Clinical trial NCT02369159
Conditions: Influenza
Sponsor: BioCryst Pharmaceuticals
Start date: 2015-03-11; Completion date: 2020-05-14
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, pharmacokinetics and effectiveness of a single dose of IV peramivir compared to a standard 5 day course of oral oseltamivir in the treatment of pediatric subjects with acute uncomplicated influenza.

Detailed description:

Arms: arm 1: Subjects randomized to peramivir will receive an age appropriate single dose, diluted to a maximum volume of 100 mL in normal saline, administered as a short intravenous infusion over a minimum of 15 minutes.

* Subjects ≥12 years will receive a dose of 600 mg.
* Subjects \<12 years will receive a dose of 12 mg/kg (to a maximum dose of 600 mg).
* Subjects \< 6 months will receive a dose of 8 mg/kg. arm 2: Subjects randomized to oral oseltamivir will receive an age appropriate dose twice daily for 5 days.

* Subjects ≥ 13 years will receive a 75mg dose administered as a capsule or oral suspension (twice daily for 5 days).
* Subjects \< 13 years of age will receive a weight-based dose administered as a capsule or oral suspension (twice daily for 5 days).
Interventions: intervention 1: Peramivir intervention 2: Oseltamivir
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Protocol 
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BioCryst Pharmaceuticals, Inc. 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-305 
IND No. 69,038 
 
A PHASE 3, RANDOMIZED, OPEN LABEL, ACTIVE-CONTROLLED STUDY TO 
EVALUATE THE SAFETY, PHARMACOKINETICS AND EFFECTIVENESS OF IV 
PERAMIVIR COMPARED TO ORAL OSELTAMIVIR IN PEDIATRIC SUBJECTS WITH 
ACUTE UNCOMPLICATED INFLUENZA 
 
Original Protocol, Version 1.0: 05 November 2014 
Amendment 1, Version 2.0: 01 December 2014 
Amendment 2, Version 3.0: 21 June 2015 
Amendment 3, Version 4.0: 20 October 2016 
Amendment 4, Version 5.0: 10 January 2017 
Amendment 5, Version 6.0: 05 November 2018 
 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703 
Phone: (+1)919-859-1302 
Fax: (+1)919-851-1416 
 
The information in this document contains proprietary and confidential information belonging 
to BioCryst Pharmaceuticals, Inc. As a result, no part of this document should be copied, 
referred to, released, published or otherwise disclosed in any manner or media without prior 
written approval from BioCryst Pharmaceuticals, Inc. 
CONFIDENTIAL 


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1. 
TITLE PAGE 
 
Protocol Number: 
BCX1812-305 
Study Title: 
A Phase 3, randomized, open label, active-controlled study to 
evaluate the safety, pharmacokinetics and effectiveness of IV 
peramivir compared to oral oseltamivir in pediatric subjects with 
acute uncomplicated influenza 
IND Number: 
69,038 
EudraCT No. 
N/A 
Investigational Product: 
Peramivir 
Indication Studied: 
Influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703 
Development Phase: 
3 
Sponsor Medical Officer: 
Sylvia Dobo, MD 
Executive Director, Product Safety and Clinical Development 
Phone: (+1) 919-859-7905 
Fax: (+1) 919-851-1416 
Email Address: mm@biocryst.com 
Principal Investigator: 
John A. Vanchiere, M.D., Ph.D.  
Chief, Pediatric Infectious Diseases 
Louisiana State University Health Sciences Center - Shreveport 
 
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and 
clinical research guidelines established by the Code of Federal 
Regulations (Title 21, CFR Parts 50, 56, and 312) and ICH 
Guidelines. Essential study documents are currently archived in 
accordance with applicable regulations. 
Final Protocol Date: 
Version 6.0: 05 November 2018 
 




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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-305 
Protocol Title: 
A Phase 3, randomized, open label, active-controlled study to evaluate the 
safety, pharmacokinetics and effectiveness of IV peramivir compared to oral 
oseltamivir in pediatric subjects with acute uncomplicated influenza 
Version Date: 
Version 6.0: 05 November 2018 
 
 
 
 
 
I have carefully read this protocol and agree that it contains all of the necessary information required to 
conduct this study. I agree to conduct this study as described and according to the Declaration of 
Helsinki, International Conference on Harmonization Guidelines for Good Clinical Practices, and all 
applicable regulatory requirements. 
 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
 
Name (Print) 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
BioCryst Pharmaceuticals, Inc. 
Name of Investigational Product: 
Peramivir 
Title of Study:  
A Phase 3, randomized, open label, active-controlled study to evaluate the safety, 
pharmacokinetics and effectiveness of IV peramivir compared to oral oseltamivir in pediatric 
subjects with acute uncomplicated influenza. 
Study Center(s):  Multi-center 
Principal Investigator:  
John A. Vanchiere, M.D., Ph.D.  
Chief, Pediatric Infectious Diseases 
Louisiana State University Health Sciences Center - Shreveport 
 
Studied Period (years):  
Estimated date first subject enrolled: December 2014 
Estimated date last subject completed: September 2020 
Phase of Development:  
3 
Objectives:  
Primary:    
• To evaluate the safety of intravenous (IV) peramivir (study drug) compared to oral 
oseltamivir in pediatric subjects with acute uncomplicated influenza. 
Secondary: 
• To describe the pharmacokinetics of IV peramivir in pediatric subjects with influenza. 
• To evaluate the effectiveness of IV peramivir compared to oral oseltamivir in pediatric 
subjects with influenza. 
• To evaluate the incidence of influenza complications, specifically otitis media, sinusitis, 
bronchitis or pneumonia requiring antibiotic use diagnosed after initiation of treatment. 
Methodology:  
Subjects meeting the inclusion/exclusion criteria may be enrolled into the study. It is expected 
that most subjects will have the Screening/Baseline visit and the Day 1 treatment visit on the 
same day. 
A subject’s duration of participation in this study is expected to be 14 days.  
Subjects ≥ 7 years old will be randomized to 1 of 2 treatment arms: 
Treatment Group 1: A single dose of intravenous peramivir 
Treatment Group 2: Oral oseltamivir given twice daily (BID) for 5 days 


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(Note: at the date of amendment 3, the dose cohorts for subjects > 7 years old were fully 
enrolled and no further subjects > 7 years will be enrolled). 
Subjects < 7 years old will receive a single dose of intravenous peramivir. 
(Note: at the date of amendment 3, the dose cohort for subjects 2-7 years old was partially 
enrolled under the previous randomization scheme that allocated subjects to peramivir or 
oseltamivir.  Following FDA feedback, remaining subjects to be enrolled in the 2 to <7 years 
old cohort, the 28 day to < 2 years old cohort, and the birth to < 28-day cohort, will all be 
assigned to receive treatment with IV peramivir. 
Following treatment on study Day 1, subjects will undergo follow-up assessments on Days 3, 
7, and 14. The Day 3 visit may be a home visit (performed by a qualified study nurse). Day 7 
is required to take place in the clinic, and Day 14 may either be a clinic visit, home visit, or 
follow-up phone call to the subject/parent/guardian.  
All parents/caregivers will record the following information in the Subject Diary: 
• Temperature measurements (oral or axillary) will be taken with an electronic 
thermometer provided by BioCryst, approximately every 12 hours until temperature 
normalizes for 48 hours (i.e., temperature without antipyretic is < 99.4 orally in 
children ≥ 6 and < 98.4 axillary in children < 6 years old for 4 measurements).With the 
exception of the baseline measurement, all temperature measurements will be obtained 
at least 4 hours after, or immediately before, administration of oral acetaminophen or 
other antipyretic medications, if taken. 
• Date and time of oral oseltamivir dose administration, if applicable.  This should be 
recorded in the Subject Diary twice a day for 5 days. 
• Doses of antipyretic medication and any medications taken for symptomatic relief, each 
day through the last follow-up assessment. 
• The ability of the child or adolescent to return to day care/school and/or resume their 
normal “pre-illness” daily activity. 
• The child or adolescent’s appetite and eating patterns assessed as normal or 
reduced/abnormal. 
All parents/caregivers of subjects 7 years of age and older will record the following additional 
information in the Subject Diary: 
• Assessment of 7 influenza symptoms [cough, sore throat, nasal obstruction, myalgia 
(muscle aches), headache, feverishness, and fatigue] on a 4-point severity scale 
(0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 
until symptom resolution or through the last follow-up visit, (whichever comes first). 
All parents/caregivers of subjects ≥ 4 years of age to ≤ 6 years of age will record the following 
additional information in the Subject Diary: 
• Assessment of 7 influenza symptoms [cough, sore throat, nasal obstruction, headache, 
feverishness, fatigue/malaise, and gastrointestinal symptoms (nausea, vomiting or 
diarrhea)] on a 4-point severity scale (0, absent; 1, mild; 2, moderate; 3, severe) twice 
daily until symptom resolution or through the last follow-up visit, (whichever comes 


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first). 
All parents/caregivers of subjects ≤ 3 years of age will record the following additional 
information in the Subject Diary: 
• Assessment of 5 influenza symptoms [cough, rhinitis, feverishness, malaise alternating 
with irritability and gastrointestinal symptoms (nausea, vomiting or diarrhea)] on a 
4-point severity scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning 
pre-dose on Day 1 until symptom resolution or through the last follow-up visit, 
(whichever comes first). 
An adequate nasal swab specimen will be collected from all enrolled subjects at Baseline 
(pre-dose) for virus sub-type identification and quantitative virologic assessments and at the 
follow-up assessments on study Days 3, 7, and where possible on Day 14. 
Specimens from all subjects yielding influenza virus will also be assessed for susceptibility to 
neuraminidase inhibitors (Day 1 and last specimen yielding influenza virus on culture). A 
central laboratory will perform all virologic assessments.  
Plasma samples for determination of drug concentration on subjects randomized to peramivir 
will be drawn as follows: 
Up to 4 blood samples will be drawn, where possible, during the following time periods, 
beginning from the end of dosing until release from the site:  
• One time point immediately following completion of the infusion 
• One time point from 30 minutes to 1 hour post-infusion 
• One time point from 1 hour to 3 hours post-infusion  
• One time point from 3 to 6 hours post-infusion 
Note: Subjects ≥ 5 kg will have four 1.0 mL blood draws at the above stated sampling times. 
Subjects < 5 kg will have two 1.0 mL blood samples; one time immediately following 
completion of the infusion and one time between 1-3 hours post-infusion. Adverse events and 
concomitant medications will be monitored at each scheduled visit from the 
Screening/Baseline assessment to final study visit. Clinical laboratory investigations 
(chemistries, hematology, and urinalysis) will be collected at Baseline and at the Day 7 visit. 
Safety and tolerability will be evaluated through assessments of adverse events, laboratory 
analyses (clinical chemistry, hematology, and urinalysis), vital signs and physical 
examinations at the time points indicated in the schedule of assessments.  
Number of subjects (planned):  
Up to 140 subjects will be enrolled in this study according to the following age groups: 
• Birth to < 28 days: up to 10 subjects will receive IV peramivir  
• 28 days - < 2 years: up to 20 subjects: subjects enrolled after the approval of 
amendment 3 will receive, IV peramivir 
• 2 <4 years: up to 10 subjects: subjects enrolled after the approval of amendment 3 will 
receive IV peramivir 


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• 4 - < 7 years:up to 30 subjects: subjects enrolled after the approval of amendment 3 
will receive IV peramivir  
• 7 - < 13 years:up to 40 subjects, randomized 4:1 to IV peramivir or oral oseltamivir 
• 13 - < 18 years:up to 30 subjects, randomized 4:1 to IV peramivir or oral oseltamivir  
Criteria for inclusion:  
 
Inclusion criteria: 
1. Male and non-pregnant female subjects age birth to 17 years of age. 
2. Clinical signs and symptoms consistent with acute influenza infection consisting of an oral 
temperature ≥ 100°F (37.8°C) or rectal temperature ≥ 101.3ºF (≥ 38.5ºC) with at least one 
respiratory symptom (cough or rhinitis) OR a positive influenza rapid antigen test.  Fever 
will either be documented at the time of screening or must be reported by the parent or 
care-giver if treatment with an antipyretic was given within 6 hours of the screening 
assessment. Note: enrollment at each site by clinical symptoms alone will be approved 
by the Sponsor at the beginning of each influenza season once influenza has been 
confirmed in the local community. The Sponsor may withdraw approval for 
symptomatic screening in any season based upon trends in influenza surveillance 
data. Prior to sponsor approval or after approval is withdrawn, criteria 2 must be 
met by a positive influenza RAT test. During the period of approval, clinical 
symptoms alone will be adequate to meet criteria 2. 
3. Onset of symptoms no more than 72 hours before presentation for screening for subjects < 
2 years old.  
4. Written informed consent by parents/guardians and assent by subjects ≥ 7 years of age (or 
as applicable by local IRB or state requirements). 
5. Females who have started their menses must either be: 
• Sexually abstinent 
• Using a highly effective form of birth control such as hormone contraception (oral, 
patch, injection, implant or vaginal ring) or 2 barrier methods (condom with 
spermicide and diaphragm) 


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Exclusion Criteria: 
1. Age > 17 years. 
2. If less than 3 months of age at screening, history of premature birth (< 36 weeks 0 days 
gestation) 
3. Weight less than 3.0 kg 
4. Receipt of a live attenuated influenza vaccine (LAIV) within 14 days of presentation.  
5. Females who are pregnant (positive urine or serum pregnancy test) or breast-feeding at 
screening. 
6. Onset of symptoms more than 72 hours before presentation for screening for subjects <2 
years old. 
7. Development of symptoms while hospitalized for another indication 
8. Subjects with identified risk factors for influenza complications but with uncomplicated 
influenza at the time of enrollment are not excluded.  This includes lung disease, heart 
disease, blood disorders such as sickle cell anemia, metabolic disorders and neurologic 
disease. In addition, mild to moderate immunocompromised status such as due to renal 
disease, diabetes mellitus or HIV infection with a last known CD4+ count ≥200 cells/µl are 
not excluded.    
9. Presence of severe immunocompromised status due to chronic disease or illness, previous 
organ transplant, or use of immunosuppressive medical therapy which would include oral 
or systemic treatment with > 10 mg prednisone or equivalent on a daily basis within 30 
days of screening.  
10. Complicated influenza characterized by any of the following: 
a. ICU care 
b. Evidence of organ dysfunction 
c. Proven or suspected concomitant bacterial infection 
d. Other known concomitant viral infection that is likely to complicate medical course 
such as RSV, parainfluenza virus and adenovirus. Co-infection with rhinovirus and 
enterovirus is allowed.  
11. Previous participation in Study BCX1812-305 or participation in a study of any 
investigational drug or device within the last 30 days. 
12. Subjects who cannot comply with all aspects of the study protocol.  
Investigational product, dosage and mode of administration:  
Subjects assigned to receive peramivir, will receive an age-appropriate single dose of 
peramivir, diluted appropriately in normal saline, administered as a short intravenous infusion 
over a minimum of 15 minutes.  
• Subjects ≥ 13 years will receive a dose of 600 mg. 
• Subjects ≥ 6 months to ≤ 12 years will receive a dose of 12mg/kg (to a maximum dose 
of 600 mg). 
• Subjects < 6 months will receive a dose of 8mg/kg. 
Reference therapy, dosage and mode of administration:  


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Subjects randomized to oral oseltamivir will receive an age appropriate dose twice daily for 
5 days. 
• Subjects ≥ 13 years will receive a 75mg dose administered as a capsule or oral 
suspension (twice daily for 5 days). 
• Subjects 28 days to < 13 years of age will receive a weight-based dose administered as 
a capsule or oral suspension (twice daily for 5 days). 
Note, as of the approval of amendment 3, no additional subjects will be randomized to receive 
oseltamivir. 
Criteria for evaluation: 
Safety: 
• Safety will be evaluated through assessments of Adverse Events (AEs), laboratory 
analyses (clinical chemistry, hematology and urinalysis), vital signs, and physical 
examinations. A review and summary of safety utilizing all collected assessments will 
be performed by a Data Safety Monitoring Committee (DSMC) after each influenza 
season as outlined in the DSMC charter.  
Pharmacokinetic: 
• Plasma peramivir concentrations will be measured by a validated liquid 
chromatography-tandem mass spectrometry (LC/MS-MS) assay. Concentrations will 
be utilized in determination of population pharmacokinetic parameters. 
Effectiveness: 
• Clinical: Time to resolution of fever; time to resolution of influenza symptoms (per 
the age appropriate symptoms); 
• Virologic: Viral shedding; virus susceptibility. 
Statistical methods: 
Sample Size: 
The study is designed to evaluate the safety and pharmacokinetics of IV administration of 
peramivir in pediatric subjects with influenza. The sample size is adequate to evaluate these 
objectives. Descriptive comparison between peramivir and oseltamivir treated subjects will be 
performed where possible. Formal hypothesis testing will not be performed. 
Safety:  
Qualitative analyses will be performed for AE type, frequency and severity, as well as vital 
sign absolute values, clinical laboratory absolute values, and physical examination findings 
and their respective changes from Baseline for all subjects. 
Pharmacokinetics:  
Plasma concentrations and covariates of interest will be evaluated in a meta-population 
analysis using mixed effect modeling techniques to estimate population pharmacokinetic 
parameters in each age group and to identify pharmacokinetically-relevant covariates. Data 
from the completed pediatric study 0918T0633 of IV peramivir in Japan will be included in 
this analysis. 
Effectiveness: 
Clinical and virologic endpoints will be summarized using descriptive statistics. 


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3. 
TABLE OF CONTENTS AND LIST OF TABLES 
 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................2 
1.1. 
Protocol Approval Signature Page ................................................................................3 
1.2. 
Clinical Study Protocol Agreement ..............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
INTRODUCTION ......................................................................................................18 
5.1. 
Influenza Overview ....................................................................................................18 
5.2. 
Antiviral therapy for influenza ...................................................................................19 
5.2.1. 
Treatment in adults .....................................................................................................20 
5.2.2. 
Treatment in children ..................................................................................................21 
5.2.3. 
Current need ................................................................................................................22 
5.3. 
Previous Experience with Peramivir ..........................................................................22 
5.3.1. 
Clinical experience in adults .......................................................................................23 
5.3.2. 
Clinical experience in children ...................................................................................25 
5.3.2.1. 
Study 0918T0633........................................................................................................26 
5.3.2.2. 
BCX1812-303 .............................................................................................................26 
5.3.2.3. 
BCX1812-301 .............................................................................................................27 
5.3.3. 
Post marketing experience in children ........................................................................27 
5.4. 
Rationale for Study .....................................................................................................29 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary objective ........................................................................................................31 
6.2. 
Secondary Objectives .................................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Endpoints ....................................................................................................................32 
7.1.1. 
Primary Endpoint ........................................................................................................32 
7.1.2. 
Secondary Endpoints ..................................................................................................32 
7.2. 
Overall Study Design and Plan ...................................................................................32 
7.3. 
Study Measurements and Visit Schedule ...................................................................33 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................36 
8.1. 
Subject Inclusion Criteria ...........................................................................................36 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
8.3. 
Withdrawal Criteria ....................................................................................................37 
9. 
TREATMENT OF SUBJECTS ..................................................................................39 
9.1. 
Study Drug Dose Rationale ........................................................................................39 
9.2. 
Treatments Administered ............................................................................................39 
9.2.1. 
Peramivir .....................................................................................................................39 
9.2.2. 
Oseltamivir .................................................................................................................40 
9.3. 
Randomization and Blinding/ Masking ......................................................................40 
9.4. 
Study Medication Preparation and Administration ....................................................40 
9.4.1. 
Peramivir .....................................................................................................................40 
9.4.2. 
Oseltamivir .................................................................................................................41 
9.5. 
Treatment Compliance ................................................................................................41 
9.6. 
Overdose and Toxicity Management ..........................................................................41 
9.7. 
Study medication accountability .................................................................................42 
9.8. 
Concomitant Medications ...........................................................................................42 
9.8.1. 
Medications for Chronic Diseases/Conditions ...........................................................42 
9.8.2. 
Antivirals ....................................................................................................................42 
9.8.3. 
Corticosteroids ............................................................................................................43 
9.8.4. 
Antipyretics and Analgesics .......................................................................................43 
9.8.5. 
Antibiotics ...................................................................................................................43 
10. 
STUDY CONDUCT ...................................................................................................44 
10.1. 
Overview .....................................................................................................................44 
10.2. 
Schedule of Assessments ............................................................................................46 
10.2.1. 
Screening Period .........................................................................................................46 
10.2.2. 
Treatment Period ........................................................................................................46 
10.2.2.1. 
Day 1/Baseline/Pre-Dose ............................................................................................46 
10.2.2.2. 
Day 1/Post-Dose .........................................................................................................47 
10.2.2.3. 
Day 3 ...........................................................................................................................48 
10.2.2.4. 
Day 7 ...........................................................................................................................49 
10.2.2.5. 
Day 14 .........................................................................................................................49 
10.2.2.6. 
Early Withdrawal ........................................................................................................50 


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10.3. 
Clinical assessments of Effectiveness ........................................................................51 
10.3.1. 
Body Temperature ......................................................................................................51 
10.3.2. 
Influenza Signs and Symptoms ..................................................................................52 
10.3.3. 
Assessment of ability to perform usual daily activities ..............................................52 
10.3.4. 
Assessment of appetite and eating patterns ................................................................52 
10.4. 
Virology Samples .......................................................................................................53 
11. 
ASSESSMENT OF SAFETY .....................................................................................54 
11.1. 
Adverse Events ...........................................................................................................54 
11.1.1. 
Definitions ..................................................................................................................54 
11.1.1.1. 
Adverse Event .............................................................................................................54 
11.1.1.2. 
Serious Adverse Event ................................................................................................55 
11.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events .............................................................................55 
11.1.3. 
Definition of Severity .................................................................................................55 
11.1.4. 
Definition of Relationship to Study Drug ...................................................................56 
11.1.5. 
Reporting Serious Adverse Events .............................................................................57 
11.1.6. 
Pregnancy ...................................................................................................................57 
11.1.7. 
Reporting DAIDS Grade 3 or 4 events .......................................................................57 
11.2. 
Clinical Laboratory Evaluations .................................................................................58 
11.2.1. 
Clinical Chemistry Profiles .........................................................................................58 
11.2.2. 
Hematology Profiles ...................................................................................................58 
11.2.3. 
Urinalysis ....................................................................................................................58 
11.2.4. 
Pregnancy Test (Urine or Serum) ...............................................................................58 
11.3. 
Vital Signs ..................................................................................................................58 
11.4. 
Physical Examination and Influenza-Related Complications Assessment .................58 
11.5. 
Safety Oversight .........................................................................................................59 
12. 
PHARMACOKINETIC ASSESSMENTS .................................................................60 
13. 
STATISTICS ..............................................................................................................61 
13.1. 
Data Collection Methods ............................................................................................61 
13.2. 
Statistical Analysis Plans ............................................................................................61 
13.3. 
Study Hypothesis ........................................................................................................61 
13.4. 
Sample Size Estimates ................................................................................................61 
13.5. 
Analysis Populations ..................................................................................................62 


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13.6. 
End of Study Analysis ................................................................................................62 
13.7. 
General Issues for Statistical Analysis .......................................................................62 
13.7.1. 
Multiple Comparisons and Multiplicity......................................................................62 
13.7.2. 
Covariates ...................................................................................................................62 
13.7.3. 
Planned Subgroups .....................................................................................................62 
13.7.4. 
Missing Data ...............................................................................................................62 
13.8. 
Effectiveness ...............................................................................................................63 
13.8.1. 
Effectiveness Endpoints ..............................................................................................63 
13.8.2. 
Effectiveness Analyses ...............................................................................................63 
13.9. 
Safety Analyses ..........................................................................................................63 
13.10. 
Exposure Response Analyses .....................................................................................64 
14. 
STUDY ADMINISTRATION ...................................................................................65 
14.1. 
Regulatory and Ethical Considerations ......................................................................65 
14.1.1. 
Regulatory Authority Approvals ................................................................................65 
14.1.2. 
Institutional Review Board Approvals .......................................................................65 
14.1.3. 
Subject Informed Consent ..........................................................................................65 
14.1.4. 
Payment to Subjects ....................................................................................................66 
14.1.5. 
Investigator Reporting Requirements .........................................................................66 
14.2. 
Study Monitoring ........................................................................................................66 
14.3. 
Quality Assurance .......................................................................................................66 
14.4. 
Study Termination and Site Closure ...........................................................................66 
14.5. 
Records Retention .......................................................................................................67 
14.6. 
Confidentiality of Information ....................................................................................67 
14.7. 
Study Publication ........................................................................................................68 
15. 
REFERENCES ...........................................................................................................69 
16. 
APPENDICES ............................................................................................................73 
 
Appendix 1:  Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events ...........................................................................................................73 
 
 


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LIST OF TABLES 
Table 1: 
Study Measurements and Visit Schedule ...................................................................34 
Table 2: 
Oseltamivir dose regimen by age ...............................................................................40 
Table 3: 
Peramivir Dilution for Children < 12 Months of Age ................................................41 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Specialist Term 
Explanation 
AAP 
American Academy of Pediatrics  
ACIP 
The Advisory Committee on Immunization Practices 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration-Time Curve 
BID 
Twice Daily 
CBC 
Complete Blood Count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Intervals  
CLCRRT 
CRRT Clearance  
CPK 
Creatine Phosphokinase  
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DSMC 
Data Safety Monitoring Committee  
EIND 
Emergency Investigational New Drug 
ESRD 
End Stage Renal Disease 
EUA 
Emergency Use Authorization 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
Hemagglutinin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 


