Conditions: Influenza
Keywords: Acute uncomplicated Elderly
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 74
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, pharmacokinetics and effectiveness of a single dose of 600 mg IV peramivir in the treatment of elderly subjects with acute uncomplicated influenza infection and in subjects with acute uncomplicated influenza infection at higher risk for influenza complications. All subjects will receive IV peramivir.

Detailed description:

Arms:
arm 1: Single dose 600 mg IV injection

Interventions: intervention 1: Peramivir
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Protocol 
BioCryst Pharmaceuticals, Inc. 
 
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BCX1812-306 
 
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BioCryst Pharmaceuticals, Inc. 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-306 
IND No. 69,038 
 
A PHASE 3, MULTICENTER, SINGLE-ARM, OPEN-LABEL, STUDY TO EVALUATE THE 
SAFETY, PHARMACOKINETICS AND EFFECTIVENESS OF INTRAVENOUS 
PERAMIVIR IN ELDERLY SUBJECTS WITH ACUTE UNCOMPLICATED INFLUENZA 
INFECTION AND IN SUBJECTS WITH ACUTE UNCOMPLICATED INFLUENZA 
INFECTION AT HIGHER RISK FOR INFLUENZA COMPLICATIONS 
 
Original Protocol, Version 1.0: 30 June 2015 
Protocol Amendment 01, Version 2.0: 03 September 2015 
Protocol Amendment 02 (Administrative), Version 3.0: 11 October 2016 
Protocol Amendment 03, Version 4.0: 09 August 2017 
 
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: 
BCX1812-306 
Study Title: 
A Phase 3, multicenter, single-arm, open-label, study to evaluate the 
safety, pharmacokinetics and effectiveness of intravenous peramivir 
in elderly subjects with acute uncomplicated influenza infection and 
in subjects with acute uncomplicated influenza infection at higher risk 
for influenza complications 
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) 773-304-8942 
Fax: (+1) 919-851-1416 
Email Address: sdobo@biocryst.com 
Principal Investigator: 
Carol L. Clark, MD 
Beaumont Health System Emergency 
Royal Oak, MI 
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 4.0; 09 Aug 2017 
 
 
 
 




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1.2. 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-306 
Protocol Title: 
A Phase 3, multicenter, single-arm, open-label, study to evaluate the safety, 
pharmacokinetics and effectiveness of intravenous peramivir in elderly 
subjects with acute uncomplicated influenza infection and in subjects with 
acute uncomplicated influenza infection at higher risk for influenza 
complications 
Version Date: 
Version 4.0; 09 Aug 2017 
 
 
 
 
 
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: 
BCX1812, Peramivir, RAPIVAB™ 
Title of Study:  
A Phase 3, multicenter, single-arm, open-label, study to evaluate the safety, pharmacokinetics and 
effectiveness of intravenous peramivir in elderly subjects with acute uncomplicated influenza infection 
and in subjects with acute uncomplicated influenza infection at higher risk for influenza complications 
Study Center(s):  Multicenter 
Principal Investigator:  
Carol L. Clark, MD, MBA, FACP 
Beaumont Hospital- Royal Oak 
Department of Emergency Medicine 
 
Studied Period (years):  
Estimated date first subject enrolled: October 2015 
Estimated date last subject completed: April 2018 
Phase of Development:  
3b 
Objectives:  
Primary:    
• 
To evaluate the safety and tolerability of peramivir administered intravenously (IV) in elderly subjects 
with acute uncomplicated influenza infection and in subjects with acute uncomplicated influenza 
infection who are at higher risk for influenza complications. 
Secondary: 
• 
To describe the pharmacokinetics (PK) of IV peramivir in elderly and high risk subjects with acute 
uncomplicated influenza. 
• 
To evaluate the effectiveness of IV peramivir in elderly and high risk subjects with acute 
uncomplicated influenza. 
• 
To evaluate the incidence of influenza complications, specifically otitis media, sinusitis, bronchitis or 
pneumonia requiring antibiotic use diagnosed after initiation of treatment 
Methodology:  
This is a multicenter, single-arm, open-label study will evaluate the safety, PK and effectiveness of a 
single dose of IV peramivir in elderly subjects (≥ 65 years of age) with acute uncomplicated influenza and 
in subjects with acute uncomplicated influenza at higher risk for influenza complications. 
Subjects meeting the inclusion/ exclusion criteria will be enrolled into the study. Following treatment on 
study Day 1, subjects will undergo in-clinic follow-up assessments on Days 3, 7, and 14.  
All subjects/caregivers will record the following information in a subject diary: 
• 
Assessment of the presence and severity of each of the 7 symptoms of influenza on a 4-point severity 
scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily through Day 13, and prior to the subject’s 
clinic visit on Day 14; or until each symptom is 0 or 1 for 48 hours. 
• 
Temperature measurements (oral) will be taken with an electronic thermometer provided by the 


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Sponsor, approximately every 12 hours until temperature normalizes for 48 hours (i.e., temperature 
without antipyretic is < 37.4○C/99.4oF orally for 4 measurements). With the exception of the 
Screening/ 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. 
• 
The type, date, and time of medications used for the symptomatic treatment of influenza-related 
symptoms. 
• 
Assessment of the subject’s ability to perform usual activities using a 0 to 10 visual analogue scale 
once daily through Day 14, where 0 = Unable to perform usual activities at all, and 10 = Able to 
perform all usual activities fully. 
An adequate nasal swab specimen will be collected from all enrolled subjects at Baseline (pre-dose) for 
virus subtype identification and quantitative virologic assessments and at the follow-up assessments on 
study Days 3, 7 and 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 3 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  
Adverse events and concomitant medications will be monitored at each scheduled visit from the 
Screening assessment to final study visit. Clinical laboratory investigations (chemistries, hematology, and 
urinalysis) will be collected at Baseline, and Day 7 visits. Day 14 clinical laboratory investigations will 
only be collected if Day 7 labs are in the opinion of the investigator, significantly abnormal or clinically 
changed from baseline.  In additional, clinical laboratory investigations may be conducted at any time for 
patient management / safety reasons.  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. 
A subject’s duration of participation in this study is expected to be approximately 14 days and will 
include up to 4 clinic visits. Subjects will be discharged from this study on Day 14. Additional, 
unscheduled visits may be required for subjects who report symptoms of influenza of moderate or severe 
intensity at Day 14 or have persistent adverse events and/or treatment-emergent laboratory findings that 
require medical monitoring or management.  
Number of subjects (planned):  
Approximately 120 subjects will be enrolled. A minimum of 80 elderly subjects (≥ 65 years) will be 
enrolled. 
Criteria for inclusion:  
Subjects must meet the following criteria to be eligible for study participation: 
1. Male and female subjects age ≥ 18 years. 
2. The subject must meet one of the following two criteria: 
a. A positive influenza Rapid Antigen Test (RAT) and/or a Food and Drug Administration 
(FDA)-approved polymerase chain reaction (PCR) test and at least one clinical sign or symptom 
consistent with influenza (see 2b below). 


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OR 
b. Clinical signs and symptoms consistent with acute influenza infection consisting of an oral 
temperature ≥100°F (37.8°C) with at least one respiratory symptom of at least moderate severity 
(cough or rhinitis) and at least one constitutional symptom of at least moderate severity (myalgia 
[aches and pains], headache, feverishness, or fatigue). 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 for 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 and/or PCR. During the period of approval, 
clinical symptoms alone will be adequate to meet Criteria 2. 
3. 
Onset of symptoms no more than 48 hours before presentation for screening. However, due to 
historically delayed presentation for medical care in the adult population, approximately 20% of the 
elderly population may be enrolled with symptoms starting > 48-hours but ≤ 72-hours prior to 
presentation for screening. Note: Time of onset of illness is defined as either (1) the time when the 
temperature (either oral or rectal) was first measured as elevated (at least one °C of elevated 
temperature), OR (2) the time when the subject experienced the presence of at least one respiratory 
symptom AND the presence of at least one constitutional symptom together. 
4. 
Either age ≥ 65 years AND/ OR presence of one of the following risk factors: 
a. Pregnancy, including women who are up to 2 weeks post-partum   
b. Resident of a nursing home or long-term care facility 
c. History of chronic lung disease including obstructive pulmonary disease (COPD), persistent 
asthma or cystic fibrosis 
d. History of heart disease including myocardial infarction, angina requiring treatment, congestive 
heart failure requiring treatment, arrhythmia including atrial fibrillation and valvular dysfunction 
e. History of blood dyscracias including sickle cell anemia and thalassemia 
f. History of renal impairment (creatinine clearance [CrCl] < 50 mL/min as determined by the 
Cockcroft-Gault formula) including patients on dialysis 
g. History of liver disease including cirrhosis 
h. Mild to moderate immunocompromised, including: history of human immunodeficiency virus 
(HIV) disease on stable highly active antiretroviral therapy (HAART) with last known CD4+ 
count ≥ 200 cells/µL: known neutropenia with ANC > 500 cells/µL; chronic corticosteroid use of 
< 20 mg/d for any indication.  
i. 
History of diabetes mellitus (Type I or II) 
j. 
Morbid obesity (body mass index [BMI] ≥ 40)  
k. American Indian or Alaskan native 
5. Written informed consent 
Criteria for Exclusion: 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subjects who in the opinion of the investigator require hospital admission to treat medical condition(s) 
which, in the Investigator’s opinion, could represent complications of influenza. Note, 
hospitalization is not an exclusion criterion when it is the usual practice of the treating 
institution to hospitalize elderly patients with acute uncomplicated influenza.  
2. Women who plan to breast-feed for the first 48 hours after study drug administration. However, 
women who agree to suspend breast feeding for 48 hours after study administration may participate. 
3. Employees of the study site, or immediate family members of study site employees 
4. Presence of clinically significant signs of acute respiratory distress 
5. Clinical evidence of worsening of any chronic medical condition (temporally associated with the onset 
of symptoms of influenza) which, in the Investigator’s opinion, indicates that such finding(s) could 


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represent complications of influenza. 
6. Current clinical evidence, including clinical signs and/or symptoms consistent with a bacterial 
infection, including: otitis media, bronchitis, sinusitis and/or pneumonia, or active bacterial infection 
of any body site that requires therapy with oral or systemic antibiotics 
7. Immunization against influenza with live attenuated virus vaccine in the previous 14 days 
8. History of alcohol abuse or drug addiction within 1 year prior to admission in the study 
9. Participation in a study of any investigational drug or device within the last 30 days 
10. Previous participation in study BCX1812-305 (pediatric study) or BCX1812-306 (this study) 
Presence of any pre-existing illness that, in the opinion of the Investigator, would place the 
subject at an unreasonably increased risk through participation in this study or would make 
the subject unable to comply with the protocol 
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.  
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 PK 
parameters. 
Effectiveness: 
Clinical:  
• 
Time to alleviation of clinical influenza symptoms 
• 
Time to resolution of fever 
• 
Time to resumption of usual activities 
• 
Incidence of influenza-related hospitalizations 
• 
Incidence of hospital admission (for any reason) post treatment 
Virologic:  
• 
Changes in viral shedding measured by quantitative viral titer assay (TCID50) and/or quantitative 
polymerase chain reaction (PCR) 
• 
Change in influenza virus susceptibility to neuraminidase inhibitors 
Investigational product, dosage and mode of administration:  
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. Subjects will receive a single dose of 600 mg peramivir diluted in 0.9 
% saline, 0.45% saline, 5% dextrose or lactated Ringer’s using the technique described in a separate drug 
preparation instruction sheet, administered intravenously over a period of 15 to 30 minutes. The drug 
product should be stored at room temperature (excursion permitted to 59° to 86°F) 
Reference therapy, dosage and mode of administration:  
Not Applicable 
Duration of Treatment: 
Following single IV dose of peramivir on Day 1, study duration for all subjects is expected to be 
approximately 14 days (including all visits). If a subject has one or more persistent or recurrent symptoms 
of influenza (of the 7 symptoms assessed) of either moderate or severe intensity at the Day 14 visit (± 2 
days), or if the subject has an unresolved AE and/or treatment-emergent laboratory finding that requires 
further medical management, then the subject may be evaluated in further follow-up visits, at the 


