further explanation).   
t The contact must be interactive and may include a telephone call, telemedicine visit, or in-person visit if requested by the P/C and/or investigator. If there is a 
safety concern or if required for medical management of the subject, an in-person visit should be conducted. 
u A single plasma PK sample is to be collected at Weeks 12, 24, 36, and 48. Additional plasma PK samples may be collected as described in Section 10.9 and 
Section 10.9.1. The date and time of the PK blood draw and the last dose of berotralstat taken prior to the blood draw will be captured in the CRF. PK sample 
collection may be discontinued following the interim data cut used to finalize the population PK model and pharmacometric analysis report, at the discretion of 
the sponsor. 
v In Cohorts 1, 2, and 3, plasma samples for PK analysis should be collected pre-dose and at 1 ± 0.5, 2 ± 0.5, 4 ± 1, and 6 ± 1 hours post dose (exact timing of the 
dose and each blood draw must be recorded). PK samples should be collected as close to the nominal collection timepoint as possible, but all scheduled PK 
samples should be collected even if they are outside the sampling window. The date and time of the PK blood draws and the last dose of berotralstat taken prior 
to the blood draw will be captured in the CRF. In Cohort 4, plasma samples for PK analysis should be collected pre-dose, 1 to 2 hours post dose, and 4 to 

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6 hours post dose. Of note, in younger and/or smaller subjects, the number of samples and/or volume of blood drawn for each sample may be reduced to ensure 
volumes collected fall within acceptable ranges. See Section 10.9 for additional details. 
w Diaries will be given to the P/C for each subject at screening. If the child does not qualify based on the results of the pending laboratory tests, the child will be 
considered a screen failure. For eligible subjects, P/Cs will complete the diary, recording HAE attacks through Part 2 (Week 48) of the study. At each visit, the 
P/C should bring the completed diary with them for review by site personnel. Diaries will be collected at each visit through Week 48, and new diaries will be 
dispensed at each visit prior to Week 48. Any issues with diary entries will be discussed with the P/C and corrections will be made by the subject or P/C as 
required. All diaries will be collected at the Week 48 visit.  
x Subjects will remain on the dose of berotralstat assigned at the Day 1 visit until the subject reports to the clinic for the Week 12 visit unless PK results from 
Week 2 indicate that the Cmax levels fall outside the protocol-specified range or there is a safety concern. At the Week 12 visit and continuing throughout 
Parts 2 and 3, the dose of berotralstat will be adjusted based on the weight of the subject.  
y Palatability/acceptability will be assessed using an age-appropriate hedonic scale for the granule formulation by those subjects who receive the granule 
formulation; presumably those in Cohorts 2, 3, and 4. 
z If an AE is ongoing at the EOS visit, additional clinic visit(s) or telephone contact(s) may be warranted (see Section 11.1.2.1). 
 

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9.2. 
Study Visits – Standard of Care Treatment Period 
For all visits and site contacts, assessments will be performed as indicated in the Schedule of 
Assessments (Table 2). 
9.2.1. 
Screening and Enrollment 
Pediatric patients who are considered good candidates for the study will report to the site for a 
screening visit. After the P/C have provided informed consent, and, where appropriate, children 
have provided assent, screening assessments may be initiated. Screening assessments will be 
conducted at the screening visit although, if necessary, the assessments may take place over a 
screening period not to exceed 14 days without prior consent of the sponsor. Subjects will be 
considered enrolled into the study as of the date of the screening visit if all available results 
satisfy the inclusion and exclusion criteria as of that date. If, after the screening visit, screening 
results are returned that indicate the subject no longer meets the inclusion and exclusion criteria, 
the subject will be considered a screen failure. The investigator will provide the P/C with study 
materials (eg, subject’s diary) at the end of the screening visit and request the P/C to record diary 
data starting at the date of the screening visit and for the next 12 weeks (ie, the SOC treatment 
period). The P/C will be subsequently contacted via tele-contact once all screening results are 
available to confirm eligibility or screen failure.  
Subjects will be dosed based on their weight at the Day 1 visit. Therefore, subjects who are 
targeted for Cohorts 1, 2, or 3 may be enrolled into the study if they are minimally below the 
required weight at screening as long as the investigator feels with great certainty that the subject 
would be at the required weight after 12 weeks in the SOC treatment period. Of note, all subjects 
targeted for Cohort 4 must weigh ≥ 12 kg before being enrolled into the study.  
A subject with an exclusionary value may be rescreened if the investigator believes the 
exclusionary value obtained was not an accurate reflection of the subject’s status (eg, out of 
range laboratory value due to compromised sample). With prior sponsor approval, subjects with 
an exclusionary C1-INH test result may be retested during the SOC treatment period if the 
results are incongruent with clinical history or considered by the investigator to be confounded 
by recent C1 inhibitor use. 
Once enrolled, subjects will begin the SOC treatment period. During this 12-week period, 
subjects will continue taking their SOC therapy for HAE (either short-term or long-term 
prophylaxis, and/or acute treatment for HAE attacks). No additional in-person visits are required 
during the SOC treatment period. 
9.2.1.1. 
Sexual Counseling 
Competent adolescents should receive age-appropriate sexual counseling by a qualified health 
care professional to determine the adherence to inclusion criterion #7 in Section 7.2.1. 
There are insufficient data in pregnant women available to inform drug-related risks with 
berotralstat use in pregnancy. If a female subject becomes pregnant during the study, study 
drug/IMP will be discontinued per Section 7.3.2 and pregnancy reporting and follow-up will be 
conducted as described in Section 11.1.3.2. 

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9.2.2. 
Weeks 4 and 8 after Enrollment 
At approximately 4 ± 1 and 8 ± 1 weeks after the date of enrollment (Section 9.2.1), the site must 
have an interactive contact with the P/C to assess AEs and status of HAE attacks. Subjects may 
be included in the contact at the discretion of the investigator. Site contact may be a telephone 
call, telemedicine visit, or an in-person clinic visit if such a visit was otherwise planned or if the 
investigator believes it would be in the best interest of the subject to return to the clinic. The 
contact may also be an in-person consultation between site staff and the P/C if requested by 
either the investigator or P/C. At 8 weeks after enrollment, where possible, the subject should 
assess their weight at home in light clothing with shoes and other heavier items removed. The 
site will obtain the results of the home weight assessment by telephone and record the results in 
source documents. 
9.3. 
Study Visits – Berotralstat Treatment Period: Part 1 
9.3.1. 
Baseline Visit (Day 1) 
Subjects will return to the clinic 12 weeks ± 4 days after the date of enrollment (Section 9.2.1) 
for the Day 1 (baseline) visit. If extenuating circumstances would result in the baseline visit 
being delayed, the site must get prior approval from the medical monitor for the visit to occur 
outside of the defined visit window and for the subject to continue in the study. Prior to the 
Day 1 visit, subjects must discontinue prophylaxis for HAE as well as other specific medications. 
At the baseline visit, the site will review prohibited medications (Section 8.7), subject diary 
entries, and discuss any AEs that occurred during the SOC treatment period. If any activities 
were not completed satisfactorily (eg, diary entries were incomplete or the P/C could not be 
contacted to assess AEs at the prescribed intervals) or the use of prohibited medications is 
discovered, the subject may be discontinued from the study and not enrolled into Part 1 at the 
sole discretion of the investigator. After final eligibility for entry into Part 1 is confirmed, 
subjects will receive their first dose of berotralstat in the clinic and those taking berotralstat 
granules for oral administration will complete the palatability/acceptability hedonic scale 
assessment as appropriate for the subject’s age. Reference Section 8.3 for berotralstat dosing 
procedures. The dose of berotralstat will be determined based on the subject’s weight at Day 1 
and will not be adjusted during Part 1 due to weight changes. If required for medical 
management, any changes in berotralstat dose during Part 1 should be discussed with the 
BioCryst medical monitor prior to implementation. Details can be found in Section 8.4. 
9.3.2. 
Weeks 2, 6, 9, and 12  
All subjects will return to the clinic for visits during Weeks 2, 6, and 12 following baseline and 
the site will contact the P/C (tele-contact) during Week 9.  
At the Week 2 visit, a series of blood samples will be collected for PK analysis (Section 10.9). 
To ensure the trough sample provides accurate PK information, the Week 2 visit should be 
scheduled as close as possible to the regularly scheduled time of dosing for the subject. The dose 
of berotralstat should be given in the clinic with food (a snack or light meal should be provided). 
A blood sample for PK analysis will be collected before dosing and at the times post dosing as 
shown in the Schedule of Assessments. 