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Abbreviation or Specialist Term 
Explanation 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRC 
Influenza Related Complications 
ITT 
Intent to Treat (Population) 
ITTI 
Intent to Treat Infected (Population) 
IV 
Intravenous 
LC/MS-MS 
Liquid Chromatography-Tandem Mass Spectrometry  
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Neuraminidase 
NAI 
Neuraminidase Inhibitor 
NP 
Nucleoprotein 
NS1 
Non-Structural Protein 1  
OSE 
Oseltamivir Phosphate  
OSE-C 
Oseltamivir Carboxylate  
PA, PB1, PB2 
Viral RNA Polymerase Complex  
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetics 
QD 
Once Daily  
RAT 
Rapid Antigen Test 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCUF 
Slow Continuous Ultrafiltration 
SD 
Standard Deviation  
TCID50 
Tissue Culture Infectious Dose 50% 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States  
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
ZNR 
Zanamivir 


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5. 
INTRODUCTION 
5.1. 
Influenza Overview 
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of 
the respiratory tract. Typical influenza illness is characterized by abrupt onset of fever, headache, 
myalgia, sore throat, and nonproductive cough (Cox and Subbarao 1999); a  significant minority 
of patients also experience gastrointestinal symptoms of nausea, vomiting, and diarrhea (Novel 
Swine-Origin Influenza, Dawood et al. 2009). Acute uncomplicated influenza is characterized 
bronchoscopically by diffuse inflammation and edema of the larynx, trachea, and bronchi; 
mucosal biopsies show lymphocytic and histiocytic inflammatory infiltrate and desquamation 
(Walsh, Dietlein et al. 1961).  
While the highest morbidity and mortality occurs in the elderly, the highest rate of infection 
occurs in children (Fiore, Timothy et al. 2012). In healthy adults and children, the illness is 
usually self-limiting, with resolution of symptoms occurring within 5 to 7 days because immune 
defenses shut down viral proliferation and shedding, clearing infected cells quickly. In acute 
uncomplicated influenza, tissue damage is limited, and secondary infections are uncommon. 
However, influenza is an important cause of morbidity and mortality in certain at-risk 
populations, and hospital admissions due to influenza-related illness place a seasonal burden on 
health care facilities. Furthermore, the symptoms of acute uncomplicated influenza are 
themselves debilitating, with return to normal health and activities delayed for 7 to 11 days 
(Treanor, Hayden et al. 2000, Kohno, Kida et al. 2010). 
The emergence in 2009 of a novel strain of influenza A (H1N1pdm09), reviewed in (Neumann, 
Noda et al. 2009), led to the first influenza pandemic since the 1960’s. The well-documented 
morbidity and mortality from the 2009 influenza pandemic, and the emergence of two avian 
influenza viruses infecting humans in recent years, A/H5N1 (Writing Committee of the Second 
World Health Organization Consultation on Clinical Aspects of Human Infection with Avian 
Influenza, Abdel-Ghafar et al. 2008) and  A/H7N9 (CDC 2013, Gao, Cao et al. 2013), serve to 
emphasize the continuing threat that influenza poses to public health as a result of emergence of 
new viral strains infecting populations with limited herd immunity to influenza in children. 
Children are subject to a high burden of influenza related disease. Despite the US Centers for 
Disease Control and Prevention (CDC’s) recommendation that all children 6 months and older 
get vaccinated against seasonal influenza, in the 2012- 2013 influenza season only 57% of 
children 6 months to 17 years received vaccination. Coverage was highest in infants and toddlers 
6 months to 23 months at 77%, but declined progressively in each subsequent age group. Only 
43% of 13-17 adolescents received vaccination (CDC 2013).  
Because testing for influenza is not uniformly performed and there are other viruses that can 
cause lower respiratory tract disease, namely respiratory syncytial virus and parainfluenza virus, 
it is difficult to know how many children are infected yearly. A population-based surveillance 
study in cohorts of children ≤ 5 years across 3 counties in the United States (US) over the 
2004-2009 influenza seasons was performed, capturing the time period when vaccine 
recommendations were expanded down to infants 6 months and older (Poehling, Edwards et al. 
2013). It was estimated that the rate of hospitalization for influenza was 0.4-1.0 per 
1000 children ≤ 5 years. Confirmed influenza infection in the outpatient setting was present in 


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8-17% of enrolled children who presented for a visit. The rate was somewhat higher in children 
seen in the emergency department (12%) than in an outpatient clinic (10%). Influenza A was the 
predominant pathogen causing 70% of influenza infections. Less than half of the infected 
children had been immunized.  
In Europe, a review of the literature from 1970 to 2011 determined that the incidence of 
influenza was 6.2% in infants ≤ 1 year and 16.7% in all children ≤ 13 years. The rate of 
hospitalization for influenza was similar to Poehling’s US estimate with varying rates among 
different European countries ranging from 1.5% (for children < 2 years), 0.7% (2-5 years), and 
0.4% (6-13 years) in Italy to 0.8% (< 3 years), 0% (3-6 years), and 0% (7-13 years) in Finland 
(Antonova, Rycroft et al. 2012). Globally, in 2008, about 90 million new cases of influenza and 
20 million episodes of influenza-associated acute lower respiratory tract infection occurred 
worldwide in children aged 0-4 years. That year, estimated deaths worldwide from influenza in 
children were 28,000 to 111,500 (Nair, Brooks et al. 2011). 
Medical resources are highly utilized by children with influenza, due to both initial visits and 
subsequent complications. Complications of influenza are common, including pharyngitis, otitis 
media and febrile seizures. While rates vary, some studies have found that almost half of all 
infections result in bacterial superinfections or seizures (Antonova, Rycroft et al. 2012). In 
addition, children miss time from school and parents lose time from work.  An estimated 1 to 
6 days of work are lost by parents caring for children ill with an influenza episode (Neuzil, 
Hohlbein et al. 2002, Heikkinen, Silvennoinen et al. 2004, Antonova, Rycroft et al. 2012). 
During pandemic years, the incidence of influenza increases and may affect children more than 
older patients. More severe illness and young adult age distribution are consistent features of 
pandemic influenza, and are linked to more severe lower respiratory tract involvement. Influenza 
viral pneumonia is more frequent in pandemics (Oseasohn, Adelson et al. 1959, Rello and Pop-
Vicas 2009) compared to seasonal epidemics, and more common in children and young adults 
compared to older patients, most likely related to lack of specific immunity to the newly 
circulating pandemic strain in those age groups. During the 2009-2010 H1N1 pandemic, 4 times 
the average number of US children died compared to the previous 5 influenza seasons, rising 
from an average 82 annually to 344 (Garg, Fry et al. 2012). 
Despite increased vaccination efforts and expanded vaccination recommendations, seasonal and 
pandemic influenza remain significant causes of morbidity and mortality in children, particularly 
in those less than 2 years of age and those with comorbidities.  
5.2. 
Antiviral therapy for influenza 
Two classes of influenza antiviral agents are currently approved in the United States: 
adamantanes and neuraminidase inhibitors (NAIs). Adamantane antivirals include amantadine, 
which is approved to treat influenza in adults and children ≥ 1 year old and rimantadine, 
approved to treat influenza in adults and children ≥ 13 year old. The neuraminidase inhibitors 
include oseltamivir, which is currently approved for adults and children ≥ 2 weeks of age and 
zanamivir, an inhaled product, which is approved for adults and children down to age 7.  


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5.2.1. 
Treatment in adults 
Adamantanes, including amantadine and rimantadine, are thought to interact with the M2 ion 
channel virus protein. Adamantanes have no activity against influenza B virus. When 
administered within 48 hours of illness onset, amantadine can reduce the severity and shorten the 
duration of acute uncomplicated influenza A illness among healthy adults. In recent years 
widespread resistance to adamantanes has been described in viruses of the H3N2 sub-type 
(Bright, Medina et al. 2005), and the influenza A (H1N1pdm09) strain also demonstrated 
adamantane resistance. This class of drugs is currently not recommended by the CDC for 
treatment of influenza (CDC 2014). 
Neuraminidase inhibitors are a newer class of drugs with activity against both influenza A and 
influenza B viruses. Approved neuraminidase inhibitors include zanamivir (ZNR), administered 
by inhalation, and oseltamivir phosphate (OSE), an oral prodrug of the active agent, oseltamivir 
carboxylate (OSE-C). Neither product is specifically approved for use in hospitalized influenza, 
although oseltamivir is used frequently in both hospitalized adults and children. Influenza 
neuraminidase is responsible for the release of new viral particles from infected cells and may 
also assist in the spreading of virus through the mucus within the respiratory tract. When 
administered within 48 hours of illness onset, neuraminidase inhibitors can reduce the severity 
and shorten the duration of acute uncomplicated influenza illness among previously healthy 
adults and children. 
There is disagreement on the degree of benefit risk provided by NAIs. A 2012 systematic 
meta-analysis (Hsu, Santesso et al. 2012) supports the conclusion that early treatment with 
neuraminidase inhibitors such as OSE is associated with reduced mortality and reduced rates of 
hospital admission. Another independent meta-analysis of 11 randomized clinical trials also 
found that oseltamivir reduced the risk of lower respiratory tract complications and the use of 
antibiotics (Hernan and Lipsitch 2011).Mortality benefits were supported by a meta-analysis of 
hospitalized patients with H1N1 pandemic influenza, although the benefit was not seen in 
children (Muthuri, Venkatesan et al. 2014).This is in contrast to 2 Cochran reviews, one 
reviewing both OSE and ZNR (Jefferson, Jones et al. 2009) and a more recent review focused on 
OSE (Jefferson, Jones et al. 2014), that found only modest efficacy as measured by time to 
alleviation of symptoms and no reduction in lower respiratory tract complications. The 2014 
review indicated that while there was modest efficacy in healthy adults and children, children 
with asthma did not benefit. There was no change in the hospital admission rate for adults and 
insufficient data in children. While OSE did appear to reduce the incidence of unverified 
pneumonia in adults, there was no decrease in the incidence for children. The review also 
asserted that there was no decrease in the common complications of influenza such as bronchitis, 
otitis media and sinusitis.  
The CDC responded (CDC 2014) by reiterating their recommendation of the use of antiviral 
treatment of patients with influenza in certain populations. 
The CDC recommendation is as follows:  
Antiviral treatment is recommended as early as possible for any patient with confirmed or 
suspected influenza who is hospitalized; has severe, complicated, or progressive illness; 
or is at higher risk for influenza complications. Persons at higher risk for influenza 
complications recommended for antiviral treatment include: children aged younger than 


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2 years; adults aged 65 years and older; persons with chronic pulmonary (including 
asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological 
(including sickle cell disease), metabolic disorders (including diabetes mellitus), or 
neurologic and neurodevelopment conditions (including disorders of the brain, spinal 
cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], 
stroke, intellectual disability [mental retardation], moderate to severe developmental 
delay, muscular dystrophy, or spinal cord injury); persons with immunosuppression, 
including that caused by medications or by human immunodeficiency virus (HIV) 
infection; women who are pregnant or postpartum (within 2 weeks after delivery); 
persons aged younger than 19 years who are receiving long-term aspirin therapy; 
American Indians/Alaska Natives; persons who are morbidly obese (i.e., body-mass 
index is equal to or greater than 40); and residents of nursing homes and other 
chronic-care facilities. 
It is apparent that the definitions of high risk in this context is empirical, and subject to further 
modifications as additional risk factors are identified in seasonal and pandemic influenza 
outbreaks. 
5.2.2. 
Treatment in children 
Adamantane antivirals, although approved for use in children ≥ 1 year old (amantadine) and 
≥ 13 year old (rimantadine) are not recommended for either treatment or prophylaxis due to 
widespread resistance and lack of activity against influenza B. Zanamivir is approved for 
treatment of influenza in children ≥ 7 years old but is not recommended in those with an 
underlying respiratory disease such as asthma because of the inhaled route of administration. 
Oseltamivir is approved for use in infants as young as 2 weeks of age for the treatment of 
influenza. 
Prior to the 2009-2010 pandemic, fewer than 1% of children with influenza were treated with 
antiviral agents. Even among children hospitalized for influenza, only 2% to 37% (Garg, Fry et 
al. 2012, Poehling, Edwards et al. 2013) received an antiviral agent. During the pandemic, 
treatment rates increased markedly and 74% of hospitalized children were treated (Garg, Fry et 
al. 2012). At the time of the pandemic, OSE was approved for children aged ≥ 1 year and ZNR 
was approved for children aged ≥ 7 years. Subsequently, in 2012, OSE received approval for use 
in infants as young as 2 weeks old (Tamiflu® package insert, 2012). It is not clear if these 
increased rates of treatment have been maintained since the pandemic. 
Recommendations regarding the use of antiviral agents were broadened after the H1N1 
pandemic. The Advisory Committee on Immunization Practices (ACIP) produced guidelines in 
2011 for the use of antiviral agents in influenza. ACIP recommended that antiviral therapy (NAIs 
but not adamantanes) be initiated as soon as possible for any patients with confirmed or 
suspected influenza with high severity, hospitalization or risk of complications. Use of antiviral 
therapy in the outpatient setting when risk factors were not present was left to clinical judgment 
as long as therapy could be initiated within 48 hours (Fiore, Fry et al. 2011). 
The most recent American Academy of Pediatrics (AAP) (Pediatrics 2008) guidelines for the 
2013-2014 influenza season are similar to and complement the ACIP’s recommendations. The 
AAP reiterates that oseltamivir remains the drug of choice, simply because zanamivir is difficult 
to administer in children. Any child hospitalized or at increased risk of complications (see 


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Section 5.3.1) should receive antiviral therapy, even if influenza is only suspected but not proven 
and even if the patients present later than 48 hours after onset of symptoms. While the AAP 
acknowledges that most patients with uncomplicated influenza do not require treatment due to 
the self-limited nature of the infection, treatment should be offered to any child who would 
benefit from a decrease in duration of the clinical symptoms (Brady, Byington et al. 2013). 
Just as with adults, the use of antiviral therapy (primarily OSE) in children has been 
demonstrated to shorten disease duration, improve complications, and reduce hospital stays.  The 
length of illness is significantly reduced by 1.25 to 1.5 days in health children with confirmed 
influenza. Complications, particularly otitis media in children less than 5 year of age, are reduced 
with NAI therapy by 44-85%. Not surprisingly, the use of antibiotics is also reduced when NAIs 
are initiated promptly (Garg, Fry et al. 2012). In children hospitalized with influenza, if OSE was 
started within 24 hours of admission, length of stay was reduced by 18%. Intensive care unit 
(ICU) stay, mortality during hospitalization and readmission within 1 week of discharge were not 
statistically significantly different in OSE-treated and untreated subjects, which indicates that 
further study is needed regarding optimal inpatient treatment of children with influenza (Coffin, 
Leckerman et al. 2011). 
5.2.3. 
Current need 
Although OSE, an oral neuraminidase inhibitor pro-drug administered twice daily for 5 days, is 
widely used for the treatment of influenza, a need still exists for an effective treatment for adult 
and pediatric influenza patients who present in the urgent care, emergency department and in the 
hospital who may not be able to tolerate an oral or inhaled product, or where compliance with a 
5-day treatment regimen is a concern. Such patients may include those who cannot comply with 
oral medications, those with poor history of compliance with oral medicines, those with 
gastrointestinal symptoms such as vomiting and diarrhea associated with influenza that could 
impair absorption of orally administered drugs, and those with gastrointestinal diseases that 
could impair drug absorption.  
5.3. 
Previous Experience with Peramivir 
BioCryst Pharmaceuticals, Inc. and its partner, Shionogi & Co., Ltd have completed a total of ten 
Phase 2 and Phase 3 clinical studies to evaluate the efficacy and safety of peramivir in the 
treatment of influenza. Seven studies exclusively or predominantly enrolled patients with acute 
uncomplicated influenza, including 1 in children. The remaining 3 studies were conducted in 
subjects who were hospitalized with influenza, 2 of which allowed children or adolescents to 
enroll. A thorough QT/QTc study of single intravenous doses of peramivir in healthy adult 
subjects (Study BCX1812-106) demonstrated that intravenous peramivir at a therapeutic dose of 
600 mg and at a supratherapeutic dose of 1200 mg was not associated with QTc prolongation or 
other repolarization abnormalities. 
During the 2009 H1N1 pandemic, before the peramivir Emergency Use Authorization (EUA) 
was issued by the US FDA, BioCryst was providing peramivir to subjects under emergency 
investigational new drug (EIND) regulations, by request from US physicians. Ultimately, 
31 patients received peramivir of which 11 were children. The youngest patient was a 3-month-
old girl who was critically ill with influenza, requiring mechanical ventilation and ultimately 
extra corporeal membrane oxygenation (ECMO). She also went into renal failure and required 


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continuous veno-venous hemofiltration. It was noted that cardiac contractility markedly 
improved with peramivir treatment and she ultimately recovered. There were 2 young children 
treated, a 5-year-old boy and an 8 year old boy, both of whom died. The 5 year old had been 
hospitalized for 16 days prior to initiation of 10 days of peramivir. He was receiving ECMO and 
was comatose with heart failure. The patient died on hospital Day 34 when medical support was 
withdrawn. The 8-year-old boy had numerous underlying medical problems including Noonan 
syndrome with congenital heart disease and pulmonary hypertension. He had a cardiac arrest at 
the time of hospitalization and was on ECMO when peramivir was initiated on hospital Day 10. 
His respiratory status improved on hospital Day 14 but due to severe cerebral ischemia, the 
family withdrew medical support and he died on hospital Day 35.  
There were 8 children aged 10-17 treated under the EIND. A 13 year old boy with a history of 
asthma died despite improvement in respiratory and hemodynamic parameters after peramivir 
treatment. A 14-year-old girl with asthma and chronic renal failure also died. The 6 other 
patients recovered although they all had respiratory failure and were on mechanical ventilation or 
ECMO, 5 were receiving vasopressor support, and 2 had renal failure. Therapeutic drug 
monitoring was completed on some of these subjects and the exposure with the 10 mg/kg daily 
dose was similar to those of adults receiving 600 mg/day (Hernandez, Adiga et al. 2011). Similar 
to the Japanese pediatric and adolescent experience, no unique safety concerns were identified in 
this series. 
During the 2009 pandemic, the US FDA also issued an Emergency Use Authorization (EUA) for 
IV peramivir to treat suspected or confirmed 2009 H1N1 influenza virus infection (Sorbello, 
Jones et al. 2012). Peramivir was provided in response to over 1300 requests, including for 
children and adolescents. While data are not available on the number of critically ill children 
treated under the EUA, FDA received adverse event reports on 28 pediatric patients < 18 years.  
In addition to clinical trial experience and emergency use experience, peramivir has been 
approved in Japan for use in children ≥ 28 days old infected with influenza with over 
1,000,000 patient exposures, which includes a large proportion of children. A pediatric post-
approval observational safety and effectiveness surveillance study was carried out in Japan 
between October 2010 and February 2012 in a routine pediatric setting and evaluated patients    
< 15 years of age. A total of 1,254 patients were evaluated at 173 institutions in Japan.  This 
study is described more fully in Section 5.3.3. 
5.3.1. 
Clinical experience in adults 
The pivotal study for the use of IV peramivir to treat subjects with acute uncomplicated 
influenza is Study 0722T0621, a Phase 2 double-blind, placebo-controlled, single dose study that 
enrolled 300 Japanese adult subjects with confirmed influenza. Both dosages of peramivir 
evaluated (single IV doses of 300 or 600 mg) significantly shortened the time to alleviation of 
influenza symptoms (duration of influenza, the primary endpoint) compared with placebo. 
Studies BCX1812-211, BCX1812-311, and BCX1812-212 provide supportive data for the use of 
single parenteral doses of peramivir to treat influenza in the outpatient setting; in these studies, 
peramivir was administered as a single dose via bilateral intramuscular (IM) injections to 
subjects with influenza. Exposure to peramivir by IM administration is bioequivalent to exposure 
from IV administration (BCX1812-111 and BCX1812-113). 


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Study BCX1812-211 was a Phase 2, randomized study that enrolled 344 subjects with acute, 
uncomplicated influenza who received placebo, 150 mg peramivir or 300 mg peramivir as a 
single, divided IM dose. Study BCX1812-311 was similar in design and was planned as a 
Phase 3 study, but was terminated early after 82 subjects had enrolled and were randomized 2:1 
to receive placebo or 300 mg peramivir in a single, divided IM dose. The study was terminated 
in order to study higher doses using a product with a higher concentration in subsequent studies. 
These 2 studies had almost identical eligibility criteria, had identical primary and secondary 
efficacy endpoints, and were conducted in successive influenza seasons. When the results from 
studies BCX1812-211 and BCX1812-311 were retrospectively combined in a post-hoc analysis, 
both primary and secondary endpoints for peramivir-treated subjects were improved compared to 
placebo.  
Study BCX1812-212 was a placebo-controlled study of 405 subjects who were randomized 1:1 
to receive either placebo or 600 mg of peramivir as a single divided IM dose. This study was 
conducted during a season in which the dominant circulating strain of influenza A showed 
reduced susceptibility to peramivir, and the results showed a non-significant trend favoring 
peramivir in the primary endpoint of time to alleviation of symptoms. 
Two additional outpatient studies in adults occurred. Study 0815T0631 was a double-blind, 
double-dummy study of 1099 subjects from Japan, Taiwan and South Korea who were 
randomized to receive a single dose of IV peramivir (300 mg or 600 mg) or 5 days of oral OSE 
BID. For the primary endpoint of time to alleviation of symptoms, both peramivir treatment 
regimens were non-inferior to OSE. Study 0816T0632 was a double-blind, non-controlled study 
in high-risk patients with influenza; in this study, the duration of influenza illness was shorter 
among subjects who received 600 mg doses of peramivir compared with those in the 300 mg 
treatment group, although the 90% confidence intervals (CI) overlapped.  
Hospitalized influenza was studied in BCX1812-201, a randomized, double-blind, trial of 
treatment with OSE 75 mg twice daily for 5 days, or IV peramivir 200 mg once daily, or 400 mg 
once daily. The study enrolled 122 evaluable subjects and employed an exploratory primary 
endpoint of “time to clinical stability.” Compared to oral OSE given for 5 days, IV doses of 
peramivir 200 mg and 400 mg had similar effects on the novel exploratory endpoint. Among the 
secondary endpoints, the median time to resumption of ability to perform usual activities was 
approximately 4 days shorter for subjects treated with either dose of peramivir compared with 
OSE. Viral titers decreased rapidly among patients with influenza A after treatment with either 
OSE 75 mg twice daily or peramivir 200 mg or 400 mg daily. Among subjects with influenza B, 
numerical trends suggest more rapid reduction in viral titer with peramivir than OSE and greater 
activity of peramivir 400 mg than peramivir 200 mg.  
During the 2009-2010 pandemic, BCX1812-303, an open-label Phase 3 study of peramivir 
300 mg BID or 600 mg once daily (QD) enrolled 230 evaluable adult and 4 evaluable adolescent 
hospitalized subjects with confirmed or suspected influenza infection. The primary endpoint was 
the reduction in influenza virus titer measured by log1050% tissue culture infective 
dose (TCID50). There were no differences in either the mean or median values in the 300 mg BID 
or 600 mg QD treatment groups. By 48 hours after the beginning of peramivir treatment, 86% of 
all subjects with positive baseline titers in the intent to treat infected (ITTI)population had a 
negative virus titer (80% in the 300 mg BID group and 91% in the 600 mg QD group, as 
measured by log10 TCID50. 


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BCX1812-301, a Phase 3, multicenter, randomized, double-blind, controlled-study of peramivir 
evaluated the efficacy and safety of peramivir administered IV in addition to standard of care 
compared to standard of care alone in subjects who were hospitalized due to influenza. The study 
failed to demonstrate a significant difference between treatment with placebo and standard of 
care and treatment with peramivir (600 mg IV, daily for 5 or 10 days) and standard of care for 
the primary endpoint of time to clinical resolution. A futility analysis was performed, and the 
study was terminated early at which point 338 evaluable (i.e. ITTI) subjects were enrolled (116 
randomized to placebo and 222 randomized to peramivir).  
Safety of various doses of peramivir in acute uncomplicated influenza has been evaluated in 
1453 adults. The most frequently observed treatment emergent AEs (TEAEs) across all adult 
subjects with acute uncomplicated influenza treated with various doses of peramivir were 
diarrhea (7.4%), decreased neutrophil count (5.5%), and increased blood glucose (5.0%).  The 
only events reported in ≥ 2% of subjects treated with peramivir 600 mg and for which the rate 
was greater than placebo were diarrhea (7.6% vs. placebo 7.0%), decreased neutrophil count 
(5.7% vs. placebo 0.0%), hyperglycemia (5.3% vs. placebo 4.8%) and urine leukocytes (2.8% vs. 
placebo 1.8%). Adverse event rates overall were similar to placebo and OSE. No safety signals 
have emerged from these trials.  
The safety of various doses of peramivir in hospitalized influenza has been evaluated in 
355 adults in studies with active or placebo control (BCX1812-201 and 301) and 230 adults in an 
open label study with 2 different peramivir dosing regimens (BCX1812-303). The hospitalized 
population was comprised of acutely ill subject; many critically ill infected with both pandemic 
and seasonal influenza strains. Overall, peramivir had a favorable safety profile. In controlled 
trials, the most common adverse events in patients receiving various doses of peramivir with and 
without other NAIs were diarrhea (6.8%), nausea (4.8%), and insomnia (3.9%).The only events 
reported in ≥ 2% of subjects treated with peramivir 600 mg monotherapy (no additional NAI) 
and for which the rate was greater than placebo were constipation (4.0% vs. placebo 2.0%), 
elevated creatine phosphokinase (CPK) (4.0% vs. placebo 0%), insomnia (3.0% vs. 0%), 
aspartate aminotransferase (AST) increase  (3.0% vs. placebo 2.0%), hypertension (2.0 vs. 
placebo 0%) and hypokalemia (1.0% vs. placebo 0%). 
In the open label trial, subjects in both arms receive a total daily dose of 600 mg peramivir (or 
equivalent in those subjects with renal function adjusted dosing). This trial ran from 
October 2009 to October 2010 and enrolled primarily subjects infected with pandemic H1N1 
virus (74% of the ITTI population). A total of 10% of all subjects in the Safety population died. 
Nearly half of all deaths were related to respiratory failure reflecting the severity of the 
pandemic. Most adverse events were attributable to the underlying infection and comorbidities 
and no clinically relevant differences in safety outcomes were noted between the two dosing 
regimens. The most common adverse events were constipation (13.0%), diarrhea (12.6%), 
hypokalemia (9.6%), anemia (7.8%), hypotension (7.8%), nausea (7.8%), peripheral edema 
(7.8%), insomnia (7.4%) hyperglycemia (6.1%) hypertension (6.1%) and headache (5.2%). 
5.3.2. 
Clinical experience in children 
There have been 3 clinical trials that enrolled children. Study 0918T0633 was an open label 
study in acute uncomplicated influenza. In addition, there were 2 studies in hospitalized 
influenza that enrolled children, BCX1812-303 and BCX1812-301. 