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Investigator’s discretion. 
Statistical methods: 
Sample Size: 
The study is designed to evaluate the safety and PK of IV administration of peramivir in elderly subjects 
(≥ 65 years) with influenza and in subjects with influenza infection at higher risk for influenza 
complications. The sample size is adequate to evaluate these objectives. 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 PK parameters in each population (≥ 65 years vs 
< 65 years and at a high risk) and to identify pharmacokinetically-relevant covariates. Data will be 
compared to available PK data from other adult studies of IV peramivir and 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 ..................................................10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Influenza Overview ....................................................................................................17 
5.2. 
Antiviral therapy for influenza ...................................................................................17 
5.3. 
Previous Experience with Peramivir ..........................................................................18 
5.3.1. 
Clinical Experience in Adults .....................................................................................18 
5.3.1.1. 
Peramivir Efficacy ......................................................................................................18 
5.3.1.2. 
Peramivir Safety .........................................................................................................19 
5.4. 
Rationale for Study .....................................................................................................20 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................22 
6.1. 
Primary objective ........................................................................................................22 
6.2. 
Secondary Objectives .................................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Endpoints ....................................................................................................................23 
7.1.1. 
Primary Endpoint ........................................................................................................23 
7.1.2. 
Secondary Endpoints ..................................................................................................23 
7.2. 
Overall Study Design and Plan ...................................................................................23 
7.3. 
Study Measurements and Visit Schedule ...................................................................23 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 
8.1. 
Subject Inclusion Criteria ...........................................................................................26 
8.2. 
Subject Exclusion Criteria ..........................................................................................27 
8.3. 
Withdrawal Criteria ....................................................................................................28 
9. 
TREATMENT OF SUBJECTS ..................................................................................29 
9.1. 
Study Drug Dose Rationale ........................................................................................29 


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9.2. 
Study Drug ..................................................................................................................29 
9.3. 
Study Drug Preparation and Administration ..............................................................29 
9.4. 
Dose Adjustments for Subjects with Renal Impairment .............................................29 
9.5. 
Study medication accountability .................................................................................29 
9.6. 
Randomization and Blinding/ Masking ......................................................................30 
9.7. 
Treatment Compliance ................................................................................................30 
9.8. 
Overdose and Toxicity Management ..........................................................................30 
9.9. 
Concomitant Medications ...........................................................................................30 
9.9.1. 
Antipyretics and Analgesics .......................................................................................30 
9.9.2. 
Medications for Chronic Diseases/Conditions ...........................................................31 
9.9.3. 
Antivirals ....................................................................................................................31 
9.9.4. 
Antibiotics ...................................................................................................................31 
9.9.5. 
Immunizations ............................................................................................................31 
10. 
STUDY CONDUCT ...................................................................................................32 
10.1. 
Overview .....................................................................................................................32 
10.1.1. 
Screening Period .........................................................................................................33 
10.1.2. 
Treatment Period ........................................................................................................34 
10.1.2.1. 
Baseline (Pre-dose)/Day 1 ..........................................................................................34 
10.1.2.2. 
Day 1/Post-dose ..........................................................................................................34 
10.1.2.3. 
Day 3 ...........................................................................................................................35 
10.1.2.4. 
Day 7 ...........................................................................................................................35 
10.1.2.5. 
Day 14 (End of Study) ................................................................................................36 
10.2. 
Clinical assessments of Effectiveness ........................................................................36 
10.2.1. 
Body Temperature ......................................................................................................36 
10.2.2. 
Influenza Signs and Symptoms ..................................................................................37 
10.2.3. 
Assessment of ability to perform usual daily activities ..............................................37 
10.2.4. 
Influenza-Related Complications ...............................................................................37 
10.2.5. 
Hospital Admission ....................................................................................................38 
10.3. 
Virology Samples .......................................................................................................38 
11. 
ASSESSMENT OF SAFETY .....................................................................................39 
11.1.1. 
Definitions ..................................................................................................................39 
11.1.1.1. 
Adverse Event .............................................................................................................39 
11.1.1.2. 
Serious Adverse Event ................................................................................................39 


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11.1.2. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events .............................................................................40 
11.1.3. 
Definition of Severity .................................................................................................40 
11.1.4. 
Definition of Relationship to Study Drug ...................................................................40 
11.1.5. 
Reporting Serious Adverse Events .............................................................................41 
11.1.6. 
Pregnancy ...................................................................................................................42 
11.1.7. 
Reporting DAIDS Grade 3 or 4 events .......................................................................42 
11.2. 
Clinical Laboratory Evaluations .................................................................................42 
11.2.1. 
Clinical Chemistry Profiles .........................................................................................42 
11.2.2. 
Hematology Profiles ...................................................................................................42 
11.2.3. 
Urinalysis ....................................................................................................................43 
11.2.4. 
Pregnancy Test (Urine or Serum) ...............................................................................43 
11.3. 
Vital Signs ..................................................................................................................43 
11.4. 
Physical Examination .................................................................................................43 
12. 
PHARMACOKINETIC ASSESSMENTS .................................................................44 
13. 
STATISTICS ..............................................................................................................45 
13.1. 
Data Collection Methods ............................................................................................45 
13.2. 
Statistical Analysis Plans ............................................................................................45 
13.3. 
Study Hypothesis ........................................................................................................45 
13.4. 
Sample Size Estimates ................................................................................................45 
13.5. 
Analysis Populations ..................................................................................................45 
13.6. 
End of Study Analysis ................................................................................................46 
13.7. 
General Issues for Statistical Analysis .......................................................................46 
13.7.1. 
Multiple Comparisons and Multiplicity......................................................................46 
13.7.2. 
Covariates ...................................................................................................................46 
13.7.3. 
Planned Subgroups .....................................................................................................46 
13.7.4. 
Missing Data ...............................................................................................................46 
13.8. 
Effectiveness ...............................................................................................................46 
13.8.1. 
Effectiveness Endpoints ..............................................................................................46 
13.8.2. 
Effectiveness Analyses ...............................................................................................46 
13.9. 
Safety Analyses ..........................................................................................................47 
13.10. 
Exposure Response Analyses .....................................................................................47 
14. 
STUDY ADMINISTRATION ...................................................................................48 


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14.1. 
Regulatory and Ethical Considerations ......................................................................48 
14.1.1. 
Regulatory Authority Approvals ................................................................................48 
14.1.2. 
Institutional Review Board Approvals .......................................................................48 
14.1.3. 
Subject Informed Consent ..........................................................................................48 
14.1.4. 
Payment to Subjects ....................................................................................................49 
14.1.5. 
Investigator Reporting Requirements .........................................................................49 
14.2. 
Study Monitoring ........................................................................................................49 
14.3. 
Quality Assurance .......................................................................................................49 
14.4. 
Study Termination and Site Closure ...........................................................................49 
14.5. 
Records Retention .......................................................................................................49 
14.6. 
Confidentiality of Information ....................................................................................50 
14.7. 
Study Publication ........................................................................................................50 
15. 
REFERENCES ...........................................................................................................51 
16. 
APPENDICES ............................................................................................................54 
16.1. 
Appendix 1: Cockcroft-Gault Equation ......................................................................54 
16.2. 
Appendix 2: Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events ............................................................................................55 
 
 
 


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LIST OF TABLES 
Table 1. 
BCX1812-306: Schedule of Assessments .............................................................................. 24 
Table 2. 
Dosage Adjustment for Subjects with Altered Creatinine Clearance .................................... 29 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
BMI 
body mass index 
CBC 
complete blood count 
CDC 
US Centers For Disease Control And Prevention 
CFR 
Code Of Federal Regulations 
CI 
confidence intervals  
COPD 
chronic obstructive pulmonary disease 
CrCl 
creatinine Clearance 
CRF 
case report form 
DAIDS 
Division Of Acquired Immune Deficiency Syndrome 
FDA 
US Food And Drug Administration 
GCP 
Good Clinical Practice 
HAART 
highly active antiretroviral therapy 
HIPAA 
Health Insurance Portability And Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form  
ICH 
International Conference On Harmonization 
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 


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Abbreviation or specialist term 
Explanation 
MedDRA 
Medical Dictionary For Regulatory Activities 
PA, PB1, PB2 
viral RNA polymerase complex  
PCR 
polymerase chain reaction 
PK 
pharmacokinetics 
QT 
electrocardiographic interval between the beginning of the Q 
wave and termination of the T wave, representing the time 
for both ventricular depolarization and repolarization to 
occur 
QTc 
QT interval corrected 
RAT 
rapid antigen test 
RBC 
red blood cell 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
SD 
standard deviation  
TCID50 
tissue culture infectious dose 50% 
TEAE 
treatment-emergent adverse event 
US 
United States  
WBC 
white blood cell 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Influenza Overview 
In healthy adults, influenza 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. Severe illness with rapid evolution to 
respiratory failure, often in young adults, was reported from many countries including the United States 
(US) (Jain, Kamimoto et al. 2009, Louie, Acosta et al. 2009, Louie, Yang et al. 2012), Mexico 
(Dominguez-Cherit, Lapinsky et al. 2009, Perez-Padilla, de la Rosa-Zamboni et al. 2009), Canada 
(Kumar, Zarychanski et al. 2009), Chile (Cornejo, Tobar et al. 2011), Australia (Investigators, Webb et al. 
2011, Muscatello, Barr et al. 2011), Italy (Nicolini, Claudio et al. 2011), South Korea (Jeon, Chung et al. 
2011) and Hong Kong (Lee, Chan et al. 2011). Analysis of the pattern of morbidity with age showed a 
shift to earlier ages for the rates of severe pneumonia, hospitalization, and admission to intensive care 
(Chowell, Bertozzi et al. 2009, Dominguez-Cherit, Lapinsky et al. 2009, Jain, Kamimoto et al. 2009), as 
well as an increased incidence of acute respiratory distress syndrome and mortality in previously healthy 
young to middle-aged adults (Perez-Padilla, de la Rosa-Zamboni et al. 2009). In some countries, around 
2% of cases developed severe illness, often with rapid progression to life-threatening pneumonia. Most 
cases of severe and fatal illnesses reported up to early June 2009 were in adults between the ages of 30 
and 50 years (World Health Organization [WHO]). Pregnant women also showed an increased risk of 
hospitalization and death (Siston, Rasmussen et al. 2010). Globally, the mortality from the pandemic 
through March to December of 2009 was estimated at 123,000 to 203,000, with the majority of patients 
under 65 (Simonsen, Spreeuwenberg et al. 2013). 
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. Changes in one or more influenza virus virulence 
determinants [recently reviewed by Tscherne. (Tscherne and Garcia-Sastre 2011)] . 
5.2. 
Antiviral therapy for influenza 
Two classes of influenza antiviral agents are currently approved: adamantanes and neuraminidase 
inhibitors. Adamantanes 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 and 
rimantadine can reduce the severity and shorten the duration of acute uncomplicated influenza A illness 
among healthy adults. However, in recent years widespread resistance to adamantanes has been described 


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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 
Centers for Disease Control and Prevention (CDC) for treatment of influenza (Centers for Disease and 
Prevention 2013). 
Neuraminidase inhibitors are a newer class of drugs with activity against both influenza A and influenza 
B viruses. Approved neuraminidase inhibitors include zanamivir (Relenza®), administered by inhalation, 
oseltamivir phosphate (Tamiflu®), an oral prodrug of the active agent, oseltamivir carboxylate, and 
peramivir (Rapivab™), administered intravenously (IV). 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.  
Peramivir is a selective inhibitor of influenza viral neuraminidase with potent activity against influenza A 
and B subtypes, including influenza A (H1N1pdm09) (CDC 2009) and the recently described novel avian 
influenza A (H7N9) virus (Cao, Xiao et al. 2013, Gao, Cao et al. 2013). Although oseltamivir is widely 
used for the treatment of influenza, a need still exists for an effective treatment for influenza patients who 
present in the urgent care and emergency room settings, and in patients for whom compliance with 
effective delivery of an oral medication is of concern (e.g., patients with vomiting and diarrhea). 
Peramivir has been studied for the treatment of influenza in 2 settings: as a single dose treatment in acute 
uncomplicated influenza, and as a multiple dose treatment in patients who are hospitalized due to 
influenza.  
5.3. 
Previous Experience with Peramivir 
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. Peramivir was recently approved in the United States (US) in 2014 for the treatment of 
acute uncomplicated influenza in patients ≥ 18 years and older who have been symptomatic for no more 
than 2 days.  
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 IV 
doses of peramivir in healthy adult subjects (Study BCX1812-106) demonstrated that intravenous 
peramivir at a therapeutic dose of 600 mg and at a supra-therapeutic dose of 1200 mg was not associated 
with QTc prolongation or other repolarization abnormalities. 
5.3.1. 
Clinical Experience in Adults 
5.3.1.1. 
Peramivir Efficacy 
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 


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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). 
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. 
Three studies are included as additional efficacy studies. Study 0815T0631was a double-blind, 
double-dummy study of 1099 subjects from Japan, Taiwan or South Korea who were randomized to 
receive a single dose of IV peramivir (300 mg or 600 mg) or 5 days of oral oseltamivir twice daily (BID). 
For the primary endpoint of time to alleviation of symptoms, both peramivir treatment regimens were 
non-inferior to oseltamivir. Study 0816T0632 was a double-blind, non-controlled study in Japan that 
enrolled 42 high-risk inpatients or outpatients with influenza; in this study, subjects were randomized to 
receive 300 mg or 600 mg peramivir. 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. Finally, Study 0918T0633 was a non-controlled, open-label 
study conducted in Japan in 117 pediatric subjects with influenza (either inpatient or outpatient). For the 
primary endpoint of duration of influenza illness, no differences were 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. 
5.3.1.2. 
Peramivir Safety 
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 (AE) rates overall were 
similar to placebo and oseltamivir. No safety signals have emerged from these trials.  


