Clinical trial NCT00610935
Conditions: Influenza
Keywords: Influenza Subjects with uncomplicated acute influenza
Sponsor: BioCryst Pharmaceuticals
Start date: 2008-01-01; Completion date: 2008-02-01
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and effectivess of a single intramuscular injection of peramivir for the treatment of subjects with acute, uncomplicated influenza.

Detailed description:

Arms: arm 1: Placebo intramuscular injection arm 2: Single intramuscular injection of 300mg peramivir
Interventions: intervention 1: Peramivir intervention 2: Placebo
Intervention descriptions: intervention 1: To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza. intervention 2: Single intramuscular injection

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-311 
IND No. 76,350 
 
 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE 
INFLUENZA 
THE IMPROVE 1 STUDY 
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy) 
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza 
Protocol Date: Version1.0: 24 August-2007 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35244, USA 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
 
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals, 
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to 
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information 
contained herein should be disclosed without prior written approval. 
CONFIDENTIAL 
 
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1 TITLE PAGE 
 
Protocol Number: 
BCX1812-311 
Study Title: 
A phase 3 m
ulticenter, random ized, double-blind, 
placebo-controlled s tudy to evaluate th e effic acy and 
safety of  intram uscular peram ivir in subjec
ts with 
uncomplicated acute influenza 
IND Number: 
76, 350 
Investigational Product: 
Peramivir (BCX1812) 
Indication Studied: 
Uncomplicated acute influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35233 
Development Phase: 
3 
Sponsor Medical 
Officer: 
W. James Alexander, M.D., M.P.H. 
Senior Vice President, Clinical and Regulatory 
Operations 
Chief Medical Officer 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
Email Address: jalexander@biocryst.com  
Compliance Statement: 
This study will be conducted in accordance with the 
ethical principles that have their origin in the 
Declaration of Helsinki and clinical research guidelines 
established by the Code of Federal Regulations (Title 
21, CFR Parts 50, 56, and 312) and ICH Guidelines. 
Essential study documents will be archived in 
accordance with applicable regulations. 
Final Protocol Date: 
Version 1.0: 24-August-2007 
Amendment(s) Date(s): 
None 
 
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1.2 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3 m
ulticenter, random ized, double-blind, placebo-
controlled study to evaluate the efficacy and safety
 of 
intramuscular peram ivir in subje cts with unc omplicated acute 
influenza 
 
 
 
 
 
I have caref ully read th is protoco l 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 
Protocol No. 
BCX1812-311 
Protocol Title: 
A Phase 3, Multicenter, Random
ized, Double-Blind, 
Placebo-Controlled Stu dy to Evaluate the Efficacy an
d 
Safety of Intram
uscular Peram ivir in Subjects with 
Uncomplicated Acute Influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
Investigators/Study 
Sites: 
Multinational 
Development Phase: 
3 
Objectives: 
Primary: 
To evaluate the efficacy of peram
ivir adm inistered 
intramuscularly com pared to p
lacebo on th
e tim e to 
alleviation of  clinica l sym ptoms in adult sub
jects with 
uncomplicated acute influenza. 
Secondary: 
1. To evalua te the saf ety and tolera bility of  pe ramivir 
administered intramuscularly; 
2. To evaluate seconda ry clinical outcom es in response to 
treatment; 
3. To evaluate changes in in
fluenza virus titer (viral 
shedding) in response to treatment;  
4. To assess p harmacoeconomic m easures in resp onse to  
treatment  
5. To assess c hanges in inf luenza vir al suscep tibility to 
neuraminidase inhibitors following treatment  
 
Number of Subjects: 
Total enrollm ent: up t o 800 subjects random
ized (160 
subjects in the placebo treatment group, 320 subjects in the 
peramivir 150mg treatment group and 320 subjects in the 
peramivir 300m g treatm ent group). The study will close 
after enrollment of at least 500 subjects who have either a 
positive Influenza A or B antigen te st (Rapid Antigen Test 
– RAT) at  screening, or who ha
ve a negative RAT at 
screening but a positive influenza A or B PCR a ssay result 
from a baseline nasopharyngeal swab. 
 