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5.3.2.1. 
Study 0918T0633 
Study 0918T0633 was a Japanese non-controlled, open-label study conducted in pediatric 
subjects with influenza (either inpatient or outpatient) that ran from September 2009 to 
December 2009. A total of 117 subjects, aged ≥ 28 days to < 16 years, were enrolled of which 
the ITTI analysis set was 112. The study excluded children with significant comorbidities such 
as encephalopathy, epilepsy, chronic respiratory disorders, congestive heart failure, 
immunosuppression and renal failure. Subjects were treated with peramivir 10 mg/kg (maximum 
dose 600 mg) IV for up to 5 days. This dose was believed to provide children with an adult 
equivalent of 300 to 600 mg peramivir a day. Two subjects received 2 doses, and the rest 
received a single infusion. The primary endpoint was the median time to alleviation of influenza 
defined as mild to no cough or nasal discharge and normal body temperature. Overall the median 
time was 27.9 hours (95% CI 21.7-31.7) with no differences noted between the age groups of 
28 days to < 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to < 16 years of age. Normal 
temperature of < 37.5°C was recovered in a median time of 20.4 hours (95% CI 19.1-20.9). If all 
influenza symptoms, including cough, sore throat, headache, nasal discharge, fever, 
myalgia/arthralgia and fatigue were taken into consideration, the median time to alleviation of 
symptoms was 30.5 hours (95% CI 22.6-45.8) with sore throat taking the longest to resolve. The 
median time to resuming activities of daily living (ADLs) was 103.0 hours (95% CI 94.9 
hours- 119.6 hours) and ranged from 54.7 hours to 126.8 hours in the consecutive age brackets. 
Adverse events were experienced by 62.4% of subjects. In the various age brackets (28 days to 
< 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to < 16 years of age) the incidence for AEs 
ranged from 54.1 to 75% and tended to be higher for patients under 12 years. No deaths occurred 
but 2 subjects experienced serious adverse events (SAEs): influenzal pneumonia in one and 
pneumonia and encephalopathy in the other. Both children recovered. Most AEs were mild to 
moderate (79.5%). Overall, the most frequent TEAEs were decreased neutrophil count (21.4%), 
diarrhea (16.2%), vomiting (9.4%), and increased eosinophil count (7.7%). Of note, there were 
3 subjects (2.6%) who experienced abnormal behavior.  
5.3.2.2. 
BCX1812-303 
BCX1812-303 was initiated in October 2009 at the request of the FDA due to the 2009 H1N1 
pandemic. Originally allowing children ≥ 12 year old to enroll, by December 2009 the protocol 
was amended to allow children as young as 6 to enroll and receive 10 mg/kg day either in a 
single or divided dose. Although at the time there was no clinical data on treating children with 
peramivir, the juvenile animal toxicology studies and the experience with the EIND in which 
11 children, one as young as 3 months old, received peramivir indicated that peramivir was 
generally safe and well tolerated in children. Four adolescents were enrolled; all aged 
14-16 years of age. Only 1 subject, a 14-year-old American Indian/Alaskan native girl, was 
positive for influenza (2009 H1N1 strain) and she was randomized to 5 mg/kg (195 mg) twice a 
day for 5 days. Her time to clinical resolution was 28.8 hours (study mean was 92 hours) and her 
time-weighted changes from Baseline in log10 TCID50 at 48 hours was similar to the overall 
mean and median (-1.51). Her only AEs occurred at follow-up when she developed a mild upper 
lip lesion on study Day 11 and a mild decrease in body temperature on study Day 13. Both 
events were assessed as unlikely related to peramivir and both events resolved.  


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Three subjects were found to be negative for influenza. A 16-year-old Asian girl received 5 days 
of peramivir 5 mg/kg (300 mg) bid and experienced no AEs. A 15-year-old Hispanic boy 
received 5 days of 10 mg/kg (600 mg) daily and had no AEs. A 14-year-old white girl had septic 
shock at baseline and required vasopressor support. She received 5 mg/kg (260 mg) BID for 
2 days. Once her influenza results were noted to be negative, her parents withdrew consent and 
she discontinued the study. Her only AE was moderate sedation assessed as unlikely related to 
peramivir but due to the use of sedative drugs.  
5.3.2.3. 
BCX1812-301 
BCX1812-301 was initiated in November 2009 as a randomized, double-blind, controlled study 
to evaluate the efficacy and safety of peramivir administered intravenously in addition to 
standard of care compared to standard of care alone in subjects who are hospitalized due to 
influenza. Originally allowing children ≥ 12 year old to enroll, by August 2010 the protocol was 
amended to allow children as young as 6 to be randomized to placebo or 10 mg/kg/day of 
peramivir for those ≥ 12 to < 18 years and 12 mg/kg/day for those ≥ 6 to < 12 years. Overall 
there were 4 children 6-11 years old and 11 adolescents 12-17 years old who enrolled. Of these 
children, 9 were randomized to peramivir (2 children and 7 adolescents). One of these subjects 
withdrew consent prior to receiving any peramivir and 1 withdrew consent on study Day 2 at the 
time of hospital discharge.  Of the 8 subjects who received peramivir, all were influenza positive: 
5 tested positive for H2N2 and 3 had the 2009 H1N1 strain. All received OSE from the time of 
hospital admission as a part of the standard of care, except for 1 subject, a 14 year old boy with a 
history of asthma and epilepsy who received peramivir monotherapy for the first 5 days but did 
not meet the protocol defined criteria for clinical resolution. He received another 5 days of 
peramivir and also initiated OSE BID for 5 days on study Day 5.  
The overall time to clinical resolution in the pediatric population treated with peramivir 
10 mg/kg/day was a mean of 39.6 hours (range 7.9 to 85.2 hours) and time to alleviation of 
clinical symptoms of influenza was a mean of 81.5 hours (range 38.0 to 121.8). Time to hospital 
discharge, a tertiary endpoint, was a mean of 4.5 days (range 2.0-10.0 days). Although the study 
did not meet its overall primary endpoint and was terminated after a futility analysis, these means 
compare favorably to the overall results of 53.9 hours mean time to clinical resolution, 
81.3 hours mean time to alleviation of clinical symptoms and 5.3 days mean time to hospital 
discharge.  
Only 2 of the pediatric subjects experienced AEs. A 17 year old boy developed mild phlebitis on 
study Day 3 that was assessed by the Investigator as possibly related. He recovered in 1 day 
without sequelae. The other subject was a 16 year old boy who developed mild nausea and mild 
gastritis on study Day 6. The nausea resolved the same day and the gastritis resolved on study 
Day 12. He also experienced cystitis on study Days 10-14 and laryngitis on study Days 10 to 28. 
None of the events were assessed as related to peramivir and all the events resolved.  
5.3.3. 
Post marketing experience in children 
Peramivir hydrate for injection was first approved in Japan on 13 January 2010 under the trade 
name Rapiacta® by Shionogi & Co., Ltd. for the treatment of viral infection with influenza type 
A and type B. Marketing authorization for the treatment of children and infants ≥ 28 days of age 
was obtained in Japan in October, 2010. Since that time 3 post marketing surveillance studies 


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have been performed, including one exclusively enrolling pediatric patients. The other 2 studies 
(one in routine use and one in high risk patients) allowed enrollment of subjects ≥ 15 years old 
and any age child respectively.   
The pediatric post-approval observational safety and effectiveness surveillance study was carried 
out between October 2010 and February 2012 in a routine pediatric setting and evaluated patients 
< 15 years of age. A total of 1,254 patients were evaluated at 173 institutions in Japan. The 
safety evaluable population was 1,199 and the efficacy evaluable population was 1186. Most 
patients (79.4%) had type A influenza and 13.2% of the patients were considered high risk. 
There were 654 (54.5%) male and 545 (45.5%) female patients in the safety evaluable group. 
Fifty-four patients (4.5%) were < 1 year of age, including 1 patient who was < 4 weeks of age. 
Forty-four percent of the patients (527) were ≥ 1 to < 7 years of age, and 51.4% (616 patients) 
were ≥ 7 to < 15 years of age. A special safety analysis compared patients < 2 years of age and 
those ≥ 2 years of age, and found that there were no significant differences in the incidence of 
AEs or the types of AEs in infants and toddlers versus older children. 
Almost all patients (1008, 84.1%) received peramivir within 1 day of the start of influenza 
symptoms. Most patients were treated in an outpatient setting, but 138 (11.5%) were hospitalized 
for influenza, and 11 patients had serious influenza, defined as either influenza encephalopathy 
or the need for mechanical ventilation. Almost all patients (96.7%) received only 1 day of 
treatment with peramivir.   
A total of 92 patients experienced 115 AEs deemed related to peramivir by the prescribing 
physicians. There were no fatal AEs reported. Fourteen of the AEs were serious including 
5 SAEs of abnormal behavior, 5 SAEs of neutropenia (2 severe), and individual SAEs of loss of 
consciousness, erythema multiforme, rash, and peripheral edema. The events of erythema 
multiforme occurred in a child with ocular pruritus prior to peramivir treatment. After treatment 
with peramivir, a rash developed on his face, neck, hands, and buttocks. He was treated with an 
anti-allergy medication but symptoms worsened 2 days after receiving peramivir, and the patient 
was diagnosed with exudative erythema multiforme. The event resolved with topical steroids and 
anti-allergy medication in 4 days. 
Most of the AEs (87.0%) occurred within 3 days after the start of treatment with peramivir. 
Almost all AEs recovered or improved (93.9%), the rest had unknown outcomes. The AE 
durations were brief, with 80.9% resolving or improving within 3 days of onset. The most 
common AEs were diarrhea (2.5%), abnormal behavior (2.3%), vomiting (0.7%), and nausea 
(0.7%). Over half of the events of abnormal behavior occurred in children with either high risk 
factors or complication of influenza such as seizures or bacterial infections. There were no 
noticeable differences in AE incidence between the various pediatric age ranges. The sole 
enrolled newborn (< 4 weeks of age) did not experience any AEs. Patients aged ≥ 4 weeks to 
< 1 year had a 9.4% incidence of AEs; those ≥ 1 to < 7 years of age had a 7.2% incidence of 
AEs; and children ≥ 7 to < 15 years of age had an 8.0% incidence of AEs.  
The reported adverse events were similar to events seen during development. There was a lower 
incidence of adverse events and no individual events were reported at an incidence greater than 
that during development. No new safety signals were found as a result of this post-approval 
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Effectiveness was assessed by time to alleviation of symptoms, which represented the day when 
all 7 symptoms of influenza (cough, sore throat, headache, nasal congestion, fever, achiness, and 
fatigue) were reported as none or mild. The median time to alleviation of symptoms was 3 days. 
The median time to resolution of fever was also 3 days. Since the assessment of symptoms and 
temperature was done only once daily, the actual time to resolution may have been less than 
reported.  
In the routine use post-approval observational safety and effectiveness surveillance study, the 
safety set included 69 children < 15 years old. The AE incidence was 7.3% compared to the adult 
population’s rate of 4.1%, However, there were only 6 AEs reports in total; diarrhea (3 events), 
vomiting, insomnia, and urticaria. The median time to alleviation of symptoms (same definition 
as used in the pediatric post-approval study) was 3 days and the median time to resolution of 
fever was 2 days. Overall, the adverse events and effectiveness measure was similar to previous 
investigations. There were no new safety signals found as a result of this post-approval study of 
routine peramivir use.  
In the high risk post-approval observational safety and effectiveness surveillance study there 
were 181 children < 15 years old evaluated of which 26 were < 2 years old. All the children had 
high-risk co-morbidities. Overall, the incidence of AEs was 7.2% in children < 15 years old. The 
median time to alleviation of symptoms was 3.0 days and the median time to resolution of fever 
was also 3.0 days. Patients ≥ 15 to < 65 years old had an AE incidence of 15.2% and those 
≥ 65 years old had an incidence of 14.0%. The pediatric effectiveness measures were identical to 
both the adult (15 to < 65 years old) and elderly (≥ 65 years old) populations.  
Children < 2 years of age had additional analyses. The only AE in a child < 2 years of age was a 
SAE of neutropenia occurring in a low-birth weight infant with a history of neonatal asphyxia 
and intracranial hemorrhage with resultant hydrocephalus who developed a neutrophil count of 
636/μL 3 days after receiving peramivir. The event resolved 2 months later without treatment. 
The median time to alleviation of symptoms was 3.5 days and the median time to resolution of 
fever was 2.0 days in this subgroup of children < 2 years of age. Overall, the adverse events and 
effectiveness outcomes were similar to previous investigations, despite this being a high risk 
population. There were no new safety signals found as a result of this post-approval study of 
peramivir use in high-risk patients. 
5.4. 
Rationale for Study 
There remains a significant unmet need for influenza therapies in children. Currently, the only 
available options are oral or inhalation, both of which have limitations, both in terms of 
administration and viral resistance. Peramivir has demonstrated efficacy and safety when used in 
acute uncomplicated influenza in adults. However, there is significant clinical and real world 
experience with pediatric use indicating that there is both efficacy and safety when used in 
healthy and high-risk children as young as 28 days. Most children treated to date have been 
Asian, so the current study will provide valuable information in other racial and ethnic groups.  
Because children bear a larger burden of infection during seasonal influenza and are at greater 
risk for complications during pandemics, new treatments for children are needed. During the last 
pandemic of 2009-2010, the rates of hospitalization, admission to intensive care units, and 
invasive life support were higher than for past seasonal influenza with the highest proportion of 
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Jain, Kamimoto et al. 2009, WHO 2009). The approved dose of peramivir in adults is a single 
dose of 600 mg because of improved efficacy without an increase in safety risk. Population 
pharmacokinetic modeling performed by the FDA (July 2009) based on the Shionogi Studies 
0816T0633 (children and adolescents) and 0722T0621 (adults) supports a target dose of 
12 mg/kg/day in children (6 to 12 years) to attain exposures similar to that in adults who receive 
a 600 mg IV dose.  
In order to provide recommendations for dosing in subjects less than 6 months of age, an updated 
population PK model was developed that included all available data from adult and pediatric 
studies, and data from an interim review of BCX1812-305.  Simulations from this model indicate 
that a dose of 8 mg/kg/day in children from birth to < 6 months of age should provide exposure 
of peramivir similar to that observed in adult subjects and pediatric subjects who have completed 
BCX1812-305. In subjects 6 month of age and older, a 12 mg/kg dose is simulated to attain 
exposures in pediatric subjects similar to that in adults administered a 600 mg IV dose.   
Simulations indicate that in subjects < 6 months of age, the predicted exposure following an 8 
mg/kg dose will not exceed that of adults.    
There is ample clinical and real world experience with peramivir. A large number of children 
have been treated in post-marketing without new safety signals arising, other than those already 
identified with other NAIs. Events of abnormal behavior have been reported occurring primarily 
in children and the elderly, often in those with underlying neurologic conditions. In addition, 
very rare hypersensitivity reactions including, anaphylaxis, erythema multiforme and Stevens-
Johnson Syndrome have occurred in the post-marketing setting, although as with all NAIs, it is 
difficult to know if this is due to concomitant medications, the viral infection, or the NAI. Many 
studies have reported benefits of NAIs in shortening complications, hospital stays and antibiotic 
use. Overall it is expected that the benefit risk ratio of peramivir will be favorable in children.  


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective 
• To evaluate the safety of IV peramivir compared to oral oseltamivir in pediatric 
subjects with acute uncomplicated influenza (here within referred to as influenza) 
6.2. 
Secondary Objectives 
• To describe the pharmacokinetics of IV peramivir in pediatric subjects with influenza 
• To evaluate the effectiveness of IV peramivir compared to oral oseltamivir in 
pediatric subjects with influenza 
• To evaluate the incidence of influenza complications, specifically otitis media, 
sinusitis, bronchitis or pneumonia requiring antibiotic use diagnosed after initiation of 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Endpoints 
7.1.1. 
Primary Endpoint 
The primary endpoints of this study will be assessment of adverse events, laboratory analyses 
(clinical chemistry, hematology and urinalysis), vital signs and physical examinations. 
7.1.2. 
Secondary Endpoints 
• Pharmacokinetic analyses. 
• Change (reduction) in influenza virus titer by log10 tissue culture infective dose50/mL 
(TCID50/mL) and by reverse transcriptase polymerase chain reaction (RT-PCR). 
• Time to alleviation of clinical symptoms of influenza (per age appropriate 
symptoms). 
• Time to resolution of fever. 
• Incidence of influenza-related complications. 
• Change in viral sensitivity to the following antiviral drugs: peramivir, oseltamivir, 
zanamivir. 
7.2. 
Overall Study Design and Plan 
This is a multi-center, open label active-controlled study to evaluate the safety, pharmacokinetics 
and effectiveness of IV peramivir in children. 
Up to 140 subjects will be enrolled in this study according to the following age groups: 
• Birth to < 28 days: up to 10 subjects will receive IV peramivir  
• 28 days - < 2 years: up to 20 subjects: subjects enrolled after the approval of amendment 
3 will receive IV peramivir  
• 2 – <4 years: up to 10 subjects: subjects enrolled after the approval of amendment 3 will 
receive IV peramivir 
• 4 - < 7 years:up to 30 subjects: subjects enrolled after the approval of amendment 3 will 
receive IV peramivir 
• 7 - < 13 years:up to 40 subjects, randomized 4:1 to IV peramivir or oral oseltamivir 
• 13 - < 18 years:up to 30 subjects, randomized 4:1 to IV peramivir or oral oseltamivir  
Once an age cohort is filled, enrollment in that cohort will be closed and communicated with all 
investigators.  
A subject’s duration of participation in this study is expected to be 14 days.   
All subjects will receive either a single dose of IV peramivir (600 mg IV for subjects ≥ 13 years, 
12 mg/kg IV for subjects ≥ 6 months - ≤ 12 years, 8 mg/kg for subjects < 6 months IV) or oral 
oseltamivir, dosed BID for 5 days. 


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 Note, as of the date of amendment 3, no additional subjects will be randomized to receive 
oseltamivir. 
Subjects will undergo follow-up assessments on Days 3, 7, and 14. The Day 3 visit may be a 
home visit (performed by a qualified study nurse). Day 7 is required to take place in the clinic, 
and Day 14 may either be a clinic visit, home visit, or follow-up phone call to the 
subject/parent/guardian.  
7.3. 
Study Measurements and Visit Schedule 
The schedule of assessments for this study is presented in Table 1. 


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Table 1: 
Study Measurements and Visit Schedule 
Assessments 
Screening1 
Baseline1 
Pre-Dose 
Day 11 
Post-Dose 
Day 32 
 
Day 7 
(+ 2 days) 
 
 
Day 142 
(+3 days) 
Early 
Withdrawal3 
Informed Consent/Assent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Pregnancy Test (Urine)4 
X 
 
 
 
X 
 
X 
Medical History 
X 
 
 
 
 
 
 
Body Temperature5 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
Influenza Related Complications (IRC)6 
 
X 
 
X 
X 
X 
X 
Vital Signs7 
 
X 
 
X 
X 
X 
X 
Concomitant Medications Review8 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistries and Hematology9 
 
X 
 
 
X 
X17 
X17 
Urinalysis9 
 
X 
 
 
X 
X17 
X17 
Assessment of influenza symptoms/ activities of 
daily living/ eating habits10 
 
X 
X 
X 
X 
X 
X 
Subject Diary Completion/ Review11 
 
X 
X 
X 
X 
X 
X 
Nasal swabs for Virology Analysis12 
 
X 
 
X 
X 
X 
X 
Study Drug Administration13 
 
X 
 
 
 
 
 
Serum sample for influenza antibody analysis14 
 
X 
 
 
X 
 
 
Pharmacokinetic (PK) Sampling15 
 
 
X 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X16 
X16 
1 
It is expected that the date of Screening, Baseline, and Day 1 (date of study drug administration) will be the same. 
2 
The Day 3 visit may be performed as a clinic visit or home visit (conducted by a qualified study nurse). The Day 14 visit may be performed as a home visit, clinic visit, or phone call. In the event 
the Day 14 assessment is a phone call the parent/ caregiver will be requested to mail the completed diary card back to the site. 
3 
An Early Withdrawal assessment should be conducted for subjects who withdraw before Day 7. For subjects who withdraw between Day 7 and Day 14 a telephone assessment should be completed, 
where possible. 
4 
Urine pregnancy test will be performed for any female post-menarche. 


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5 
The screening temperature may be performed per the site’s standard method, which will be recorded. For subsequent visits, the parent/guardian will record oral or axillary temperature with the 
electronic thermometer provided by BioCryst, Thereafter, the parent/caregiver will record temperature in the Subject Diary approximately every 12 hours until temperature is normal for 48 hours 
without antipyretic. 
6 
If an IRC is suspected, then a targeted physical examination and if needed, diagnostic testing will be conducted to record the actual presence/absence of the IRC. 
7 
Vital sign measures will include blood pressure (in children <2 only if clinically indicated), pulse rate, and respiration rate. Vital signs will be recorded at Baseline, and vital signs will be taken once 
on remaining study visit days. 
8 
Antipyretic medications will be recorded in the Subject Diary by the parent/caregiver daily from Day 1 through Day 14. 
9 
Clinical laboratory assessments performed at Baseline are for the purpose of establishing a baseline. Subjects may be enrolled and begin treatment with study drug prior to receiving results. 
10 The severity of age appropriate influenza signs and symptoms will be recorded by the parent/caregiver in the Subject Diary twice daily, until all symptoms are resolved (Grade 0). Assessments of 
activities of daily living and eating habits will be recorded once daily until all symptoms are resolved. 
11 On Day 1, the parents/caregivers of subjects and/or adolescent subjects are to be provided training by the study staff on completing the Subject Diary. Instructions will be reviewed with the 
adolescent subject or parent/caregiver at each study visit.  
12 Swabs for virology analysis will be collected on Day 14 where possible. 
13 Only for those subjects randomized to peramivir. The parents/caregivers of subjects randomized to the oral oseltamivir arm of the study, will record the date and time of each drug administration, 
from Day 1 until Day 5 (or last scheduled dose).  The first dosing will be administered at the site and documented by the study staff following completion of required predose activities.    
14 A single serum specimen will be collected, where possible, pre-dose on Day 1 and on Day 7 for analysis of influenza antibody titers. Subjects whose weight is < 10kg do not require a serum 
antibody sample. 
15 Only for those subjects randomized to peramivir. A PK sample will be drawn immediately following the end of study drug infusion/administration, between 30 minutes to 1 hour post-infusion, 
between 1 and 3 hours post-infusion, and between 3 and 6 hours post-infusion. Note: Subjects ≥ 5 kg will have four 1.0 mL blood draws at the above stated sampling times. Subjects < 5 kg will 
have two 1.0 mL blood samples; one time immediately following completion of the infusion and one time between 1-3 hours post-infusion. 
16 Any subject with unresolved moderate or severe intensity influenza symptoms or an unresolved AE and/or treatment-emergent laboratory finding that requires further medical management may be 
evaluated in further follow-up visits, at the Investigator’s discretion. 
17   If previous lab results are abnormal and considered clinically significant by the Investigator or significantly changed from baseline, blood specimen collection for clinical chemistry or clinical 
hematology tests as specified in Sections 11.2.1 and 11.2.2 may be drawn. If previous urinalysis lab results are abnormal and considered clinically significant by the Investigator or significantly 
changed from baseline, a urine collection for urinalysis may be completed. 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Male and non-pregnant female subjects age birth to 17 years of age. 
2. Clinical signs and symptoms consistent with acute influenza infection consisting of an 
oral temperature ≥ 100°F (37.8°C) or rectal temperature ≥ 101.3ºF (≥ 38.5ºC) with at 
least one respiratory symptom (cough or rhinitis) OR a positive influenza rapid antigen 
test.  Fever will either be documented at the time of screening or must be reported by the 
parent or care-giver if treatment with an antipyretic was given within 6 hours of the 
screening assessment. Note: enrollment at each site by clinical symptoms alone will 
be approved by the Sponsor at the beginning of each influenza season once influenza 
has been confirmed in the local community. The Sponsor may withdraw approval 
for symptomatic screening in any season based upon trends in influenza surveillance 
data. Prior to sponsor approval or after approval is withdrawn, criteria 2 must be 
met by a positive influenza RAT test. During the period of approval, clinical 
symptoms alone will be adequate to meet criteria 2. 
3. Onset of symptoms no more than 72 hours before presentation for screening for subjects 
< 2 years old . 
4. Written informed consent by parents/guardians and assent by subjects ≥ 7 years of age1,2 
5. Females who have started their menses must either be: 
• Sexually abstinent 
• Using a highly effective form of birth control such as hormone contraception (oral, 
patch, injection, implant or vaginal ring) or 2 barrier methods (condom with 
spermicide and diaphragm) 
8.2. 
Subject Exclusion Criteria 
1. Age > 17 years. 
2. If less than 3 months of age at screening, history of premature birth (< 36 weeks 0 days 
gestation) 
3. Weight less than 3.0 kg  
4. Receipt of a live attenuated influenza vaccine (LAIV) within 14 days of presentation. 
5. Females who are pregnant (positive urine or serum pregnancy test) or breast-feeding at 
screening. 
                                                 
1 Where permitted by local IRB or state requirements.  
2  If age of assent is limited by local IRB or state requirements, assent must be obtained by all adolescents ≥ 14 years 
of age. While development varies across individual children, existing data suggest most children are capable of 
assent by approximately age 14. Wendler, D. S. (2006). "Assent in paediatric research: theoretical and practical 
considerations." J Med Ethics 32(4): 229-234.  