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5.4. 
Rationale for Study 
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 oseltamivir 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 oseltamivir and zanamivir (Jefferson, Jones et al. 2009) and a 
more recent review focused on oseltamivir (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 oseltamivir 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 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. 
There remains a significant unmet need for influenza therapies for patients who are specifically at an 
increased risk of complications. Peramivir has demonstrated efficacy and safety when used in acute 
uncomplicated influenza in adults in the general population. This study aims to develop additional data on 
the safety, pharmacokinetics and effectiveness of IV peramivir in patient groups that are at risk of 
complications from influenza. In particular, this study will target elderly adults (≥ 65 years of age) as well 
as other groups at increased risk of complications (e.g., pregnant women, residents of long term care 
facilities, American Indians and Alaskan Natives) and adults with comorbidities that increase the risk of 


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complications (e.g., adults with asthma, heart disease, diabetes). A complete list of chronic health 
conditions is provided in the inclusion criteria in Section 8.1. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary objective 
 
To evaluate the safety and tolerability of peramivir administered intravenously in elderly 
•
subjects with acute uncomplicated influenza and in subjects with acute uncomplicated 
influenza who are at higher risk for influenza complications 
6.2. 
Secondary Objectives 
 
To describe the pharmacokinetics of IV peramivir in elderly and high risk subjects with acute 
•
uncomplicated influenza. 
 
To evaluate the effectiveness of IV peramivir in elderly and high risk subjects with acute 
•
uncomplicated influenza. 
 
To evaluate the incidence of influenza complications, specifically otitis media, sinusitis, 
•
bronchitis or pneumonia requiring antibiotic use diagnosed after initiation of treatment 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Endpoints 
7.1.1. 
Primary Endpoint 
The primary endpoint of this study will be safety and include the assessment of AEs, laboratory 
abnormalities (clinical chemistry, hematology and urinalysis), vital signs and physical examinations. 
7.1.2. 
Secondary Endpoints 
Secondary endpoints will include: 
 
Pharmacokinetic (PK) analyses 
•
 
Change (reduction) in influenza virus titer by log10 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 
•
 
Incidence of hospital admission post treatment 
•
 
Changes in viral shedding measured by quantitative viral titer assay (TCID50) and/or 
•
quantitative PCR 
 
Change in influenza virus susceptibility to neuraminidase inhibitors 
•
7.2. 
Overall Study Design and Plan 
This is a multicenter, single-arm, open-label study to evaluate the safety, PK and effectiveness of a single 
dose of IV peramivir in elderly subjects (≥65 years of age) with acute uncomplicated influenza and in 
subjects with acute uncomplicated influenza at higher risk for influenza complications.  
A subject’s duration of participation in this study is expected to be 14 days and will include up to 4 clinic 
visits. Following treatment on study Day 1, subjects will undergo follow-up assessments on Days 3, 7, 
and 14 in the clinic.  Additional, unscheduled visits may be required for subjects who report symptoms of 
influenza of moderate or severe intensity at Day 14 or have persistent AEs and/or treatment-emergent 
laboratory findings that require medical monitoring or management. 
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. 
BCX1812-306: Schedule of Assessments 
Assessments 
Screening1 Baseline1 
(Pre-dose) 
Day 1 
Treatment  
Day1 
Day 3 
Day 7 
(+ 2 days) 
Day 14 
(+ 3 days) / 
End of Study 
Early 
Withdrawal 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History/Physical Exam 
X 
 
 
X6 
X6 
 
 
Vital Signs2 
X 
 
 
X 
X 
X 
X 
Body Temperature3 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistries and Hematology4 
 
X 
 
 
X 
 
X 
Urinalysis4 
 
X 
 
 
X 
 
X 
Pregnancy Test (Urine or Serum) 
X 
 
 
 
 
X 
X 
Assessment of influenza symptoms5 
X 
  
X 
X 
X 
X 
X 
Ability to Perform Usual Daily 
Activities5 
 
X 
 
X 
X 
X 
X 
Influenza Related Complications (IRC)7 
X 
 
 
X7 
X 
X 
X 
Concomitant Medications Review 
X 
 
X 
X 
X 
X 
X 
Subject Diary Review 
 
 
X 
X 
X 
X 
X 
Pharmacokinetic (PK) Sampling 
 
 
X 
 
 
 
 
Serum sample for influenza antibody 
analysis8 
 
X 
 
X 
X 
 
X 
Swabs for Virology Analysis 
 
X 
 
X 
X 
 
X 
Rapid antigen test (RAT) or FDA-
approved PCR test for influenza A and B 
on nasal specimen 
X 
 
 
 
 
 
 


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Assessments 
Screening1 Baseline1 
(Pre-dose) 
Day 1 
Treatment  
Day1 
Day 3 
Day 7 
(+ 2 days) 
Day 14 
(+ 3 days) / 
End of Study 
Early 
Withdrawal 
Study Drug Administration 
 
 
X 
 
 
 
 
Adverse Events9 
X 
X 
X 
X 
X 
X 
X 
1 It is expected that the date of Screening, Baseline, and Day 1 (date of study drug administration) will be the same.  Day 1 consists of pre and 
post-dose assessments. 
2 Vital sign measures will include blood pressure, pulse rate, and respiration rate. Vital signs will be recorded once during Screening, and vital 
signs will be taken once on remaining study visit days. 
3 The investigator will record oral body temperature at Screening. Thereafter, the subject or care giver will record oral body temperature 
approximately every 12 hours in the Subject Diary until temperature normalizes for 48 hours (i.e. temperature without antipyretic is < 
37.4oC/ 99.4oF orally for 4 measurements). 
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subjects may be enrolled and begin 
treatment with study drug prior to receiving results.  These labs may be done at any visit if necessary for patient management or adverse event 
monitoring purposes. 
5. Influenza signs and symptoms will be recorded by the study personnel at Screening, then by the subject or care giver twice daily beginning on 
Day 1 through Day 13, and prior to the subject’s clinic visit on Day 14 or until each symptom is 0 or 1 for 48 hours. 
6 Perform a targeted physical exam on Day 3 and Day 7 
7  If an influenza related complication (IRC) is suspected the subject will be instructed to return to the clinic as appropriate to confirm the 
presence or absence of IRCs. 
8    A single serum specimen will be collected, where possible, pre-dose on Day 1, Day 3 and on Day 7 for analysis of influenza antibody titers. 
9    Adverse events are to be collected from the time of informed consent through the follow-up period ending on Day 14. 
 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be eligible to 
participate in the study. 
8.1. 
Subject Inclusion Criteria 
1. Male and female subjects age ≥ 18 years. 
2. The subject must meet one of the following two criteria: 
a. A positive influenza Rapid Antigen Test (RAT) and/or a FDA-approved PCR test and at 
least one clinical sign or symptom consistent with acute influenza infection as listed in 2b 
below. 
OR 
b. Clinical signs and symptoms consistent with acute influenza infection consisting of an oral 
temperature ≥ 100°F (37.8°C) with at least one respiratory symptom of at least moderate 
severity (cough or rhinitis) and at least one constitutional symptom of at least moderate 
severity (myalgia [aches and pains], headache, feverishness, or fatigue). 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 
and/or PCR. During the period of approval, clinical symptoms alone will be adequate 
to meet Criteria 2. 
3. Onset of symptoms no more than 48 hours before presentation for screening. However, due to 
historically delayed presentation for medical care in the adult population, approximately 20% of 
the elderly population may be enrolled with symptoms starting > 48-hours but ≤ 72-hours prior to 
presentation for screening. Note: Time of onset of illness is defined as either (1) the time when 
the temperature (either oral or rectal) was first measured as elevated (at least one ºC of elevated 
temperature), OR (2) the time when the subject experienced the presence of at least one 
respiratory symptom AND the presence of at least one constitutional symptom together. 
4. Either age ≥ 65 years AND/ OR presence of one of the following risk factors: 
a. Pregnancy, including women who are up to 2 weeks postpartum 
b. Resident of a nursing home or long-term care facility  
c. History of chronic lung disease including obstructive pulmonary disease (COPD), 
persistent asthma or cystic fibrosis 
d. History of heart disease including myocardial infarction, angina requiring treatment, 
congestive heart failure requiring treatment, arrhythmia including atrial fibrillation and 
valvular dysfunction 
e. History of blood dyscracias including sickle cell anemia and thalassemia 
f. History of renal impairment (creatinine clearance [CrCl] < 50 mL/min as determined by 
the Cockcroft-Gault formula) (Cockcroft and Gault 1976), including dialysis. 


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g. History of liver disease including cirrhosis 
h. Mild to moderate immunocompromise, including: history of HIV disease on stable 
HAART with last known CD4+ count ≥ 200 cells/µL: known neutropenia with ANC 
> 500 cells/µL; chronic corticosteroid use of < 20 mg/d for any indication. 
i. 
History of diabetes mellitus 
j. 
Morbid obesity (body mass index [BMI] ≥ 40)  
k. American Indian or Alaskan native 
5. Written informed consent 
8.2. 
Subject Exclusion Criteria 
1. Subjects who in the opinion of the investigator require hospital admission to treat medical 
condition(s) which, in the Investigator’s opinion, could represent complications of influenza. 
Note, hospitalization is not an exclusion criterion when it is the usual practice of the 
treating institution to hospitalize elderly patients with acute uncomplicated influenza. 
2. Women who plan to breast-feed for the first 48 hours after study drug administration.  However, 
women who suspend breast feeding for 48 hours after study administration may participate. 
3. Employees of the study site, or immediate family members of study site employees 
4. Presence of clinically significant signs of acute respiratory distress. 
5. Clinical evidence of worsening of any chronic medical condition (temporally associated with the 
onset of symptoms of influenza) which, in the Investigator’s opinion, indicates that such 
finding(s) could represent complications of influenza 
6. Current clinical evidence, including clinical signs and/or symptoms consistent with a bacterial 
infection, including: otitis media, bronchitis, sinusitis and/or pneumonia, or active bacterial 
infection of any body site that requires therapy with oral or systemic antibiotics 
7. Immunization against influenza with live attenuated virus vaccine (FluMist®) in the previous 
14 days 
8. History of alcohol abuse or drug addiction within 1 year prior to admission in the study 
9. Participation in a study of any investigational drug or device within the last 30 days 
10.  Previous participation in study BCX1812-305 (pediatric study) or BCX1812-306 (this study) 
11. Presence of any pre-existing illness that, in the opinion of the Investigator, would place the 
subject at an unreasonably increased risk through participation in this study or would make the 
subject unable to comply with the protocol. 
 