Study Design: 
This is a multinational, random
ized, double-blind study  
comparing the efficacy  and safety  of two single dos
e 
regimens of peramivir administered intramuscularly versus 
placebo in adults with uncom
plicated acute influenza.   
Each subjec t’s ass ignment to trea tment will be stra tified 
according to the Rapid Antigen Test (RAT) result at 
screening and current sm
oking be havior, with 80% of 
subjects ce ntrally rand omized to one of
 the two activ
e 
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single dose regimens of peramivir (2:2:1 randomization) 
 
Treatment Group 1:  Peramivir 150mg 
Treatment Group 2:  Peramivir 300mg 
Treatment Group 3:  Placebo 
 
Enrollment of subjects into the RAT negative s tratum will 
be permitted at individual sites that have identified 3 RAT 
positive su bjects a t s creening within a  10 d ay per iod, 
indicating activity of influenza in the site ’s vicinity. After 
identification of 3 RAT positive subjects within 10 days, a 
site m ay enroll 1 RAT negative s
ubject tha t f ulfills the  
inclusion/ exclusion criteria. One additional RAT negative 
subject may be enrolled thereafter for each preceding RAT 
positive subject that is identified. 
 
Study drug will be adm inistered as one 2mL intramuscular 
injection in each glu teal muscle (total of 4m L injected in 
divided doses). 
 
Subjects eligible for s creening will have an anterior nasal 
or pharyngeal swab collected
 for t esting by RAT for
 
influenza A and B, in accordan ce with the co mmercially 
available RAT kit instructi
ons.  I f the in itial RAT is  
negative, th e te st shou ld be  repeated with a differen
t 
commercially availab le RAT kit. Subjects m
eeting the 
inclusion/ exclusion criteria may be enrolled into the study. 
 
All enrolled subjects will record the following in a Study 
Diary: 
• Oral temperature measurements taken with an electronic 
thermometer every 12 hours. W ith the exception of the 
baseline m easurement, all tem perature m easurements 
will be ob tained at least 4 hours after, or imm ediately 
before, adm
inistration of oral acetaminophen
 
(paracetamol), aspirin, ibuprofen or other NSAID. 
• Assessment of severity of each  of s even  sym ptoms of 
influenza on a 4-point scale (0, absent; 1, m
ild; 2, 
moderate; 3, severe) twice daily (AM, PM) through Day 
9 following treatm ent, then once daily (AM) through 
Day 14 
• Assessment of  subjec t’s ability  to p
erform usual 
activities, (rated as 0–10 on a visual analog scale) once 
daily through Day 14 
• Assessment of subject’s tim e lost from  work or usual 
activities and productivity compared to normal (rated as 
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0-10 on a visual analog scal e) once daily through Day 
14 
• Doses of antipyretic, expe
ctorant, and/ or t hroat 
lozenges taken for symptomatic relief each day through 
Day 14 
 
Anterior nose (bilateral) and posterior pharynx specim ens 
(swabs) will be collected at Day 1 (pre-treatm
ent) and at 
Days 3, 5, and 9, for quantitative virologic assessments.  In 
a subset of  a m inimum of 200 subjects, an additional 
virology sample will b e co llected on day 2. Specim
ens 
from all subjects yielding influenza virus will also be 
assessed for susceptibility to neuraminidase inhibitors (Day 
1 and last specimen yielding positive result). 
 
All virolog ic ass essments will b e p erformed by a c entral 
laboratory.  
 
At the study day 3 visit, when all subjects are evaluated for 
safety and a blood draw is com
pleted for clinical 
laboratory investigations, a single pharm
acokinetic (PK) 
sample will also be  drawn. This sin gle PK sam ple will b e 
analyzed for plasm a concentrations of peram ivir (ng/mL) 
and evaluated in an exposure response analysis. 
 
At selected sites a separate sub-s tudy will be conducted to 
collect limited PK sam ples for the purpose of conducting 
an exposure-respons e analysis.  T
his sub-stud y will be 
conducted under a separate protocol, BCX1812-311PK. 
 