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6. Onset of symptoms more than 72 hours before presentation for screening for subjects < 2 
years old. 
7. Development of influenza while hospitalized for another indication. 
8. Subjects with identified risk factors for influenza complications but with uncomplicated 
influenza at the time of enrollment are not excluded.  This includes lung disease, heart 
disease, blood disorders such as sickle cell anemia, metabolic disorders and neurologic 
disease. In addition, mild to moderate immunocompromised status such as due to renal 
disease, diabetes mellitus or HIV infection with a last known CD4+ count ≥200 cells/µl 
are not excluded 
9. Presence of severe immunocompromised status due to chronic disease or illness, previous 
organ transplant, or use of immunosuppressive medical therapy which would include oral 
or systemic treatment with > 10 mg prednisone or equivalent on a daily basis within 30 
days of screening.  
10. Complicated influenza characterized by any of the following: 
a. ICU care 
b. Evidence of organ dysfunction 
c. Proven or suspected concomitant bacterial infection 
d. Other known concomitant viral infection that is likely to complicate medical course 
such as RSV, parainfluenza virus and adenovirus. Co-infection with rhinovirus and 
enterovirus is allowed.  
As a note, hospitalization is not an exclusion criterion when it is the usual practice of the 
treating institution to hospitalize children with influenza. However, the subject must have 
acute uncomplicated influenza.  
11. Previous participation in Study BCX1812-305 or participation in a study of any 
investigational drug or device within the last 30 days. 
12. Subjects who cannot comply with all aspects of the study protocol.  
8.3. 
Withdrawal Criteria 
Participation in the study is strictly voluntary. Parents/guardians have the right to withdraw their 
children from the study at any time and for any reason. A subject’s participation will be 
terminated: 
• At their parent’s/guardian’s request; 
• At the subject’s request if ≥ 7 years old and able to give assent; in cases where a 
subject is < 7 years of age and expresses a wish to stop the study, the parent/caregiver and 
the Investigator will use their best judgments to determine what is in the best interest for 
the child in question; 
• If, in the Investigator’s or Sponsor’s opinion, continuation in the study would be 
detrimental to the subject’s well-being; 
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• If the Sponsor terminates the study; 
• If a regulatory authority requires that all study activities be halted. 
In all cases, the reason for withdrawal must be recorded in the subject’s medical records (source 
documents). If the reason for subject withdrawal is not known, the subject must be followed to 
establish whether the reason was an AE, and if so, this must be reported in accordance with the 
procedures outlined in Section 11.1.2. Vigorous attempts should be made for follow-up of all 
subjects who miss a study visit. In general, although study drug may be stopped, subjects will be 
encouraged to complete the scheduled procedures. The subject will require an Early Withdrawal 
Visit if withdrawn from the study prior to scheduled study completion. If a subject’s 
participation in this study is terminated, the responsible Investigator at the site will complete a 
termination form. 
To the extent possible, all scheduled end-of-study assessments (including the Early Withdrawal 
Visit) should be performed on all participating subjects who withdraw from the study before the 
Day 7 Visit. For subjects who withdraw between Day 7 and Day 14, a telephone assessment 
should be conducted, where possible. 
Subjects withdrawn from the study at any time other than during the screening period will not be 
replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose Rationale 
In Study 0816T0633 conducted by Shionogi & Co. Ltd in Japan, 117 pediatric and adolescent 
patients with type A or type B influenza infection who were ≥ 28 days but < 16 years of age, 
were treated with 1 to 5 daily doses of IV peramivir in the outpatient setting.  The dose of 
peramivir used in that study (10 mg/kg of body weight to a maximum of 600 mg) was based on 
pharmacokinetic modeling and target area under the plasma concentration-time curve (AUC). 
Peramivir, administered IV, was generally safe and well tolerated in this population. Plasma 
concentrations from the pediatric patients in this study were found to be within the range of 
plasma concentrations following administration of peramivir at 300 mg or 600 mg in adult 
patients with influenza, and did not exceed mean plasma concentrations following administration 
at 800 mg in healthy adults. 
The approved dose of peramivir in adults is a single dose of 600 mg. Population pharmacokinetic 
modeling performed by the FDA (July 2010) based on the Shionogi Studies 0816T0633 
(children and adolescents) and 0722T0621 (adults) supports a target dose of 12 mg/kg in children 
(≤ 12 years) to attain exposures similar to that in adults who receive a 600 mg IV dose. Children 
13 and over can be treated with 600 mg/day, the adult dose. Per CDC, the average weight of a 
13-year-old boy and girl are 45 kg (99 lbs) and 46 kg (101 lbs) respectively. In adult trials of 
peramivir in acute uncomplicated influenza, at least 30 subjects with weights between 40 kg 
(88 lbs) and 50 kg (110 lbs) were treated without additional risk or complication. In addition, 
peramivir elimination is almost exclusively renal. Renal size reaches adult at age 12 and function 
(i.e., glomerular filtration rate) reaches that of an adult by age 2. The population PK model built 
using interim PK data from BCX1812-305 included a renal maturation factor to account for the 
development of renal function prior to age 2.  Simulations support a dose of 8 mg/kg from birth 
to less than 6 months of age, and 12 mg/kg in subjects 6 months of age and older.  Subjects < 6 
months of age are not predicted to have higher exposure of peramivir than that of adults.   
9.2. 
Treatments Administered 
9.2.1. 
Peramivir 
Peramivir solution for infusion is a clear, iso-osmotic, sterile, nonpyrogenic solution in 200 mg 
per 20 mL (10 mg/mL) single-use glass vials fitted with rubber stoppers and aluminum flip-off 
seals. The drug product should be stored at room temperatures up to 30°C. 
Subjects < 6 months of age at time of consent will receive a single dose of IV peramivir at a dose 
of 8 mg/kg. Subjects ≥ 6 months - ≤ 12 years of age at time of consent will receive a single dose 
of IV peramivir at a dose of 12 mg/kg (up to a maximum dose of 600 mg). Subjects ≥ 13 years of 
age will receive a single dose of 600 mg IV peramivir administered as a short IV infusion over a 
minimum of 15 minutes.  Peramivir must be diluted in normal saline normal saline United States 
Pharmacopeia (SUP).: 
Because of the risk of vasovagal reactions, particularly in children with needle phobia, it is 
recommended that subjects be in a supine position during peramivir administration. Appropriate 
post infusion observation should be performed.  


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9.2.2. 
Oseltamivir 
Oseltamivir will be provided by the site’s pharmacy as capsules or powder for oral suspension 
and prepared and used according to the manufacturer’s instructions. Subjects will be dosed 
according to Table 2 below: 
Table 2: 
Oseltamivir dose regimen by age 
Age 
Dose regimen 
≥ 13 years 
75 mg BID for 5 days.  Dose may be given as capsules or an oral 
suspension may be used by patients who cannot swallow a capsule.  
 
7-12 years 
Weight based dosing: 
 
 
        ≤ 15 kg 30 mg BID for 5 days 
15.1 – 23 kg 45 mg BID for 5 days 
23.1 – 40 kg 60 mg BID for 5 days 
        > 40 kg 75 mg BID for 5 days 
 
Dose may be given as capsules or an oral suspension may be used by 
subjects who cannot swallow a capsule. 
 
9.3. 
Randomization and Blinding/ Masking 
Subjects ≥ 7 to 17 years of age will be randomized to 1 of 2 treatment arms, at a ratio of 4:1: 
Treatment Group 1: A single dose of IV peramivir 
Treatment Group 2: Oral oseltamivir given BID for 5 days 
Following approval of amendment 3, all subjects < 7 years old will receive a single dose of 
intravenous peramivir.  
As this is an open label study, blinding is not applicable. 
9.4. 
Study Medication Preparation and Administration 
9.4.1. 
Peramivir 
The Principal Investigator at each study center will designate a pharmacist (or other qualified 
study staff member) to prepare IV peramivir as described in a separate study Pharmacy Manual. 
Prior to infusion, an appropriate amount of the peramivir 10 mg/mL stock solution will be 
diluted in saline using aseptic techniques with a maximum volume of 100 mL. Once prepared, 
solutions of peramivir in saline should be refrigerated and infused within 24 hours of 
preparation. 
In children ≥ 12 months, the total peramivir dose should be diluted to a total volume of 100 mL. 
For children < 12 months, the following dilution should be followed: 
 


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Table 3: 
Peramivir Dilution for Children < 12 Months of Age 
Age 
Dosing 
Anticipated 
Approximate 
Volume of 
Undiluted Drug 
Product 
Volume of 
Diluted 
Drug 
Product 
Infused 
Total 
mEq of 
Na 
Infused 
Number 
of Vials 
Per 
Dose 
0 - < 28 days  
(3 kg to 5.5 kg) 
Dilute dose 
to 12 mL 
total  
2.4 to 4.4 mL  
12 mL  
1.5 to 1.2 
1  
28 days to < 3 months 
(3 kg to 7.5 kg)  
Dilute dose 
to 20 mL 
total  
2.4 to 6.0 mL  
20 mL  
2.7 to 2.2 
1  
3 months to < 6 
months 
(4.5 kg to 11.2 kg) 
Dilute dose 
to 25 mL 
total  
3.6 to 4.7 mL 
25 mL  
3.3 to 3.1 
1 
6 months to < 12 
months 
(4.5 kg to 11.2 kg) 
Dilute dose 
to 25 mL 
total  
7.2 to 13.4 mL 
25 mL  
2.7 to 1.8 
1 
 
The study drug should be given as soon as possible after enrollment and randomization on 
Day 1. The calendar date and 24-hour clock time (start and end of the IV infusion) will be 
recorded. If the intravenous line used to administer peramivir is also to be used to administer any 
other medications, it should be flushed with at least 5 mL of saline before and after peramivir 
administration. Peramivir should not be piggy-backed to any other medication being 
administered. 
9.4.2. 
Oseltamivir 
Oseltamivir will be prepared and administered in accordance with the manufacturer’s 
instructions. 
9.5. 
Treatment Compliance 
Intravenous peramivir will be administered by study staff or other qualified personnel. Details of 
the infusion (to include date of dose, start time, and stop time) will be recorded by a member of 
the study staff. 
The first dose of oral oseltamivir will be administered in capsule or oral solution form at the site 
by study staff or other qualified personnel. Details of the first and all subsequent doses 
(administered at home by the subject/parent/guardian) will be recorded in the Subject Diary.  
Details will include the date and time of drug administration.  
9.6. 
Overdose and Toxicity Management 
To date there is no experience with overdose of IV peramivir. If overdose occurs, subjects should 
receive indicated supportive therapy and evaluation of hematologic and clinical chemistry 


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laboratory tests should be conducted. Peramivir is cleared by hemodialysis; the decision to use 
hemodialysis should be addressed on a case-by-case basis with the Sponsor. 
9.7. 
Study medication accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study drug 
received from the Sponsor and administered to the subject (including date and time), and any 
drug accidentally destroyed. The Sponsor will supply a specific Drug Accountability Form. At 
the end of the study, information describing study drug supplies (e.g., lot numbers) and 
disposition of supplies for each subject must be provided, signed by the Investigator or designee, 
and collected by the Study Monitor. If any errors or irregularities in any shipment of study 
medication to the site are discovered at any time, the Sponsor Project Manager must be contacted 
immediately. 
At the end of the study, all medication that was neither dispensed or administered, as well as 
packaging materials will be collected with supervision of the monitor and returned to the 
Sponsor or destroyed on site as dictated by the appropriate Standard Operating Procedure (SOP) 
at the participating site 
9.8. 
Concomitant Medications 
Administration of a concomitant medication during the study period must be recorded within the 
subject’s medical records. This includes prescription medications as well as over-the-counter 
medications. 
Medications used for the symptomatic treatment of influenza-related symptoms will be 
discouraged for children 2-5 years of age as per American Academy of Pediatrics guidance and 
the January 2008 FDA public health advisory. Parents/caregivers will be requested to follow 
package labeling for over-the-counter cold and influenza symptom relief medications for 
children 2-5. The use of symptomatic medication will be prohibited in children < 2 years of age. 
Antipyretics will be permitted in all age groups.  Parents/caregivers will record the date, time, 
and dose of symptomatic medications and antipyretics in the Subject Diary. All other 
concomitant medications will be transcribed from the source onto the Case Report Form (CRF) 
by study staff. 
Use of concomitant medications will be assessed and recorded at Screening/ Baseline, and daily 
throughout the duration of the study through the study follow-up visit. 
9.8.1. 
Medications for Chronic Diseases/Conditions 
Subjects with chronic medical conditions may continue to receive prescribed treatments during 
participation in this protocol. The exception is high dose steroids > 10 mg/day (see exclusion 
criteria, Section 8.2). 
9.8.2. 
Antivirals 
There are no known adverse interactions of peramivir with other influenza antivirals (such as 
oseltamivir, zanamivir, amantadine, and rimantadine); however, their concomitant use is not 
permitted during administration of study drug and in the post-treatment follow-up period.  


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9.8.3. 
Corticosteroids 
Corticosteroids at dose < 10 mg a day are allowed during administration of the study drug and 
throughout study participation. 
9.8.4. 
Antipyretics and Analgesics 
Resolution of fever is a major component of some of the clinical effectiveness endpoints for this 
study. Accordingly, use of any antipyretics or analgesics with antipyretic properties must be 
carefully controlled and documented. Antipyretics and analgesics may be administered while the 
subject is enrolled in this study. The names and dosages of these medications will be recorded in 
the Subject Diary. To avoid the confounding effects of antipyretic medications, temperature 
measurements, including those recorded by study staff while in the emergency department or 
clinic and those recorded by the subjects during the follow-up period, will be taken, whenever 
possible, at least 4 hours after administration of the antipyretic medication or immediately prior 
to administration. Following discharge from the hospital, the names and dosages of all other 
medications will be recorded in the Subject Diary by the parent/ care-giver. 
Temperature measurements that are recorded for the purpose of analyzing effectiveness in this 
study < 4 hours after administration of the antipyretic medication, regardless of the dose, will not 
be counted in the effectiveness analyses. 
9.8.5. 
Antibiotics 
Oral or parenteral antibiotics may be administered, if medically indicated. If such use is a result 
of proven or suspected influenza-related complication, appropriate assessments should be carried 
out (see Section 11.4). 


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10. 
STUDY CONDUCT 
10.1. 
Overview 
Up to 140 subjects will be enrolled in this study according to the following age groups: 
• Birth to < 28 days: up to 10 subjects, given IV peramivir 
• 28 days to < 2 years: up to 20 subjects: subjects enrolled after the approval of amendment 
3 will receive IV peramivir  
• 2 - < 4 years: up to 10 subjects: subjects enrolled after the approval of amendment 3 will 
receive IV peramivir 
• 4 - < 7 years:up to 30 subjects: subjects enrolled after the approval of amendment 3 will 
receive IV peramivir 
• 7 - < 13 years:up to 40 subjects, randomized 4:1 to IV peramivir or oral oseltamivir 
• 
13 - < 18 years:up to 30 subjects, randomized 4:1 to IV peramivir or oral oseltamivir 
 
Once an age cohort is filled, enrollment in that cohort will be closed and communicated with all 
investigators. 
A subject’s duration of participation in this study is expected to be 14 days.   
Subjects meeting the inclusion/exclusion criteria may be enrolled into the study. It is expected 
that most subjects will have the Screening/Baseline Visit and the Day 1 Treatment Visit on the 
same day. 
All subjects will receive either a single dose of IV peramivir (600 mg, or12 mg/kg or 8 mg/kg or 
depending on age) or oral oseltamivir, dosed BID for 5 days. Note, as of the approval of 
amendment 3, no additional subjects will be randomized to receive oseltamivir. 
Subjects will undergo follow-up assessments on Days 3, 7, and 14. The Day 3 visit may be a 
home visit (performed by a qualified study nurse). Day 7 is required to take place in the clinic, 
and Day 14 may either be a clinic visit, home visit, or follow-up phone call to the 
subject/parent/guardian.   
All parents/caregivers will record the following information in the Subject Diary.  
• Temperature measurements (oral or axillary) will be taken with an electronic 
thermometer provided by BioCryst, approximately every 12 hours until temperature 
normalizes for 48 hours (i.e., temperature without antipyretic is < 99.4 orally in 
children ≥ 6 and < 98.4 axillary in children < 6 years old for 4 measurements). With 
the exception of the baseline measurement, all temperature measurements will be 
obtained at least 4 hours after, or immediately before, administration of oral 
acetaminophen or other antipyretic medications, if taken. 
• Date and time of oral oseltamivir dose administration, if applicable.  This should be 
recorded in the Subject Diary twice a day for 5 days. 
• Doses of antipyretic medication and any medications taken for symptomatic relief, 
each day through the last follow-up assessment. 


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• The ability of the child or adolescent to return to day care/school and/or resume their 
normal “pre-illness” daily activity will be assessed once daily until the child or 
adolescent returns to day care/school and/or resume normal “pre-illness” daily 
activity. 
• The child or adolescent’s appetite and eating patterns assessed as normal or 
reduced/abnormal will be assessed once daily until they return to normal “pre-illness” 
level. 
All parents/caregivers of subjects 7 years of age and older will record the following additional 
information in the Subject Diary: 
• Assessment of 7 influenza symptoms (cough, sore throat, nasal obstruction, myalgia 
[muscle aches), headache, feverishness, and fatigue) on a 4-point severity scale 
(0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 
until symptom resolution or through the last follow-up visit, (whichever comes first). 
All parents/caregivers of subjects ≥ 4 years of age to ≤ 6 years of age will record the following 
additional information in the Subject Diary: 
• Assessment of 7 influenza symptoms [cough, sore throat, nasal obstruction, myalgia 
(muscle aches), headache, feverishness, fatigue/malaise, and gastrointestinal 
symptoms (nausea, vomiting or diarrhea)] on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 until 
symptom resolution or through the last follow-up visit, whichever comes first. 
All parents/caregivers of subjects≤ 3 years of age will record the following additional 
information in the Subject Diary: 
• Assessment of 5 influenza symptoms [cough, rhinitis, feverishness, 
malaise/irritability and gastrointestinal symptoms (nausea, vomiting or diarrhea)] on a 
4-point severity scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, 
beginning pre-dose on Day 1 until symptom resolution or through the last follow-up 
visit, (whichever comes first). 
An adequate nasal swab specimen will be collected from all enrolled subjects at Baseline 
(pre-dose) for virus sub-type identification and quantitative virologic assessments and at the 
follow-up assessments on study Days 3, 7, and where possible Day 14. 
Specimens from all subjects yielding influenza virus will also be assessed for susceptibility to 
neuraminidase inhibitors (Day 1 and last specimen yielding influenza virus on culture). A central 
laboratory will perform all virologic assessments.  
Plasma samples for determination of drug concentration on subjects randomized to peramivir 
will be drawn as follows: 
Up to 4 blood samples will be drawn, where possible, during the following time periods, 
beginning from the end of dosing until release from the site 
• One time point immediately following completion of the infusion 
• One time point from 30 minutes to 1 hour post-infusion 


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• One time point from 1 hour to 3 hours post-infusion  
• One time point from 3 hours to 6 hours post-infusion 
Note: Subjects ≥ 5 kg will have four 1.0 mL PK blood draws at the above stated sampling 
times. Subjects < 5 kg will have two 1.0 mL blood samples; one time immediately 
following completion of the infusion and one time between 1-3 hours post-infusion. 
Adverse events and concomitant medications will be monitored at each scheduled visit from the 
screening/baseline assessment to final study visit. Clinical laboratory investigations (chemistries, 
hematology, and urinalysis) will be collected at baseline and at the final study visit. Safety and 
tolerability will be evaluated through assessments of adverse events, laboratory analyses (clinical 
chemistry, hematology, and urinalysis), vital signs and physical examinations at the time points 
indicated in the schedule of assessments.  
10.2. 
Schedule of Assessments 
10.2.1. 
Screening Period 
The Screening Period begins at the time of consent/assent of the study subject. Subjects whose 
parents/guardians have provided written informed consent (and assent for subjects ≥ 7 years of 
age or as permitted by local IRB and state requirements) will be assigned a unique study subject 
number and the following screening procedures will be conducted: 
• Evaluation of study eligibility requirements. 
• Urine pregnancy test (females of childbearing potential only).  
• Review of medical history and concomitant medications. 
• Body temperature (obtained in the site’s usual fashion). 
Eligible subjects will be enrolled. The study pharmacist will prepare an order for study drug as 
defined in Section 11.4, which includes the subject’s study number. 
10.2.2. 
Treatment Period 
Randomization (prior to the approval of amendment 3) and study drug administration should 
begin as soon as possible following determination that the subject is eligible for enrollment at 
Screening. Therefore, it is anticipated that the date of Screening/Baseline and Day 1 (date of 
administration of the first dose of study medication) will be the same day. Day 1 represents the 
first day of dosing. Subjects will receive IV peramivir in a single dose or oral oseltamivir BID 
for five days.  Note, following the approval of amendment 3, no additional subjects will be 
randomized to receive oseltamivir. 
10.2.2.1. Day 1/Baseline/Pre-Dose 
The following procedures/evaluations will be performed pre-dose at Baseline on Day 1: 
• Body temperature just prior to study drug administration (using the study electronic 
thermometer via the oral or axillary method). 


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• Physical examination, including assessment of presence of possible influenza-related 
complications. 
• Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), 
heart rate, respiration rate). 
• Review and recording of concomitant medications. 
• Blood specimen collection for clinical chemistry and clinical hematology tests as 
specified in Sections 11.2.1 and 11.2.2  and a serum sample for future influenza 
antibody analysis. Subjects whose weight is < 10kg do not require a serum antibody 
sample. 
(Clinical laboratory specimens collected at Screening are for the purpose of 
establishing a baseline and the results are not required to determine subject 
eligibility).  
• Urine sample collection for routine urinalysis. 
• Determination (and recording in the Subject Diary) of the presence and severity of 
each of the age specific symptoms of influenza (see Section 10.1). Questions asked of 
subjects age 6 years and older, if possible. 
• Determination [with assistance from the subject (if possible)] of the subject’s ability 
to perform usual daily activities.  
• Determination [with assistance from the subject (if possible)] of the subject’s appetite 
and eating patterns assessed as either normal or reduced/abnormal. 
• Bilateral adequate nasal swab specimen collection for viral subtyping, culture, 
quantitative PCR assay and susceptibility to neuraminidase inhibitors.  
• Administration of the study medication (at Hour 0) and recording of the calendar date 
and 24-hour clock time for the start and finish of the IV infusion, if applicable. Each 
subject will receive peramivir, if ≤ 12 then adjusted for body weight, and oseltamivir 
adjusted for weight in subjects ≤ 12. 
10.2.2.2. Day 1/Post-Dose 
The following procedures/evaluations will be performed post-dose on Day 1: 
• For subjects randomized to peramivir: collection of up to 4 plasma samples, where 
possible, during the following time periods, beginning from the end of dosing until 
release from the site. For each plasma sample the calendar date and 24-hour clock 
time of sample collection will be recorded: 
1. One time point immediately following completion of the infusion  
2. One time point from 30 minutes to 1 hours post-infusion 
3. One time point from 1 hour to 3 hours post-infusion 
4. One time point from 3 hours to 6 hours post-infusion 


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Note: Subjects ≥ 5 kg will have four 1.0 mL blood draws at the above stated sampling 
times. Subjects < 5 kg will have two 1.0 mL blood samples; one time immediately 
following completion of the infusion and one time between 1-3 hours post-infusion. 
• Training of the parent/ caregiver and the recording of the following in the Subject 
Diary: 
− Subject’s body temperature, obtained at approximately 12-hour intervals each day 
(and 4 hours from last antipyretic medication administration or immediately prior 
to administration). 
− Subject’s ability to perform usual activities, obtained once daily. 
− Subject’s appetite and eating patterns assessed as either normal or 
reduced/abnormal. 
− The age specific signs and symptoms of influenza (see Section 10.3.2). 
• Review and recording concomitant medications. 
• Recording of AEs. 
10.2.2.3. Day 3 
The following procedures/assessments will be performed on Day 3. The Day 3 assessment may 
be performed in the subject’s home by a qualified study nurse, or as a clinic visit. 
• Body temperature (using the study electronic thermometer via the oral or axillary 
method). 
• Assessment of presence of possible influenza-related complications. 
• Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), 
heart rate, respiration rate). 
• Review of the Subject Diary for completeness and instruction to the parent/caregiver 
on need to ensure complete recording of required assessments, if needed. 
• Determination (and recording in the Subject Diary) of the presence and severity of 
each of the age specific symptoms of influenza. Questions asked of subjects age 
6 years and older, if possible. 
• Determination (and recording in the Subject Diary) [with assistance from the subject 
(if possible)] of the subject’s ability to perform usual daily activities.  
• Determination (and recording in the Subject Diary) of the subject’s appetite and 
eating patterns assessed as either normal or reduced/abnormal. 
• Bilateral adequate nasal swab specimen collection for viral culture and quantitative 
PCR assay.  
• Review and recording of concomitant medications. 
• Recording of AEs.  