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At the Week 12 visit, the subject will move from Part 1 into Part 2. The subject will be weighed 
and the dose of berotralstat will be adjusted according to the current weight of the subject 
(Table 1).  
9.4. 
Study Visits – Berotralstat Treatment Period: Part 2 
9.4.1. 
Week 16, 20, 28, 32, 40, and 44 Contacts 
The investigator (or designee) must contact the P/C at the weeks shown in the Schedule of 
Assessments via an interactive method, eg, telephone discussion or telemedicine visit. During the 
contact, the investigator (or designee) will assess the subject’s overall wellbeing, collect 
information on any AEs that may have been experienced by the subject, discuss compliance, and 
proper recording of attack details (if applicable). If warranted for medical management of the 
subject or if requested, the contact may be an in-person visit. In this case, visit information 
should be recorded in the CRF according to directions provided in the CRF completion 
instructions.  
9.4.2. 
Week 24, 36, and 48 Visits 
All subjects will return to the clinic during study Weeks 24, 36, and 48 for appropriate 
assessments.  
A plasma sample for PK analysis will be collected at these visits. The date and time of the 
preceding dose of berotralstat must be captured and recorded in the source documents and CRF. 
9.5. 
Study Visits – Berotralstat Treatment Period: Part 3 
9.5.1. 
Week 60, 84, 108, and 132 Contacts 
The investigator (or designee) must contact the P/C at the weeks shown in the Schedule of 
Assessments via an interactive method, eg, telephone discussion or telemedicine visit. During the 
contact, the investigator (or designee) will assess the subject’s overall wellbeing, collect 
information on any AEs that may have been experienced by the subject, concomitant 
medications taken by the subject, and discuss compliance (if applicable). If warranted for 
medical management of the subject or if requested, the contact may be an in-person visit. In this 
case, visit information should be recorded in the CRF according to directions provided in the 
CRF completion instructions. 
9.5.2. 
Week 72, 96, and 120 Visits 
Following the Week 48 visit, subjects should return to the clinic every 24 ± 1 weeks for clinic 
visits.  
9.5.3. 
Week 144 / End of Treatment (EOT)  
Subjects will return to the clinic for the EOT visit at Week 144 (± 1 week). Any subject who 
discontinues the study during Part 3 should return to the site as soon as possible to complete the 
Week 144 (EOT) assessments.  
If an AE is ongoing at the last study visit, additional clinic visit(s) or telephone contact(s) may be 
warranted (see Section 11.1.1.4). 

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9.6. 
End-of-Study (EOS) Follow-up Visit  
Subjects who discontinue berotralstat either at the Week 144 visit or earlier will be required to 
attend a follow-up visit 3 weeks (21 ± 3 days) after study drug discontinuation. Subjects will be 
discontinued from the study at this visit. Subjects who discontinue the study but will continue to 
receive berotralstat via another mechanism will have end-of-study assessments performed at 
their last regularly scheduled visit. After Week 48, subjects who discontinue study drug but 
continue to receive berotralstat via another mechanism will be considered completers. 
If an AE is ongoing at the EOS visit, additional clinic visit(s) or telephone contact(s) may be 
warranted (see Section 11.1.2.1). 
10. 
ASSESSMENTS 
The schedule of procedures and assessments to be conducted throughout the study are outlined in 
the Schedule of Assessments (Table 2). 
To the extent possible, the following chronology of events should be adhered to during the 
scheduled visits: 
• ECGs: obtain prior to vital signs and blood specimen collection 
• Vital signs: obtain prior to blood specimen collection 
• Study drug dispensing/dosing: end of the visit 
10.1. 
Demographics 
Demographic information, including month and year of birth, sex, race, and ethnicity (as 
applicable or as permissible by country requirements) will be captured for each subject 
participating in the study at the screening visit. Medical and medication history will be captured 
at the screening visit and updated at enrollment (if different from the screening visit).  
10.2. 
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 P/C or 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 CRF. 
10.3. 
Physical Examination 
A full physical examination will be conducted at screening, baseline (Day 1), and at Week 12 
(beginning of Part 2). Targeted or symptom-directed examinations will be performed only as 
necessary at all other visits.  
Genitourinary and breast examinations may be omitted when not required by normal site 
practice. With female subjects past the age of menarche, the age of menarche should be 
determined.  

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10.4. 
Weight/Height/Body Mass Index 
Subject weight is important for this study as the dose of berotralstat will be based on subject 
weight. Therefore, the site should be diligent in accurately taking and recording subject weight. 
Subjects should be weighed in light clothing with shoes and other heavier items (eg, belts or 
phones) removed. Heavier outer clothing (eg, jackets or sweaters) should also be removed.   
Height should be recorded at the indicated visits. Body mass index (BMI) should be calculated at 
all visits where weight and height are measured using the following formula:  
BMI = weight (kg)/height (m)2 
10.5. 
12-lead Electrocardiograms  
A standard bedside or routine 12-lead ECG machine that calculates heart rate and measures the 
PR, QRS, QT, RR, and QTc intervals will be used. Prior to obtaining an ECG, subjects should 
rest quietly for at least 10 minutes. Resting may be in a supine position or other position (eg, on 
the P/C’s lap) as age appropriate for the subject. 
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 post-baseline 
ECGs, a change from baseline). For all ECGs, the clinical interpretation of the ECG and 
calculated QTc should be recorded directly on a hard copy of the ECGs. Copies of the ECGs 
may be requested by the sponsor. All subject identifiers will be masked prior to provision to the 
sponsor. 
Baseline (pre-dose) ECGs will be obtained in triplicate (ie, 3 separate readings taken at 1- to 
5-minute intervals) with baseline values calculated from an average of the 3 readings. All other 
ECGs will be single assessments.  
An ECG should be repeated for a change from baseline in QTc > 60 msec or a QTc interval 
> 500 msec. 
If AEs commonly associated with prolonged QTc interval (eg, unexplained intermittent or 
continuous lightheadedness, syncope, palpitation, chest pain) are reported or the dose is 
modified, additional ECGs should be recorded. ECGs obtained due to dose modification should 
be taken approximately 2 to 6 weeks after dose modification and should be aligned with PK 
blood sample timelines described in Section 10.9.1 to the extent possible. 
10.6. 
Vital Signs 
Blood pressure (systolic and diastolic) and pulse rate should be taken after the subject has rested 
in the supine position for at least 5 minutes. For younger subjects who cannot rest for 5 minutes 
in a supine position, sitting quietly on the P/C’s lap is an acceptable alternative. Blood pressure 
measurements must be obtained with an age-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. Respiratory rate will be captured at screening, baseline, and Week 12 
(beginning of Part 2) only. 

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10.7. 
Clinical Laboratory Evaluations 
Blood samples will be obtained per the schedule of events. Numbing options (eg, numbing cream 
or ice spray) may be used per site standard practice. Blood sample volume limits should not 
exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 1% at 
any single time (European Commission 2008). Further details and guidance on maximum blood 
draws will be provided in the laboratory manual. Urine samples will be collected from all 
children old enough to provide a reasonable clean-catch sample. If very young children are not 
able to provide a urine sample, the lack of a sample should be noted in the source documents; 
lack of sample collection in small children will not be considered a protocol deviation. Individual 
laboratory tests to be performed are provided in Table 3.  
All laboratory samples will be collected using kit supplies provided by the central laboratory, 
which will also analyze all samples. The use of a local laboratory is permitted in specific 
circumstances with the permission of the sponsor medical monitor. If any results are obtained 
from both central and local laboratories for the same assessments at a single study time point, 
only the central laboratory results will be used for study purposes. A laboratory reference manual 
will be provided to the site detailing 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 laboratory findings, the 
interpretation of clinically significant or not clinically significant should be denoted in the source 
records. Clinically significant laboratory findings in the opinion of the investigator should be 
recorded as an AE and handled as described in Section 11. 