Study Population:   
Male and fem ale subjects, 18 y ears of age and older, with 
symptoms consisten t with a diagnosis of uncomplicated 
acute influenza infectio n may be screened for e nrollment.  
Subject eligibility will be dependent on the presence of two 
or more symptoms consistent with acute inf luenza as well 
as the results obtained f rom a rapid antigen test (RAT) for 
influenza A and B at screening. 
 
Inclusion Criteria: 
1. Male and non-pregnant female subjects age ≥18 years 
2. A positive Influenza A or B Rapid Antigen Test (RAT) 
performed with a commercially available test kit on an 
adequate specimen collected from an anterior nasal or 
pharyngeal swab, in accordance with the 
manufacturer’s instructions.  A negative initial RAT 
should be repeated with a different commercially 
available RAT kit. A limited number of RAT negative 
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subjects may be enrolled in accordance with a defined 
screening algorithm. 
3. Presence of fever at time of screening of ≥38.0 ºC 
(≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken 
rectally. For subjects with a positive RAT at the time of 
screening, a subject self-report of a history of fever or 
feverishness within the 24 hours prior to screening will 
also qualify for enrollment in the absence of 
documented fever at time of screening.  For subjects 
with no positive RAT  at screening, fever as defined  
above must be documented at time of screening 
4. Presence of at least one respiratory symptom (cough, 
sore throat, or nasal symptoms) of any severity (mild, 
moderate, or severe) 
5. Presence of at least one constitutional symptom 
(myalgia [muscle aches], headache, feverishness, or 
fatigue) of any severity (mild, moderate, or severe) 
6. Onset of symptoms no more than 48 hours before 
presentation for screening 
7. Written informed consent 
 
Exclusion Criteria: 
1. Women who are pregnant or breast-feeding 
2. Presence of clinically significant signs of acute 
respiratory distress 
3. History of severe  chronic obstructive pulmonary 
disease (COPD) or  severe persistent asthma 
4. History of congestive heart failure requiring daily 
pharmacotherapy with symptoms consistent with New 
York Heart Association Class IV functional status 
within the past 12 months 
5. History of chronic renal impairment requiring 
hemodialysis and/or known or suspected to have 
moderate or severe renal impairment (actual or 
estimated creatinine clearance <50 mL/min) 
6. Current clinical evidence of active bacterial infection at 
any body site that requires therapy with oral or 
systemic antibiotics 
7. Presence of immunocompromised status due to chronic 
illness, previous organ transplant, or use of 
immunosuppressive medical therapy 
8. Current treatment for active viral hepatitis C 
9. Presence of known HIV infection  with a CD4 count 
<350 cell/mm3 
10. Current therapy with oral warfarin or other systemic 
anticoagulant 
11. Receipt of any doses of  rimantadine, amantadine, 
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zanamivir, or oseltamivir in the 7 days prior to 
screening 
12. Immunized against influenza with live attenuated virus 
vaccine (FluMist®) in the previous 21 days 
13. History of alcohol abuse or drug addiction within 1 
year prior to admission in the study 
14. Participation in a previous study of peramivir as 
treatment for acute influenza or previous participation 
in this study 
15. Participation in a study of any investigational drug 
within the last 30 days 
16. Screening ECG which suggests acute ischemia or 
presence of medically significant dysrhythmia. 
 
Study Endpoints: 
Primary Endpoint: 
Clinical: 
Time to alleviation of clinical symptoms of influenza 
Secondary 
Endpoint(s): 
Safety 
Incidence of treatm
ent-emergent adverse events and
 
treatment-emergent changes in  clinical laboratory tests 
 
Clinical: 
Time to resum ption of subjec t’s ab ility to perf orm usual 
activities 
Time to resolution of fever 
Incidence of influenza related complications 
 
Virologic: 
Quantitative change in influenza virus shedding, measured 
by viral titer assay (TCID
50) and/or by quantitative 
polymerase chain reaction (PCR) assay  
 
Pharmacoeconomic: 
Medical resource utilization (M RU), missed days of work, 
and im pact of inf
luenza illn ess on subject’s work 
performance and/or productivity. 
 