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8.3. 
Withdrawal Criteria 
Participation in the study is strictly voluntary. Subjects have the right to withdraw from the study at any 
time and for any reason. A subject’s participation will be terminated: 
 
At the subject’s request  
•
 
If, in the Investigator’s or Sponsor’s opinion, continuation in the study would be detrimental 
•
to the subject’s well-being 
 
If the subject is not able to comply with the study requirements 
•
 
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, 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.  
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 14 Visit.  
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 
Subjects will be dosed with peramivir at the dosage levels currently approved in the US package insert for 
peramivir. The standard dose will be a single IV dose of 600 mg for subjects with CrCL ≥ 50 ml/min and 
reduced for subjects with CrCL < 50 ml/min as described in Section 9.4.  
9.2. 
Study Drug 
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 temperature (excursion permitted to 59° to 86°F). 
9.3. 
Study Drug Preparation and Administration 
The Principal Investigator at each study center will designate a pharmacist (or other qualified study staff 
member) to prepare IV peramivir. 
Subjects will receive a single dose of 600 mg peramivir (or less if renally impaired) diluted in 0.9% 
saline, 0.45% saline, 5% dextrose or lactated Ringer’s using the technique described in a separate drug 
preparation instruction sheet, administered IV over a period of 15 to 30 minutes. The calendar date and 
24-hour clock time (start and end of the IV infusion) will be recorded.  
The intravenous line used to administer peramivir must be flushed prior to and after peramivir 
administration.  No other medications should be administered through the same IV line during peramivir 
administration. 
9.4. 
Dose Adjustments for Subjects with Renal Impairment 
Table 2 provides dose adjustments based on creatinine clearance for subjects with renal impairment. In 
subjects with chronic renal impairment maintained on hemodialysis, peramivir should be administered 
after dialysis at a dose adjusted based on renal function as shown in the table below. 
Table 2. 
Dosage Adjustment for Subjects with Altered Creatinine Clearance 
 
Creatinine Clearance (mL/min)a 
 
≥ 50 
30 to 49 
10 to 29 
Recommended Dose (mg) 
600 mg 
200 mg 
100 mg 
a Calculated using the Cockroft -Gault equation. 
9.5. 
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 


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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. 
Periodically during the trial and 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 
9.6. 
Randomization and Blinding/ Masking 
As this is a single-arm, open-label study, randomization and blinding are not applicable. 
9.7. 
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 on Day 1; treatment compliance is expected to be 100% for this study. 
9.8. 
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 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. 
9.9. 
Concomitant Medications 
With the exception of medications used for the symptomatic treatment of influenza-related symptoms, 
administration of any dose of a concomitant medication during the study period must be recorded by the 
study staff within the subject’s study source documents (e.g., chart). This includes prescription 
medications as well as over-the-counter medications. 
Medications, such as antipyretics and analgesics, used for the symptomatic treatment of influenza-related 
symptoms will be recorded separately. Subjects will record the type, date, and time of symptomatic 
medications in the subject diary supplied by BioCryst including the date and time of administration. 
Study staff will provide diary completion instructions to subjects during their first study visit. 
Use of concomitant medications will be assessed and recorded at Screening, and daily throughout the 
duration of the study through the study completion visit at Day 14 or later. 
9.9.1. 
Antipyretics and Analgesics 
Resolution of fever is an important efficacy endpoint 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 times of 
administration of these medications will be recorded by the subject/caregiver in the subject diary. To 
avoid the confounding effects of antipyretic medications, temperature measurements recorded by the 
subjects will be taken, whenever possible, at least 4 hours after administration of the antipyretic 
medication. 
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9.9.2. 
Medications for Chronic Diseases/Conditions 
Subjects with chronic medical conditions may continue to receive prescribed treatments during 
participation in this protocol. For example, treatment for cardiovascular conditions, endocrine conditions, 
rheumatologic conditions, respiratory conditions, dermatologic conditions, and neurologic conditions may 
be continued if not otherwise contraindicated within this protocol. 
9.9.3. 
Antivirals 
Subjects must not have received any doses of oseltamivir, zanamivir, amantadine, or rimantadine in the 
7 days prior to study drug administration. Concomitant use of oseltamivir, zanamivir, amantadine, and/or 
rimantadine is not permitted during administration of study drug and during the post-treatment follow-up 
period. Antivirals for other infections such as HIV or herpes simplex may be taken. 
9.9.4. 
Antibiotics 
Oral or parenteral antibiotics may be administered at any time after enrollment if medically indicated. If 
such use is a result of proven or suspected influenza-related complication, the appropriate assessments 
should be carried out (see Section 10.2.4). 
9.9.5. 
Immunizations 
Subjects must not have received a live attenuated influenza vaccine in the 14 days prior to study drug 
administration.  Immunizations of any kind should not be administered during study participation. 
Subjects who are candidates for pneumococcal immunization or other immunization should not receive 
such immunizations during the study period. 
 
 


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10. 
STUDY CONDUCT 
10.1. 
Overview 
Approximately 120 subjects will be enrolled in this open-label study (a minimum of 80 elderly subjects 
[≥ 65 years] will be enrolled). A subject’s duration of participation in this study is expected to be 14 days 
and will include up to 4 clinic visits. It is expected that most subjects will have the Screening visit and the 
Day 1 Treatment visit on the same day. Subjects will be discharged from this study on Day 14. 
Additional, unscheduled visits may be required for subjects who report symptoms of influenza of 
moderate or severe intensity at Day 14 or have persistent adverse events and/or treatment-emergent 
laboratory findings that require medical monitoring or management. 
All subjects will receive a single dose of IV peramivir (600 mg or reduced for renal impairment). Subjects 
will undergo follow-up clinical assessments on Days 3, 7, and 14.  
An adequate nasal swab specimen will be collected from all enrolled subjects at Baseline (pre-dose) for 
virus subtype identification and quantitative virologic assessments and at the follow-up assessments on 
study Days 3, 7 and 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.  
Up to 3 blood samples will be drawn to obtain plasma samples for drug concentration determinations, 
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  
•
Adverse events and concomitant medications will be monitored at each scheduled visit from the 
Screening assessment to final study visit. Clinical laboratory investigations (chemistries, hematology, and 
urinalysis) will be collected at Baseline, Day 7 and Day 14 visits. Safety and tolerability will be evaluated 
through assessments of AEs, laboratory analyses (clinical chemistry, hematology, and urinalysis), vital 
signs and physical examinations at the time points indicated in the schedule of assessments. 
All subjects/caregivers will record the following information in a Subject Diary: 
 
Assessment of the presence and severity of each of 7 symptoms of influenza on a 4-point 
•
severity scale (0, absent; 1, mild; 2, moderate; 3, severe) at Screening, then twice daily 
through Day 13, and prior to the subject’s clinic visit on Day 14 or until each symptom is 0 or 
1 for 48 hours.  Symptoms will be reviewed at each clinic visit. 
 
Temperature measurements (oral) will be taken with an electronic thermometer provided by 
•
the Sponsor, approximately every 12 hours until temperature normalizes for 48 hours (i.e. 
temperature without antipyretic is < 37.4°C/ 99.4°F orally for 4 measurements). With the 
exception of the Screening/ Baseline measurement, all temperature measurements will be 


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obtained at least 4 hours after, or immediately before, administration of oral acetaminophen 
or other antipyretic medications, if taken. 
 
The type, date, and time of medications used for the symptomatic treatment of influenza-
•
related symptoms. 
 
Assessment of the subject’s ability to perform usual activities using a 0 to 10 visual analogue 
•
scale once daily through Day 14, where 0 = Unable to perform usual activities at all, and 
10 = Able to perform all usual activities fully. 
10.1.1. 
Screening Period 
The Screening Period begins at the time of consent of the study subject. The Investigator will conduct the 
following assessments: 
 
Review of inclusion and exclusion criteria 
•
 
Review and record medical history and concomitant medications 
•
 
Conduct an assessment for IRC; if an IRC is suspected, then the physical examination will 
•
confirm the actual presence/absence of the IRC. If an IRC is present, the subject meets 
exclusion criteria 6 and is ineligible for the study. 
 
Measure oral body temperature  
•
 
Conduct a RAT or Food and Drug Administration (FDA)-approved PCR test for influenza A 
•
and B on an adequate nasal specimen, in accordance with the manufacturer’s instructions. 
The subject must have a positive RAT result and/or a Food and Drug Administration (FDA) 
approved PCR test and at least one clinical sign or symptom consistent with influenza (see 2b 
below). 
OR have clinical signs and symptoms consistent with acute influenza infection consisting of 
an oral temperature ≥ 100°F (37.8°C) with at least one respiratory symptom of at least 
moderate severity (cough or rhinitis) and at least one constitutional symptom of at least 
moderate severity (myalgia [aches and pains], headache, feverishness, or fatigue) (See 
Section 8.1). 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 and/or PCR. During the period of approval, clinical 
symptoms alone will be adequate to meet Criteria 2. 
The subject must have at least 1 respiratory symptom (cough, sore throat or nasal symptoms) 
of at least moderate severity, in addition to at least 1 constitutional symptom (myalgia, 
headache, feverishness, or fatigue) of at least moderate severity to be eligible for the study 
 
Measure vital signs (blood pressure, pulse rate, and respiration rate) 
•
 
Perform a complete physical examination. Examination of the breast and urogenital system 
•
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Perform a urine or serum pregnancy test (non-pregnant females of childbearing potential 
•
only)  
 
Eligible subjects will be enrolled. The study pharmacist/designee will prepare an order for study drug as 
defined in Section 9.3 , which includes the subject’s study number. 
10.1.2. 
Treatment Period 
Randomization 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 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. 
10.1.2.1. 
Baseline (Pre-dose)/Day 1 
The following Baseline procedures/evaluations will be performed after Screening and prior to dosing on 
Day 1: 
 
Obtain a bilateral adequate nasal swab specimen for viral subtyping, culture, quantitative 
•
PCR assay and susceptibility to neuraminidase inhibitors. 
 
Obtain and record body temperature 
•
 
Blood and urine 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. 
Following completion of the baseline procedures administer study drug: 
 
Administer study drug (at hour 0) and record the calendar date and 24-hour clock time for the 
•
start and finish of the IV infusion.  
 
Obtain and record body temperature 
•
10.1.2.2. 
Day 1/Post-dose 
The following procedures/evaluations will be performed post-dose on Day 1: 
 
Collect up to 3 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: 
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 
 
Train the subject/caregiver on the recording of the following in the subject diary: 
•
o Subject’s body temperature, obtained at approximately 12-hour intervals each day 
until the temperature normalizes for 48 hours (and 4 hours from last antipyretic 
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o Instruct the subject to assess his/her time lost from work, if applicable, and the 
recording of the subject’s ability to perform usual daily activities using a 0 to 10 
visual analogue scale.  
o Assessment of signs and symptoms of influenza twice daily beginning on Day 1 (see 
Section10.2.2). 
 
Review and record concomitant medications 
•
 
Obtain and record body temperature 
•
 
Review and record AEs 
•
10.1.2.3. 
Day 3 
The following procedures/assessments will be performed on Day 3. The Day 3 assessment will be 
performed as a clinic visit. 
 
Measure vital signs (blood pressure, pulse rate, and respiration rate) 
•
 
Conduct an assessment for IRC; if an IRC is suspected, then the physical examination will 
•
confirm the actual presence or absence of the IRC 
 
Conduct a targeted physical examination 
•
 
Measure oral body temperature  
•
 
A serum sample for future influenza antibody analysis 
•
 
Review the subject diary for completeness and instruct the subject/caregiver on the need to 
•
ensure complete recording of required assessments, if needed. 
 
Collect a bilateral adequate nasal swab specimen for viral culture, quantitative PCR assay and 
•
susceptibility to neuraminidase inhibitors.  
 
Review and record concomitant medications 
•
 
Review and record AEs 
•
10.1.2.4. 
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. 
 
Measure vital signs (blood pressure, pulse rate, and respiration rate) 
•
 
Conduct an assessment for IRC; if an IRC is suspected, the physical examination will confirm 
•
the actual presence or absence of the IRC 
 
Conduct a targeted physical examination 
•
 
Measure oral body temperature  
•
 
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. 
 
Collect urine for urinalysis 
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Review the subject diary for completeness and instruct the subject/caregiver on the need to 
•
ensure complete recording of required assessments, if needed. 
 
Collect a bilateral adequate nasal swab specimen for viral culture, quantitative PCR assay and 
•
susceptibility to neuraminidase inhibitors.  
 
Review and record concomitant medications 
•
 
Review and record AEs 
•
10.1.2.5. 
Day 14 (End of Study) 
The Day 14 assessments will be performed as a clinic visit. The following procedures/assessments will be 
performed on Day 14 (+ 3 days) or at the time of early withdrawal, where possible:  
 
Measure vital signs (blood pressure, pulse rate, and respiration rate) 
•
 
Measure and record oral body temperature  
•
 
Perform a urine or serum pregnancy test (non-pregnant females of childbearing potential 
•
only) 
 
Conduct an assessment for the presence of possible IRC; if an IRC is suspected, a targeted 
•
physical exam should be conducted to confirm the absence or presence of the IRC 
 
Review the subject diary for completeness  
•
 
Collect a bilateral adequate nasal swab specimen for viral culture, quantitative PCR assay and 
•
susceptibility to neuraminidase inhibitors.  
 
Review and record concomitant medications 
•
 
If Day 7 labs are, in the opinion of the investigator, significantly abnormal or significantly 
•
changed from baseline, collect blood specimen for clinical chemistry and/or clinical 
hematology tests as specified in Sections 11.2.1 and 11.2.2  and a serum sample for future 
influenza antibody analysis. 
 