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Table 3: 
Clinical Laboratory Evaluations 
Chemistry 
Coagulation 
• Albumin 
• Alkaline phosphatase (ALP) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Bilirubin (total and direct) 
• Blood glucose   
• Blood urea nitrogen (BUN) 
• Electrolytes (calcium, sodium, 
potassium, chloride, bicarbonate [CO2], 
phosphorus) 
• Lipid panel (total cholesterol, 
triglycerides) 
• Creatine kinase 
• Creatinine and calculated creatine 
clearance (CLCR) 
• Gamma-glutamyl transferase (GGT) 
• Lactate dehydrogenase (LDH) 
• Total serum protein 
• Uric acid 
• If amylase is > 2 × upper limit of 
normal (ULN), reflex to lipase 
• Prothrombin time (PT) and international 
normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
Pregnancy Test  
Only for girls who have begun to menstruate: 
Serum (screening) and urine (other specified 
visits) beta-human chorionic gonadotropin 
(βHCG) for girls of childbearing potential onlya 
Hematology 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration 
(MCHC) 
• Mean corpuscular volume (MCV) 
• White blood cell count, with differential 
(lymphocytes, monocytes, neutrophils, 
eosinophils, and basophils) 
• Platelets 
Urinalysis 
• Specific gravity 
• Blood  
• Bilirubin 
• Glucose  
• Leukocytes 
• Ketones 
• Nitrites 
• pH 
• Protein 
• Urobilinogen 
• Microalbumin to creatinine ratio 
• Reflex microscopy if dipstick is 
abnormal  
Additional Tests 
• C1 esterase inhibitor (C1-INH) level and 
functionb 
• C4b 
• SERPING-1 analysis b 
 
a A serum pregnancy test should immediately be drawn and sent for analysis for any positive urine pregnancy test. 
b Only if required to confirm HAE diagnosis. 

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CLCR will be calculated using the Modified Schwartz formula and actual body weight as shown 
in the laboratory manual. 
10.8. 
Confirmation of HAE Diagnosis 
Subjects must have confirmed HAE to be eligible for study participation. Several methods may 
be used to confirm an HAE diagnosis. 
• C1-INH functional level and C4 level: If necessary to satisfy eligibility criteria, blood 
samples for C1-INH functional level and C4 will be drawn at the screening visit; 
samples should not be drawn within 3 days of C1-INH administration (eg, use for 
treatment of an HAE attack). 
− Immunogenic C1-INH antigenic level results below the LLN or functional 
C1-INH results < 50%, and a C4 level 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, as assessed during the screening period OR a repeat C1-INH functional level 
< 50% will be considered acceptable for enrollment 
• Laboratory documentation of historical C1-INH functional level below the assay 
LLN. 
• Historical or new laboratory documentation of a SERPING-1 mutation known or 
likely to be associated with HAE. 
• For subjects currently receiving C1-INH based prophylactic therapies, a confirmed 
family history of C1-INH deficiency. The investigator should document this based on 
either the investigator’s personal knowledge (ie, if a relative of the screening subject 
is also a patient of the same investigator/practice) or interaction with medical staff of 
the treatment facility where the relative receives HAE care, who confirms the 
diagnosis. No historical laboratory documentation on the relative should be collected 
in the source documents.  
10.9. 
Pharmacokinetics  
All plasma samples for determination of berotralstat will be analyzed using a validated liquid 
chromatography-mass spectrometry assay.  
Blood samples for analysis of PK parameters will be drawn on all subjects as indicated in the 
Schedule of Assessments. At the Week 2 visit, a series of samples will be collected for PK 
analysis to allow for determination of PK parameters including Cmax.   
Actual date and time of sample collection will be recorded in the CRF. Sites will ensure that the 
time of the dose of berotralstat taken prior to the blood draw is recorded in the source documents 
and CRF. Sites should communicate to the P/C the importance of providing the most accurate 
time of dosing prior to the PK sample collection. 
Instructions for collection, processing, storage, and shipment of PK samples will be provided to 
the clinical site in a separate document.  

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In Cohorts 1, 2, and 3, at the Week 2 study visit where multiple PK samples are to be collected, 
plasma samples for PK analysis should be collected pre-dose and at 1 ± 0.5, 2 ± 0.5, 4 ± 1, and 
6 ± 1 hours post dose (exact timing of the dose and each blood draw must be recorded). In 
Cohort 4, plasma samples for PK analysis should be collected pre-dose, 1 to 2 hours post dose, 
and 4 to 6 hours post dose. PK samples should be collected as close to the nominal collection 
timepoint as possible, but all scheduled PK samples should be collected even if they are outside 
the sampling window. The date and time of the PK blood draws and the last dose of berotralstat 
taken prior to the blood draw will be captured in the CRF. Of note, in younger and/or smaller 
subjects, the number of samples and/or volume of blood drawn for each sample may be reduced 
to ensure volumes collected fall within acceptable ranges. If plasma samples for PK analysis 
cannot be collected as described above at Week 2, sites are required to document the reason in 
source notes and collect samples for PK analysis prior to or during the Week 6 visit.  
A single plasma PK sample is to be collected at Weeks 12, 24, 36, and 48. Additional plasma PK 
samples may be collected during the study if prescribed by the principal investigator as indicated 
for clinical management of the subject or if a previously scheduled sample was not collected 
and/or evaluable. The date and time of the PK blood draw, the last dose of berotralstat taken 
prior to the blood draw, and if the dose was taken with food will be captured in the CRF. As 
noted above, accuracy of the previous dose time of berotralstat is important.  
PK sample collection may be discontinued following the interim data cut used to finalize the 
population PK model and pharmacometric analysis report, at the discretion of the sponsor. 
10.9.1. 
Plasma Pharmacokinetic Samples for Dose Modifications 
Adjustments to the berotralstat dose may be required during the study based on safety and/or PK 
findings. If the berotralstat dose is adjusted due to an AE or high exposure level, the subject will 
be required to provide blood samples for analysis of PK parameters as follows: 
• Subjects in Cohorts 1 and 2 will provide a PK sample 20 to 24 hours after their previous 
dose of berotralstat, and another sample 2 to 4 hours after taking their daily dose of 
berotralstat. 
• Subjects in Cohorts 3 and 4 will provide a PK sample 20 to 24 hours after their previous 
dose and, if possible, another sample at 2 to 4 hours after taking their daily dose of 
berotralstat. 
These samples will be collected approximately 2 to 6 weeks after the dose adjustment. If a 
telephone call or telemedicine appointment is scheduled for the next visit, an in-person clinic 
visit may be conducted instead. Note: home health collection may be an option if available per 
country requirements. 
Subjects with dose adjustment will be asked to take their daily dose in the morning for a 
minimum of 2 weeks before the PK draw will be completed. On the day of PK draw, subjects 
should take their daily dose during the visit with food. 
The date and time of berotralstat dosing and PK sample collection, as well as whether the dose 
was taken with food, will be recorded in the source documents and the CRF. 
Subjects with dose adjustments based on weight in Part 2 or Part 3 of the study should provide 
PK samples approximately 2 to 6 weeks after the dose adjustment, as described in the bulleted 

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list above. If samples cannot be collected in this timeframe, they must be collected at the next 
visit. 
PK sample collection may be discontinued following the interim data cut used to finalize the 
population PK model and pharmacometric analysis report, at the discretion of the sponsor. 
10.10. 
Adverse Events 
AEs will be assessed and recorded from the time that the informed consent form (ICF) is signed 
through the last follow-up visit or until the AE is resolved or the subject is in a clinically stable 
condition with regard to the AE. Full details on recording and reporting AEs are provided in 
Section 11.1.1.4. 
10.11. 
HAE Attack Diary 
The sponsor will supply paper diaries to sites to be distributed to the P/C for recording the 
subject’s HAE attacks. The P/C will fill out the HAE attack diary whenever an attack (or 
suspected attack) occurs. If the subject reports an attack or if the P/C suspects that an attack has 
occurred, additional details should be entered into the diary including start and stop time of the 
attack, attack symptoms, anatomical location of swelling (if applicable), severity, treatment(s) 
administered and times of administration, and whether additional medical care was sought for the 
attack. Subjects will complete the diaries from enrollment through the end of Part 2 
(ie, Week 48).  
The P/C will be instructed to bring the subject’s diary with them to each study visit. Diaries will 
be collected at each visit through Week 48, and new diaries will be dispensed at each visit prior 
to Week 48.  
Subjects who withdraw from the study should continue to record the occurrence of HAE attacks 
in their diary until they return to the site for the appropriate EOS visit.  
Once a subject completes or discontinues the study, the site must collect all diaries from the P/C.  
Study staff are not permitted to make any entries into the diary.  
11. 
ADVERSE EVENT MANAGEMENT AND REPORTING 
11.1. 
Adverse Events 
11.1.1. 
Definitions 
11.1.1.1. 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 significant results of diagnostic procedures including abnormal 
laboratory findings (eg, requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be AEs. If the diagnostic procedure 
prompts no additional treatment, visits, or monitoring, it will not meet the definition of an AE. 