Exploratory 
Endpoint: 
Viral Susceptibility: 
Change in influenza virus susceptibility to neu raminidase 
inhibitors 
 
Investigational Product, 
Dose, and Mode of 
Administration:   
Peramivir (BCX-1812), 75m g/mL or placebo (buffered 
diluent), 2mL per injection, ad ministered intramuscularly 
in the gluteal muscle, bilaterally. 
 
Duration of Treatment: 
Following treatment on day 1, study duration for individual 
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subjects is expected to  be  up to 14 days (including all 
visits). 
 
Statistical Methods: 
Descriptive statistical methods  will be used to summ arize 
the data from this study, with statistical testing utilized for 
the p rimary and secondary efficacy endpoints. Unless 
otherwise n oted, a ll s tatistical testing will be  two-sided, 
and will be performed using a significance (alpha) level of 
0.05. For assessment of the prim ary efficacy endpoint, th e 
overall sig nificance level 
will be m
aintained by a 
Bonferroni adjustm ent fo r the planned com
parisons 
between the two active trea
tment groups and placebo. 
 
Detailed sta tistical pro cedures will be provided  in a f ull 
statistical analysis plan (SAP) completed prior to database 
lock and study unblinding. 
 
Sample Size: 
From previous studies of neuram
inidase treatm ent of 
uncomplicated influenza it is expected that the median time 
to alleviation of symptoms will be 103.3 hours for subjects 
receiving placebo.  Addition ally, it is expected that the 
median time to alleviation for the low dose peram ivir arm 
will be 69.9  hours, yielding a hazard ratio of 0. 68.  Using 
these assumptions, a sample si ze of 200 influenza-infected 
subjects per active treatm
ent group and 100 infected 
subjects in the placebo  group (a total of 500 influenza-
infected su bjects) is s ufficient to  provide at least 80% 
power to detect a hazard ratio of 0.68 using a log-rank 
statistic and  α = 0.025 (SAS version 9.1.3; total accrual 
time 7 months; total enrollment time 6 months).  Up to 800 
subjects will be enrolled to ach ieve the target number of at 
least 500 subjects with  diagnostic evidence (R AT or PCR) 
of an acute influenza infection. 
 
Efficacy:  
The intent-to-treat infected  population will include all 
subjects who are random ized, received study drug, and 
have proven influenza by any one of the following: 
primary viral culture, PCR, or  paired serology showing ≥ 
4-fold increase in antibody to
 influenza A or B.  The 
primary efficacy v ariable is th e tim e to alleviation of 
symptoms, defined as the time from injection of study drug 
to the start of the tim
e period when each
 of seven
 
symptoms of influenza are either absent or are present at 
no more than mild severity level and remain at no worse 
than this severity status for a 24 hour period. 
 
Descriptive statistics for the primary efficacy variable will 
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be tabulated by treatm ent group.  Alleviation of sym ptoms 
will be determined by assessment of symptoms as reported 
on each su bject’s diary card.  Tim
e to alle viation of 
symptoms will b e sum marized for each  treatm ent group.  
Treatment dif ference will be
 as sessed us ing a Cox 
Regression model with effects for RAT result at screening, 
current smoking behavior, tr eatment group, and influenza 
season at random ization.  Pa irwise com parisons between  
each active group and placebo will be constructed from the 
Cox Regression m odel.  Subj ects who do not experience 
alleviation of  sym ptoms will be c ensored a t the date of  
their last non-m issing assessment.  Tim e to resum ption of 
usual activities and tim
e to resolution of
 f ever will be  
analyzed in a similar manner.   
 
Changes in viral titer s will be compared using the van 
Elteren sta tistic con trolling f or RAT result at screen
ing, 
current smoking behavior 
and influenza season at 
randomization.  Analyses of other continuous endpoints 
will be analyzed in a similar manner. 
 
Safety: 
Safety analyses will b e presen ted f or all sub jects in the  
safety population, defined as all randomized subjects who 
receive at least one dose of study drug.  Adverse events 
will be m apped to a Medica l Dictiona ry f or Regulatory 
Activities (MedDRA) preferred term
 and system  organ 
classification.   
The occurrence of treatm
ent-emergent AEs will be 
summarized using preferre
d term
s, system organ 
classifications, and severit
y.  Separate summ
aries of 
treatment-emergent SAEs and treatm
ent-emergent AEs  
that are related to study m edication will be generated.  All 
AEs will be listed f
or individua l subjec ts sho wing both 
verbatim and preferred terms.   
 