If Day 7 urinalysis is, in the opinion of the investigator, significantly abnormal or 
•
significantly changed from baseline, collect urine for urinalysis 
 
Review and record AEs 
•
10.2. 
Clinical assessments of Effectiveness 
Effectiveness will be evaluated through assessments of body temperature, clinical symptoms of influenza, 
usual daily activities assessments, incidence of influenza-related complications (see Section 10.2.4) for 
details), influenza virus titers, and changes in viral sensitivity to other antiviral drugs. 
10.2.1. 
Body Temperature 
The Investigator will record oral body temperature at Screening. The baseline temperature will be 
recorded at the Day 1 visit prior to dosing, regardless of whether the subject had recently taken an 
antipyretic. Thereafter, the subject or caregiver will record oral body temperatures approximately every 
12 hours through Day 14 in the subject diary. Subjects or caregivers will measure their oral temperature 
with an electronic thermometer (provided by the Sponsor for the study). With the exception of the 


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baseline measurement, subjects will be instructed to take all temperature measurements at least 4 hours 
after, or immediately before, administration of oral acetaminophen or other antipyretic medications. The 
times of each temperature determination will be recorded in the Subject Diary.  
10.2.2. 
Influenza Signs and Symptoms 
Subjects will be asked to provide an assessment of 7 influenza symptoms (cough, sore throat, nasal 
congestion, myalgia [aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, 
absent; 1, mild; 2, moderate; 3, severe) beginning at Screening then twice daily beginning on Day 1 
through Day 13, and prior to the subject’s clinic visit on Day 14. Once all symptoms are score a 0 or 1 for 
at least 48 hours the can discontinue recordings. The definitions to be used to assign severity are as 
follows: 
0, Absent 
no symptom present (no cough, no sore throat, etc.) 
1, Mild 
symptom present and slightly uncomfortable 
2, Moderate symptom is very uncomfortable 
3, Severe 
symptom is intolerable 
The subject diary will be reviewed by study staff at each visit for completion of the record of all required 
items, with particular emphasis on alleviation of clinical symptoms as well as relapse of symptoms. Study 
staff will not attempt to ask subjects or caregiver to retrospectively complete missing subject diary data 
for any scheduled assessments that have not been completed prior to the clinic visit. However, study staff 
should, however, remind the subject or caregiver to complete the subject diary at all scheduled times. 
10.2.3. 
Assessment of ability to perform usual daily activities 
If possible, subjects/caregivers will be asked to provide a daily assessment of the subject’s ability to 
perform usual daily activities using a 0 to 10 visual analogue scale, where 0 = Unable to perform usual 
activities at all, and 10 = Able to perform usual activities fully. The subject will also assess his/her time 
lost from work, if applicable. The subject/care giver will be asked to record these assessments in the 
subject diary once daily from Baseline through Day 13 and prior to the subject’s clinic visit on Day 14. 
10.2.4. 
Influenza-Related Complications 
Study personnel will evaluate the subject at Screening and Days 3, 7, and 14 for the presence of clinical 
signs and/or symptoms of the following IRC:  
 
Sinusitis 
•
 
Otitis media 
•
 
Bronchitis 
•
 
Pneumonia  
•
Note that subjects with clinical signs and/or symptoms consistent with bacterial infections, 
including:  otitis media, bronchitis, sinusitis, and/or pneumonia at screening are not eligible for 
enrollment in this study (see exclusion criteria in Section 8.2). 
If an IRC is suspected, then a targeted physical examination will be conducted to confirm the presence or 
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experience) an IRC as noted above, he/she will record that assessment and any medication used to treat 
the condition in the source record and record the IRC and medications in the case report form (CRF). The 
Investigator will promptly provide appropriate treatment for any suspected or proven IRC. Such 
information describing IRC signs and/or symptoms should not be reported as AEs. Any reactions at the 
site of the IV drug administration will be recorded as an AE. 
10.2.5. 
Hospital Admission 
In the event that a subject requires admission to a hospital at any time during the study additional 
information on the hospital admission will be collected. See Section 11.1.5 for serious adverse event 
(SAE) reporting details. 
10.3. 
Virology Samples 
Bilateral mid-nasal swab specimens will be collected for virologic analysis. Samples will be collected at 
Baseline, Day 3, Day 7, and 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 
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11. 
ASSESSMENT OF SAFETY 
Safety will be evaluated through assessments of AEs, pregnancy outcomes, laboratory analyses (clinical 
chemistry, hematology, and urinalysis), vital signs, and physical examinations. 
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 Screening, 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 16.2). 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 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. 
AEs are designated as “non-serious” or “serious.” 
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 
•
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• 
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 influenza in elderly patients is not 
considered an SAE and should not be reported as such. Any adverse event that 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 signs the informed consent 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 Section 16.2). Any adverse events not covered by the DAIDS criteria will be assessed and classified 
into one of 4 clearly defined categories as follows: 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no intervention 
required. The AE does not interfere with the participant’s normal functioning 
level. It may be an annoyance. 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; no or 
minimal intervention required. The AE produces some impairment of 
functioning, but it is not hazardous to health. It is uncomfortable or an 
embarrassment. 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; medical 
intervention may be required. The AE produces significant impairment of 
functioning or incapacitation. 
Life threatening 
(Grade 4): Symptoms causing inability to perform basic self-care functions OR 
Medical or operative intervention indicated to prevent permanent impairment, 
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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). 
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 case report form (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: safety@biocryst.com and drugsafety@prosarcorp.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 SAE 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 
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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 Investigational New 
Drug (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 
Any pregnancy in an enrolled subject or discovered in a subject during the course of the trial must be 
reported to BioCryst or designee on the Pregnancy Notification Form (to be 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), and the outcome needs to be reported on the 
Pregnancy Outcome Form (to be supplied by BioCryst). Pregnancy outcomes of miscarriage, elective 
termination, stillbirth or birth defects will be considered SAEs and should be reported as per 
Section 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. 
11.2. 
Clinical Laboratory Evaluations 
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 Screening and at Day 7 or early 
termination visit (if the early termination visit occurs prior to Day 7). Clinically significant results should 
be reported as AEs.  If Day 7 clinical chemistry profiles are, in the opinion of the investigator, 
significantly abnormal or significantly changed from baseline at Day 7, they should be repeated at the 
Day 14 visit. 
At screening, creatinine clearance will be calculated by the Cockroft-Gault equation (using actual body 
weight and serum creatinine) (see Appendix 16.1). 
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 Day 7 or early termination visit (if the early 
termination visit occurs prior to Day 7).  If Day 7 hematology profiles are, in the opinion of the 
investigator, significantly abnormal or significantly changed at Day 7, repeat at the Day 14 visit. 
Clinically significant results should be reported as AEs.  


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11.2.3. 
Urinalysis 
Urinalysis will include tests for protein, glucose, ketones, blood, urobilinogen, nitrite, pH, and specific 
gravity and microscopic evaluation (if initial assessment is abnormal) for red blood cells (RBCs) and 
white blood cells (WBCs).  
Urine samples for urinalysis will be collected at Screening, Day 7 and/or at early termination visit (if the 
early termination visit occurs prior to Day 7). If a urinalysis result for any analyte is, in the opinion of the 
investigator, significantly abnormal and/or unexplained, repeat testing may be obtained at periodic 
intervals as deemed appropriate by the Investigator, and should be repeated during the Day 14 visit. 
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 and at the Day 14 or early 
termination visit (if the early termination visit occurs prior to Day 14) assessment using a urine pregnancy 
test performed locally unless they are already pregnant. If local regulatory guidelines require a serum 
pregnancy test, then this modality should be completed in addition to the urine test to complete the 
pregnancy test. 
11.3. 
Vital Signs 
Vital sign measurements (blood pressure, heart rate, respiration rate) will be recorded once at Screening 
and once at each study visit on Days 3, 7, 14 and/or early termination visit. 
11.4. 
Physical Examination  
The Investigator will perform a full physical examination at Screening, including the subject’s height and 
weight, and a targeted physical examination on Day 3 and Day 7 and/or early termination. Examination of 
the breast and urogenital system may be omitted as per the institution’s/investigator’s clinical routine. At 
each follow-up visit, study personnel will evaluate the subject for the presence of clinical signs and/or 
symptoms of influenza-related complications (see Section 10.2.4). If an IRC is suspected, a targeted 
physical exam should be conducted to confirm the absence or presence of the IRC. 


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12. 
PHARMACOKINETIC ASSESSMENTS 
Up to 3 plasma samples will be drawn for determination of peramivir drug concentrations. The samples 
will be drawn, where possible, during the following time periods, beginning from the end of dosing: 
 
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  
•
Plasma samples will be processed and shipped for analysis in accordance with instructions provided in the 
Laboratory Manual.  
Plasma peramivir concentrations will be measured by a validated liquid chromatography-tandem mass 
spectrometry (LC/MS-MS) assay. 


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13. 
STATISTICS 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects, mean, median, standard deviation 
(SD), minimum, and maximum for continuous data and frequencies and percentages for categorical data. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
13.1. 
Data Collection Methods 
The data will be transcribed from the subjects’ source documents into the Case Report Form (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 statistical analysis plan (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, PK, and effectiveness of IV administration of peramivir in 
subjects ≥ 65 years of age with influenza infection and in subjects with influenza infection who are at an 
increased risk of influenza complications. The sample size is not based on statistical considerations, rather 
a sample size of up to 120 subjects is considered adequate to evaluate the stated objectives.  
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 PCR. The ITTI population will be used for 
analyses of effectiveness. 
 
Safety Population: The safety population will include all subjects who received any amount 
•
of study drug. This population will be used for all safety analyses. 


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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 
1 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 (≥ 65 years vs < 65 years) and viral subtype at Screening. 
Additional subgroups based on risk of complication may be evaluated. Subgroups will be defined in the 
SAP. 
13.7.4. 
Missing Data 
Every effort will be made to obtain required data at each scheduled visit from all subjects who have been 
enrolled. 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. 
13.8. 
Effectiveness 
13.8.1. 
Effectiveness Endpoints 
All effectiveness endpoints will be summarized using descriptive statistics overall, and by age group and 
study day/time, if appropriate. 
13.8.2. 
Effectiveness Analyses 
Time to resolution of fever, defined as a temperature < 99.4°F oral with no antipyretic medications taken 
for at least 12 hours, will be estimated overall and by each age 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 overall and for each age 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 
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Reduction in viral shedding will be assessed as the change from baseline in log10 TCID50/mL and 
RT-PCR, and will be summarized overall, by age group, and by 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 overall, and 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 Section 16.2). The number and percentage of subjects experiencing treatment-emergent graded 
toxicities will be summarized overall and by age group. Laboratory toxicity shifts from baseline to 
post-baseline assessments will be summarized overall and by age group. 
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 
overall and by age 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 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/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 subject prior to performing any study-related 
procedures. The informed consent process should take place under conditions where the subject has 
adequate time to consider the risks and benefits associated with his/her participation in the study. Subjects 
will not be screened or treated until the subject has signed an approved informed consent form (ICF) 
written in a language in which the subject is fluent. 
The ICF 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 the aims, methods, reasonably anticipated benefits, and 
potential hazards of the trial and any discomfort it may entail. Each subject will be informed that they are 
free not to participate in the trial and that they may withdraw consent to participate at any time. They will 
be told that refusal to participate in the study will not prejudice future treatment. They will also be told 
that their records may be examined by competent authorities and authorized persons but that personal 
information will be treated as strictly confidential and will not be publicly available. 


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Subjects must be given the opportunity to ask questions. After this explanation and before entry into the 
trial, consent should be appropriately recorded by means of the subject’s dated signature. The subject 
should receive a signed and dated copy of the ICF. The original signed 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 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 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 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. 