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AEs include the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period (see Section 11.1.1.4).  
• Findings from protocol-mandated interventions. This can include laboratory 
assessments performed in the clinical study. AEs should be reported only if the 
abnormalities are adverse changes from baseline and clinically significant as 
described above. 
• Pre-existing medical conditions (other than HAE) judged by the investigator to have 
worsened in severity or frequency or undergone an adverse change in character 
during the protocol-specified AE reporting period. When recording such events on an 
AE/SAE CRF page, it is important to convey the concept that the preexisting 
condition has adversely changed by including applicable descriptors (eg, “more 
frequent headaches” or “worsened headache”). 
• Untoward and unintended responses resulting from medication errors and uses 
outside what is foreseen in the protocol, including misuse and abuse of the product, 
should be reported as an AE. 
Surgical procedures should not be reported as AEs. The condition for which the surgery is 
required should be reported as an AE if it occurs or is detected during the study period. Planned 
surgical measures permitted by the clinical study protocol and the condition(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. 
For the purposes of this protocol, HAE attacks and their associated symptoms will not be defined 
as AEs, even if the subject requires hospitalization. HAE attacks and associated symptoms are 
reported in the subject’s diary and are a reflection of the disease under study. Events that trigger 
an HAE attack and meet the definition of an AE, such as an infection or trauma, should be 
reported as AEs. 
AEs are designated as “nonserious” or “serious”. 
11.1.1.2. Serious Adverse Event 
An SAE is an AE/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 (see below for details on hospitalization 
SAE criteria) 
• Results in persistent or significant disability/incapacity (ie, there is a substantial 
disruption of a person's ability to carry out normal life functions) 
• Is a congenital anomaly/birth defect 

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• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject’s health or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. For this 
study, examples of such events may include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in subject hospitalization.  
In addition, abortion (spontaneous or induced), fetal demise, and still birth along with congenital 
abnormalities in the newborn should be reported as separate SAEs (see Section 11.1.3). 
Some hospitalization scenarios do not require reporting as an SAE if there is no occurrence of an 
AE. These scenarios include a planned hospitalization or prolonged hospitalization to: 
• Perform a routine control screening for a preexisting illness or to diagnose a suspected 
illness. In the case of the latter, the symptomatology should be reported as an AE and 
amended if a diagnosis is confirmed. 
• Undergo a diagnostic or elective surgical procedure for a preexisting medical condition 
that has not changed (eg, a joint replacement for which the subject was on a waiting list). 
• Undergo medical observation due to HAE (eg, admission after routine dental procedure 
in a subject with HAE). 
• Undergo medical observation without the occurrence of an AE due to standard of care in 
the region or hospital. 
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 11.2.3). Details of signs or symptoms, clinical 
management, and outcome should be reported, if available. Overdose without associated signs or 
symptoms should not be recorded as AEs but should be recorded as protocol deviations. 
11.1.1.3. Adverse Events of Special Interest 
For this protocol, no events of special interest have been identified. 
11.1.1.4. Definition of Severity 
All AEs and SAEs will be assessed (graded) for severity by the investigator and classified using 
the Division of AIDS (DAIDS) table for grading the severity of adult and pediatric AEs (Publish 
date July 2017). Any AEs not covered by the DAIDS table will be assessed and classified into 
1 of 5 clearly defined categories as follows: 
Mild: 
(Grade 1): Mild symptoms causing no or minimal interference with usual social 
& functional activities with intervention not indicated. 
Moderate: 
(Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated. 

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Severe: 
(Grade 3): Severe symptoms causing inability to perform usual social & 
functional activities with intervention or hospitalization indicated. 
Life-
threatening: 
(Grade 4): Potentially life-threatening symptoms causing inability to perform 
basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death. 
Death: 
(Grade 5): Indicates death related to the AE. 
The investigator should report the highest severity experienced during the course of the event. It 
is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
defined above, whereas seriousness is defined by the criteria under Section 11.1.1.4. An AE of 
severe intensity may or may not be considered serious. An example would be a severe headache 
that does not result in any serious outcome is a non-serious AE; conversely, a mild event that 
results in hospitalization is a serious AE.  
11.1.1.5. Definition of Relationship to Study Drug 
Using the following guidelines, an investigator who is qualified in medicine must make the 
determination of relationship to berotralstat or SOC HAE medication used for prophylaxis and/or 
acute therapy for each AE (not related or related). The investigator should decide whether, in his 
or her medical judgment, there is a reasonable possibility that the event may have been caused by 
berotralstat or SOC HAE medication. If no valid reason exists for suggesting a relationship, then 
the AE should be classified as “not related.” If there is any valid reason, even if undetermined, 
for suspecting a possible cause-and-effect relationship between berotralstat or SOC HAE 
medication and the occurrence of the AE, then the AE should be considered “related.” 
Because multiple study drugs are being administered in this study, the investigator should assess 
causality individually to berotralstat or SOC HAE medication, taking into consideration the 
timing of the AEs in relation to berotralstat or SOC HAE medication dosing as well as the 
known safety profile of berotralstat or SOC HAE medication. 
The degree of certainty with which an AE is attributed to berotralstat or SOC HAE medication 
(or alternative causes, eg, natural history of the underlying disease, concomitant therapy) will be 
determined by how well the experience can be understood in terms of one or more of the 
following: 
• 
Known pharmacology of berotralstat or SOC HAE medication 
• 
Reactions of a similar nature have been previously observed with berotralstat or SOC 
HAE or these classes of drugs 
• 
The experience being related by time to berotralstat or SOC HAE medication, 
terminating with their withdrawal or recurring on re-challenge 
• 
Alternative cause 

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The investigator should assess causality by determining whether the AE/SAE is suspected to be 
caused by the investigational product based on facts, evidence, science-based rationales, and 
clinical judgement as follows:  
Not Related: 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship unlikely, OR other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the AE/SAE. 
Related: 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship possible, AND other drugs, 
therapeutic interventions or underlying conditions do not provide sufficient 
explanation for the AE/SAE. 
The sponsor may upgrade causality if deemed appropriate. 
11.1.2. 
Recording Adverse Events  
Information about AEs and SAEs will be collected from the signing of the ICF until the end of 
the study and will be recorded during the study at the investigational site in the CRF according to 
the instructions provided in the CRF completion guidelines.  
The AE term should be recorded using standard medical terminology (not lay language). 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 
signs/symptoms. 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 by replacing the individual signs and symptoms with this diagnosis. 
11.1.2.1. Time Period for Follow-up of Adverse Events 
All AEs that are ongoing at the time of the last study follow-up visit must be followed until they 
are resolved, or the subject is in a clinically stable condition with regard to the AE. 
11.1.3. 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions 
11.1.3.1.  Initial and Follow-up Reports 
The investigator must report all SAEs immediately and in no case later than within 24 hours of 
their knowledge of the event. Investigators should adhere to their country or region requirements 
for the reporting timeframe which may not allow any delay. The initial and follow-up SAE 
reports will identify subjects by the unique subject numbers assigned to ensure that the sponsor 
will have the necessary information to continuously assess the benefit-risk profile of the study 
drug in the clinical study. 

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SAEs should be reported to the medical monitor and via the AE and SAE electronic CRFs 
(eCRFs). The SAE eCRF is an additional form to the AE eCRF that provides important details 
on the SAE. All additional follow-up evaluations of the SAE must be reported to BioCryst or its 
designee as soon as they are available. A notification of the SAE should be sent to the following 
email addresses: 
Email: safety@biocryst.com 
In the event the eCRF system is not functioning, the reporting of an SAE must not be delayed. 
Sites will have SAE report forms (electronic Word document) that can be completed and emailed 
to the above recipients. As soon as the eCRF system is functioning, that particular SAE must be 
entered into the AE eCRF. 
11.1.3.2. Pregnancy 
Any female subject who becomes pregnant during the course of the study must 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. 
The Pregnancy Notification Form and Pregnancy Outcome Form should be sent to the following 
email address: 
Email: safety@biocryst.com 
Consent from partners of study participants who become pregnant will be obtained prior to 
reporting any details of the pregnancy. Information related to the pregnancy must be given on a 
“Pregnancy Notification Form” and “Pregnancy Outcome Form” that will be provided by 
BioCryst 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 in Section 11.1.2 and 
Section 11.1.3. Any complications reported in a subject’s pregnant partner should be reported on 
the “Pregnancy Notification Form” and “Pregnancy 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. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, normal birth, or congenital abnormality) must be followed up and documented, even 
if the subject was discontinued from the study. 
11.1.3.3. Record Retention and Reporting to Regulatory Authorities 
Investigators or designees at each site are responsible for retaining copies of all suspected 
unexpected serious adverse reaction (SUSAR) reports (initial and follow-up) and other safety 
information (eg, revised IB or Summary of Product Characteristics [SmPC]) in their investigator 
site files. 
BioCryst or its designee will submit all SUSAR reports (initial and follow-up) or other safety 
information (eg, revised IB) to the required authorities, in accordance with the locally applicable 
regulations. 