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10.2.2.4. Day 7 
The following procedures/assessments will be performed on Day 7 (+ 2 days). The Day 7 
assessment will be performed as a clinic visit. 
• Urine pregnancy test (females of childbearing potential only).  
• Body temperature (using the study electronic thermometer via the oral or axillary 
method). 
• Blood specimen collection for clinical chemistry and clinical hematology tests as 
specified in Sections 11.2.1 and 11.2.2 and a serum sample for future influenza 
antibody analysis. Subjects whose weight is < 10kg do not require a serum antibody 
sample. 
• Urine collection for urinalysis 
• Assessment of presence of possible influenza-related complications. 
• Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), 
heart rate, respiration rate). 
• Review of the Subject Diary for completeness and instruction to the parent/caregiver 
on need to ensure complete recording of required assessments, if needed. 
• Determination (and recording in the Subject Diary) of the presence and severity of 
each of the age appropriate symptoms of influenza. Questions asked of subjects age 
6 years and older, if possible. 
• Determination (and recording in the Subject Diary) [with assistance from the subject 
(if possible)] of the subject’s ability to perform usual daily activities.  
• Determination (and recording in the Subject Diary) of the subject’s appetite and 
eating patterns assessed as either normal or reduced/abnormal 
• Bilateral adequate nasal swab specimen collection for viral culture, quantitative PCR 
assay and susceptibility to neuraminidase inhibitors.  
• Review and recording of concomitant medications. 
• Recording of any AEs.  
10.2.2.5. Day 14 
The following procedures/assessments will be performed on Day 14 (+ 3 days). The Day 14 
assessments will be performed as a clinic visit, home visit (conducted by a qualified study nurse) 
or, if either of these options are not possible, by phone call. If conducted by phone, the Day 14 
assessments will be limited to interview assessment for the presence of possible influenza-related 
complications, concomitant medication use and AEs.  The subject’s parent/ caregiver will be 
asked to return the completed Subject Diary by mail. 
• Body temperature (using the study electronic thermometer via the oral or axillary 
method). 
• Assessment of presence of possible influenza-related complications. 


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• Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), 
heart rate, respiration rate). 
• Review of the Subject Diary for completeness. 
• Determination (and recording in the Subject Diary) of the presence and severity of 
each of age appropriate symptoms of influenza. Question asked of subjects age 
6 years and older, if possible. 
• Determination (and recording in the Subject Diary) [with assistance from the subject 
(if possible)] of the subject’s ability to perform usual daily activities.  
• Determination (and recording in the Subject Diary) of the subject’s appetite and 
eating patterns assessed as either normal or reduced/abnormal 
• Bilateral adequate nasal swab specimen collection for viral culture, quantitative PCR 
assay and susceptibility to neuraminidase inhibitors.  
• Review and recording of concomitant medications. 
• Recording of any AEs.  
• If previous lab results are abnormal and considered clinically significant by the 
Investigator or significantly changed from baseline, blood specimen collection for 
clinical chemistry or clinical hematology tests as specified in Sections 11.2.1 and 
11.2.2 may be drawn. 
• If previous lab results are abnormal and considered clinically significant by the 
Investigator or significantly changed from baseline, urine collection for urinalysis 
may be completed. 
10.2.2.6. Early Withdrawal 
For subjects who withdraw before the Day 7 assessment, the following procedures/assessments 
will be performed at an Early Withdrawal visit, where possible. Assessments will be performed 
as a clinic visit or home visit (conducted by a qualified study nurse). For subjects who withdraw 
between the Day 7 and day 14 assessments, a phone assessment will be performed, where 
possible. A phone assessment will be limited to interview assessment for the presence of possible 
influenza-related complications and AEs.  The subject’s parent/caregiver will be asked to return 
the completed Subject Diary by mail. 
• Urine pregnancy test (females of childbearing potential only).  
• Body temperature (using the study electronic thermometer via the oral or axillary 
method). 
• If previous lab results are abnormal and considered clinically significant by the 
Investigator or significantly changed from baseline, blood specimen collection for 
clinical chemistry or clinical hematology tests as specified in Sections 11.2.1 and 
11.2.2 may be drawn 


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• If previous lab results are abnormal and considered clinically significant by the 
Investigator or significantly changed from baseline, urine collection for urinalysis 
may be completed 
• Assessment of presence of possible influenza-related complications. 
• Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), 
heart rate, respiration rate). 
• Review of the Subject Diary for completeness. 
• Determination (and recording in the Subject Diary) of the presence and severity of 
each of the age appropriate symptoms of influenza. Questions asked of subjects age 
6 years and older, if possible. 
• Determination (and recording in the Subject Diary) [with assistance from the subject 
(if possible)] of the subject’s ability to perform usual daily activities.  
• Determination (and recording in the Subject Diary) of the subject’s appetite and 
eating patterns assessed as either normal or reduced/abnormal 
• Bilateral adequate nasal swab specimen collection for viral culture, quantitative PCR 
assay and susceptibility to neuraminidase inhibitors.  
• Review and recording of concomitant medications. 
• Recording of any AEs.   
10.3. 
Clinical assessments of Effectiveness 
Effectiveness will be evaluated through assessments of body temperature, clinical symptoms of 
influenza, usual daily activities, appetite/eating patterns, incidence of influenza-related 
complications (see Section 11.4 for details), influenza virus titers, and changes in viral sensitivity 
to other antiviral drugs. 
10.3.1. 
Body Temperature 
Body temperature measurements will be recorded once at Screening/Baseline by the site’s 
normal method, and then via an electronic thermometer provided by the Sponsor twice per day 
until temperature normalizes for 48 hours without the use of anti-pyretic medication. Acceptable 
means by which to record body temperature will be oral or axillary measurements. Study staff 
will record temperature measurements while the subject is on-site. Parents/care givers will be 
instructed to measure and record the subject’s body temperature in the Subject Diary, using the 
electronic thermometer provided by the Sponsor. To avoid the confounding effects of antipyretic 
medications, temperature measurements will be taken, whenever possible, at least 4 hours after 
administration of any antipyretic medication or immediately prior to dosing. Temperature 
measurements that are recorded for the purpose of analyzing effectiveness in this study < 4 hours 
after administration of the antipyretic medication, regardless of the dose, will not be counted in 
the effectiveness analyses. The method of temperature measurement must be recorded. 


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10.3.2. 
Influenza Signs and Symptoms 
Subjects (or parent/guardian) will be asked to provide an assessment of influenza symptoms on a 
4-point severity scale (0, absent; 1, mild; 2, moderate; 3, severe) beginning pre-dose on Day 1 
until symptom resolution and through the last follow-up visit, (whichever comes first). These 
assessments will be recorded on each day that the medical condition allows. Study staff will 
obtain this assessment pre-dose and post-dose on Day 1, and the subject’s trained parent-
guardian will then obtain it until returning to the site for the final visit. Influenza signs and 
symptoms vary by age. In addition, younger children may not be able to verbalize specific 
symptoms. Therefore, the assessment of influenza symptoms will be based on the subject’s age, 
as follows: 
• Parent/guardian of subjects birth to ≤ 3 years of age will provide/record an 
assessment of 5 influenza symptoms [cough, rhinitis, feverishness, malaise/irritability 
and gastrointestinal symptoms (nausea, vomiting or diarrhea)]  
• Subjects ≥ 4 years of age to ≤ 6 years of age will be asked to provide an assessment 
of 7 influenza symptoms [cough, sore throat, nasal obstruction, myalgia (muscle 
aches), headache, feverishness, and gastrointestinal symptoms (nausea, vomiting or 
diarrhea)].  
• Subjects 7 years of age and older will be asked to provide an assessment of 
7 influenza symptoms (cough, sore throat, nasal obstruction, myalgia (muscle aches), 
headache, feverishness, and fatigue).  
During the first visit, the study staff will instruct the parent/care giver on completing these 
assessments and recording responses directly into the Subject Diary. Although the parent/care 
giver will be recording the responses, the subject should be involved in the assessment of the 
symptoms. 
10.3.3. 
Assessment of ability to perform usual daily activities 
If possible, subjects or parents/care givers will be asked to provide a daily assessment of the 
subject’s ability to perform usual daily activities using a 0-10 visual analogue scale, where 
0 = Unable to perform usual activities at all, and 10 = Able to perform usual activities fully. The 
parent/care giver will be asked to record these assessments in the Subject Diary, with appropriate 
input from the subjects, once daily from Day 2 until resolution or the final follow-up assessment, 
whichever comes first.  
10.3.4. 
Assessment of appetite and eating patterns 
Subjects or parents/caregivers will be asked to provide a daily assessment of the subject’s 
appetite and eating pattern as either normal or abnormal/reduced. The parent/ caregiver will be 
asked to record this assessment in the Subject Diary, with appropriate input from subjects, once 
daily from Day 2 until resolution or the final follow-up assessment, whichever comes first. 


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10.4. 
Virology Samples 
Bilateral mid-nasal swab specimens will be collected for virologic analysis. Samples will be 
collected at Baseline, Day 3, Day 7, and, where possible, Day 14. 
Virology laboratory tests will include viral sub type characterization from the baseline sample, 
laboratory culture and analysis by log10 TCID50, RT-PCR assay, viral susceptibility to peramivir, 
oseltamivir, and zanamivir, and genotypic analysis of primary virus isolates. 


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11. 
ASSESSMENT OF SAFETY 
Safety will be evaluated through assessments of AEs, laboratory analyses (clinical chemistry, 
hematology, and urinalysis), vital signs, and physical examinations. 
11.1. 
Adverse Events 
Adverse events will be assessed and recorded at the indicated time points (see schedule of 
assessments, Table 1). AEs will be recorded on Day 1, Day 3, Day 7 and Day 14/Early Withdraw 
visits. Adverse events will be graded through use of the Division of Acquired Immune 
Deficiency Syndrome (DAIDS) Tables for Grading Adult and Pediatric Adverse Experiences 
(see Appendix 1). Any Grade 3 and Grade 4 clinical AEs or laboratory abnormalities that are 
judged to be possibly, probably, or definitely related to study treatment will be promptly (within 
72 hours) reported to the study medical monitor unless the event meets criteria for an SAE, in 
which case they must be reported within 24 hours. Influenza-related complications are not 
considered AEs unless they meet the criteria for SAEs. Full details on recording and reporting 
AEs are provided in Section 11.1.2. 
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 or with the clinical study itself is implied. An AE may be an unfavorable and 
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical 
study. Clinically relevant abnormal results of diagnostic procedures including abnormal 
laboratory findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be AEs. 
Surgical procedures are not AEs but may constitute therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case the condition should be 
reported as medical history. 
Assessment of the age appropriate symptoms of influenza symptoms will be documented and 
analyzed as a measure of effectiveness of the study treatment. These symptoms will not be 
reported as AEs unless the symptom(s) worsen to the extent that the outcome fulfills the 
definition of an SAE, which then must be recorded as such. Likewise, a RAT for influenza is 
required at screening in order to determine eligibility for the study, and therefore a positive RAT 
is not considered an AE. 
AEs are designated as “nonserious” or “serious.” 


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11.1.1.2. Serious Adverse Event 
An SAE is an adverse event 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 in-subject hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (i.e., there is a substantial 
disruption of a person’s ability to carry out normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in subject hospitalization, or the development of drug dependency or drug 
abuse. 
Hospitalization, as per the institution’s standard of care (SOC) to treat pediatric influenza is not 
considered an SAE and should not be reported as such. Any adverse event the causes a 
prolongation of an existing hospitalization must be reported as per Section 11.1.5. 
11.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events 
Reports of AEs are to be collected from the time the subject consents to participate through the 
follow-up period ending on Day 14. The Investigator or designee must completely and promptly 
record each AE. The Investigator should attempt, if possible, to establish a diagnosis based on 
the presenting signs and symptoms. In such cases, the diagnosis should be documented as the AE 
and not the individual sign/symptom. If a clear diagnosis cannot be established, each sign and 
symptom must be recorded individually. If a final diagnosis is established during evaluation or 
treatment, the source documents will be updated accordingly. 
The Investigator should attempt to follow all unresolved AEs and/or SAEs observed during the 
study until they are resolved, or are judged medically stable, or are otherwise medically 
explained. 
11.1.3. 
Definition of Severity 
All AEs will be assessed (graded) for severity and classified using the DAIDS criteria for 
grading AEs (see Appendix 1). Any adverse events not covered by the DAIDS criteria will be 
assessed and classified into one of three clearly defined categories as follows:  


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Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required. The AE does not interfere with the participant’s 
normal functioning level. It may be an annoyance. 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; 
no or minimal intervention required. The AE produces some impairment 
of functioning, but it is not hazardous to health. It is uncomfortable or an 
embarrassment. 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; medical 
intervention may be required. The AE produces significant impairment 
of functioning or incapacitation. 
Life threatening 
(Grade 4): Symptoms causing inability to perform basic self-care 
functions OR Medical or operative intervention indicated to prevent 
permanent impairment, persistent disability, or death 
11.1.4. 
Definition of Relationship to Study Drug 
The Principal Investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug using the following guidelines: 
Not Related: 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident, and no 
temporal relationship exists between the study drug and the event. 
Unlikely: 
The event does not follow a reasonable temporal sequence from drug 
administration and is readily explained by the subject’s clinical state or by 
other modes of therapy administered to the subject. 
Possibly Related: There is some temporal relationship between the event and the 
administration of the study drug and the event is unlikely to be explained 
by the subject’s medical condition, other therapies, or accident. 
Probably 
Related: 
The event follows a reasonable temporal sequence from drug 
administration, abates upon discontinuation of the drug, and cannot be 
reasonably explained by the known characteristics of the subject’s clinical 
state. 
Definitely 
Related: 
The event follows a reasonable temporal sequence from administration of 
the medication, follows a known or suspected response pattern to the 
medication, is confirmed by improvement upon stopping the medication 
(dechallenge), and reappears upon repeated exposure (rechallenge, if 
rechallenge is medically appropriate). 


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11.1.5. 
Reporting Serious Adverse Events 
Any SAE must be reported by phone or email to the Sponsor medical monitor and in writing via 
email or fax using the SAE report form within 24 hours of the Investigator’s awareness of the SAE. 
In addition, all SAEs must be recorded on the AE CRF in real time. 
All additional follow-up evaluations of the SAE must be reported to BioCryst or its designee as soon 
as they are available.  
The SAE report forms should be sent to the following email addresses or fax numbers: 
Email: mm@biocryst.com and clinicalsafety@propharmagroup.com 
OR 
Fax: +1 919 226-5888 and +1 866-681-1063 
Immediate reporting should allow BioCryst to take the appropriate measures to address potential new 
risks in a clinical trial. Therefore, the initial report should be submitted by the Investigator within a 
very short period of time and under no circumstances should this period exceed 24 hours following 
awareness of the SAE.  
The follow-up report should allow BioCryst to determine whether the serious adverse event requires 
a reassessment of the benefit-risk profile of the study drug in clinical trial, if the relevant information 
was not already available and provided in the initial report. 
Any SAEs considered possibly, probably or definitely related to treatment and not in accordance 
with information in the Investigator’s Brochure will be reported to the FDA and other Regulatory 
Competent Authorities as applicable via the MedWatch / CIOMS reporting system in accordance 
with FDA and other applicable regulations. 
The Principal Investigator or designee at each site is responsible for submitting the IND safety 
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) 
to the Institutional Review Board (IRB) and for retaining a copy in their files. 
11.1.6. 
Pregnancy 
Pregnancy is not considered an AE but any pregnancy discovered in a subject during the course 
of the trial must be reported to BioCryst or designee on a pregnancy report form (supplied by 
BioCryst) in the same manner as SAEs (see Section 11.1.5). All pregnancies will be followed to 
an outcome (i.e. miscarriage, elective termination, stillbirth, live birth). Pregnancy outcomes of 
miscarriage, elective termination, stillbirth or birth defect will be considered SAEs and should be 
reported as per 11.1.5. 
11.1.7. 
Reporting DAIDS Grade 3 or 4 events 
Any DAIDS Grade 3 and Grade 4 clinical AE or laboratory abnormality that is judged to be 
possibly, probably, or definitely related to study treatment but does not meet seriousness criteria 
will be promptly (within 72 hours) reported to the study medical monitor via telephone or email. 


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11.2. 
Clinical Laboratory Evaluations 
For any subject that is hospitalized, clinical chemistry, hematology and urinalysis samples will 
be analyzed by the local laboratory.  Duplicate samples will not be drawn for analysis by the 
central laboratory. 
11.2.1. 
Clinical Chemistry Profiles 
Clinical chemistry profiles will include a Chemistry 20 panel (includes sodium, potassium, 
chloride, total CO2 [bicarbonate], creatinine, glucose, urea nitrogen, albumin, total calcium, total 
magnesium, phosphorus, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total 
protein, total creatine kinase, and uric acid). 
Blood samples for clinical chemistry profiles will be collected at Baseline and at the Day 7 
follow-up assessment. Clinically significant results should be reported as AEs. 
11.2.2. 
Hematology Profiles 
Hematology profiles will include complete blood count (CBC) with differential. 
Blood samples for hematology profiles will be collected at Baseline, and at the Day 7 follow-up 
assessment. Clinically significant results should be reported as AEs.  
11.2.3. 
Urinalysis 
Routine urinalysis evaluations will include dipstick evaluations for protein, glucose, ketones, 
hemoglobin, and specific gravity. If indicated by dipstick results, the urine should be sent for 
microscopy.  
Urinalysis will be conducted on urine samples obtained at Baseline, and at the Day 7 follow-up 
assessment. Clinically significant results should be reported as AEs.  
11.2.4. 
Pregnancy Test (Urine or Serum) 
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and at 
the Day 7 follow-up assessment using a urine pregnancy test performed locally.  
11.3. 
Vital Signs 
Vital sign measurements (blood pressure (in children < 2 only if clinically indicated), heart rate, 
respiration rate, temperature) will be recorded once at Baseline and once at each follow-up visit. 
11.4. 
Physical Examination and Influenza-Related Complications 
Assessment 
The Investigator will perform a full physical examination at Baseline, including the subject’s 
height or length and weight. At each follow-up visit, study personnel will evaluate the subject for 
the presence of clinical signs and/or symptoms of the following influenza-related complications: 
sinusitis, otitis media, bronchitis and pneumonia. 


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If the Investigator determines that the subject has (or is presumed to have) one of the 
influenza-related complications noted above, he/she will note that in the subject’s source 
documents and on the influenza-related complications CRF page. Any medication used to treat 
the condition must also be recorded (on the concomitant medication page). The Investigator will 
promptly provide appropriate treatment for any suspected or proven influenza-related 
complication(s). Signs and symptoms associated with influenza-related complications will not be 
reported on the adverse event CRF page unless they meet criteria for an SAE. 
11.5. 
Safety Oversight 
Since the study is open label, a sponsor-led Data Safety Management Committee (DSMC) will 
oversee safety. A full review and summary of safety utilizing all collected safety assessments 
will occur after each influenza season. This will be described in the separate DSMC charter. 


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12. 
PHARMACOKINETIC ASSESSMENTS 
For subjects randomized to peramivir, up to 4 plasma samples will be drawn for determination of 
drug concentration. The samples will be drawn, where possible, during the following time 
periods, beginning from the end of dosing: 
1. One time point immediately following completion of the infusion  
2. One time point from 30 minutes to 1 hours post-infusion 
3. One time point from 1 hour to 3 hours post-infusion  
4. One time point from 4 hours to 6 hours post-infusion 
Plasma samples will be processed and shipped for analysis in accordance with instructions 
provided in the Laboratory Manual. 
Note: Subjects ≥ 5 kg will have four 1.0 mL blood draws at the above stated sampling times. 
Subjects < 5 kg will have two 1.0 mL blood samples; one time immediately following 
completion of the infusion and one time between 1-3 hours post-infusion. 


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13. 
STATISTICS 
 
Descriptive statistical methods will be used to summarize the data from this study.  Data will be 
summarized by treatment group, age group, and study day/time, if appropriate.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation (SD), minimum, and maximum for continuous data and frequencies and 
percentages for categorical data.  The term “treatment group” refers to treatment assignment:  
single dose peramivir IV or oseltamivir BID for 5 days.  The term "age group" refers to the 
following: 0 – 28 days; 28 days - < 2 years, ≥ 2 years - < 7 years, ≥ 7 years - < 13 years, and ≥ 13 
years - < 18 years.  All data collected during the study will be included in data listings.  Unless 
otherwise noted, the data will be sorted first by treatment group, age group, subject number, and 
then by date within each subject number.   
The statistical analyses will be conducted with the SAS® software package version 9.2 or higher. 
All analyses will be subject to formal verification procedures.  Specifically, results will be 
verified utilizing independent programming prior to issuance of the draft statistical report.  All 
documents will be verified by the lead statistician to ensure accuracy and consistency of 
analyses. 
13.1. 
Data Collection Methods 
The data will be transcribed from the subjects’ source documents into the CRF approved by 
BioCryst. The data collection methods may be either a paper CRF or an electronic CRF, at 
BioCryst’s discretion. All documentation supporting the CRF data, such as laboratory or hospital 
records must be readily available to verify entries in the CRF. 
To ensure subject confidentiality, any documents (including laboratory reports, hospital records 
subsequent to SAEs, etc.) transmitted to BioCryst should not carry the subject’s name. 
13.2. 
Statistical Analysis Plans 
A SAP will be created and approved prior to the review of any data. This document will provide 
a more technical and detailed description of the proposed data analysis methods and procedures. 
13.3. 
Study Hypothesis 
There are no hypotheses to be formally tested in this study. 
13.4. 
Sample Size Estimates 
The study is designed to evaluate the safety, pharmacokinetics, and effectiveness of IV 
administration of peramivir compared to oral oseltamivir in pediatric subjects with acute 
uncomplicated influenza. The sample size is not based on statistical considerations, rather a 
sample size of up to 140 subjects (approximately 117 randomized to peramivir) is considered 
adequate to evaluate the stated objectives.  


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13.5. 
Analysis Populations 
The populations defined for analysis will include the intent-to-treat (ITT) population, 
intent-to-treat infected (ITTI) population, safety population, and an exposure-response 
population. Additional analysis populations may be defined to evaluate study results. Any 
additional analysis populations will be defined in the SAP. 
• Intent-To-Treat Population: The ITT population will include all subjects who are 
randomized. The ITT population will be used for analyses of accountability and 
demographics. 
• Intent-To-Treat Infected Population: The ITTI population will include all subjects 
who are enrolled, treated, and have influenza confirmed by RT-PCR. The ITTI 
population will be used for analyses of effectiveness. 
• Safety Population: The safety population will include all subjects who received at 
least one dose of study drug. This population will be used for all safety analyses. 
• Exposure-Response Population: The exposure-response population will include all 
subjects in the ITTI population who have a quantifiable plasma concentration of 
peramivir and at least one post-baseline effectiveness assessment. This population 
will be used for all exposure-response analyses. 
13.6. 
End of Study Analysis 
A final analysis is planned to occur after the last subject completes or discontinues the study, and 
the resulting clinical database has been cleaned, quality checked, and locked. 
13.7. 
General Issues for Statistical Analysis 
13.7.1. 
Multiple Comparisons and Multiplicity 
No adjustments are currently planned. 
13.7.2. 
Covariates 
Not applicable. 
13.7.3. 
Planned Subgroups 
Analyses will be displayed by age group and viral subtype at Screening. 
13.7.4. 
Missing Data 
Every effort will be made to obtain required data at each scheduled visit from all subjects who 
have been randomized. In situations where it is not possible to obtain all data, it may be 
necessary to impute missing data. In assessing the time to event endpoints, subjects who 
withdraw or never achieve resolution/alleviation, missing data will be censored using the date of 
subject’s last non-missing assessment. Additional details on the handling of missing data will be 
presented in the SAP. 


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13.8. 
Effectiveness 
13.8.1. 
Effectiveness Endpoints 
All effectiveness endpoints will be summarized using descriptive statistics by treatment group, 
age group, and study day/time, if appropriate. 
13.8.2. 
Effectiveness Analyses 
Time to resolution of fever, defined as a temperature < 99.4 oral or < 98.4 axillary with no 
antipyretic medications taken for at least 12 hours, will be estimated for each age group and 
overall by treatment group using the method of Kaplan-Meier. Subjects who do not achieve 
resolution of fever will be censored at the time of their last assessment. 
Time to resolution of influenza symptoms, defined as the time from initiation of study drug until 
the start of the 21.5-hour period (24 hours- 10%) where all symptoms of influenza are recorded 
as none or mild, will be estimated for each age group and treatment group using the method of 
Kaplan-Meier. Subjects who do not experience alleviation of symptoms will be censored at the 
time of the last non-missing symptom assessment. As the number and type of symptoms varies 
by age, the analysis of time to resolution of symptoms will not be presented as an overall 
assessment. 
Reduction in viral shedding will be assessed as the change from baseline in log10 TCID50/mL and 
RT-PCR, and will be summarized for each age group, treatment group and study visit. 
Changes in virus susceptibility to neuraminidase inhibitors between virus cultured at Baseline 
and the last post-treatment sample from which virus can be cultured will be assessed using 
virology laboratory tests. Virology laboratory tests will include phenotypic characterizations of 
influenza virus recovered (hemagglutinin and neuraminidase) and viral susceptibility to 
peramivir, and genotypic analysis of primary virus isolates. These analyses will be presented 
separately by age group and viral subtype. 
13.9. 
Safety Analyses 
Adverse Events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA)-
preferred term and system organ classification. The occurrence of treatment-emergent AEs 
(TEAEs) will be summarized by age group and treatment group using MedDRA-preferred terms, 
system organ classifications, and severity. All AEs will be listed for individual subjects showing 
both verbatim and preferred terms. Separate summaries of treatment-emergent SAEs and AEs 
related to study drug will be generated. 
Descriptive summaries of vital signs and clinical laboratory results will be presented by age 
group, treatment group and study visit. Laboratory abnormalities will be graded according to the 
DAIDS Table for Grading Adverse Events for Adults and Pediatrics (Publish Date: December 
2004 Clarification, 2009, see Appendix 1). The number and percentage of subjects experiencing 
treatment-emergent graded toxicities will be summarized by age group and treatment group. 
Laboratory toxicity shifts from baseline to post-baseline assessments will be summarized by age 
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Previous and concomitant medications will be mapped to a WHO preferred term and drug 
classification. The number and percent of subjects taking concomitant medications will be 
summarized using preferred terms and drug classifications. 
The number and percent of subjects experiencing influenza related complications will be 
summarized by age group and treatment group. 
Subject disposition will be presented for all subjects. The number of subjects who completed the 
study and discontinued from the study will be provided. The reasons for early discontinuation 
also will be presented. 
13.10. 
Exposure Response Analyses 
The data from the PK samples will be used together with data from prior trials to complete a 
separate exposure-response analysis. The methods for the exposure-response analysis will be 
presented in a separate SAP. 