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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 or 
authorization in writing from the appropriate individual. HIPAA authorizations are required for US sites 
only. 
14.7. 
Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict confidence along 
with all information furnished by BioCryst. 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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Mickiene, D. Mikic, K. G. Mohn, A. Moradi, P. Nymadawa, M. E. Oliva, M. Ozkan, D. Parekh, M. Paul, 
F. P. Polack, B. A. Rath, A. H. Rodriguez, E. B. Sarrouf, A. C. Seale, B. Sertogullarindan, M. M. 
Siqueira, J. Skret-Magierlo, F. Stephan, E. Talarek, J. W. Tang, K. K. To, A. Torres, S. H. Torun, D. 
Tran, T. M. Uyeki, A. Van Zwol, W. Vaudry, T. Vidmar, R. T. Yokota, P. Zarogoulidis, P. C. 
Investigators and J. S. Nguyen-Van-Tam (2014). "Effectiveness of neuraminidase inhibitors in reducing 
mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis 
of individual participant data." Lancet Respir Med 2(5): 395-404. 
Neumann, G., T. Noda and Y. Kawaoka (2009). "Emergence and pandemic potential of swine-origin 
H1N1 influenza virus." Nature 459(7249): 931-939. 
Nicolini, A., S. Claudio, F. Rao, L. Ferrera, M. Isetta and M. Bonfiglio (2011). "Influenza A (H1N1)-
associated pneumonia." J Bras Pneumol 37(5): 621-627. 
Perez-Padilla, R., D. de la Rosa-Zamboni, S. Ponce de Leon, M. Hernandez, F. Quinones-Falconi, E. 
Bautista, A. Ramirez-Venegas, J. Rojas-Serrano, C. E. Ormsby, A. Corrales, A. Higuera, E. Mondragon, 
J. A. Cordova-Villalobos and I. W. G. o. Influenza (2009). "Pneumonia and respiratory failure from 
swine-origin influenza A (H1N1) in Mexico." N Engl J Med 361(7): 680-689. 
Simonsen, L., P. Spreeuwenberg, R. Lustig, R. J. Taylor, D. M. Fleming, M. Kroneman, M. D. Van 
Kerkhove, A. W. Mounts and W. J. Paget (2013). "Global Mortality Estimates for the 2009 Influenza 
Pandemic from the GLaMOR Project: A Modeling Study." PLoS Medicine 10(11): e1001558. 
Siston, A. M., S. A. Rasmussen, M. A. Honein, A. M. Fry, K. Seib, W. M. Callaghan, J. Louie, T. J. 
Doyle, M. Crockett, R. Lynfield, Z. Moore, C. Wiedeman, M. Anand, L. Tabony, C. F. Nielsen, K. 
Waller, S. Page, J. M. Thompson, C. Avery, C. B. Springs, T. Jones, J. L. Williams, K. Newsome, L. 
Finelli, D. J. Jamieson and H. N. I. i. P. W. G. Pandemic (2010). "Pandemic 2009 influenza A(H1N1) 
virus illness among pregnant women in the United States." JAMA 303(15): 1517-1525. 
Treanor, J. J., F. G. Hayden, P. S. Vrooman, R. Barbarash, R. Bettis, D. Riff, S. Singh, N. Kinnersley, P. 
Ward and R. G. Mills (2000). "Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in 
treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group." JAMA 
283(8): 1016-1024. 
Tscherne, D. M. and A. Garcia-Sastre (2011). "Virulence determinants of pandemic influenza viruses." J 
Clin Invest 121(1): 6-13. 
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human 
Infection with Avian Influenza, A. V., A. N. Abdel-Ghafar, T. Chotpitayasunondh, Z. Gao, F. G. Hayden, 
D. H. Nguyen, M. D. de Jong, A. Naghdaliyev, J. S. Peiris, N. Shindo, S. Soeroso and T. M. Uyeki 
(2008). "Update on avian influenza A (H5N1) virus infection in humans." N Engl J Med 358(3): 261-273. 
 
 


Protocol 
BioCryst Pharmaceuticals, Inc. 
 
Version 4.0 
CONFIDENTIAL 
BCX1812-306 
 
54 
16. 
APPENDICES 
16.1. 
Appendix 1: Cockcroft-Gault Equation 
Creatinine clearance to be calculated using the Cockcroft Gault Equation (Cockcroft and Gault 1976) 
using actual body weight (BW) and serum creatinine (Scr). 
• 
Male:  
CLcr (mL/min) = [140 - age (years)] × BW(kg) 
 
 
 
 
 
 
 
 
 
 
 
72 × Scr (mg/dL)
 
 
Female: CLcr (mL/min) = [140 - age (years)] × BW(kg) × 0.85 
 
 
 
 
 
 
 
 
 
 
 
72 × Scr (mg/dL) 
An on-line calculator can also be found at: http://nephron.com/cgi-bin/CGSI.cgi 
 


Protocol 
BioCryst Pharmaceuticals, Inc. 
 
Version 4.0 
CONFIDENTIAL 
BCX1812-306 
 
55 
16.2. 
Appendix 2: 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.  
28-Dec-04/Clarification Aug 09 
Page 1 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  
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.). 
28-Dec-04/Clarification Aug 09 
Page 2 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 
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 
Page 4 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 
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 
Page 5 of 21
 
 
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 
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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 
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 
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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 
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 
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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 
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 
Page 12 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 
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 
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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 
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 
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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 
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 
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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 
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 
Page 20 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 
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. 
BCX1812-306 
 
Statistical Analysis Plan                                                                                                                 Final Version 1.0 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 3, multicenter, single-arm, open-label, study to evaluate 
the safety, pharmacokinetics and effectiveness of intravenous 
peramivir in elderly subjects with acute uncomplicated influenza 
infection and in subjects with acute uncomplicated influenza 
infection at higher risk for influenza complications 
 
 
Phase: 
3 
 
 
Protocol No.: 
BCX1812-306  
 
 
Protocol Date 
30 June 2015 (Version 1.0) 
 
03 September 2015 (Version 2.0) 
 
11 October 2016 (Version 3.0) 
09 August 2017 (Version 4.0) 
 
 
 
 
 
 
Analysis Plan Version and 
Date 
Final Version 1.0  13 June 2018 
 
 
Prepared By: 
Andrew Garrison, MS 
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. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
CONFIDENTIAL 
Page 3 
13 June 2018 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ............................. 2 
1. 
INTRODUCTION ............................................................................................ 5 
1.1. 
Study Overview ...................................................................................................................... 5 
1.2. 
Schedule of Events/Study Visits .............................................................................................. 7 
1.3. 
Glossary of Abbreviations .................................................................................................. 9 
2. 
OBJECTIVES .................................................................................................. 9 
3. 
GENERAL STATISTICAL CONSIDERATIONS ............................................. 9 
3.1. 
Sample size and power ............................................................................................................ 9 
3.2. 
Randomization and Masking ................................................................................................ 10 
3.3. 
Handling of data ................................................................................................................... 10 
3.3.1. 
Strata and Covariates .......................................................................................................... 10 
3.3.2. 
Examination of Subject Subsets ........................................................................................... 10 
3.3.3. 
Multiple Testing and Comparisons ...................................................................................... 10 
3.3.4. 
Missing Data and Outliers ................................................................................................... 10 
3.3.5. 
Imputation of Incomplete Dates ........................................................................................... 11 
3.3.6. 
By Study Visit Displays ...................................................................................................... 11 
3.3.7. 
Derived and Transformed Data ............................................................................................ 11 
3.3.8. 
Definitions and Terminology ............................................................................................... 11 
3.4. 
TIMING OF ANALYSES ..................................................................................................... 14 
4. 
ANALYSIS POPULATIONS .......................................................................... 14 
4.1. 
Intent-to-Treat Population .................................................................................................... 15 
4.2. 
Intent-to-Treat Infected Population ...................................................................................... 15 
4.3. 
Safety Population .................................................................................................................. 15 
4.4. 
Exposure-Response Population ............................................................................................. 15 
5. 
STATISTICAL METHODS ........................................................................... 15 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
CONFIDENTIAL 
Page 4 
13 June 2018 
 
5.1. 
Subject Disposition, Demographic and Baseline Characteristics ............................................ 16 
5.2. 
Effectiveness Analysis ........................................................................................................... 16 
5.2.1. 
Effectiveness Endpoints ...................................................................................................... 16 
5.2.2. 
Effectiveness Analyses ....................................................................................................... 17 
5.2.3. 
Exploratory Exposure Response Analyses ............................................................................ 18 
5.2.4. 
Subgroup Analyses ............................................................................................................. 18 
5.3. 
Safety.................................................................................................................................... 18 
5.3.1. 
Adverse Events .................................................................................................................. 18 
5.3.2. 
Concomitant Medications ................................................................................................... 19 
5.3.3. 
Clinical Laboratory Assessments ......................................................................................... 19 
5.3.4. 
Other Safety Analyses ........................................................................................................ 19 
5.4. 
Protocol deviations ............................................................................................................... 20 
6. 
CHANGES IN THE PLANNED ANALYSES .................................................. 20 
7. 
REVISION HISTORY .................................................................................... 20 
8. 
PROGRAMMING CONVENTIONS .............................................................. 21 
9. 
PROPOSED TABLES, LISTINGS, AND FIGURES FOR FINAL ANALYSIS 23 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 5 
13 June 2018 
 
1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of data from Protocol BCX1812-306.  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, respectively. 
This document describes all analyses of safety, clinical effectiveness, pharmacokinetics (PK) and 
virology analyses. PK and virology analyses will be written as separate reports from the clinical 
study report.  
1.1. 
STUDY OVERVIEW 
Protocol BCX1812-306 is a multicenter, single-arm, open-label study to evaluate the safety, PK, 
and effectiveness of a single dose of peramivir administered intravenously (IV) in elderly subjects 
(≥ 65 years of age) with acute uncomplicated influenza and in younger subjects (< 65 years of age) 
with acute uncomplicated influenza who are at higher risk for influenza complications. Elderly 
subjects will not be classified as high or low risk and will be captured as elderly only. 
Approximately 120 subjects will be enrolled in this open-label study (a minimum of 80 elderly 
subjects will be enrolled). A subject’s duration of participation in this study is expected to be 14 
days and will include up to 4 clinic visits. It is expected that most subjects will have the Screening 
visit and the Day 1 Treatment visit on the same day. Following treatment on study Day 1, subjects 
will undergo follow-up assessments on Days 3, 7, and 14 in the clinic.  Subjects will be discharged 
from this study on Day 14. Additional unscheduled visits may be required for subjects who report 
symptoms of influenza of moderate or severe intensity at Day 14 or have persistent adverse events 
(AEs) and/or treatment-emergent laboratory findings that require medical monitoring or 
management. 
Eligible subjects will have a positive influenza Rapid Antigen Test (RAT) and/or a Food and Drug 
Administration (FDA) approved polymerase chain reaction (PCR) test and at least one clinical sign 
or symptom consistent with influenza OR clinical signs and symptoms consistent with acute 
influenza infection consisting of an oral temperature ≥ 37.8°C/ 100°F with at least one respiratory 
symptom of at least moderate severity (cough or rhinitis) and at least one constitutional symptom 
of at least moderate severity (myalgia, headache, feverishness, or fatigue). 
Subjects will receive a single IV dose of 600 mg peramivir (or less if renally impaired), which will 
occur over 15 to 30 minutes.   
An adequate nasal swab specimen will be collected from all enrolled subjects at Baseline (predose) 
for virus subtype identification and quantitative virologic assessments and at the follow-up 
assessments on study Days 3, 7, and 14. 


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Specimens obtained from all subjects on Day 1 and the last specimen that yields influenza virus on 
culture will also be assessed for susceptibility to neuraminidase inhibitors. A central laboratory will 
perform all virologic assessments. 
Up to 3 blood samples will be drawn to obtain plasma samples for drug concentration 
determinations, where possible, during the following time periods, beginning from the end of 
dosing until release from the site on the day of dosing: 
•
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
AEs and concomitant medications will be monitored at each scheduled visit from the Screening 
assessment to final study visit. Clinical laboratory investigations (chemistries, hematology, and 
urinalysis) will be collected at Baseline, Day 7, and Early Withdrawal visits. Safety and tolerability 
will be evaluated through assessments of AEs, laboratory analyses (clinical chemistry, hematology, 
and urinalysis), vital signs, and physical examinations at the time points indicated in the schedule 
of assessments (see Section 1.2). 
All subjects or their caregivers will record the following information in a Subject Diary: 
•
Assessment of the presence and severity of each of 7 symptoms of influenza on a 4-point
severity scale (0, absent; 1, mild; 2, moderate; 3, severe) at Screening, then twice daily
through Day 13, and prior to the subject’s clinic visit on Day 14 or until each symptom is
rated as a 0 or 1 for 48 consecutive hours. Diaries will be reviewed at each clinic visit.
•
Temperature measurements (oral) will be taken with an electronic thermometer provided
by the Sponsor, approximately every 12 hours until temperature normalizes for 48 hours
(ie, temperature without antipyretic is < 37.4°C/99.4°F orally for 4 consecutive
measurements). With the exception of the Screening/ 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.
•
The type, date, and time of medications used for the symptomatic treatment of
influenza-related symptoms.
•
Assessment of the subject’s ability to perform usual activities using a 0 to 10 visual analog
scale once daily through Day 14, where 0 = Unable to perform usual activities at all, and
10 = Able to perform all usual activities fully.