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BioCryst or its designee shall ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to all relevant competent authorities, 
and to the independent ethics committee (IEC)/institutional review board (IRB) 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 IEC/IRBs, as 
applicable according to local regulations, as soon as possible but in no case later than 15 calendar 
days of first knowledge by BioCryst. BioCryst or its designee shall also inform all investigators 
in accordance with local regulations. The investigator is responsible for ensuring that the 
IEC/IRB is also informed of the event, in accordance with local regulations. 
11.1.4. 
Unanticipated Problems 
11.1.4.1. Definition of Unanticipated Problems 
Any incident, experience, or outcome that meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document, and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at 
a greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or expected. 
The investigator is responsible for ensuring that the IEC/IRB is also informed of the 
unanticipated problem, in accordance with local regulations. 
11.2. 
Toxicity Management 
The investigator (or qualified designee) will grade clinically significant events and laboratory 
abnormalities (if considered AEs) as described in Section 11.1.1.4. Grade 3 and 4 clinically 
significant laboratory abnormalities should be confirmed by repeat testing and before any 
contemplated study drug discontinuation, unless such a delay is not consistent with good medical 
practice. 
In the event that a new clinically significant safety signal emerges, a meeting of the DMC may 
be convened by the sponsor to evaluate risk to subjects and recommend appropriate actions. 
Based on the data presented, a decision will be made as to whether to halt the study, to continue 
dosing, or to continue dosing with provisions introduced into the protocol via substantial 
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11.2.1. 
Treatment Interruptions 
Treatment interruptions as a result of investigator management of AEs potentially related to 
berotralstat are permissible. Resumption of berotralstat is also permissible upon resolution of the 
event, as assessed by the investigator, with a plan for stringent monitoring of the subject for 
recurrence of the AE as appropriate. In addition, other extenuating circumstances may lead to 
treatment interruptions such as vomiting during an abdominal HAE attack or required fasting for 
medical procedures; in these cases, berotralstat should be resumed once the extenuating 
circumstance is resolved. The sponsor medical monitor should be notified in the event of a 
treatment interruption due to an AE. Any treatment interruption will be recorded in the CRF and 
source documents, including the reason for the interruption. 
Treatment interruptions due to confirmed QTcF > 500 msec or increase more than 60 msec from 
baseline associated with Cmax exceeding the adult range are permissible. If interrupted, subjects 
may resume berotralstat at a reduced dose at the investigator’s discretion. Subjects may remain 
on the reduced berotralstat dose if they no longer meet QTcF stopping criteria at steady state (see 
Section 7.3.2). 
Other treatment interruptions may be permissible following consultation with the medical 
monitor.  
11.2.2. 
Dose Reductions 
Dose reductions are allowed based on emerging PK and/or safety data (see Section 8.4). 
Dose reductions due to confirmed QTcF > 500 msec or increase more than 60 msec from 
baseline associated with Cmax exceeding the adult range are permissible. Subjects may remain on 
the reduced berotralstat dose if they no longer meet QTcF stopping criteria at steady state (see 
Section 7.3.2). 
If the berotralstat dose is reduced, see Section 10.9.1 for collection of PK samples. 
Other dose reductions may be permissible following consultation with the medical monitor. The 
previous dose of berotralstat may be resumed upon resolution of the safety event at the discretion 
of the medical monitor based on PK and/or safety review (see Section 8.4).  
11.2.3. 
Overdose 
To date, there is no experience with overdose of oral berotralstat. Single doses of up to 1000 mg, 
7 days of dosing up to 500 mg/day, and 14 days of dosing with 350 mg/day revealed no 
clinically significant safety concerns in healthy subjects. Safety data generated in 
Study BCX7353-203 with 28-day dosing of up to 350 mg/day revealed no clinically significant 
safety concerns in subjects with HAE. Subsequently, subjects enrolled in Study BCX7353-106 
were exposed to berotralstat 450 mg QD for 14 days without any unanticipated AEs or increased 
AE severity. 
In the event that study personnel become aware of an overdose of berotralstat (> 1 dose per 
calendar day) that is associated with an AE, both the overdose and the resultant event should be 
reported as AEs. An overdose without associated signs or symptoms should not be recorded as 
an AE but should be reported as a protocol deviation.  

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If an overdose occurs with or without associated AEs, subjects should undergo clinical and 
laboratory monitoring as appropriate for their clinical condition and, if indicated, should receive 
clinically indicated supportive therapy.  
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 and, where 
applicable, SAE along with the overdose (see Section 11.1.3). Details of signs or symptoms, 
clinical management, and outcome should be included in the AE report, if available. 
Additional information about overdose as an AE or SAE is discussed in Section 11.1.1.2. 
11.3. 
Data Monitoring Committee 
An independent DMC will be established for interim safety monitoring. The specific 
responsibilities and composition of the DMC are outlined in a separate DMC charter. The charter 
will include, at a minimum, a description of DMC membership, roles, timing of DMC review 
and responsibilities of DMC members. In addition, the details of outputs provided for the 
meetings will be referenced in this charter. 
The DMC will be convened according to FDA guidelines. In general, the DMC will review 
safety data on an ongoing basis and SAEs considered related to berotralstat as they occur. Prior 
to initiating dosing with berotralstat (ie, initiation of Part 1) in Cohorts 3 and 4 (and any 
subsequent cohorts), the DMC will meet and review safety data and endorse opening of all 
subsequent cohorts.  
11.4. 
COVID-19 
The study will be conducted in accordance with relevant local, regional, and national guidance 
around coronavirus disease 2019 (COVID-19). In order to minimize the risk of COVID-19 
transmission, additional procedures or assessments (which may include but are not limited to 
symptom assessment, temperature assessment, and viral ribonucleic acid testing) may be 
implemented at the discretion of the investigator beyond those required in this protocol. Study 
visits or procedures may be modified in accordance with relevant local, regional, and national 
guidance as necessary to preserve subject safety during trial conduct. All protocol deviations 
resulting from COVID-19 will be identified as such. All study activities will be conducted in 
accordance with relevant local, regional, and national guidance around COVID-19. 
12. 
STATISTICS 
12.1. 
Sample Size Considerations 
The study is designed to evaluate the PK and safety/tolerability of oral administration of 
berotralstat in pediatric subjects ages 2 to < 12 years of age who have HAE. A sample size of 
approximately 30 subjects enrolled in 4 or more cohorts is adequate to evaluate the PK and to 
describe safety and tolerability. The sample size was selected based on feasibility considerations; 
however, with 30 subjects enrolled in the study, there is an approximately 96% chance of 
observing at least 1 treatment-emergent adverse event (TEAE) that occurs 10% of the time. 
Formal inferential testing of effectiveness and safety endpoints is not planned. 

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12.2. 
Statistical Methods 
A detailed statistical analysis plan (SAP) will be developed to describe the methods of analyses 
and summaries, including all endpoints, time points, populations, missing data, prior to the 
review of any data. Deviations from the analyses outlined in the SAP will be described in the 
clinical study report.  
12.2.1. 
Analysis Populations 
The analysis populations are defined in subsections that follow. 
12.2.1.1. Intent to Treat Population 
The intent to treat (ITT) population will include all subjects who satisfy all entry criteria and who 
enroll into the study. As this study focuses on safety and PK of berotralstat, analyses of the ITT 
population will likely be limited.  
Note that subjects for whom their P/C provided written informed consent but who are not 
enrolled in the study will be considered screen failures. Subjects who are “preliminary enrollees” 
awaiting final confirmation of eligibility will also be considered screen failures if found to be 
ineligible for study participation. 
12.2.1.2. Completer Population 
For study Parts 1 and 2, the subset of subjects who complete the 12 and 48 weeks of dosing may 
be analyzed for a subset of effectiveness endpoints. 
12.2.1.3. Safety Population 
The safety population will include all subjects who received at least 1 dose of berotralstat. This 
population will be used for analyses of accountability, demographics, berotralstat drug dosing 
and compliance, and safety. Effectiveness endpoints will also be summarized using this 
population. 
12.2.1.4. PK Population 
The PK population will include subjects in the safety population who have at least one dose of 
the study medication and had at least one evaluable and quantifiable post-dose PK sample 
obtained. 
12.2.2. 
General Considerations for Data Analysis 
Descriptive statistics will be used to summarize the data from this study. Data will be 
summarized by cohort, overall, and by study day or time, if appropriate. Unless stated otherwise, 
the term “descriptive statistics” refers to number of subjects (n), mean, standard deviation (SD) 
or standard error of the mean (SEM), median, minimum, and maximum for continuous data, and 
frequencies and percentages for categorical data. For TEAE data, both the number of subjects 
and total number of events will be reported. For PK endpoints, please see Section 12.2.4 for 
further details.  
Data summaries will be provided to the DMC as specified in the DMC Charter. Interim analysis 
of PK, safety, and effectiveness data may be conducted after at least 15 subjects complete 