Descriptive summaries of vital signs and quantitative 
clinical laboratory changes will be presented by study visit.  
Frequency and percentages 
of subjects with abnorm
al 
laboratory test r esults will be su mmarized b y toxic ity 
grade.   
 
Concomitant m edications w ill be m
apped to a W
HO 
preferred term and drug classification.  The num
ber and 
percent of subjects taking concomitant medications will be 
summarized using preferred terms and drug classifications.  
The num ber and percent of subjects experiencing each 
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abnormal physical examination finding will be presented.  
 
The number and percent of s ubjects discontinuing study as 
well as the reasons for discontinuation will be summarized 
by treatment group.   
 
Protocol Date 
Version 1.0: 24-August-2007 
 
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3 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.................................................................................. 13 
3.1 
LIST OF FIGURES................................................................................................ 15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................... 16 
5 
INTRODUCTION ............................................................................................ 18 
5.1 
BACKGROUND.................................................................................................... 18 
5.2 
RATIONALE FOR STUDY..................................................................................... 18 
5.3 
NON-CLINICAL EXPERIENCE WITH PERAMIVIR.................................................. 19 
5.3.1 In vitro Assays .............................................................................................. 19 
5.3.2 Animal Models.............................................................................................. 20 
5.4 
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR.................. 20 
5.5 
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR................ 21 
5.6 DOSE RATIONALE .................................................................................................... 22 
6 
STUDY OBJECTIVES..................................................................................... 23 
6.1 
OBJECTIVES ....................................................................................................... 23 
6.1.1 Primary Objective......................................................................................... 23 
6.1.2 Secondary Objective(s)................................................................................. 23 
6.2 
STUDY ENDPOINTS............................................................................................. 23 
6.2.1 Primary Endpoint.......................................................................................... 23 
6.2.2 Secondary Endpoint(s).................................................................................. 23 
6.2.3 Exploratory Endpoint.................................................................................... 23 
7 
STUDY DESIGN ............................................................................................. 24 
7.1 
OVERALL STUDY DESIGN AND PLAN ................................................................. 24 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS.................................... 25 
8.1.1 Inclusion Criteria .......................................................................................... 25 
8.1.2 Exclusion Criteria ......................................................................................... 26 
8.1.3 Removal of Subjects from Therapy or Assessment...................................... 27 
9 
TREATMENTS................................................................................................ 28 
9.1 
TREATMENTS ADMINISTERED............................................................................ 28 
9.2 
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .................................................... 28 
9.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................. 28 
9.4 
STUDY MEDICATION ACCOUNTABILITY............................................................. 29 
9.5 
BLINDING/UNBLINDING OF TREATMENTS.......................................................... 29 
9.6 
PRIOR AND CONCOMITANT THERAPIES.............................................................. 29 
9.7 
OVERDOSE AND TOXICITY MANAGEMENT......................................................... 29 
9.8 
DOSE INTERRUPTION.......................................................................................... 29 
10 
STUDY CONDUCT......................................................................................... 29 
10.1 
EVALUATIONS.................................................................................................... 30 
10.1.1 
Medical History ........................................................................................ 30 
10.1.2 
Rapid Antigen Test for Influenza ............................................................. 30 
10.1.3 
Physical Examination and Influenza-related Complications Assessments30 
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10.1.4 
Vital Signs................................................................................................. 30 
10.1.5 
Electrocardiogram Measurements ............................................................ 31 
10.1.6 
Clinical Chemistry Profiles....................................................................... 31 
10.1.7 
Hematology Profiles ................................................................................. 31 
10.1.8 
Serology for Influenza .............................................................................. 31 
10.1.9 
Urinalysis and Evaluation of Protein in Urine.......................................... 31 
10.1.10 Urine Pregnancy Test................................................................................ 31 
10.1.11 Samples for Virologic Laboratory Assessments....................................... 31 
10.1.12 Subject Self Assessments.......................................................................... 32 
10.1.13 Concomitant Medications......................................................................... 32 