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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1.2. SCHEDULE OF EVENTS/STUDY VISITS 
  
 
                  
Assessments 
                  
Screening1 
                    
Baseline1  (Pre-
dose) 
Day 1  Treatment 
Day1 
                    
Day 3 
                    
Day 7 (+2 days) 
Day 14 (+3 days) / 
End of Study 
                    
Early Withdrawal 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical 
History/Physical Exam 
X 
 
 
X6 
X6 
 
 
Vital Signs2 
X 
 
 
X 
X 
X 
X 
Body Temperature3 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistries 
and Hematology4 
 
X 
 
 
X 
 
X 
Urinalysis4 
 
X 
 
 
X 
 
X 
Pregnancy Test (Urine 
or Serum) 
X 
 
 
 
 
X 
X 
Assessment of 
Influenza Symptoms5 
X 
 
X 
X 
X 
X 
X 
Ability to Perform 
Usual Daily Activities5 
 
X 
 
X 
X 
X 
X 
Influenza Related 
Complications (IRC)7 
X 
 
 
X7 
X 
X 
X 
Concomitant 
Medications Review 
X 
 
X 
X 
X 
X 
X 
Subject Diary Review 
 
 
X 
X 
X 
X 
X 
Pharmacokinetic (PK) 
Sampling 
 
 
X 
 
 
 
 
Serum Sample for 
Influenza Antibody 
Analysis8 
 
X 
 
X 
X 
 
X 
Swabs for Virology 
Analysis 
 
X 
 
X 
X 
 
X 
Rapid Antigen Test 
(RAT) or FDA-
approved PCR Test for 
Influenza A and B on 
Nasal Specimen 
X 
 
 
 
 
 
 
Study Drug 
Administration 
 
 
X 
 
 
 
 
Adverse Events9 
X 
X 
X 
X 
X 
X 
X 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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1 It is expected that the date of Screening, Baseline, and Day 1 (date of study drug administration) will be the same. Day 1 consists of pre and post-dose assessments.  
2 Vital sign measures will include blood pressure, pulse rate, and respiration rate. Vital signs will be recorded once during Screening, and vital signs will be taken once on remaining study visit days.  
3 The investigator will record oral body temperature at Screening. Thereafter, the subject or care giver will record oral body temperature approximately every 12 hours in the Subject Diary until 
temperature normalizes for 48 hours (ie, temperature without antipyretic is < 37.4°C/ 99.4°F orally for 4 measurements).  
4 Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline. Subjects may be enrolled and begin treatment with study drug prior to receiving results. These 
labs may be done at any visit if necessary for subject management or adverse event monitoring purposes.  
5 Influenza signs and symptoms will be recorded by the study personnel at Screening, then by the subject or care giver twice daily beginning on Day 1 through Day 13, and prior to the subject’s clinic 
visit on Day 14 or until each symptom is 0 or 1 for 48 hours.  
6 Perform a targeted physical exam on Day 3 and Day 7  
7 If an influenza related complication (IRC) is suspected the subject will be instructed to return to the clinic as appropriate to confirm the presence or absence of IRCs.  
8 A single serum specimen will be collected, where possible, pre-dose on Day 1, Day 3 and on Day 7 for analysis of influenza antibody titers.  
9 Adverse events are to be collected from the time of informed consent through the follow-up period ending on Day 14. 
 
 
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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1.3. 
GLOSSARY OF ABBREVIATIONS 
AE  
adverse event 
CRF 
case report form 
FDA 
Food and Drug Administration 
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IV 
Intravenous 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
RAT 
rapid antigen test 
RT-PCR 
real time polymerase chain reaction 
SAE 
serious adverse event 
TCID50 
Tissue-culture infective dose50 
TEAEs 
treatment-emergent adverse events 
 
2. 
OBJECTIVES 
The primary objective is to evaluate the safety and tolerability of peramivir administered IV in 
elderly subjects with acute uncomplicated influenza and in subjects with acute uncomplicated 
influenza who are at higher risk for influenza complications. 
 
The secondary objectives for this study are as follows: 
• 
To describe the PK of IV peramivir in elderly and high-risk subjects with acute 
uncomplicated influenza 
• 
To evaluate the effectiveness of IV peramivir in elderly and high-risk subjects with acute 
uncomplicated influenza 
• 
To evaluate the incidence of influenza complications, specifically otitis media, sinusitis, 
bronchitis, or pneumonia requiring antibiotic use diagnosed after initiation of treatment. 
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
The study is designed to evaluate the safety, PK, and effectiveness of IV administration of 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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peramivir in subjects ≥ 65 years of age with influenza infection and in subjects with influenza 
infection who are at an increased risk of influenza complications. A sample size of up to 
120 subjects, and a minimum of 80 elderly subjects (aged ≥ 65 years), is considered adequate to 
evaluate the stated objectives. A formal sample size calculation was not performed. 
3.2. 
RANDOMIZATION AND MASKING 
As this is a single-arm, open-label study, randomization and masking are not applicable.   
3.3.             HANDLING OF DATA 
3.3.1. Strata and Covariates 
There will be no stratification for this study. 
3.3.2. Examination of Subject Subsets 
All analyses will be presented by age group (≥ 65 years, 65-75 years, >75 years, and < 65 years). 
Time to resolution of fever, time to alleviation of symptoms, change in tissue-culture infective dose 
50 (TCID50), viral shedding, real-time PCR (RT-PCR) results, and change of influenza virus 
susceptibility to neuraminidase inhibitors analyses will be presented by age group and viral subtype 
at Screening. Additional subgroups defined based on risk of complications may be evaluated. 
 
3.3.3. Multiple Testing and Comparisons  
All analyses will be conducted without adjustments for multiple testing. 
3.3.4. 
Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been enrolled. No attempt will be made retrospectively to obtain missing subject reported 
data (such as influenza symptom severity assessments and temperature) 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. For the subject diary data, 
the following data conventions will be utilized. Diary completion times will use a 24-hour clock. 
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 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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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. 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. 
3.3.5. 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 (ie, 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 
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.     
3.3.6. 
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 will be used, as 
determined by the time collected, if available. 
3.3.7. 
Derived and Transformed Data  
TCID50 will be log10 transformed prior to performing the analyses. 
3.3.8. Definitions and Terminology 
 
Age 
Age will be defined as the age in years at time of signing of informed consent for all subjects.  


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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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 (eg, 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. 
 
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 Day 14/End of Study/Early Withdrawal 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 are either absent or are present at no more than mild severity level and at this 
status for a 21.5 hour period (24 hours less 10%). 
Composite Symptom Score 
The Composite Symptom Score is defined as the sum of the seven symptoms of influenza (cough, 
sore throat, stuffy nose, muscle aches, headache, feverishness, fatigue/tired) assessed on a given 
time point within the subject diary. 
Baseline Composite Symptom Score 
The Baseline Composite Symptom Score is defined as the sum of the symptoms of influenza 
recorded by the subject in the diary corresponding to the assessment of a subject’s symptoms prior 
to the initiation of study drug. 
Resolution of Fever 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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A subject has Resolution of Fever if he/she has a temperature < 37.4°C/99.4°F oral 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. 
Ability to Perform Usual Activities 
The ability to perform usual activities is defined as a subject rating of 10 (able to perform all usual 
activities fully) on the visual analog scale the subject uses to rate his or her current ability to 
perform usual activities compared with normal ability. 
Time to Event 
Time to a given event is defined as the number of hours (days) 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 21.5 hour period (24 hours less 10%) where all symptoms of influenza are recorded as none or 
mild. 
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 (eg, 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 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 a serious 
adverse event (SAE), which then must be recorded as such (see Protocol Section 11.1.1.2).  
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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All AEs will be recorded on the ADVERSE EVENTS CRF. 
 
Treatment-emergent Adverse Events (TEAEs) 
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 AE which was reported to have started on Day 1 without an 
associated onset time may have occurred after the initiation of study drug. Hence, AEs occurring 
on Day 1 with no associated onset time are assumed to be treatment-emergent. 
 
Treatment-emergent Laboratory Abnormalities  
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 
missing, then any graded abnormality (ie, at least Grade 1) is considered to be treatment-emergent. 
 
Concomitant Medications 
Concomitant medications are those medications taken upon or after the initiation of study drug. 
 
Prior Medications 
Prior medications are those medications taken prior to the initiation of study drug. Subjects will 
record all medications they are currently taking. 
3.4. 
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 intent-to-treat infected (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 PK and virology data are not available at the time of the analysis of the 
clinical data.   
4. 
ANALYSIS POPULATIONS 
All subjects enrolled (eg, signed the 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), ITTI, safety, and exposure-response populations.   