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48 weeks of treatment (Part 2) and/or after all subjects complete 48 weeks of treatment. 
Additional interim analyses may be performed during the course of the study as needed to 
support regulatory filings, safety updates, and publications, as documented in the SAP. 
Effectiveness data are not collected after Week 48. Disposition and safety data will be 
summarized through the end of study (Week 144). 
The final analysis of disposition, dosing, and safety data collected in Parts 1, 2, and 3 will be 
conducted once the last subject completes or discontinues his or her respective parts, the 
resulting clinical database has been cleaned and quality checked, the analysis populations have 
been finalized, and after database lock has occurred. Disposition, dosing, and safety data will be 
summarized through the end of study (Week 144). 
Data collected during the study will be included in data listings as measured or recorded in 
patient diaries. Unless otherwise noted, data listings will be sorted by subject and study 
visit/date. 
Statistical analyses will be conducted using SAS® software version 9.2 or higher (SAS Institute, 
Cary, North Carolina, US). All analyses will be subject to formal verification procedures. All 
tables and figures generated to summarize data will be reviewed by the lead statistician to ensure 
accuracy and consistency of analyses; the lead clinical pharmacologist will review data 
summarized for the PK endpoints to ensure their accuracy and consistency. 
12.2.3. 
Subject Demographic and Disposition Data 
Demographic data and baseline characteristics including age, gender, race, ethnicity, height, 
weight, BMI, and HAE history, including medication history, will be summarized by weight 
cohort and for all subjects. 
Subject disposition will be presented for all subjects. The number of subjects who complete each 
study part as well as the entire study and those who discontinue from the study will be provided. 
The reasons for early discontinuation will be presented. A tabulation of the number of subjects 
exposed to berotralstat and the duration of exposure will also be presented. Treatment adherence, 
dose interruptions, and reason for dose interruptions will be provided as summaries or listed as 
appropriate. 
12.2.4. 
Pharmacokinetic Analyses 
Plasma samples for determination of berotralstat concentrations are planned to be collected at 
times indicated in the Schedule of Assessments. All plasma concentrations that are part of the PK 
population will be incorporated into the population PK analyses.  
The results of these analyses will be reported in a separate pharmacometric report. 
12.2.5. 
Analysis of Safety Variables 
Adverse events will be mapped to the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification. The occurrence of TEAEs will be summarized 
using MedDRA preferred terms, system organ classifications, and severity (eg, Grade 3 or 4) by 
cohort and for all subjects. Separate summaries of treatment-emergent SAEs and AEs related to 
study drug will be generated, as well as AEs leading to study drug being interrupted or study 
withdrawal. All AEs will be listed for individual subjects showing both verbatim and preferred 

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terms. Adverse events that are reported during the SOC treatment period will be summarized 
separately. 
Descriptive summaries of clinical laboratory results will be presented by study visit by cohort. 
Laboratory abnormalities will be graded according to the DAIDS Table for Grading Adverse 
Events for Adults and Pediatrics (Corrected Version 2.1, July 2017) unless otherwise specified. 
In addition to DAIDS requirements, creatinine increases from baseline must also meet certain 
minimum thresholds, to appropriately target meaningful changes in creatinine in pediatric 
patients with low baseline values, as summarized below:  
• Grade 1 mild: 1.1 to 1.3 x ULN OR increase ≥ 0.2 mg/dL from participant's baseline 
• Grade 2 moderate: > 1.3 to 1.8 x ULN OR increase ≥ 1.3 x baseline AND increase 
≥ 0.3 mg/dL from baseline 
• Grade 3 severe: > 1.8 to 3.5 x ULN OR increase ≥ 1.5 x baseline AND increase 
≥ 0.5 mg/dL from baseline) 
• Grade 4 potentially life threatening: > 3.5 x ULN OR Increase ≥ 2 x baseline AND 
increase ≥ 0.7 mg/dL from baseline 
The number and percentage of subjects experiencing treatment-emergent graded toxicities will 
be summarized. Laboratory toxicity shifts from baseline to post-baseline assessments will be 
summarized or listed by cohort.  
Effects of berotralstat on pediatric patient growth (weight, height, and BMI) will be assessed 
over time by cohort. Vital signs, laboratory data (eg, chemistry, hematology, and urinalysis 
results), and ECGs will also be summarized over time by cohort. 
Previous and concomitant medications will be mapped to a World Health Organization preferred 
term and drug classification. The number and percentage of subjects taking concomitant 
medications will be summarized using preferred terms and drug classifications (including during 
the SOC treatment period). 
12.2.6. 
Analysis of Effectiveness Variables  
Summary statistics will be provided for the number and rate of HAE attacks, duration of 
symptoms, anatomical location of attacks, use of on-demand rescue medication, number of days 
with angioedema symptoms, P/C assessment of attack severity, and number of hospitalizations 
and clinic visits during Part 1 (Weeks 1 through 12) and in Parts 1 and 2 combined (Weeks 1 
through 48) by cohort. The rate of HAE attacks over time will be provided. Subjects who 
discontinue the study due to “lack of efficacy” will be identified and provided in a listing.  
12.2.7. 
Analysis of Exploratory Variables 
Summary statistics for the exploratory endpoints related to assessment of palatability and 
acceptability for the berotralstat granules will be provided for subjects enrolled in Cohorts 2 to 4.  

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13. 
STUDY ADMINISTRATION 
13.1. 
Direct Access to Source Data/Documents 
13.1.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of BioCryst will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regards 
to protocol adherence, and the responsibilities of BioCryst or its representatives. This 
will be documented in a Clinical Study Agreement between BioCryst and the 
investigator. 
During study conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP) are being followed. The monitors will review 
source documents to confirm that the data recorded on eCRFs are 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(s) and their relevant personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
During the study, a monitor from BioCryst or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to BioCryst. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to BioCryst and those SAEs that met criteria for reporting 
have been forwarded to the IEC/IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.1.2. 
Audits and Inspections 
Authorized representatives of BioCryst, US FDA and other regulatory authorities, and/or ethics 
committees may visit the site to perform audits or inspections, including source data verification. 

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The purpose of a BioCryst audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, standard 
operating procedures, ICH/GCP guidelines, and any applicable regulatory requirements. The 
investigator will permit study-related audits mandated by the sponsor, after reasonable notice, 
and inspection by domestic or foreign regulatory authorities. The investigator should contact 
BioCryst immediately if contacted by a regulatory agency about an inspection. 
It is important that the investigator and relevant personnel are available during the possible audits 
or inspections and that sufficient time is devoted to the process. 
13.1.3. 
Ethics Committee 
Ethics approval for the investigation must be obtained prior to commencing the study. Initial 
ethics approval, and all materials approved by the ethics committee, including the ICF and any 
recruitment materials, must be maintained by the investigator and made available for inspection. 
13.1.4. 
Serious Breaches of GCP 
It is the responsibility of the sponsor to notify the competent authority of any serious breach of 
GCP that is likely to affect, 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 competent authority in accordance with locally applicable regulations. The reporting to 
the sponsor will be performed by the party who suspects the serious breach. 
13.2. 
Quality Control and Quality Assurance 
During study conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure 
that the protocol and GCP are being followed as described in Section 13.1.1. 
To ensure compliance with GCP and all applicable regulatory requirements, BioCryst or its 
designee may conduct a quality assurance audit. Please see Section 13.3.2 for more details 
regarding the audit process. The investigator agrees to allow the auditors to inspect the drug 
storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
13.3. 
Regulatory and Ethical Considerations 
13.3.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval to BioCryst before he or she can enroll any patient/subject into the study. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 

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The principal investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product. 
BioCryst will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
13.3.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and BioCryst’s policies.  
This study will also be conducted in accordance with EU Clinical Trial Regulation 536/2014 
(CTR). 
13.3.3. 
Written Informed Consent and Assent 
Signed informed consent must be obtained from each P/C prior to performing any study-related 
procedures. Each P/C and, where age appropriate, 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 P/C has adequate time to consider 
the risks and benefits associated with his/her child’s participation in the study. Subjects will not 
be screened or treated until the P/C has signed an approved ICF written in a language in which 
the P/C is fluent. 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. 
The investigator must explain to the P/C the aims, methods, reasonably anticipated benefits, and 
potential hazards of the trial and any discomfort it may entail. Each P/C will be informed that 
they are free for their child not to participate in the trial and that they may withdraw consent for 
their child to participate at any time. They will be told that refusal for their child to participate in 
the study will not prejudice future treatment. They will also be told that their child’s records may 
be examined by competent authorities and authorized persons, but that personal information will 
be treated as strictly confidential and will not be publicly available.  
P/C must be given the opportunity to ask questions. After this explanation and before entry into 
the trial, consent and assent should be appropriately recorded by means of the P/C’s dated 
signature. The P/C should receive a signed and dated copy of the ICF. The original signed 
informed consent should be retained in the study files. The investigator shall maintain a log of all 
subjects for whom consent was signed and indicate if the subject was enrolled into the study or 
reason for non-enrollment. 
Similarly, subject assent will be obtained from each child according to local 
regulations/requirements. If assent is required based on the subject’s age and local requirements, 
then the subject will not be screened or treated until the assent is received. Additionally, if 
required by local regulation, as the subject ages during the study and reaches an age requiring 
assent, then the subject will be assented to continue in the study at the next scheduled visit. 