10.1.14 Adverse Events ......................................................................................... 32 
10.1.15 Single Pharmacokinetic Exposure Sample ............................................... 33 
10.2 
SCREENING ........................................................................................................ 33 
10.2.1 
Informed Consent...................................................................................... 33 
10.2.2 
Screening/Baseline Evaluation and Enrollment........................................ 33 
10.3 
TREATMENT PERIOD—STUDY DAY 1................................................................ 33 
10.3.1 
Pre-dose Evaluations................................................................................. 34 
10.4 
POST-TREATMENT ASSESSMENT PERIOD........................................................... 34 
10.4.1 
Days 2, 3, 5, 9 and 14................................................................................ 34 
11 
ADVERSE EVENT MANAGEMENT............................................................ 37 
11.1 
DEFINITIONS ...................................................................................................... 37 
11.1.1 
Adverse Event........................................................................................... 37 
11.1.2 
Serious Adverse Event.............................................................................. 37 
11.2 
METHOD, FREQUENCY, AND TIME PERIOD F OR DETECTING ADVERSE EVENTS 
AND REPORTING SERIOUS ADVERSE EVENTS..................................................... 38 
11.2.1 
Definition of Severity ............................................................................... 38 
11.2.2 
Definition of Relationship to Study Drug................................................. 38 
11.2.3 
Reporting Serious Adverse Events ........................................................... 39 
11.2.4 
Emergency Procedures.............................................................................. 40 
12 
STATISTICAL METHODS............................................................................. 40 
12.1 
DATA COLLECTION METHODS........................................................................... 40 
12.2 
STATISTICAL ANALYSIS PLAN ........................................................................... 41 
12.3 
SAMPLE SIZE ESTIMATES................................................................................... 41 
12.4 
ANALYSIS POPULATIONS ................................................................................... 41 
12.4.1 
Intent-To-Treat Population ....................................................................... 41 
12.4.2 
Intent-To-Treat Infected Population ......................................................... 41 
12.4.3 
Safety Population...................................................................................... 42 
12.5 
INTERIM AND END OF STUDY ANALYSES........................................................... 42 
12.6 
EFFICACY ANALYSES......................................................................................... 42 
12.6.1 
Primary Efficacy Endpoint ....................................................................... 42 
12.6.2 
Secondary Efficacy Endpoints.................................................................. 43 
12.6.3 
Exploratory Endpoint................................................................................ 44 
12.7 
SAFETY ANALYSES ............................................................................................ 44 
12.8 
SUB-STUDY AND PHARMACOKINETIC ANALYSIS............................................... 45 
12.9 
GENERAL ISSUES FOR STATISTICAL ANALYSIS .................................................. 45 
12.9.1 
Multiple Comparisons and Multiplicity.................................................... 45 
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12.9.2 
Covariates ................................................................................................. 45 
12.9.3 
Planned Sub-Groups ................................................................................. 45 
12.9.4 
Missing Data............................................................................................. 45 
13 
STUDY ADMINISTRATION ......................................................................... 46 
13.1 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................. 46 
13.1.1 
Regulatory Authority Approvals............................................................... 46 
13.1.2 
Ethics Committee Approvals.................................................................... 46 
13.1.3 
Subject Informed Consent......................................................................... 46 
13.1.4 
Payment to Subjects.................................................................................. 47 
13.1.5 
Investigator Reporting Requirements ....................................................... 47 
13.2 
STUDY MONITORING.......................................................................................... 47 
13.3 
QUALITY ASSURANCE........................................................................................ 47 
13.4 
STUDY TERMINATION AND SITE CLOSURE......................................................... 48 
13.5 
RECORDS RETENTION ........................................................................................ 48 
13.6 
STUDY ORGANIZATION...................................................................................... 48 
13.6.1 
Data Monitoring Committee..................................................................... 48 
13.7 
CONFIDENTIALITY OF INFORMATION ................................................................. 48 
13.8 
STUDY PUBLICATION ......................................................................................... 49 
14 
REFERENCES ................................................................................................. 50 
15 
APPENDICES .................................................................................................. 52 
15.1 
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA
.......................................................................................................................... 52 
 