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14. 
STUDY ADMINISTRATION 
14.1. 
Regulatory and Ethical Considerations 
14.1.1. 
Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; Good Clinical Practices (GCPs), 
including International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in 
accordance with the ethical principles of the Declaration of Helsinki. In addition, all applicable 
local laws and regulatory requirements relevant to the use of new therapeutic agents in the 
countries involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB) annually or more frequently if requested by the IRB. A final study 
notification will also be forwarded to the IRB after the study is completed or in the event of 
premature termination of the study in accordance with the applicable regulations. Copies of all 
contact with the IRB should be maintained in the study documents file. Copies of clinical study 
status reports (including termination) should be provided to BioCryst. 
14.1.2. 
Institutional Review Board Approvals 
Before initiation of the study at each investigational site, the protocol, the informed consent and 
assent forms, the subject information sheet, and any other relevant study documentation will be 
submitted to the appropriate IRB. Written approval of the study must be obtained before the 
investigational medicinal product is released to the Investigator and the study site may be opened 
for enrollment. Any necessary extensions or renewals of IRB approval must be obtained, in 
particular, for changes to the study such as modification of the protocol, the informed consent 
and assent forms, the written information provided to subjects/ parents/caregivers and/or other 
procedures. 
The Investigator will report promptly to the IRB any new information that may adversely affect 
the safety of the subjects or the conduct of the study. On completion of the study, the 
Investigator will provide the IRB with a report of the outcome of the study. 
14.1.3. 
Subject Informed Consent 
Signed informed consent must be obtained from each parent/caregiver prior to performing any 
study-related procedures. Similarly, subject assent by subjects ≥ 7 years will be obtained from 
each child or adolescent prior to performing any study-related procedures. If the local IRB or 
state requirements limit the age of assent, then assent will be obtained based on those 
requirements but in all cases assent will be obtained for adolescents 14 and older.  Each 
parent/caregiver should be given both verbal and written information describing the nature and 
duration of the clinical study. The informed consent process should take place under conditions 
where the parent/caregiver has adequate time to consider the risks and benefits associated with 
his/her child’s participation in the study. Subjects will not be screened or treated until the 
parent/caregiver has signed an approved informed consent form (ICF) written in a language in 
which the subject is fluent. 


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The ICF and assent form that is used must be approved both by BioCryst and by the reviewing 
IRB. The informed consent 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 potential subjects and their parent/ caregiver the aims, methods, 
reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may 
entail. Each parent/caregiver will be informed that they are free for their child not to participate 
in the trial and that they may withdraw consent for their child to participate at any time. They 
will be told that refusal for their child to participate in the study will not prejudice future 
treatment. They will also be told that their child’s records may be examined by competent 
authorities and authorized persons but that personal information will be treated as strictly 
confidential and will not be publicly available. 
Parents/caregivers and subjects must be given the opportunity to ask questions. After this 
explanation and before entry into the trial, consent should be appropriately recorded by means of 
the parent’s/caregiver’s dated signature. The parent/ caregiver should receive a signed and dated 
copy of the ICF, and, if applicable, the assent. 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. 
14.1.4. 
Payment to Subjects 
Reasonable compensation to parents/caregivers of study subjects may be provided if approved by 
the IRB responsible for the study at the Investigator’s site. 
14.1.5. 
Investigator Reporting Requirements 
The Investigator will provide timely reports regarding safety to his/her IRB as required. 
14.2. 
Study Monitoring 
During trial conduct, BioCryst or its designee will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed. The monitors may review source documents to 
confirm that the data recorded on CRFs is accurate. The Investigator and treating institution, if 
applicable, will allow BioCryst monitors or its designees and appropriate regulatory authorities 
direct access to source documents to perform this verification. 
14.3. 
Quality Assurance 
The trial site may be subject to review by the IRB, and/or to quality assurance audits performed 
by BioCryst, or designee, and/or to inspection by appropriate regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
14.4. 
Study Termination and Site Closure 
BioCryst reserves the right to discontinue the trial prior to inclusion of the intended number of 
subjects but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the Investigator must contact all participating subjects’ parents/ care givers 


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immediately after notification. As directed by BioCryst, all study materials must be collected and 
all case report forms completed to the greatest extent possible. 
14.5. 
Records Retention 
To enable evaluations and/or audits from regulatory authorities or BioCryst, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, case report forms and hospital records), all original signed informed consent and 
assent forms, copies of all case report forms and detailed records of treatment disposition. The 
records should be retained by the Investigator according to local regulations or as specified in the 
Clinical Trial Agreement, whichever is longer. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another Investigator, another 
institution, or to BioCryst. The Investigator must obtain BioCryst’s written permission before 
disposing of any records. 
14.6. 
Confidentiality of Information 
BioCryst affirms the subject’s right to protection against invasion of privacy. Only a subject 
identification number, initials and/or date of birth 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. 
BioCryst will ensure that the use and disclosure of protected health information obtained during 
a research study complies with the Health Insurance Portability and Accountability Act (HIPAA) 
Privacy Rule, where this rule is applicable. The Rule provides federal protection for the privacy 
of protected health information by implementing standards to protect and guard against the 
misuse of individually identifiable health information of subjects participating in BioCryst-
sponsored Clinical Trials. “Authorization” is required from each research subject, i.e., specified 
permission granted by an individual to a covered entity for the use or disclosure of an 
individual's protected health information. A valid authorization must meet the implementation 
specifications under the HIPAA Privacy Rule. Authorization may be combined in the Informed 
Consent document (approved by the IRB) or it may be a separate document, (approved by the 
IRB) or provided by the Investigator or Sponsor (without IRB approval). It is the responsibility 
of the Investigator and treating institution, if applicable, to obtain such waiver/authorization in 
writing from the appropriate individual. HIPAA authorizations are required for U.S. sites only. 


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14.7. 
Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict 
confidence along with all information furnished by BioCryst. Independent analysis and/or 
publication of these data by the Investigator or any member of his/her staff are not permitted 
without prior written consent of BioCryst. Written permission to the Investigator will be 
contingent on the review by BioCryst of the statistical analysis and manuscript and will provide 
for nondisclosure of BioCryst confidential or proprietary information. In all cases, the parties 
agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This 
will enable all parties to protect proprietary information and to provide comments based on 
information that may not yet be available to other parties. 


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W. Zhu, Z. Gao, N. Xiang, Y. Shen, Z. He, Y. Gu, Z. Zhang, Y. Yang, X. Zhao, L. Zhou, X. Li, 
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Jain, S., L. Kamimoto, A. M. Bramley, A. M. Schmitz, S. R. Benoit, J. Louie, D. E. Sugerman, J. 
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A. Rath, A. H. Rodriguez, E. B. Sarrouf, A. C. Seale, B. Sertogullarindan, M. M. Siqueira, J. 


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16. 
APPENDICES 
Appendix 1:  Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE 
Grading Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A 
grading (severity) scale is provided for each AE term. 
This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s provides 
additional explanation of the DAIDS AE Grading Table and clarifies some of the parameters.  
I. 
Instructions and Clarifications 
Grading Adult and Pediatric AEs 
The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs.  When a 
single set of parameters is not appropriate for grading specific types of AEs for both Adult and Pediatric 
populations, separate sets of parameters for Adult and/or Pediatric populations (with specified respective 
age ranges) are given in the Table.  If there is no distinction in the Table between Adult and Pediatric 
values for a type of AE, then the single set of parameters listed is to be used for grading the severity of 
both Adult and Pediatric events of that type.   
Note: In the classification of adverse events, the term “severe” is not the same as “serious.” 
Severity is an indication of the intensity of a specific event (as in mild, moderate, or severe chest 
pain). The term “serious” relates to a participant/event outcome or action criteria, usually 
associated with events that pose a threat to a participant’s life or functioning.  
Addenda 1-3 Grading Tables for Microbicide Studies 
For protocols involving topical application of products to the female genital tract, male genital area or 
rectum, strong consideration should be given to using Appendices I-III as the primary grading scales for 
these areas. The protocol would need to specifically state that one or more of the Appendices would be 
primary (and thus take precedence over the main Grading Table) for items that are listed in both the 
Appendix and the main Grading Table. 
• 
Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF 
Grade 5  
For any AE where the outcome is death, the severity of the AE is classified as Grade 5.   
Estimating Severity Grade for Parameters Not Identified in the Table 
In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the category 
“Estimating Severity Grade” located on Page 3. 
Determining Severity Grade for Parameters “Between Grades” 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could 
be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory value that is 
graded as a multiple of the ULN or LLN falls between two grades, select the higher of the two grades for 
the AE. For example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a parameter. If the lab value is 
2.53 x ULN (which is between the two grades), the severity of this AE would be Grade 2, the higher of the 
two grades. 
Values Below Grade 1  
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded.  
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Page 1 of 21
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DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 Ranges 
In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, even 
when there is a reference to the local lab LLN. 
For example: Phosphate, Serum, Low, Adult and Pediatric > 14 years (Page 20) Grade 1 range is 2.50 
mg/dL - < LLN. A particular laboratory’s normal range for Phosphate is 2.1 – 3.8 mg/dL. A participant’s 
actual lab value is 2.5.  In this case, the value of 2.5 exceeds the LLN for the local lab, but will be graded 
as Grade 1 per DAIDS AE Grading Table. 
. 
II.
Definitions of terms used in the Table:
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer/movement, 
continence, and feeding. 
Young Children 
Activities that are age and culturally appropriate (e.g., feeding self with 
culturally appropriate eating implement). 
LLN 
Lower limit of normal 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment of an AE. 
NA
Not Applicable
Operative Intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual Social & Functional 
Activities 
Adult 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Young Children 
Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
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DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE Grading 
Table  
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 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
SYSTEMIC 
Acute systemic 
Localized urticaria 
Localized urticaria with 
Generalized urticaria 
Acute anaphylaxis OR 
allergic reaction 
(wheals) with no 
medical intervention 
indicated 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
OR Angioedema with 
medical intervention 
indicated OR 
Symptomatic mild 
bronchospasm 
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 
Fatigue 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Incapacitating fatigue/ 
Malaise 
or minimal 
interference with 
usual social & 
functional activities 
greater than minimal 
interference with usual 
social & functional 
activities 
inability to perform usual 
social & functional 
activities 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C 
Pain (indicate body 
site) 
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain) 
See also Headache, 
Arthralgia, and 
Myalgia 
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 (other 
than emergency room 
visit) indicated 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.   
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).   
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 3 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Unintentional weight 
NA 
5 – 9% loss in body 
10 – 19% loss in body 
≥ 20% loss in body 
loss 
weight from baseline 
weight from baseline 
weight from baseline OR  
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
INFECTION 
Infection (any other 
Localized, no 
Systemic antimicrobial 
Systemic antimicrobial 
Life-threatening 
than HIV infection) 
systemic antimicrobial 
treatment indicated 
treatment indicated 
consequences (e.g., 
treatment indicated 
OR Symptoms 
AND Symptoms causing 
septic shock) 
AND Symptoms 
causing greater than 
inability to perform usual 
causing no or minimal 
minimal interference 
social & functional 
interference with 
with usual social & 
activities OR Operative 
usual social & 
functional activities 
intervention (other than 
functional activities 
simple incision and 
drainage) indicated 
INJECTION SITE REACTIONS 
Injection site pain 
Pain/tenderness 
Pain/tenderness 
Pain/tenderness 
Pain/tenderness causing 
(pain without touching) 
causing no or minimal 
limiting use of limb OR 
causing inability to 
inability to perform basic 
Or 
limitation of use of 
Pain/tenderness 
perform usual social & 
self-care function OR 
Tenderness (pain 
when area is touched)  
limb 
causing greater than 
minimal interference 
with usual social & 
functional activities 
functional activities 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction (localized) 
Adult > 15 years 
Erythema OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm2 – 81cm2) 
Erythema OR 
Induration OR Edema 
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Pediatric ≤ 15 
Erythema OR 
Erythema OR 
Erythema OR Induration 
Necrosis (involving 
years 
Induration OR Edema 
Induration OR Edema 
OR Edema involving 
dermis and deeper 
present but ≤ 2.5 cm 
> 2.5 cm diameter but 
≥ 50% surface area of 
tissue) 
diameter 
< 50% surface area of 
the extremity segment 
the extremity segment 
(e.g., upper arm/thigh) 
(e.g., upper arm/thigh) 
OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.   
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).   
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
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Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pruritis associated 
with injection  
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to 
injection site AND 
Relieved 
spontaneously or with 
< 48 hours treatment  
Itching beyond the 
injection site but not 
generalized OR Itching 
localized to injection 
site requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable 
by study participant 
(or by caregiver for 
young children and 
disabled adults) 
Thinning or patchy hair 
loss detectable by 
health care provider 
Complete hair loss 
NA 
Cutaneous reaction – 
rash 
Localized macular 
rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no 
skin lesions) 
(See also Injection 
Site Reactions: 
Pruritis associated 
with injection) 
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 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
exam) 
Asymptomatic AND 
No intervention 
indicated 
Asymptomatic AND 
Non-urgent medical 
intervention indicated 
Symptomatic, non-life­
threatening AND Non-
urgent medical 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Cardiac­
ischemia/infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR 
Testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).   
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
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Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
PARAMETER 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY 
 
LIFE-THREATENING 
Hemorrhage 
NA 
Symptomatic AND No 
Symptomatic AND 
 
Life-threatening 
(significant acute 
 
transfusion indicated 
Transfusion of ≤ 2 units 
hypotension OR 
blood loss) 
packed RBCs (for 
Transfusion of > 2 units 
children ≤ 10 cc/kg) 
packed RBCs (for 
indicated  
children > 10 cc/kg) 
indicated 
Hypertension 
 
Adult > 17 years 
140 – 159 mmHg 
160 – 179 mmHg 
 
≥ 
 
180 mmHg systolic 
 
Life-threatening 
 
systolic 
systolic 
consequences (e.g., 
(with repeat testing 
OR 
malignant hypertension) 
at same visit) 
OR 
OR 
 
≥ 
 
110 mmHg diastolic 
OR Hospitalization 
 
90 – 99 mmHg 
100 – 109 mmHg 
 
indicated (other than 
 
diastolic 
 
diastolic 
emergency room visit) 
 
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to ≥ 100 -109 from > 100-109 (diastolic) and  
  
in Grade 3 to ≥ 
 
  
180 from > 180 (systolic) and to ≥ 
 
110 from > 110 (diastolic). 
91st 
94th
Pediatric ≤ 17 
NA 
– 
 percentile 
≥ 95th percentile 
 
Life-threatening 
 
years 
adjusted for age, 
adjusted for age, height, 
consequences (e.g., 
height, and gender 
and gender (systolic 
malignant hypertension) 
(with repeat 
 
(systolic and/or 
and/or diastolic) 
OR Hospitalization 
 
testing at same 
 
diastolic) 
indicated (other than 
visit) 
emergency room visit) 
 
Hypotension 
 
NA 
Symptomatic, 
Symptomatic, IV fluids 
Shock requiring use of 
 
corrected with oral 
 
indicated 
vasopressors or 
fluid replacement 
mechanical assistance 
to maintain blood 
 
pressure 
 
 
Pericardial effusion 
Asymptomatic, small 
Asymptomatic, 
Effusion with non-life 
 
Life-threatening 
effusion requiring no 
moderate or larger 
threatening physiologic 
consequences (e.g., 
intervention 
effusion requiring no 
consequences OR 
tamponade) OR Urgent 
intervention 
Effusion with non-urgent 
intervention indicated 
 
intervention indicated 
 
 
Prolonged PR interval 
 
Adult > 16 years 
PR interval 
PR interval 
Type II 2nd degree AV 
Complete AV block 
0.21 – 0.25 sec 
> 0.25 sec 
block OR Ventricular 
pause > 3.0 sec 
 
Pediatric ≤ 16 
1st degree AV block 
Type I 2nd degree AV 
Type II 2nd degree AV 
Complete AV block 
 
years 
(PR > normal for age 
block 
block 
and rate) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).   
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 6 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
PARAMETER 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY 
 
LIFE-THREATENING 
Prolonged QTc 
Adult > 16 years 
Asymptomatic, QTc 
Asymptomatic, QTc 
Asymptomatic, QTc 
 
Life-threatening 
interval 0.45 – 0.47 
interval 0.48 – 0.49 
 
interval ≥ 0.50 sec OR 
consequences, e.g. 
 
sec OR Increase 
sec OR Increase in 
Increase in interval  
Torsade de pointes or 
interval < 0.03 sec 
interval 0.03 – 0.05 
≥ 0.06 sec above 
other associated serious 
above baseline 
 
sec above baseline 
baseline 
ventricular dysrhythmia 
Pediatric ≤ 16 
Asymptomatic, QTc 
Asymptomatic, QTc 
Asymptomatic, QTc 
 
Life-threatening 
years 
interval 0.450 –  
interval 0.465 –  
 
interval ≥ 0.480 sec  
consequences, e.g.  
0.464 sec  
0.479 sec  
Torsade de pointes  or 
other associated serious 
ventricular dysrhythmia 
Thrombosis/embolism 
NA 
Deep vein thrombosis 
Deep vein thrombosis 
Embolic event (e.g., 
AND No intervention 
AND Intervention 
pulmonary embolism, 
indicated (e.g., 
indicated (e.g., 
 
life-threatening 
anticoagulation, lysis 
anticoagulation, lysis 
thrombus) 
 
filter, invasive 
 
filter, invasive 
procedure)  
procedure)  
Vasovagal episode 
Present without loss 
Present with transient 
NA 
NA 
 
(associated with a 
of consciousness 
 
loss of consciousness 
procedure of any kind) 
Ventricular 
NA 
Asymptomatic 
 
New onset with 
 
Life-threatening 
 
dysfunction 
diagnostic finding AND 
symptoms OR 
congestive heart failure 
(congestive heart 
intervention indicated 
Worsening symptomatic 
failure) 
congestive heart failure 
GASTROINTESTINAL 
 
Anorexia 
Loss of appetite 
Loss of appetite 
Loss of appetite 
 
Life-threatening 
without decreased 
 
associated with 
 
associated with 
consequences OR 
 
oral intake 
 
decreased oral intake 
 
significant weight loss 
Aggressive intervention 
without significant 
indicated [e.g., tube 
 
weight loss 
 
feeding or total 
parenteral nutrition 
(TPN)] 
 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when 
grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment.  
Ascites 
Asymptomatic 
Symptomatic AND 
Symptomatic despite 
 
Life-threatening 
Intervention indicated 
intervention 
consequences 
(e.g., diuretics or 
therapeutic 
paracentesis) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).   
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 7 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
Radiologic, endoscopic, 
or operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis or 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 
Adult and 
Pediatric ≥ 1 year 
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 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pediatric < 1 year 
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 
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR 
Hypotensive shock 
Dysphagia-
Odynophagia  
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral intake 
Mucositis/stomatitis  
(clinical exam) 
Indicate site (e.g., 
larynx, oral) 
See Genitourinary for 
Vulvovaginitis  
Erythema of the 
mucosa 
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
See also Dysphagia-
Odynophagia and 
Proctitis 
Nausea 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 8 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional-
Rectal discomfort 
Symptoms causing 
Symptoms causing 
Life-threatening 
symptomatic) 
AND No intervention 
greater than minimal 
inability to perform usual 
consequences (e.g., 
Also see 
indicated 
interference with usual 
social & functional 
perforation) 
Mucositis/stomatitis  
social & functional 
activities OR Operative 
for clinical exam 
activities OR Medical 
intervention indicated 
intervention indicated 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting 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) 
NEUROLOGIC 
Alteration in 
Alteration causing no 
Alteration causing 
Alteration causing 
Behavior potentially 
personality-behavior 
or minimal 
greater than minimal 
inability to perform usual 
harmful to self or others 
or in mood (e.g., 
interference with 
interference with usual 
social & functional 
(e.g., suicidal and 
agitation, anxiety, 
usual social & 
social & functional 
activities 
homicidal ideation or 
depression, mania, 
functional activities  
activities 
attempt, acute 
psychosis) 
psychosis) OR Causing 
inability to perform basic 
self-care functions 
Altered Mental Status  
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
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 
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with 
usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities  
Disabling ataxia causing 
inability to perform basic 
self-care functions 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 9 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder)  
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 
CNS ischemia 
(acute) 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (CVA, stroke) 
with neurological deficit  
Developmental delay 
– Pediatric ≤ 16 
years 
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 
(other than emergency 
room visit) OR 
Headache with 
significant impairment of 
alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities 
Disabling insomnia 
causing inability to 
perform basic self-care 
functions 
Neuromuscular 
weakness  
(including myopathy & 
neuropathy)  
Asymptomatic with 
decreased strength 
on exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with 
usual social & 
functional activities 
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 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 10 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Neurosensory 
Asymptomatic with 
Sensory alteration or 
Sensory alteration or 
Disabling sensory 
alteration (including 
sensory alteration on 
paresthesia causing 
paresthesia causing 
alteration or paresthesia 
paresthesia and 
exam or minimal 
greater than minimal 
inability to perform usual 
causing inability to 
painful neuropathy) 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional activities  
interference with usual 
social & functional 
activities 
social & functional 
activities 
perform basic self-care 
functions 
Seizure: (new onset) 
NA 
1 seizure  
2 – 4 seizures  
Seizures of any kind 
– Adult ≥ 18 years 
which are prolonged, 
See also Seizure: 
repetitive (e.g., status 
(known pre-existing 
epilepticus), or difficult 
seizure disorder) 
to control (e.g., 
refractory epilepsy) 
Seizure: (known pre­
existing seizure 
disorder) 
– Adult ≥ 18 years 
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of these 
levels. 
NA 
Increased frequency of 
pre-existing seizures 
(non-repetitive) without 
change in seizure 
character OR 
Infrequent break­
through seizures while 
on stable medication 
in a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or  
focality)  
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure  
Seizure, generalized 
Seizure, generalized 
Seizure, generalized 
Seizure, generalized 
– Pediatric < 18 
onset with or without 
onset with or without 
onset with or without 
onset with or without 
years 
secondary 
generalization, lasting 
< 5 minutes with < 24 
hours post ictal state 
secondary 
generalization, lasting 
5 – 20 minutes with 
< 24 hours post ictal 
state 
secondary 
generalization, lasting  
> 20 minutes 
secondary 
generalization, requiring 
intubation and sedation 
Syncope (not 
associated with a 
procedure) 
NA 
Present 
NA 
NA 
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 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
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Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to  
70 – 80% 
FEV1 or peak flow 
50 – 69% 
FEV1 or peak flow 
25 – 49% 
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities  
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities  
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support 
indicated 
Pediatric < 14 
years 
Wheezing OR 
minimal increase in 
respiratory rate for 
age 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
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 
See also Arthralgia 
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 
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score 
-2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
Pediatric < 21 
years 
BMD z-score 
-2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
Myalgia 
(non-injection site) 
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 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
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Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain 
with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
GENITOURINARY 
Cervicitis 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Symptoms causing 
(symptoms) 
or minimal 
greater than minimal 
inability to perform usual 
inability to perform basic 
(For use in studies 
interference with 
interference with usual 
social & functional 
self-care functions 
evaluating topical  
usual social & 
social & functional 
activities 
study agents) 
functional activities  
activities 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
Cervicitis 
Minimal cervical 
Moderate cervical 
Severe cervical 
Epithelial disruption 
(clinical exam) 
abnormalities on 
abnormalities on 
abnormalities on 
> 75% total surface 
(For use in studies 
examination 
examination 
examination (erythema, 
evaluating topical  
(erythema, 
(erythema, 
mucopurulent 
study agents) 
mucopurulent 
mucopurulent 
discharge, or friability) 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
discharge, or friability) 
OR Epithelial 
disruption  
< 25% of total surface 
discharge, or friability) 
OR Epithelial 
disruption of 25 – 49% 
total surface 
OR Epithelial disruption 
50 – 75% total surface 
Inter-menstrual 
Spotting observed by 
Inter-menstrual 
Inter-menstrual bleeding 
Hemorrhage with life-
bleeding (IMB) 
participant OR 
bleeding not greater in 
greater in duration or 
threatening hypotension 
Minimal blood 
duration or amount 
amount than usual 
OR Operative 
observed during 
than usual menstrual 
menstrual cycle 
intervention indicated 
clinical or colposcopic 
cycle 
examination 
Urinary tract 
NA 
Signs or symptoms of 
Signs or symptoms of 
Obstruction causing life-
obstruction (e.g., 
urinary tract 
urinary tract obstruction 
threatening 
stone) 
obstruction without 
hydronephrosis or 
renal dysfunction 
with hydronephrosis or 
renal dysfunction 
consequences 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
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Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vulvovaginitis  
(symptoms) 
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
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 
Vulvovaginitis  
(clinical exam) 
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
< 25% of total surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption of 
25 - 49% total surface 
Severe vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
50 - 75% total surface 
Vaginal perforation OR 
Epithelial disruption 
> 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention indicated 
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Visual changes (from 
Visual changes 
Visual changes 
Visual changes causing 
Disabling visual loss in 
baseline) 
causing no or minimal 
interference with 
usual social & 
functional activities 
causing greater than 
minimal interference 
with usual social & 
functional activities 
inability to perform usual 
social & functional 
activities 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
Detectable by study 
Detectable on physical 
Disfiguring OR Obvious 
NA 
accumulation 
participant (or by 
exam by health care 
changes on casual 
(e.g., back of neck, 
caregiver for young 
provider 
visual inspection 
breasts, abdomen) 
children and disabled 
adults) 
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of current 
medications to regain 
glucose control 
New onset with initiation 
of medication indicated 
OR Diabetes 
uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non­
ketotic coma) 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 14 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Gynecomastia 
Detectable by study 
participant or 
caregiver (for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic 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 
Asymptomatic 
Symptomatic 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) 
Lipoatrophy 
(e.g., fat loss from the 
face, extremities, 
buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.  
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally  
appropriate eating implement).  
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking,  
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
28 Dec 04/Clarification Aug 09 
Page 15 of 21
 