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The ICF and assent forms (if applicable) must be approved both by BioCryst and the reviewing 
ethics committee. The ICF and assent forms should be in accordance with the current revision of 
the Declaration of Helsinki, current ICH/GCP guidelines, and BioCryst policy. 
13.4. 
Data Handling and Recordkeeping 
13.4.1. 
Inspection of Records 
BioCryst will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
13.4.2. 
Records Retention 
The investigator will maintain adequate records for the study, including the identity of all 
participating subjects (sufficient information to link records, CRFs, and medical/hospital 
records), all original signed ICFs, all original signed assents (if applicable), all CRFs, drug 
dispensing and disposition records, safety reports, information regarding participants who 
discontinued, and other pertinent data.  
The investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for BioCryst or the 
Regulatory Authority to review any documentation relating to the study, the investigator must 
permit access to such records. It is the responsibility of BioCryst to inform the 
investigator/institution as to when these documents no longer need to be retained. It is the 
investigator’s responsibility to notify BioCryst if they relocate or retire so that document storage 
can be addressed. 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. 
13.5. 
Confidentiality of Information and Data 
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 General Data Protection Regulation 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 

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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. 
13.6. 
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 with BioCryst, independent analysis and/or publication of these data by the 
investigator or any member of his/her staff is not permitted. Such consent will not be withheld 
unreasonably. BioCryst is in agreement with the principle of full disclosure of clinical trial 
results. 

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14. 
REFERENCES 
Agostoni, A. and M. Cicardi (1992). "Hereditary and acquired C1-inhibitor deficiency: 
biological and clinical characteristics in 235 patients." Medicine (Baltimore) 71(4): 206-215. 
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. 
Christiansen, S. C., D. K. Davis, A. J. Castaldo and B. L. Zuraw (2016). "Pediatric Hereditary 
Angioedema: Onset, Diagnostic Delay, and Disease Severity." Clin Pediatr (Phila) 55(10): 935-
942. 
European Medicines Agency (2006). Guideline on the role of pharmacokinetics in the 
development of medicinal products in the paediatric population. C. f. M. P. f. H. U. (CHMP). 
London, UK. 
European Commission (2008). ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON 
MEDICINAL PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION. 
Farkas, H. (2010). "Pediatric hereditary angioedema due to C1-inhibitor deficiency." Allergy 
Asthma Clin Immunol 6(1): 18. 
FDA (2022). General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and 
Biological Products, Including Biological Product Guidance for Industry - DRAFT GUIDANCE. 
C. f. D. E. a. R. (CDER). 
Han, E. D., R. C. MacFarlane, A. N. Mulligan, J. Scafidi and A. E. Davis, 3rd (2002). "Increased 
vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor." 
J Clin Invest 109(8): 1057-1063. 
ICH (2018). E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric 
Population. 
Kaplan, A. P. (2010). "Enzymatic pathways in the pathogenesis of hereditary angioedema: the 
role of C1 inhibitor therapy." J Allergy Clin Immunol 126(5): 918-925. 
Kaplan, A. P. and B. Ghebrehiwet (2010). "The plasma bradykinin-forming pathways and its 
interrelationships with complement." Mol Immunol 47(13): 2161-2169. 
Longhurst, H. and M. Cicardi (2012). "Hereditary angio-oedema." Lancet 379(9814): 474-481. 
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. 
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. 
Zuraw, B. L. and S. C. Christiansen (2011). "Pathophysiology of hereditary angioedema." Am J 
Rhinol Allergy 25(6): 373-378. 
 

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15. 
APPENDICES 
15.1. 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events – July 2017 
Copies of the DAIDS Table will be available to the medical staff throughout the project. 

 
 
Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
Corrected Version 2.1 
July 2017 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 
 

 
Table of Contents 
Glossary and Acronyms ....................................................................................................................... 1 
Introduction ........................................................................................................................................... 3 
Instructions for Use .............................................................................................................................. 4 
Major Clinical Conditions .................................................................................................................... 7 
Cardiovascular ................................................................................................................................ 7 
Dermatologic .................................................................................................................................. 9 
Endocrine and Metabolic ............................................................................................................. 10 
Gastrointestinal ............................................................................................................................. 12 
Musculoskeletal ............................................................................................................................ 14 
Neurologic..................................................................................................................................... 15 
Pregnancy, Puerperium, and Perinatal ........................................................................................ 17 
Psychiatric ..................................................................................................................................... 18 
Respiratory .................................................................................................................................... 19 
Sensory .......................................................................................................................................... 20 
Systemic ........................................................................................................................................ 21 
Urinary .......................................................................................................................................... 23 
Site Reactions to Injections and Infusions ........................................................................................ 24 
Laboratory Values .............................................................................................................................. 25 
Chemistries ................................................................................................................................... 25 
Hematology ................................................................................................................................... 29 
Urinalysis ...................................................................................................................................... 31 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates ............................................. 32 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 1 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS.  It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency.  
INR 
International normalized ratio  

Glossary and Acronyms 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 2 
Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event.  
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization  
WNL 
Within normal limits 
 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 3 
Introduction 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and 
internationally, which evaluate the safety and efficacy of therapeutic products, vaccines, and 
other preventive modalities.  Adverse event (AE) data collected during these clinical trials form 
the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices.  Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants and 
future patients using pharmaceutical products.  
 
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating 
revisions of the DAIDS grading table which serves as a guide for assessing the severity of AEs 
(including clinical and laboratory abnormalities) in participants enrolled in DAIDS-sponsored 
and -supported clinical trials.  The Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) updates and replaces 
version 2.1 (March 2017).  
 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS grading table. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 4 
Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are written 
to maintain data consistency across clinical trials.  However, since some parameters can be 
reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with 
descriptions for each AE based on the following general guidelines:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
• Use age and sex values as applicable. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
• Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.  
 

Instructions for Use 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 5 
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions.  
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades  
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the clinical case report forms.  
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 

Instructions for Use 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 6 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion.  
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies- 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5.  
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated 
Potentially life-threatening 
symptoms causing inability 
to perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 7 
Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arrhythmia   
(by ECG or physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND 
Non-urgent 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
                                                          
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 
2011; DOI: 10.1542/peds.2009-2107C. 

Cardiovascular 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 8 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of  ≤ 2 
units packed RBCs 
indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated 
Prolonged PR Interval  
or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block  
≤ 16 years of age 
1st degree AV block 
(PR interval  
> normal for age 
and rate) 
Type I 2nd degree 
AV block  
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated  
Symptoms AND 
Intervention 
indicated  
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)  
 
 
                                                          
2 As per Bazett’s formula. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 9 
Dermatologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alopecia (scalp only)  
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities  
NA 
Rash 
Specify type, if 
applicable 
Localized rash  
Diffuse rash OR 
Target lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
 
                                                          
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 10 
Endocrine and Metabolic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
                                                          
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 

Endocrine and Metabolic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 11 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes  
NA 
                                                          
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 12 
Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
unformed stools OR 
Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to  6 
stools over baseline 
per 24-hour period 
Increase of  ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or  
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 

Gastrointestinal 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 13 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 to 48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 14 
Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care functions  
Myalgia (generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score  
-2.5 to -1 
NA 
NA 
NA 
   < 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA  
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
 
                                                          
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment 
of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for 
Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.  