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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4.1. 
INTENT-TO-TREAT POPULATION 
The ITT population will include all enrolled subjects. The ITT population will be the primary 
population for analyses of demography and subject accountability. 
4.2. 
INTENT-TO-TREAT INFECTED POPULATION 
The ITTI population will include all subjects who are enrolled, treated, and have influenza type A 
or B confirmed by PCR. The ITTI population will be used for analyses of effectiveness. 
4.3. 
SAFETY POPULATION 
The safety population will include all enrolled subjects who receive any amount of study drug. The 
safety population will be the primary population for all analyses of safety data. 
4.4. 
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. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study. Data will be 
summarized by 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 "age group" refers to the following: < 65 years, 65-75 years, > 75 years, and ≥ 65 years. 
Note that 65-75 years and > 75 years are subsets of the ≥ 65 years group. No formal statistical 
hypothesis testing is planned.     
All data collected during the study will be included in data listings. Unless otherwise noted, the 
data will be sorted first by age group, subject number, and then by date within each subject 
number.   
The statistical analyses will be conducted with the SAS® software package version 9.4 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. 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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5.1. 
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 will be summarized.  
A CONSORT diagram will be produced showing the number of subjects screened, number of 
screening failures, number of subjects by age group, number in each of the study populations, and 
number who complete the study. 
Demographic data and baseline characteristics including age, gender, race, ethnicity, Baseline 
Composite Symptom Score, baseline viral titer status, the number subjects who had hypothermia  
(< 35°C/95°F), normal temperature (35 to < 37.4°C / 95 to < 99.4°F), or fever (≥ 37.4°C/99.4°F) at 
baseline, height, weight, and body mass index (BMI) will be summarized using descriptive 
statistics for the ITT, ITTI, safety, and exposure-response populations. 
Enrollment by site, eligibility, treatment status, and screening RAT and PCR test results will be 
summarized by age group and overall.  
This information will be reviewed for baseline differences, but no statistical testing will be 
performed. 
Subject diary completion will be summarized including the days of diary completion. 
5.2. 
EFFECTIVENESS ANALYSIS 
5.2.1. 
Effectiveness Endpoints 
The effectiveness endpoints include: 
• 
Time to resolution of fever 
• 
Time to alleviation of clinical symptoms of influenza 
• 
Change (reduction) in influenza virus titer by log10 TCID50/mL 
• 
Change (reduction) in influenza virus titer by  RT-PCR results 
• 
Changes in viral shedding measured by quantitative viral titer assay (TCID50) and/or 
quantitative PCR. 
• 
Change in influenza virus susceptibility to neuraminidase inhibitors 
• 
Incidence of influenza-related complications as determined by investigator 
• 
Incidence of hospitalization admission post treatment 
• 
Usage of antipyretic medication 
• 
Change in daily activities per the visual analog scale 
• 
Time to resumption of usual daily activities per the visual analog scale 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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5.2.2. 
Effectiveness Analyses 
A subject’s oral temperature taken by subjects and recorded in the diary by subjects/caregivers will 
be summarized by age group and overall by study visit. A subject has Resolution of Fever if he/she 
has an oral temperature < 37.4°C/99.4°F oral 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 
using the Kaplan-Meier method with 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, defined as the time from initiation of study 
drug until the start of the 21.5 hour period (24 hours less 10%) where all symptoms of influenza are 
recorded as none or mild, will be estimated overall and for each age group using the Kaplan- Meier 
method. 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 log10 TCID50/mL through Day 3, Day 7, and Day 14 will be presented by 
age group and overall 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 and age group. In 
addition, the median change from baseline in TCID50/mL will be presented by visit and age group. 
The number and percent of subjects with positive viral titers at baseline (log10 TCID50/mL > 0.5) 
that shed virus at each visit will be presented by age group and overall. 
The RT-PCR results at each visit will be presented by age group and overall 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 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 and viral subtype.   
The number and percentage of subjects experiencing influenza related complications will be 
summarized by age group and overall by complication MedDRA version 18.0 preferred term.   
 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
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The number and percentage of subjects who are hospitalized due to any TEAE and due to any 
TEAE related to study drug after initiation of treatment will be summarized by age group and 
overall. 
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.  
The change in daily activities will be summarized each day by age group and overall. The ability to 
perform usual activities is defined as a subject rating of 10 (able to perform all usual activities 
fully) on the visual analog scale the subject uses to rate his or her current ability to perform usual 
activities compared with normal ability. The time to return to usual activities will be estimated for 
each age group and overall using the Kaplan-Meier method. Subjects who do not return to normal 
activities will be censored at the time of their last non-missing post-baseline assessment.  
5.2.3. 
Exploratory Exposure Response Analyses 
Summaries of plasma concentrations of peramivir will be presented by time point and age 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 may be used 
to complete a separate exposure-response analysis. The methods for the exposure-response analysis 
will be presented in a separate Statistical Analysis Plan.   
5.2.4. 
Subgroup Analyses 
The effectiveness analyses will also be presented by viral subtype determined at Screening. 
5.3. 
SAFETY 
5.3.1. 
Adverse Events 
AEs 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. An overall summary of TEAEs will be generated, 
showing the number of subjects with at least one AE, SAE, AE related to study drug, AE leading to 
discontinuation of study, SAE related to study drug, severe or life-threatening AE, and severe or 
life-threatening AE related to study drug. Summaries of TEAEs will include any AEs reported 
beginning with the initiation of study drug on Day 1. The occurrence of TEAEs will be 
summarized by age group using preferred terms, system organ classifications, and severity. 
Separate summaries of TEAEs, treatment-emergent SAEs, TEAEs related to study drug, events 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
CONFIDENTIAL 
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leading to the discontinuation of study, and events leading to the discontinuation of study drug will 
be generated by preferred term and system organ classification. TEAEs occurring in ≥10% of 
subjects will be summarized by preferred term. All AEs reported will be listed for individual 
subjects showing both verbatim and preferred terms. A separate listing of all SAEs will be 
generated. All AEs 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 3.3.5 as required to 
determine whether AEs were treatment-emergent. 
5.3.2. Concomitant Medications 
Prior and concomitant medications, as well as symptom relief medications recorded on the subject 
diary, will be coded using the World Health Organization (WHO) drug dictionary (Version: March, 
2015). All concomitant medications, antipyretic concomitant medications, and concomitant 
medications used to treat influenza symptoms will be summarized by frequency of drug 
classification and generic drug name. Prior and concomitant medications will be presented in a data 
listing. Symptom relief medications will be presented in a data listing. 
5.3.3. Clinical Laboratory Assessments 
Descriptive summaries of selected (quantitative) clinical laboratory results will be presented by 
study visit for each age group and overall. The clinical chemistry profile will include: albumin, 
alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
bicarbonate, direct bilirubin, bilirubin, blood urea nitrogen, calcium, creatine kinase, chloride, 
creatinine, gamma glutamyl transferase, glucose, potassium, lactate dehydrogenase (LDH), 
magnesium, phosphate, protein, sodium, and urate. The hematology profile will include: basophils, 
basophils/leukocytes, eosinophils, eosinophils/leukocytes, hematocrit, hemoglobin, lymphocytes, 
lymphocytes/leukocytes, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular 
hemoglobin concentration, erythrocyte mean corpuscular volume, monocytes, neutrophils, 
neutrophils/leukocytes, platelets, erythrocytes, and leukocytes. Laboratory abnormalities 
(toxicities) will be graded according to the Division of AIDS (DAIDS) Table for Grading Adverse 
Events for Adults and Pediatrics (Published Date: December 2004). The number and percentage of 
subjects who experience treatment-emergent toxicities will be summarized for each age group and 
overall. Laboratory toxicity shifts from baseline to Day 7 will be summarized 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.  
5.3.4. Other Safety Analyses 
Exposure to study drug, including infusion time treatment status, will be summarized by age group 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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and overall. 
Descriptive summaries of vital signs measured by study site personnel will be presented by study 
visit for each age group and overall. 
All physical examination findings will be listed by age group and study visit.  
 
5.4. 
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. 
In cases where the statistical analysis plan differs from the protocol, the statistical analysis plan 
will supersede the protocol.  
6. 
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. 
 
7. 
REVISION HISTORY 
Date 
Revision 
Rationale 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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8. 
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 (eg, 
Arial point size 10). 
• 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized.  All listings will be prepared for all subjects 
enrolled. 
• 
Group headers: In the summary tables, the group headers will identify the age 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 age 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. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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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. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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9. 
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 
Eligibility and Treatment Status: Intent-to-Treat Population 
 Figure 14.1.2.2 
BCX1812-306 Study Population Disposition: Intent-to-Treat 
Population 
 Table 14.1.3 
Populations for Analysis: Intent-to-Treat Population 
 Table 14.1.4.1 
Demographics and Baseline Characteristics: Intent-to-Treat Population 
 Table 14.1.4.2 
Demographics and Baseline Characteristics: Intent-to-Treat Infected 
Population 
 Table 14.1.4.3 
Demographics and Baseline Characteristics: Safety Population 
 Table 14.1.4.4 
Demographics and Baseline Characteristics: Exposure-Response 
Population 
 Table 14.1.5 
Summary of Subject Diary Completion: Intent-to-Treat-Infected 
Population 
 Table 14.2.1.1 
Summary of Oral Temperature Diary Assessments (°C): Intent-to-Treat
Infected Population 
 Table 14.2.1.2 
Time to Resolution of Fever: Intent-to-Treat Infected Population 
 Table 14.2.1.2.X 
Time to Resolution of Fever: Viral Subtype: Intent-to-Treat Infected 
Population 
 Figure 14.2.1.3 
Time to Resolution of Fever (Kaplan-Meier Plot): ITTI Population 
 Figure 14.2.1.4 
Median (95% CI) Time to Resolution of Fever: ITTI Population 
 Figure 14.2.1.5 
Box Plots of Time to Resolution of Fever: ITTI Population 
 Table 14.2.2.1 
Time to Alleviation of Symptoms: Intent-to-Treat Infected Population  


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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Output Number 
Output Title 
 Table 14.2.2.1.X 
Time to Alleviation of Symptoms: Viral Subtype: Intent-to-Treat 
Infected Population 
 Figure 14.2.2.2 
Time to Alleviation of Symptoms (Kaplan-Meier Plot): ITTI 
Population 
 Figure 14.2.2.3 
Median (95% CI) Time to Alleviation of Symptoms: ITTI Population 
 Figure 14.2.2.4 
Box Plots of Time to Alleviation of Symptoms: ITTI Population 
 Table 14.2.3.1 
Summary of Changes log10  Tissue Culture Infective Dose50 (TCID50 
/mL) by Study Visit: Subjects with Positive Baseline Titers; Intent-to-
Treat Infected Population 
 Table 14.2.3.1.X 
Summary of Changes log10  Tissue Culture Infective Dose50 (TCID50 
/mL) by Study Visit: Subjects with Positive Baseline Titers: Viral 
Subtype: Intent-to-Treat Infected Population 
 Figure 14.2.3.2 
Box Plots of Viral Titers (TCID50 /mL) by Study Visit; Subjects with 
Positive Baseline Titers: Intent-to-Treat Infected Population 
 Figure 14.2.3.3 
Histograms of Viral Titers (TCID50 /mL) by Study Visit; Subjects with 
Positive Baseline Titers: Intent-to-Treat Infected Population 
 Figure 14.2.3.4 
Median (with IQR) Change from Baseline Viral Titers (TCID50 /mL) 
by Study Visit: Subjects with Positive Baseline Titers: Intent-to-Treat 
Infected Population 
 Table 14.2.4.1 
Summary of Viral Shedding by Study Visit; Subjects with Positive 
Baseline Titers: Intent-to-Treat Infected Population 
 Table 14.2.4.1.X 
Summary of Viral Shedding by Study Visit: Subjects with Positive 
Baseline Titers: Viral Subtype: Intent-to-Treat Infected Population 
 Table 14.2.5.1 
Summary of RT-PCR Result by Study Visit: Subjects with Positive 
Baseline RT-PCR:  Intent-to-Treat Infected Population 
 Table 14.2.5.1.X 
Summary of RT-PCR Result by Study Visit: Subjects with Positive 
Baseline RT-PCR: Viral Subtype:  Intent-to-Treat Infected Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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Output Number 
Output Title 
 Table 14.2.6  
Change of Influenza Virus Susceptibility to Neuraminidase Inhibitors: 
Intent-to-Treat Infected Population  
 Table 14.2.7 
Summary of Influenza-Related Complications and Hospitalizations: 
Intent-to-Treat Infected Population 
 Table 14.2.8 
Number of Doses of Antipyretic Medications: Intent-to-Treat Infected 
Population 
 Table 14.2.9.1 
Summary of Subject-Rated Assessment of Ability to Perform Daily 
Activities: Intent-to-Treat Infected Population 
 Table 14.2.9.2 
Time to Return to Usual Activities: Intent-to-Treat Infected Population 
 Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events: Safety 
Population 
 Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Classification, 
Preferred Term and Greatest Severity: Safety Population 
 Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Classification 
and Preferred Term: Safety Population  
 Table 14.3.1.4 
Treatment-Emergent Adverse Events Possibly, Probably, or Definitely 
Related to Study Drug by System Organ Classification and Preferred 
Term: Safety Population 
 Table 14.3.1.5 
Treatment-Emergent Serious Adverse Events by System Organ 
Classification and Preferred Term: Safety Population 
 Table 14.3.1.6 
Treatment-Emergent Adverse Events Leading to the Discontinuation of
Study by System Organ Classification and Preferred Term: Safety 
Population 
 Table 14.3.1.7 
Treatment-Emergent Adverse Events Leading to the Discontinuation of
Study Drug by System Organ Classification and Preferred Term: 
Safety Population 
 Table 14.3.1.8 
Treatment-Emergent Adverse Events Occurring in ≥10% of Subjects 
by Preferred Term: Safety Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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Output Number 
Output Title 
 Table 14.3.4.1.1 
Summary of Chemistry Laboratory Values by Study Visit: Safety 
Population 
 Table 14.3.4.1.2 
Summary of Hematology Laboratory Values by Study Visit: Safety 
Population  
 Table 14.3.4.2 
Graded Laboratory Toxicities: Safety Population 
 Table 14.3.4.3.1 
Laboratory Shifts from Baseline to Day 7 - Chemistry: Safety 
Population 
 Table 14.3.4.3.2 
Laboratory Shifts from Baseline to Day 7 - Hematology: Safety 
Population 
 Table 14.3.4.3.3 
Laboratory Shifts from Baseline to Day 7 - Urinalysis: Safety 
Population 
 Table 14.3.5 
Study Drug Exposure: Safety Population 
 Table 14.3.6 
Summary of Vital Signs by Study Visit: Safety Population 
 Table 14.3.7.1 
Concomitant Medications by Generic Name and Drug Classification: 
Safety Population 
 Table 14.3.7.2 
Antipyretic Concomitant Medications by Generic Name and Drug 
Classification: Safety Population 
 Table 14.3.7.3 
Concomitant Medications Used to Treat Influenza Symptoms by 
Generic Name and Drug Classification: Safety Population 
 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 by Time Point: 
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 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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Output Number 
Output Title 
 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: 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: Intent-to-Treat-Infected 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 
 Listing 16.2.6.5 
Viral Titers and Viral Susceptibility: Intent-to-Treat Population 
 Listing 16.2.6.6 
Symptom Relief Medications: Intent-to-Treat Population 
 Listing 16.2.6.7 
Influenza-Related Complications: Intent-to-Treat Population 
 Listing 16.2.7.1 
Adverse Events: Intent-to-Treat Population 
 Listing 16.2.7.2 
Serious Adverse Events: Intent-to-Treat Population 


BioCryst Pharmaceuticals, Inc. 
BCX1812-306                                                                                            
Statistical Analysis Plan                                                                                                            Final Version 1.0 
 
 
 
 
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Output Number 
Output Title 
 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 16.2.8.2 
Blood and Urine Collection and Pregnancy Tests: Intent-to-Treat 
Population 
 Listing 16.2.8.3 
Virology Specimen Collection and Influenza Antibodies Analysis: 
Intent-to-Treat Population 
 Listing 16.2.8.4 
Vital Signs, Height, and Weight: Intent-to-Treat Population 
 Listing 16.2.8.5 
Physical Examinations: Intent-to-Treat Population