 
Version 1.0/Clarification 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute CD4+ count 
– Adult and Pediatric 
> 13 years 
(HIV NEGATIVE ONLY) 
300 – 400/mm3 
300 – 400/µL 
200 – 299/mm3 
200 – 299/µL 
100 – 199/mm3 
100 – 199/µL 
< 100/mm3 
< 100/µL 
Absolute lymphocyte 
count 
– Adult and Pediatric 
> 13 years 
(HIV NEGATIVE ONLY) 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
< 350/mm3 
< 0.350 x 109/L 
Comment:  Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are variable. 
Absolute neutrophil count (ANC)  
Adult and Pediatric, 
> 7 days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
< 500/mm3 
< 0.500 x 109/L 
Infant∗† , 2 – ≤ 7 days 
1,250 – 1,500/mm3 
1.250 x 109 – 
1.500 x 109/L 
1,000 – 1,249/mm3 
1.000 x 109 – 
1.249 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
< 750/mm3 
< 0.750 x 109/L 
Infant∗† , ≤1 day 
4,000 – 5,000/mm3 
4.000 x 109 – 
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 – 
3.999 x109/L 
1,500 – 2,999/mm3 
1.500 x 109 – 
2.999 x 109/L 
< 1,500/mm3 
< 1.500 x 109/L 
Comment:  Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 50 mg/dL  
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR 
Associated with gross 
bleeding  
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
Page 16 of 21
 Version 1.0/Clarification 1  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor).  For grading Hgb results obtained by an analytic 
method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor 
for that lab. 
Adult and Pediatric 
≥ 57 days 
(HIV POSITIVE ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62–5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03–4.61 mmol/L 
< 6.5 g/dL 
< 4.03 mmol/L 
Adult and Pediatric 
≥ 57 days 
(HIV NEGATIVE 
ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR 
Any decrease  
2.5 – 3.4 g/dL 
1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease  
3.5 – 4.4 g/dL 
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 
4.34 - 5.54 mmol/L 
OR 
Any decrease  
≥ 4.5 g/dL 
> 2.79 mmol/L 
< 7.0 g/dL 
< 4.34 mmol/L 
Comment: The decrease is a decrease from baseline 
Infant∗†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
5.24 – 5.86 mmol/L 
7.0 – 8.4 g/dL 
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL 
3.72 – 4.30 mmol/L 
< 6.00 g/dL 
< 3.72 mmol/L 
Infant∗†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
5.87 - 6.54 mmol/L 
8.0 – 9.4 g/dL 
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL 
4.34 – 4.92 mmol/L 
< 7.00 g/dL 
< 4.34 mmol/L 
Infant∗† , ≤ 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL 
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL 
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL 
5.59- 6.17 mmol/L 
< 9.0 g/dL 
< 5.59 mmol/L 
Correction:  Parameter changed from “Infant < 21 days” to “Infant ≤ 21 days” 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 – 
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 – 
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 – 
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 
1.999 x 109/L 
1,000 – 1,499/mm3 
1.000 x 109 – 
1.499 x 109/L 
< 1,000/mm3 
< 1.000 x 109/L 
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
Page 17 of 21
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DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
CHEMISTRIES 
 
Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Comment:  Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). These 
are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant∗† , ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant∗† , ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high 
Adult and Pediatric 
≥ 7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Infant∗†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low 
Adult and Pediatric 
≥ 7 days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
Infant∗†, < 7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Comment:  Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
Page 18 of 21
 Version 1.0/Clarification 1  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL 
OR 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
Adult and Pediatric 
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Infant∗†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
ULN - < 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  
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
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 Version 1.0/Clarification 1  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Comment: Added ULN to Grade 1 parameter  
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Pediatric > 2 - < 18 
years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric 
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 
years  
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
≤ 120 mEq/L 
≤ 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
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 Version 1.0/Clarification 1  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF   
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS 
Standard International Units are listed in italics 
Hematuria (microscopic)
 6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC 
casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric 
≥ 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
> 3.500 g/d 
Pediatric > 3 mo - 
< 10 years 
201 – 499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 h 
0.500 – 0.799 g/d 
800 – 1,000 
mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 h 
> 1.000 g/d 
∗ Values are for term infants.  Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).  
28 Dec-04/Clarification Aug 09 
Page 21 of 21
 Version 1.0/Clarification 1  

SAP_001.pdf: 
BioCryst Pharmaceuticals, Inc. 
BCX1812-305 
 
Statistical Analysis Plan                                                                                                              Final Version 1.0 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 3, Randomized, Open Label, Active-Controlled Study 
to Evaluate the Safety, Pharmacokinetics and Effectiveness of 
IV Peramivir Compared to Oral Oseltamivir in Pediatric 
Subjects with Acute Uncomplicated Influenza 
 
 
Phase: 
3 
 
 
Protocol No.: 
BCX1812-305  
 
 
Protocol Date 
05 November 2014 (Version 1.0) 
 
01 December 2014 (Version 2.0) 
 
21 June 2015 (Version 3.0) 
 
 
 
 
 
 
Analysis Plan Version and 
Date 
Final Version 1.0  11 July 2016 
 
 
Prepared By: 
Amy Flynt, PhD 
PharPoint Research, Inc. 
5003 South Miami Blvd., Suite 100 
Durham, NC 27703 
 
 
Prepared For: 
BioCryst Pharmaceuticals, Inc. (BioCryst) 
4505 Emperor Boulevard, Suite 200 
Durham, NC 27703 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION




BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
CONFIDENTIAL 
Page 3 
11 July 2016 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ............................. 2 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 5 
2. 
INTRODUCTION ............................................................................................ 6 
2.1. 
Study Overview ...................................................................................................................... 6 
2.2. 
Schedule of Events/Study Visits .............................................................................................. 9 
3. 
OBJECTIVES ................................................................................................ 11 
4. 
GENERAL STATISTICAL CONSIDERATIONS ........................................... 11 
4.1. 
Sample size and power .......................................................................................................... 11 
4.2. 
Randomization and Masking ................................................................................................ 11 
4.3. 
Handling of data ................................................................................................................... 11 
4.3.1. 
Strata and Covariates .......................................................................................................... 11 
4.3.2. 
Examination of Subject Subsets ........................................................................................... 11 
4.3.3. 
Multiple Testing and Comparisons ...................................................................................... 12 
4.3.4. 
Missing Data and Outliers ................................................................................................... 12 
4.3.5. 
Imputation of Incomplete Dates ........................................................................................... 12 
4.3.6. 
By Study Visit Displays ...................................................................................................... 13 
4.3.7. 
Derived and Transformed Data ............................................................................................ 13 
4.3.8. 
Definitions and Terminology ............................................................................................... 13 
4.4. 
TIMING OF ANALYSES ..................................................................................................... 16 
5. 
ANALYSIS POPULATIONS .......................................................................... 16 
5.1. 
Intent-to-Treat Population .................................................................................................... 16 
5.2. 
Intent-to-Treat Infected Population ...................................................................................... 16 
5.3. 
Safety Population .................................................................................................................. 16 
5.4. 
Exposure-Response Population ............................................................................................. 17 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
CONFIDENTIAL 
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5.5. 
Virology population .............................................................................................................. 17 
6. 
STATISTICAL METHODS ........................................................................... 17 
6.1. 
Subject Disposition, Demographic and Baseline Characteristics ............................................ 17 
6.2. 
Effectiveness Analysis ........................................................................................................... 18 
6.2.1. 
Effectiveness Endpoints ...................................................................................................... 18 
6.2.2. 
Effectiveness Analyses ....................................................................................................... 18 
6.2.3. 
Exploratory Exposure Response Analyses ............................................................................ 19 
6.2.4. 
Subgroup Analyses ............................................................................................................. 19 
6.3. 
Safety.................................................................................................................................... 20 
6.3.1. 
Adverse Events .................................................................................................................. 20 
6.3.2. 
Concomitant Medications ................................................................................................... 20 
6.3.3. 
Clinical Laboratory Assessments ......................................................................................... 20 
6.3.4. 
Other Safety Analyses ........................................................................................................ 21 
6.4. 
Protocol deviations ............................................................................................................... 21 
7. 
CHANGES IN THE PLANNED ANALYSES .................................................. 21 
8. 
REVISION HISTORY .................................................................................... 21 
9. 
PROGRAMMING CONVENTIONS .............................................................. 22 
10. 
PROPOSED TABLES, LISTINGS, AND FIGURES FOR FINAL ANALYSIS
 
24 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
 
 
CONFIDENTIAL 
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1. 
GLOSSARY OF ABBREVIATIONS 
AE  
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCX-1812 
Peramivir 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CRF 
case report form 
DAIDS 
Division of Acquired Immunodeficiency Syndrome, National Institute of 
Allergy and Infectious Diseases, National Institutes of Health 
FDA 
Food and Drug Administration 
HGB 
hemoglobin 
IRC 
influenza-related complications 
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCR 
polymerase chain reaction 
PK 
Pharmacokinetic 
RAT 
rapid antigen test 
SD 
standard deviation 
TCID50 
Tissue-culture infective dose50 
TEAEs 
treatment-emergent adverse events 
TWAUC 
time-weighted area under the curve 
WHO 
World Health Organization 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
 
 
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2. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of data from Protocol BCX1812-305.  Background information is provided for the 
overall study design and objectives.  The reader is referred to the study protocol and case report 
forms (CRFs) for details of study conduct and data collection. 
This document describes all analyses of safety, clinical effectiveness, pharmacokinetics and 
virology analyses. Pharmacokinetic and virology analyses will be written as separate reports from 
the clinical study report.  
2.1. 
STUDY OVERVIEW 
Protocol BCX1812-305 is a multicenter, randomized, open-label, active-controlled study to 
evaluate the safety, pharmacokinetics and effectiveness of a single dose of intravenous (IV) 
peramivir (600 mg IV or 12 mg/kg IV depending on age) compared to oral oseltamivir (dosed BID 
for 5 days) in children with uncomplicated acute influenza.  Approximately 140 subjects will be 
enrolled. Up to 10 subjects ages from birth to <– 28- days will be enrolled and will receive a single 
dose of intravenous (IV) peramivir 12 mg/kg.  Up to 20 subjects 28 days to less than 2 years old 
will be enrolled.  Subjects enrolled in this cohort prior to version 4.0 of the protocol will be 
randomized 4:1 (4 IV peramivir: 1 oral oseltamivir) whereas subjects enrolling in this cohort under 
version 4.0 or higher of the protocol will receive IV peramivir 12mg/kg.  Up to 110 subjects 2 
years to < 18 years of age will be randomized 4:1 (4 IV peramivir: 1 oral oseltamivir) according to 
the following age groups: 
• 
2 years - < 7 years: up to 40 subjects 
• 
7 years - < 13 years: up to 40 subjects 
• 
13 years - < 18 years: up to 30 subjects 
Eligible subjects with have clinical signs and symptoms consistent with acute influenza infection 
consisting of an oral temperature ≥ 100°F or rectal temperature ≥ 101.3°F with at least one 
respiratory symptom (cough or rhinitis) OR a positive influenza rapid antigen test (RAT).  
Enrollment of eligible subjects based on clinical symptoms alone will be approved by the Sponsor 
at the beginning of each influenza season.   
The formulation of the peramivir drug to be used in this study contains peramivir at a concentration 
of 10 mg/mL.  The peramivir 10 mg/mL stock solution will be diluted in saline using aseptic 
techniques with a maximum volume of 100 mL.  Oseltamivir will be prepared and administered in 
accordance with the manufacturer's instructions.   
Subjects will record temperature, influenza symptoms, date and time of oral oseltamivir dose 
administration (if applicable), the ability to return to day care/school and/or resume their normal 
daily activities, appetite and eating patterns, and doses of symptomatic relief medication in a 
Subject Diary.  Temperature measurements will be taken every 12 hours until temperature 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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normalizes for 48 hours (i.e., temperature without antipyretic is < 99.4 orally in children ≥ 6 and < 
98.4 axillary in children < 6 years old for 4 measurements).  Subjects 7 years of age and older will 
have the following 7 influenza symptoms recorded using a 4-point severity scale twice daily 
beginning pre-dose on Day 1 assessment until symptom resolution and through the last follow-up 
visit (whichever comes first): cough, sore throat, nasal obstruction, myalgia, headache, 
feverishness, and fatigue.  Subjects ≥ 4 and ≤ 6 years of age will have the following 7 influenza 
symptoms recorded using a 4-point severity scale twice daily beginning pre-dose on Day 1 
assessment until symptom resolution and through the last follow-up visit (whichever comes first): 
cough, sore throat, nasal obstruction, myalgia, headache, feverishness, fatigue/malaise, and 
gastrointestinal symptoms (nausea, vomiting, or diarrhea).  Subjects 28 days to < 4 years old will 
have the following 5 influenza symptoms recorded using a 4-point severity scale twice daily 
beginning pre-dose on Day 1 assessment until symptom resolution and through the last follow-up 
visit (whichever comes first): cough, rhinitis, feverishness, malaise/irritability, and gastrointestinal 
symptoms (nausea, vomiting, or diarrhea). 
Subjects will undergo follow-up assessments on Days 3, 7, and 14. The Day 3 visit may be a home 
visit (performed by a qualified study nurse). Day 7 is required to take place in the clinic, and Day 
14 may either be a clinic visit, home visit, or follow-up phone call to the subject/parent/guardian. 
An adequate nasal swab specimen will be collected from all enrolled subjects on Day 1 prior to 
dosing and at the follow-up assessments on study Days 3, 7, and 14 for virus sub-type 
identification and quantitative virologic assessments.   Specimens from all subjects yielding 
influenza virus will also be assessed for susceptibility to neuraminidase inhibitors (Day 1 and last 
specimen yielding influenza virus on culture).   
Plasma samples for determination of drug concentration on subjects randomized to peramivir will 
be drawn as follows:  
 
Up to 4 blood samples will be drawn, where possible, during the following time periods, 
beginning from the end of dosing until release from the site:  
o One time point immediately following completion of the infusion  
o One time point from 30 minutes to 1 hour post-infusion  
o One time point from 1 hour to 3 hours post-infusion  
o One time point from 3 hours to 6 hours post-infusion  
Adverse events, physical examinations, laboratory tests, concomitant medications, and vital signs 
will be used to monitor subject safety, while daily subject-rated assessments of influenza symptoms 
and viral titers will be measured to determine effectiveness.  The primary safety endpoints include 
the incidence of treatment-emergent adverse events and treatment-emergent changes in clinical 
laboratory test.  The secondary effectiveness endpoints include the time to alleviation of clinical 
symptoms of influenza (per age appropriate symptoms), defined as the start of the time period 
when all of the symptoms assessed are either absent or are present at no more than mild severity 
level and at this status for a 21.5 hour (24 hours – 10%) period, time to resolution of fever, change 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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in influenza virus titer by log10 tissue culture infective dose50/mL (TCID50), and change in viral 
sensitivity.   


 
 
2.2. SCHEDULE OF EVENTS/STUDY VISITS 
Assessments 
Screening 1 
 
Baseline1 
Pre-Dose 
Day 11 
Post-Dose 
Day 32 
Day 7 
(±2 day) 
Day 142 
(±3 day) 
End of Study 
Early 
Withdrawal3 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Pregnancy Test (Urine)4 
X 
 
 
 
X 
 
X 
Medical History 
X 
 
 
 
 
 
 
Body Temperature5 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
Influenza-related complications (IRC) 
checklist6 
 
X 
 
X 
X 
X 
X 
Vital Signs7 
 
X 
 
X 
X 
X 
X 
Concomitant Medications Review8 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistries and Hematology9 
 
X 
 
 
X 
 
X 
Urinalysis9 
 
X 
 
 
X 
 
X 
Assessment of influenza symptoms/ 
activities of daily living/ eating habits10 
 
X 
X 
X 
X 
X 
X 
Subject Diary Completion/ Review11 
 
X 
X 
X 
X 
X 
X 
Nasal swabs for Virology Analysis12 
 
X 
 
X 
X 
X 
X 
Study Drug Administration13 
 
X 
 
 
 
 
 
Serum sample for influenza antibody 
analysis14 
 
X 
 
 
X 
 
 
Pharmacokinetic (PK) Sampling15 
 
 
X 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X16 
X16 
Study Measurements and Visit Schedule Figure Legend on Next Page 


 
 
Study Measurements and Visit Schedule Figure Legend 
1  It is expected that the date of Screening, Baseline, and Day 1 (date of administration of study drug) will be the same. 
2  The Day 3 visit may be performed as a clinic visit or home visit (conducted by a qualified study nurse).  The Day 14 visit may be performed as a home 
visit, clinic visit, or phone call.  In the event the Day 14 assessment is a phone call the parent/caregiver will be requested to mail the completed diary 
card back to the site.  
3  An Early Withdrawal assessment should be conducted for subjects who withdraw before Day 7.  For subjects who withdraw between Day 7 and Day 14 
a telephone assessment should be completed, where possible. 
4  Urine pregnancy test will be performed for any female post-menarche.  
5  The screening temperature may be performed per the site's standard method, which will be recorded.  For subsequent visits, the parent/guardian will 
record oral or axillary temperature with the electronic thermometer provided by BioCryst.  Thereafter, the parent/caregiver will record temperature in 
the Subject Diary approximately every 12 hours until temperature is normal for 48 hours without antipyretic. 
6  If an IRC is suspected then a targeted physical examination and if needed, diagnostic testing will be conducted to record the actual presence/absence of 
the IRC. 
7  Vital sign measures will include blood pressure (in children <2 only if clinically indicated), pulse rate and respiration rate.  Vital signs will be recorded 
at Baseline, and vital signs will be taken once on remaining study visits.  
8  Antipyretic medications will be recorded in the Subject Diary by the parent/caregiver daily from Day 1 through Day 14. 
9  Clinical laboratory assessments performed at Baseline (by a local lab) are for the purpose of establishing a baseline.  Subject may be enrolled and begin 
treatment with study drug prior to receiving results. 
10  The severity of age appropriate influenza signs and symptoms will be recorded by the parent/caregiver in the Subject Diary twice daily, until all 
symptoms are resolved (Grade 0).  Assessments  of activities of daily living and eating habits will be recorded once daily until all symptoms are 
resolved. 
11   On Day 1, the parents/caregivers of subjects and/or adolescent subjects are to be provided training by the study staff on completing the Subject Diary.  
Instructions will be reviewed with the adolescent subject or parent/caregiver at each study visit.  
12  Swabs for virology analysis will be collected on Day 14 where possible.  
13  Only for those subject randomized to peramivir.  The parents/caregivers of subject randomized to the oral oseltamivir arm of the study, will record the 
date and time of each drug administration, from Day 1 until Day 5 (or last scheduled dose).  The first dosing will be administered at the site and 
documented by the study staff following completion of required predose activities.  
14  A single serum specimen will be collected, where possible, pre-dose on Day 1 and on Day 7 for analysis of influenza antibody titers. .  
15  Only for those subjects randomized to peramivir.  A PK sample will be drawn immediately following the end of study drug infusion/administration, 
between 30 minutes to 1 hour post-infusion, between 1 and 3 hours post-infusion, and between 3 and 6 hours post-infusion.  
16  Any subject with unresolved moderate or severe intensity influenza symptoms or an unresolved AE and/or treatment-emergent laboratory finding that 
requires further medical management may be evaluated in further follow-up visits, at the Investigator's discretion. 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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3. 
OBJECTIVES 
The primary objective of the study is to evaluate the safety of IV peramivir compared to oral 
oseltamivir in pediatric subjects with acute uncomplicated influenza. 
 
The following secondary objectives are planned for this study. 
• 
To describe the pharmacokinetics of IV peramivir in pediatric subjects with influenza. 
• 
To evaluate the effectiveness of IV peramivir compared to oral oseltamivir in pediatric 
subjects with influenza. 
• 
To evaluate the incidence of influenza complications, specifically otitis media, sinusitis, 
bronchitis or pneumonia requiring antibiotic use diagnosed after initiation of treatment. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
SAMPLE SIZE AND POWER 
The study is designed to evaluate the safety and pharmacokinetics of IV administration of 
peramivir in pediatric subjects with influenza.  A formal sample size calculation was not 
performed. 
4.2. 
RANDOMIZATION AND MASKING 
Approximately 140 subjects will be enrolled. Up to 10 subjects from birth to < 28 days will be 
enrolled to receive a single dose of IV peramivir. Up to 20 subjects from 28 days to < 2 years will 
either be randomized to 1 of 2 treatment arms at a ratio of 4:1 or will receive a single dose of IV 
peramivir.  Up to 110 subjects from 28-days to < 18 years of age will be randomized to 1 of 2 
treatment arms at a ratio of 4:1: 
• 
Treatment Group 1: A single dose of IV peramivir 
• 
Treatment Group 2: Oral oseltamivir given BID for 5 days 
This is an open label study and as such, blinding is not applicable.   
4.3. HANDLING OF DATA 
4.3.1. Strata and Covariates 
Analyses will be presented by the stratification factor of age group at randomization. 
4.3.2. Examination of Subject Subsets 
Some analyses will be displayed by viral subtype at Screening. 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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4.3.3. Multiple Testing and Comparisons  
All analyses will be conducted without adjustments for multiple testing. 
4.3.4. 
Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized.  No attempt will be made retrospectively to obtain missing subject 
reported data (such as influenza symptom severity assessments, temperature, and injection site 
discomfort) that has not been completed by the subject at the time of return of the subject diary to 
the investigative site.  In situations where it is not possible to obtain all data, it may be necessary to 
impute missing data, as described in the following paragraph.   
In assessing the effectiveness endpoint of time to alleviation of symptoms, for subjects who 
withdraw or who do not experience alleviation of symptoms, missing data will be censored using 
the date of subject’s last non-missing assessment of influenza symptoms.  Missing assessments of 
influenza symptoms will be imputed using the last observation carried forward.  For the subject 
diary data, the following data conventions will be utilized.  Missing diary completion times will be 
imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily reported 
values.  Entries with values exceeding the 24-hour clock will be handled on a case-by-case basis 
and reviewed by a member of the clinical project team prior to implementation.  In general, values 
recorded between 24:01 – 24:59 will be interpreted as values past midnight and will be 
implemented as such.  Values recorded as 60:00, 70:00, and 80:00 will be interpreted as 06:00, 
07:00, and 08:00, respectively.  Should additional data conventions be required, these will be 
documented in the derived variable specifications and in the final clinical study report.  Select 
exploratory sensitivity analyses may be conducted to ascertain the effect, if any, of these methods.  
These sensitivity analyses are further described in section 6.2.2.1.  Other secondary effectiveness 
endpoints with time to event data will be censored using the date of subject’s last non-missing 
assessment of the given endpoint. 
Unless otherwise specified, no other missing data will be imputed. 
4.3.5. Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month or year is unknown, but at least one 
field is known.  An incomplete date occurs when the exact date an event occurred or ended cannot 
be obtained from a subject.  For many of the analyses, a complete date is necessary in order to 
determine if the event should be included in the analysis (i.e., if the event is treatment-emergent) or 
to establish the duration of an event.  In such cases, incomplete dates will be imputed. 
For purposes of imputation, all events with an incomplete end date are assumed to have ended on 
or before the day the form was completed. In an effort to minimize bias, the project statistician will 
impute incomplete start dates in a systematic, but reasonable manner.  For diary data, missing dates 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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will be imputed based on the nominal visit day relative to Day 1.  For other data, if the month/year 
is the same as the Day 1 month/year then the date will be set to the date of Day 1.  In other cases, 
missing days will be imputed as the day component of Day 1; missing months/years will be 
imputed as the month/year of Day 1.  A list of incomplete and imputed dates will be prepared by 
the project statistician or statistical programmer(s) and will be submitted for review by the clinical 
project manager and sponsor. 
4.3.6. 
By Study Visit Displays 
When data are collected serially over time, individual data presentations may include by-visit 
displays.  For these presentations, visits will be presented according to the nominal visit as obtained 
from the CRF or laboratory data.  If assessments are collected with multiple dates or times within a 
given visit, the result closest to the scheduled visit date will be used for summary presentations.  If 
two measurements have the same distance to the expected date, the earlier value will be used.  If a 
subject has multiple non-missing values on the same date, then the last one is used, as determined 
by the time collected, if available. 
4.3.7. 
Derived and Transformed Data  
TCID50 will be log10 transformed prior to performing the analyses. 
4.3.8. Definitions and Terminology 
 
Age 
Age will be defined as the age in days for the cohort of subjects <28 days old, months for the 
cohort of subjects from 28 days - 2 years, or years for the cohorts of subjects greater than 2 years 
old at the time of randomization.  For all subjects, age in years will also be derived and rounded 
down to the tenth decimal place for the summary statistics that are presented for all subjects 
combined. 
Confirmed Influenza 
A subject will be confirmed as having acute influenza infection if any specimen for assay of 
influenza A or B antigen by RT-PCR obtained during the study is positive. 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last value obtained prior to initiation 
of study drug (e.g., the Baseline Pre-Dose value). Should this value be obtained after the injection 
of study drug, then the most recent value obtained prior to initiation of study drug will be used for 
the baseline value. 
 