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 15 
Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below)  
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional 
activities 
Delirium OR  
Obtundation OR  
Coma 
Ataxia  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function  

Neurologic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 16 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or  paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA  
1 to  3 seizures  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with  
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality  
(e.g., severity or  
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Syncope  
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 17 
Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Stillbirth (report using 
mother’s participant ID) 
Report only one 
NA 
NA 
Fetal death occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to  
< 37 weeks  
gestational age 
Live birth at 28 to  
< 34 weeks 
gestational age 
Live birth at 24 to  
< 28 weeks 
gestational age 
Live birth at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
                                                          
7 Definition:  A pregnancy loss occurring at < 20 weeks gestational age. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 18 
Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities  
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal interference 
with usual social & 
functional activities 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early causing 
inability to perform 
usual social & 
functional activities 
requiring intervention 
or hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 19 
Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to  
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to  
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to  
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal  
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 
90 to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 20 
Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hearing Loss 
≥ 12 years of age 
 
NA 
 
Hearing aid or 
intervention not 
indicated 
 
Hearing aid or 
intervention indicated 
 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 
6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing 
aids 
Audiologic indication 
for cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medical intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional 
activities 
Disabling visual loss in 
affected eye(s) 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 21 
Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion)  
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain9 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Pain causing inability 
to perform usual 
social & functional 
activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
                                                          
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   

Systemic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 22 
Serum Sickness10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight11 
> 5 to 19 years of 
age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score  
< -3 
WHO BMI z-score  
< -3 with life-threatening 
consequences 
2 to 5 years of age 
WHO Weight-for-
height z-score  
< -1 to -2 
WHO Weight-for-
height z-score  
< -2 to -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences 
< 2 years of age 
WHO Weight-for-
length z-score  
< -1 to -2 
WHO Weight-for-
length z-score  
< -2 to -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences 
Unintentional 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
 
                                                          
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea. 
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:  
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 23 
Urinary 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary Tract 
Obstruction  
NA 
Signs or symptoms 
of urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 24 
Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Injection Site Pain or  
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site Erythema 
or Redness12 
Report only one 
> 15 years of age 
 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus  
 
Itching localized to 
the injection site 
that is relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities  
NA 
                                                          
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 25 
Laboratory Values*  
Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0  
≥ 20  to < 30  
< 2.0  
< 20  
NA 
Alkaline Phosphatase,  
High 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0  
11.0  to < 16.0  
8.0  to < 11.0  
8.0  to < 11.0  
< 8.0  
< 8.0  
Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
 
 
NA 
 
NA 
 
> ULN with other 
signs and symptoms 
of hepatotoxicity. 
 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
 
1.1 to < 1.6 x ULN 
 
1.6 to < 2.6 x ULN 
 
2.6 to < 5.0 x ULN  
 
≥ 5.0 x ULN  
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
                                                          
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to DAIDS in an 
expedited time frame unless it meets protocol-specific reporting requirements. 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 

Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 26 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
≥  13.5  
≥  3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
≥  13.5 
≥  3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s baseline 
≥ 3.5 x ULN OR 
Increase of  ≥ 2.0 x 
participant’s baseline 
Creatinine Clearance 14 
or eGFR, Low 
*Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease  
from participant’s 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
 30 to < 50% 
decrease from 
participant’s baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
participant’s baseline or 
dialysis needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125 
6.11 to < 6.95 
 
 
> 125 to 250 
6.95 to < 13.89 
 
 
 > 250 to 500  
13.89 to < 27.75 
 
 
≥  500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250  to 500 
13.89  to < 27.75  
≥  500 
≥ 27.75  
                                                          
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
  
*Reminder: Choose the method that selects for the higher grade. 

Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 27 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glucose, Low  
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64  
3.05  to <3.55  
40  to < 55 
2.22  to < 3.05  
30  to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
< 1 month of age 
50 to 54 
2.78  to < 3.00  
40 to < 50 
2.22 to < 2.78  
30 to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders  
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
 
200  to < 240 
5.18  to < 6.19  
 
240  to < 300  
6.19  to < 7.77  
 
≥  300 
≥  7.77  
 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15  
200 to < 300 
5.15  to < 7.77  
≥  300  
≥  7.77  
NA 
LDL, Fasting, High 
≥ 18 years of age 
 
130  to < 160  
3.37  to < 4.12  
 
160 to < 190  
4.12  to < 4.90  
 
≥ 190  
≥ 4.90  
 
NA 
> 2 to < 18 years of 
age 
110  to < 130  
2.85  to < 3.34  
130 to < 190  
3.34  to < 4.90  
≥ 190 
≥ 4.90  
NA 
Triglycerides, Fasting, 
High 
150 to 300  
1.71 to 3.42  
>300  to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4 
Magnesium15, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4  
0.60  to < 0.70  
0.9  to < 1.2  
0.45  to < 0.60  
0.6  to < 0.9  
0.30  to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low  
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65  
1.0 to < 1.4 
0.32 to < 0.45  
< 1.0 
< 0.32  
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13  
2.5  to < 3.0 
0.81  to < 0.97  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45  
2.5  to < 3.5 
0.81  to < 1.13  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0  
6.0  to < 6.5 
6.0  to < 6.5  
6.5  to < 7.0 
6.5  to < 7.0  
≥ 7.0 
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4  
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5  
< 2.0 
< 2.0  
                                                          
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 

Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 28 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150  
150  to < 154 
150  to < 154  
154  to < 160 
154  to < 160  
≥ 160 
≥ 160  
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135  
125  to < 130 
125  to < 130 
121  to < 125 
121  to < 125  
≤ 120 
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59  
10.0  to < 12.0 
0.59  to < 0.71  
12.0  to < 15.0 
0.71  to < 0.89  
≥ 15.0 
≥ 0.89  

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 29 
Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
300 to < 400 
300 to < 400 
 
 
 
200 to < 300 
200 to < 300 
 
 
 
100 to < 200 
100 to < 200 
 
 
 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
600 to < 650 
0.600 x 109 to 
< 0.650 x 109 
 
 
 
500 to < 600 
0.500 x 109 to 
< 0.600 x 109 
 
 
 
350 to < 500 
0.350 x 109 to 
< 0.500 x 109 
 
 
 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
 
 
 
600 to 799 
0.600 x 109 to 0.799 
x 109 
 
 
 
400 to 599 
0.400 x 109 to 0.599 
x 109 
 
 
 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 
x LLN 
75 to < 100 
0.75  to < 1.00  
OR 
≥ 0.50 to < 0.75 
x LLN  
50 to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin16, Low 
(g/dL; mmol/L) 17 
≥ 13 years of age  
(male only) 
 
 
10.0 to 10.9 
6.19 to 6.76 
 
 
 
9.0 to < 10.0 
5.57 to < 6.19 
 
 
7.0 to < 9.0 
4.34 to < 5.57 
 
 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
                                                          
16 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender 
female should be graded using the female sex at birth hemoglobin laboratory values). 
 
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory.  
 

Hematology 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 30 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
57 days of age to < 13 
years of age  
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin  
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.66  
x ULN 
1.66 to < 2.33  
x ULN 
2.33 to < 3.00  
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 125,000  
100.000 x 109  to 
< 125.000 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000  
25.000 x 109  to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High  
(not on anticoagulation 
therapy 
1.1  to < 1.25  
x ULN 
1.25  to < 1.50  
x ULN 
1.50  to < 3.00  
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
 
 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
 
 
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109 
 
 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109 
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109 
< 2,500 
< 2.500 x 109 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 31 
Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to   
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 

 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 32 
Appendix A.  
Total Bilirubin Table for Term and Preterm Neonates 
   PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Total Bilirubin18, High 
(mg/dL; µmol/L) 19 
 
Term Neonate20 
 < 24 hours of age 
 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10 to < 17  
171 to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of 
age 
5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12 to < 19  
205.2 to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of 
age 
8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15 to < 22  
256.5 to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days 
of age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18 to < 24  
307.8 to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
32 to < 35 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
≥ 10  
≥ 171  
< 28 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
 5 to < 8  
85.5 to < 136.8  
≥ 8  
≥ 136.8  
7 to  28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
 
                                                          
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first 
week of life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this 
appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 
4. 
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; preterm, as < 35 weeks 
gestational age; and neonate, as 0 to 28 days of age. 

Signature Page for VV-CLIN-004817 v5.0
Signature Page for VV-CLIN-004817 v5.0
Approval Task
Clinical
Clinical
05-Nov-2024 17:41:31 GMT+0000
Approval Task
Clinical
Clinical
05-Nov-2024 21:12:33 GMT+0000
PPD
PPD

Signature Page for VV-CLIN-004817 v5.0
Signature Page for VV-CLIN-004817 v5.0
Approval Task
Clinical
Clinical
05-Nov-2024 17:41:31 GMT+0000
Approval Task
Clinical
Clinical
05-Nov-2024 21:12:33 GMT+0000
PPD
PPD