Day 1  
Day 1 is the day/time that study drug is initiated. 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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Study Day  
Study Day is defined relative to Baseline (Day 1). Thus, the study day of an event is calculated as: 
Study Day = event date – date of Day 1 +1. 
Days on Study 
Days on Study is the number of days from Day 1 to the date of study completion or early 
termination as recorded on the EARLY TERMINATION/STUDY COMPLETION CRF. 
Days of Subject Diary Completion 
Days of Subject Diary Completion is defined as the number of days from Day 1 to the date of last 
Subject Diary completion.  For the purposes of this analysis, the date of last Subject Diary 
completion is defined as the last date in which the Subject Diary had at least one complete 
assessment of symptoms recorded. 
Alleviation of Symptoms 
A subject has Alleviation of Symptoms if all of the assessed symptoms of influenza assessed on 
his/her subject diary based on age are either absent or are present at no more than mild severity 
level and at this status for a 21.5 hour (24 hours – 10%) period. 
Composite Symptom Score 
The Composite Symptom Score is defined as the sum of the symptoms of influenza (per age 
appropriate symptoms) assessed on a given time point within the subject diary. 
Initial Composite Symptom Score 
The Initial Composite Symptom Score is defined as the Composite Symptom Score corresponding 
to the first assessment of a subject’s symptoms. 
Resolution of Fever 
A subject has Resolution of Fever if he/she has a temperature < 99.4°F oral or < 98.4°F axillary 
and no antipyretic medications have been taken for at least 12 hours.  Resolution of Fever is based 
on information obtained from the individual subject diaries. 
Time to Event 
Time to a given event is defined as the number of hours from initiation of earliest study treatment 
until the event occurs.  The unit of measurement will vary based upon the endpoint and its 
respective schedule of assessment. 
Time to Alleviation of Symptoms 
Time to Alleviation of Symptoms is the number of hours from initiation of study drug to start of 
the period in which a subject has Alleviation of Symptoms. 
 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the Baseline 
Value. 
 
Adverse Event (AE) 
According to the protocol, an AE is any untoward medical occurrence in a clinical study subject. 
No causal relationship with the study drug or with the clinical study itself is implied. An AE may 
be an unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens 
during the clinical study. Clinically relevant abnormal results of diagnostic 
procedures including abnormal laboratory findings (e.g., requiring unscheduled diagnostic 
procedures or treatment measures, or resulting in withdrawal from the study) are considered to be 
AEs. 
 
AEs may be designated as “nonserious” or “serious” (see Protocol Section 11.1.1.1). Surgical 
procedures are not AEs but may constitute therapeutic measures for conditions that require surgery. 
The condition for which the surgery is required is an AE, if it occurs or is detected during the study 
period. Planned surgical measures permitted by the clinical study protocol and the conditions(s) 
leading to these measures are not AEs, if the condition(s) was (were) known before the start of 
study treatment. In the latter case the condition should be reported as medical history. 
 
Assessment of age appropriate symptoms of influenza will be documented in a Subject Diary and 
analyzed as a measure of effectiveness of the study treatment. These symptoms will not be reported 
as AEs unless the symptom(s) worsen to the extent that the outcome fulfills the definition of an 
SAE, which then must be recorded as such (see Protocol Section 11.1.1.2).   Likewise, a RAT for 
influenza is required at screening in order to determine eligibility for the study, and therefore a 
positive RAT is not considered an AE.  
 
All adverse events will be recorded on the ADVERSE EVENTS CRF. 
 
Treatment-emergent Adverse Event  
Any event reported on the CRF that occurs on or after the initiation of study drug and not more 
than 14 days after the last dose of study medication is considered treatment-emergent.  
Additionally, it is assumed that an Adverse Event which was reported to have started on Day 1 
without an associated onset time may have occurred after the initiation of study drug.  Hence, 
Adverse Events occurring on Day 1 with no associated onset time are assumed to be treatment-
emergent. 
 
Treatment-emergent Laboratory Abnormality  
A treatment-emergent laboratory abnormality is defined as an increase of at least one toxicity grade 
from the baseline assessment at any post baseline visit up to and including 14 days after the last 
dose date of study drug.  If no assessment is available at baseline, the screening assessment will be 
used to assign the baseline toxicity grade.  If the relevant baseline and screening assessments are 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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missing, then any graded abnormality (i.e., at least Grade 1) is considered to be treatment-
emergent. 
 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study drug. 
 
Previous Medications 
Previous medications are those medications taken prior to the initiation of study drug. 
4.4. 
TIMING OF ANALYSES 
If final results to analyze secondary virologic or PK endpoints are delayed unexpectedly and 
significantly, then analysis of the clinical data will proceed based on cleaned and locked clinical 
CRF data and virologic data to identify the ITTI population, and analysis of the secondary 
virologic and PK endpoints will be performed based on available preliminary results.  A final 
analysis of secondary virologic and PK endpoints will be conducted once final data are available.  
Secondary analyses to evaluate the exposure response of peramivir, and to assess changes in 
influenza viral susceptibility to neuraminidase inhibitors following treatment, may be conducted at 
a later date, if the required pharmacokinetic and virology data are not available at the time of the 
analysis of the clinical data.   
5. 
ANALYSIS POPULATIONS 
All subjects enrolled (e.g., signed informed consent) will be included in the summary of subject 
disposition and all data listings.  The populations for analysis of safety and effectiveness endpoints 
will include the Intent-to-Treat (ITT), Intent-to-Treat Infected (ITTI ), safety populations, and an 
exposure-response population.   
5.1. 
INTENT-TO-TREAT POPULATION 
The ITT population will include all randomized subjects. The ITT population will be the primary 
population for analyses of demography and subject accountability. 
5.2. 
INTENT-TO-TREAT INFECTED POPULATION 
The ITTI population will include all subjects who are enrolled, treated, and have influenza 
confirmed by RT-PCR.  The ITTI population will be used for analyses of effectiveness. 
5.3. 
SAFETY POPULATION 
The safety population will include all randomized subjects who receive at least one partial 
dose/injection of study drug.  The safety population will be the primary population for all analyses 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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of safety data. 
5.4. 
EXPOSURE-RESPONSE POPULATION 
The exposure-response population will include all subjects in the ITTI population who have a 
quantifiable peramivir concentration on day 1 and have at least one post-baseline effectiveness 
assessment.  This population will be used for all exposure-response analyses. 
5.5. 
VIROLOGY POPULATION 
The virology population will include all subjects in the ITTI population who have a laboratory-
confirmed influenza infection denoted by a positive RT-PCR assay. This population will be used 
for all virologic analyses. 
6. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study.  Data will be 
summarized by treatment group, age group, and study day/time, if appropriate.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, standard 
deviation (SD), minimum, and maximum for continuous data and frequencies and percentages for 
categorical data.  The term “treatment group” refers to randomized treatment assignment:  single 
dose peramivir IV or oseltamivir BID for 5 days.  The term "age group" refers to the following: 28 
days - < 2 years, ≥ 2 years - < 7 years, ≥ 7 years - < 13 years, and ≥ 13 years - < 18 years.  All data 
collected during the study will be included in data listings.  Unless otherwise noted, the data will be 
sorted first by treatment group, age group, subject number, and then by date within each subject 
number.   
The statistical analyses will be conducted with the SAS® software package version 9.2 or higher. 
All analyses will be subject to formal verification procedures.  Specifically, results will be verified 
utilizing independent programming prior to issuance of the draft statistical report.  All documents 
will be verified by the lead statistician to ensure accuracy and consistency of analyses. 
6.1. 
SUBJECT DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS  
Subject disposition will be presented for all subjects.  The number of subjects who completed the 
study and discontinued from the study will be provided. The reasons for early discontinuation also 
will be presented.  Additionally, the number of days on study and study medication will be 
summarized. 
Demographic data and baseline characteristics including age, gender, race, ethnicity, and Initial 
Composite Symptom Score will be summarized using descriptive statistics for the ITT population. 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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This information will be reviewed for baseline differences, but no statistical testing will be 
performed. 
Subject diary completion will be summarized included the days of diary completion. 
6.2. 
EFFECTIVENESS ANALYSIS 
6.2.1. 
Effectiveness Endpoints 
The effectiveness endpoints include: 
• 
Time to resolution of fever 
• 
Time to alleviation of influenza symptoms  
• 
Change in influenza virus titer by TCID50/mL 
• 
Change in RT-PCR results 
• 
Change in virus susceptibility to neuraminidase inhibitors 
• 
Incidence of influenza-related complications 
• 
Usage of antipyretic medication 
• 
Change in daily activities 
• 
Appetite and Eating patterns 
6.2.2. 
Effectiveness Analyses 
A subject’s oral temperature will be summarized by age group and overall by study visit and 
treatment group.  A subject has Resolution of Fever if he/she has an oral temperature <99.4°F oral 
or <98.4°F axillary and no antipyretic medications have been taken for at least 12 hours. The time 
to resolution of fever will be estimated for each age group and overall by treatment group using the 
method of Kaplan-Meier using temperature and symptom relief medication information obtained 
from the subject diary data. Subjects who do not have resolution of fever will be censored at the 
time of their last non-missing post-baseline temperature assessment. 
Alleviation of symptoms will be determined by assessment of symptoms as reported on each 
Subject Diary.  The time to alleviation of symptoms will be estimated overall and for individual 
symptoms for each age group by treatment group using the method of Kaplan-Meier.  Subjects who 
do not experience alleviation of symptoms will be censored at the date of their last non-missing 
post-baseline assessment.   
Change from baseline in TCID50/mL through Day 3, Day 7 and Day 14 respectively will be 
presented by age group and overall by treatment group for subjects with positive viral titers at 
baseline (log10 TCID50/mL > 0.5).  A box plot and a histogram of the TCID50/mL values will be 
presented by visit, age group, and treatment group.  In addition, the median change from baseline 
in TCID50/mL will be presented by visit, age group, and treatment group.  
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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The number and percent of subjects with positive viral titers at baseline (log10 TCID50/mL > 0.5) 
that are shedding virus at each visit will be presented by age group and overall by treatment group.  
The RT-PCR results at each visit will be presented by age group and overall by treatment group for 
subjects with positive RT-PCR results at baseline. 
Change from baseline to last positive value of influenza virus susceptibility to neuraminidase 
inhibitors will be assessed using virology laboratory tests. Virology laboratory tests will include 
phenotypic characterizations of influenza virus recovered (hemaglutinin and neuraminidase) and 
viral susceptibility to zanamivir, oseltamivir, and peramivir, as well as genotyping of virus isolates. 
These analyses will be presented overall and by age group, treatment group and viral subtype.   
The development of any post treatment genotypic changes in neuraminidase and hemagglutinin 
will be assessed by comparison of sequences from baseline and last positive post-treatment virus 
samples. These analyses will be presented overall and by age group, treatment group and viral 
subtype.   
 
The number and percentage of subjects experiencing influenza related complications will be 
summarized by age group and overall by complication preferred term and treatment group.  
 
The number of doses of antipyretic medications, as recorded in the subject diary, taken throughout 
the study and by study day will be summarized by age group and overall by treatment group.  
The change in daily activities will be summarized each day by treatment group for each age group 
and overall. 
The shift in the assessment of appetite and eating patterns from baseline to each day will be 
summarized by treatment group for each age group and overall. 
6.2.3. 
Exploratory Exposure Response Analyses 
Summaries of plasma concentrations will be presented by time point, age group, and treatment 
group.  Scatter plots will be generated for time to alleviation of influenza symptoms and change 
from baseline in log10 TCID50/mL versus peramivir plasma concentration at 30-60 minutes 
following study drug administration. The data from this trial together with data from prior trials 
will be used to complete a separate exposure-response analysis.  The methods for the exposure-
response analysis will be presented in a separate SAP.   
6.2.4. 
Subgroup Analyses 
The effectiveness analyses will also be presented by viral subtype at Screening. 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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6.3. 
SAFETY 
6.3.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.0 preferred term and system organ classification.  If a subject experiences multiple 
events that map to a single preferred term, the greatest severity grade and strongest investigator 
assessment of relation to study medication will be assigned to the preferred term for the appropriate 
summaries.  Should an event have a missing severity or relationship, it will be classified as having 
the highest severity and/or strongest relationship to study medication.  Summaries of treatment-
emergent AEs will include any AEs reported beginning with the initiation of study drug on Day 1.  
The occurrence of treatment-emergent adverse events (TEAEs) will be summarized by treatment 
group using preferred terms, system organ classifications, and severity.  Separate summaries of 
treatment-emergent serious adverse events, treatment-emergent adverse events related to study 
drug, and events leading to the discontinuation of study will be generated.  All adverse events 
reported will be listed for individual subjects showing both verbatim and preferred terms. All 
adverse events that occurred prior to the initiation of study treatment or more than 14 days post-
study drug discontinuation will be excluded from the tables but will be included in the listings.  
Missing onset dates will be imputed as previously outlined in Section 4.3.5 as required to 
determine treatment-emergent events. 
6.3.2. Concomitant Medications 
Previous and concomitant medications, as well as symptom relief medications recorded on the 
subject diary, will be coded using the World Health Organization (WHO) dictionary (Version: 
March, 2015).  Concomitant medications will be summarized by frequency of drug classification 
and generic drug name.  Previous and concomitant medications will be presented in a data listing.  
Symptom relief medications will be presented in a data listing. 
6.3.3. Clinical Laboratory Assessments 
Descriptive summaries of the following selected (quantitative) clinical laboratory results will be 
presented by study visit and treatment group for each age group and overall: ALT, AST, Serum 
Creatinine, BUN, HGB, Albumin, and Alkaline Phosphatase.  Laboratory abnormalities (toxicities) 
will be graded according to the DAIDS Table for Grading Adverse Events for Adults and 
Pediatrics (Publish Date: December 2004).  The number and percentage of subjects experiencing 
treatment-emergent graded toxicities will be summarized by treatment group for each age group 
and overall. Laboratory toxicity shifts from baseline to Day 7 will be summarized by treatment 
group for each age group and overall. 
All laboratory toxicities that occurred before the initiation of study treatment or more than 14 days 
post study drug discontinuation will be excluded from the tables but will be included in the listings.  


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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6.3.4. Other Safety Analyses 
Descriptive summaries of vital signs will be presented by study visit and treatment group for each 
age group and overall.   
 
All abnormal physical examination findings will be summarized by study visit and treatment group 
for each age group and overall.  
6.4. 
PROTOCOL DEVIATIONS 
Any deviation from protocol will be listed by subject and date.  The type of deviation along with a 
description and any additional comments about the deviation will be listed. 
7. 
CHANGES IN THE PLANNED ANALYSES 
An analysis of the number of doses of antipyretic medications will be prepared.   
There are no further changes anticipated to the protocol specified analyses.  Should any more 
deviations occur, these changes will be fully described in the Clinical and Statistical Report. 
 
8. 
REVISION HISTORY 
Date 
Revision 
Rationale 
29JUN2016 
Clarification of units for age based on 
cohort and  imputation methods for missing 
symptom scores.  Addition of virology 
population.  Removal of analyses for time 
weighted area under the curve for TCID50.  
Changed imputation method to last 
observation carried forward.  
Incorporation of review 
comments from BioCryst. 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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9. 
PROGRAMMING CONVENTIONS 
• 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
landscape orientation.  There should be a minimum of a 1.25” boundary on the upper (bound) 
edge, and a minimum of a 1.0” boundary on the remaining three edges.  Output should be 
printed in Courier New with a point size of 8.  Titles may be printed using a larger font (e.g., 
Arial point size 10). 
• 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized.  Listings will be prepared for all subjects 
randomized. 
• 
Group headers: In the summary tables, the group headers will identify the treatment group and 
the within-group sample size for the indicated analysis population.  Of note, the header’s 
sample size does not necessarily equal the number of subjects actually summarized within any 
given summary module; some subjects in the analysis population may have missing values and 
thus may not be summarized. 
• 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
• 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of subjects actually contributing to the summary statistics presented in any given 
summary module.  As mentioned above, this may be less than the number of subjects in the 
analysis population. 
♦ In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations 
♦ For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category.  Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation. 
• 
Sorting: Listings will be sorted by treatment group, subject number and date, if applicable.  If a 
listing is sorted in a different manner, a footnote will indicate as such.  
• 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures.  No intermediate rounding will 
be performed on derived variables.  The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.   
• 
The presentation of numerical values will adhere to the following guidelines:  


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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♦ Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.   
♦ Standard deviations will be reported to one decimal place beyond the number of decimal 
places the original parameter is presented. 
♦ Means will be reported to the same number of significant digits as the parameter.  
♦ Calculated percentages will be reported with no decimals. 
• 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
• 
Time will be presented according to the 24-hour clock (HH:MM). 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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10. 
PROPOSED TABLES, LISTINGS, AND FIGURES FOR FINAL ANALYSIS 
Output Number 
Output Title 
 Table 14.1.1 
Subject Follow-Up and Termination from Study; Intent-to-Treat 
Population  
 Table 14.1.2.1 
Randomization, Eligibility, and Treatment Status; Intent-to-Treat 
Population 
 Figure 14.1.2.2 
BCX1812-305 Study Population Disposition; Intent-to-Treat 
Population 
 Table 14.1.3 
Demographics and Baseline Characteristics; Intent-to-Treat Population 
 Table 14.1.4 
Populations for Analysis; Intent-to-Treat Population 
 Table 14.1.5 
Summary of Subject Diary Completion; Intent-to-Treat-Infected 
Population 
 Table 14.2.1.1 
Summary of Oral Temperature; Intent-to-Treat Infected Population 
 Table 14.2.1.2.1.1 
Time to Resolution of Fever; Intent-to-Treat Infected Population 
 Figure 14.2.1.2.1.2 
Time to Resolution of Fever (Kaplan-Meier Plot) ; ITTI Population 
 Figure 14.2.1.2.1.3 
Median (95% CI) Time to Resolution of Fever; ITTI Population 
 Table 14.2.1.2.2 
Time to Resolution of Fever by Viral Sub-Type; Intent-to-Treat 
Infected Population 
 Table 14.2.2.1.1.1 
Time to Alleviation of Symptoms [1]; Intent-to-Treat Infected 
Population  
 Figure 14.2.2.1.1.2 
Time to Alleviation of Symptoms (Kaplan-Meier Plot) ; ITTI 
Population 
 Figure 14.2.2.1.1.3 
Median (95% CI) Time to Alleviation of Symptoms; ITTI Population 
 Table 14.2.2.1.2.1 
Time to Alleviation of Symptoms [1] by Viral Sub-Type; Missing 
Values are Censored at the Last Available Assessment; Intent-to-Treat 
Infected Population  


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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Output Number 
Output Title 
 Figure 14.2.2.1.2.2 
Median (95% CI) Time to Alleviation of Symptoms by Viral Sub-
Type; ITTI Population 
 Table 14.2.3.1.1.1 
Summary of Changes log10  Tissue Culture Infective Dose50 (TCID50 
/mL) by Study Visit; Intent-to-Treat Infected Population 
 Figure 14.2.3.1.1.2 
Box Plots of Viral Titers (TCID50 /mL) by Study Visit; Subjects with 
Negative Baseline Viral Titers are Excluded; Intent-to-Treat Infected 
Population 
 Figure 14.2.3.1.1.3 
Histograms of Viral Titers (TCID50 /mL) by Study Visit; Subjects with 
Negative Baseline Viral Titers are Excluded; Intent-to-Treat Infected 
Population 
 Figure 14.2.3.1.1.4 
Median (with IQR) Change from Baseline Viral Titers (TCID50 /mL) 
by Study Visit; Subjects with Negative Baseline Viral Titers are 
Excluded; Intent-to-Treat Infected Population 
 Table 14.2.3.1.2 
Summary of Changes log10  Tissue Culture Infective Dose50 (TCID50 
/mL) by Study Visit and Viral Sub-Type; Intent-to-Treat Infected 
Population 
 Table 14.2.3.2.1 
Summary of Viral Shedding by Study Visit; Intent-to-Treat Infected 
Population 
 Table 14.2.3.2.2 
Summary of Viral Shedding by Study Visit and Viral Sub-Type; 
Intent-to-Treat Infected Population 
 Table 14.2.3.3.1 
Summary of RT-PCR Result by Study Visit; Intent-to-Treat Infected 
Population 
 Table 14.2.3.3.2 
Summary of RT-PCR Result by Study Visit and Viral Sub-Type; 
Intent-to-Treat Infected Population 
 Table 14.2.3.4 
Change of Influenza Virus Susceptibility to Neuraminidase Inhibitors 
by Viral Subtype; Intent-to-Treat Infected Population  
 Table 14.2.4 
Summary of Influenza-Related Complications; Intent-to-Treat Infected 
Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
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Output Number 
Output Title 
 Table 14.2.5 
Number of Doses of Antipyretic Medications; Intent-to-Treat Infected 
Population 
 Table 14.2.6 
Summary of Subject-Rated Assessment of Ability to Perform Daily 
Activities; Intent-to-Treat Infected Population 
 Table 14.2.7 
Summary of Assessment of Appetite and Eating Patterns; ITTI 
Population 
 Table 14.3.1.1 
Treatment-Emergent Adverse Events by System Organ Classification, 
Preferred Term and Greatest Severity; Safety Population 
 Table 14.3.1.2 
Treatment-Emergent Adverse Events Possibly, Probably, or Definitely 
Related to Study Drug by System Organ Classification and Preferred 
Term; Safety Population 
 Table 14.3.1.3 
Treatment-Emergent Serious Adverse Events by System Organ 
Classification and Preferred Term; Safety Population 
 Table 14.3.1.4 
Treatment-Emergent Adverse Events Leading to the Discontinuation of 
Study by System Organ Classification and Preferred Term; Safety 
Population 
 Table 14.3.5.1 
Summary of Select Laboratory Values by Study Visit; Safety 
Population 
 Table 14.3.5.2 
Graded Laboratory Toxicities; Safety Population 
 Table 14.3.5.3.1 
Laboratory Shifts from Baseline: Chemistry; Safety Population 
 Table 14.3.5.3.2 
Laboratory Shifts from Baseline: Hematology; Safety Population 
 Table 14.3.5.3.3 
Laboratory Shifts from Baseline: Urinalysis; Safety Population 
 Table 14.3.6 
Summary of Vital Signs by Study Visit; Safety Population 
 Table 14.3.7 
Abnormal Physical Examinations; Safety Population 
 Table 14.3.8 
Concomitant Medications by Generic Name and Drug Classification; 
Safety Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
CONFIDENTIAL 
Page 27 
11 July 2016 
 
Output Number 
Output Title 
 Table 14.4.1.1 
Summary of Plasma Concentrations of Peramivir by Time point; 
Intent-to-Treat Population 
 Table 14.4.1.2 
Summary of Plasma Concentrations of Peramivir; Exposure Response 
Population 
 Figure 14.4.2 
Relationship between Time to Alleviation of Influenza Symptoms and 
Peramivir Plasma Concentrations at 30-60 Minutes Post-Dose; 
Exposure-Response Population 
 Figure 14.4.3 
Relationship between Viral Change from Baseline and Peramivir
Plasma Concentrations at 30-60 Minutes Post-Dose; Exposure-
Response Population 
 Listing 16.2.1 
Study Completion; Intent-to-Treat Population 
 Listing 16.2.2 
Protocol Deviations; Intent-to-Treat Population 
 Listing 16.2.4.1 
Inclusion/Exclusion Criteria; Intent-to-Treat Population 
 Listing 16.2.4.2 
Subject Eligibility and Randomization; Intent-to-Treat Population 
 Listing 16.2.4.3 
Demographics; Intent-to-Treat Population 
 Listing 16.2.4.4 
Medical History; Intent-to-Treat Population 
 Listing 16.2.4.5 
Prior and Concomitant Medications; Intent-to-Treat Population 
 Listing 16.2.5.1 
Study Medication Administration; Intent-to-Treat Population 
 Listing 16.2.5.2 
Pharmacokinetic Sample Collection Time and Concentrations; PK 
Population 
 Listing 16.2.6.1.1 
Summary of Efficacy Variables; ITTI Population 
 Listing 16.2.6.2 
Influenza Symptoms; Intent-to-Treat Population 
 Listing 16.2.6.3  
Temperature; Intent-to-Treat Population 
 Listing 16.2.6.4 
Subject-Rated Assessment of Daily Activities and Assessment of 
Appetite and Eating Patterns; Intent-to-Treat Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-305                                                                                            
Statistical Analysis Plan                                                                                                         Final Version 1.0 
 
 
 
 
CONFIDENTIAL 
Page 28 
11 July 2016 
 
Output Number 
Output Title 
 Listing 16.2.6.5 
Viral Titers and Viral Susceptibility; Intent-to-Treat Population 
 Listing 16.2.6.6 
RT-PCR for Influenza; Intent-to-Treat Population 
 Listing 16.2.6.7 
Symptom Relief Medications; Intent-to-Treat Population 
 Listing 16.2.6.8 
Influenza-Related Complications; Intent-to-Treat Population 
 Listing 16.2.7 
Adverse Events; Intent-to-Treat Population 
 Listing 16.2.8.1.1 
Laboratory Tests -  Hematology; Intent-to-Treat Population 
 Listing 16.2.8.1.2 
Laboratory Tests -  Chemistry; Intent-to-Treat Population 
 Listing 16.2.8.1.3 
Laboratory Tests -  Urinalysis; Intent-to-Treat Population 
 Listing 16.2.8.1.4 
Laboratory Tests -  Virology; Intent-to-Treat Population 
 Listing 16.2.8.1.5 
Laboratory Tests -  Other; Intent-to-Treat Population 
 Listing 16.2.8.2 
Blood and Urine Collection and Pregnancy Tests; Intent-to-Treat 
Population 
 Listing 16.2.8.3 
Vital Signs, Height, and Weight; Intent-to-Treat Population 
 Listing 16.2.8.4 
Physical Examinations; Intent-to-Treat Population 
 Listing 16.2.9.1 
Changes in NA Amino Acids from Baseline to Post-Baseline 
 Listing 16.2.9.2 
Changes in HA Amino Acids from Baseline to Post-Baseline 
 Listing 16.2.9.3 
NA Sequence Alignment 
 Listing 16.2.9.4 
HA Sequence Alignment