3.1 
 List of Figures 
Figure 1 
Study Measurements and Visit Schedule...................................................... 36 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE  
adverse event 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the curve 
AUC0–72 
area under the curve from time 0 to 72 hours 
AUC0–∞ 
area under the curve extrapolated from time 0 to infinity 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
Cmax  
maximum plasma concentration 
CK 
creatine kinase 
CNS  
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
GCP  
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IC50  
median inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
influenza related complications  
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IUD 
intrauterine device 
IVRS 
interactive voice response system 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
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RAT 
Rapid Antigen Test 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2  
elimination half-life 
t1/2 λz 
terminal half-life 
TCID50 
time weighted change
 f rom baseline in log
10 tissue -culture 
infective dose50 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to attain maximum plasma concentration 
UPEP 
urine protein electrophoresis 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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5 INTRODUCTION 
5.1 
Background 
Influenza v irus is a m ember of the orthomyxovirus fam ily and cau ses an acu te v iral 
disease of the respiratory tract.  Typical influenza illness is characterized by abrupt onset 
of fever, headache, myalgia, sore throat, and nonproductive cough.1  The illness is usually 
self-limiting, with relief of symptoms occurring within 5 to 7 days.  Nevertheless, it is an 
important disease for several reasons, 
including ease of comm
unicability, short 
incubation time, rapid rate of viral mutation, morbidity with resultant loss of productivity, 
risk of com plicating conditions, and increased risk of death, pa rticularly in the e lderly.  
During 19 of the 23 influenza seasons
 between 1972/1973 a nd 1994/1995, estim ated 
influenza-associated deaths in the U nited States ranged from approxim ately 25 to m ore 
than 150 per 100,000 persons above 65 years of age, accounting for more than 90% of the 
deaths attributed to pneumonia and influenza.2 
Presently, o nly a few m easures are availab le that can red uce th e im pact of influenza: 
active immunoprophylaxis with an inactivat
ed or live attenu
ated vaccine and 
chemoprophylaxis or therapy with an influe nza-specific antiviral drug.  Neuram inidase 
inhibitors are the current m
ainstay of an tiviral treatm ent for influenza. Mark
eted 
neuraminidase inhib itors inc lude zanam ivir (Relenza®, GlaxoSm
ithKline) an d 
oseltamivir (Tamiflu®, Roche-Gilead) , an oral prodrug of the activ e agent, oseltamivir 
carboxylate.  Influenza neuram inidase is a surface glycoprotei n that cleaves sialic acid 
residues from glycoproteins and glycolipids.  The enzyme is responsible for the release of 
new viral p articles from infected cells and 
may also ass ist in the sp reading of virus  
through the mucus within the respiratory tract.  The neuraminidase inhibitors represent an 
important advance in the treatment of influenza with respect to activity against influenza 
A and B viruses, with p roven therapeutic value in reduc ing influenza lower resp iratory 
complications,3 and lower rates of antiviral drug resistance4. 
The use of curren tly av ailable neu raminidase inhibitors has been  lim ited by concerns  
including, the degree of effectiv eness, the requirement for an inhaler device (zanamivir), 
and the em ergence of resistant influenza vi rus variants in som e treated populations. 5 In 
addition, there are risks of bronchospasm
 w ith zanam ivir; and gastrointestinal side 
effects, with oseltamivir. 
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to 
the armamentarium of drugs for the treatment of influenza infections due to its potential 
for parenteral administration and lower frequency of dosing. 
5.2 
Rationale for Study 
An oral formulation of peram ivir has previously been evaluated in a f ull range of safety, 
tolerability, pharmacokinetic, and efficacy studies.  In  a m ultinational phase 3  clinical 
trial conducted in 1999-2001, oral peram
ivir de monstrated antiviral activity against 
influenza A  and B inf
ections, and  im provement in the r
elief of  clin ical sym ptoms.  
Because of the lim ited bioavailability of peramivir following oral administration (<5%), 
it was de termined that the paren teral route of  administration is m ore appropriate for the 
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delivery of peram ivir.  Subsequent phase 
1 studies of intrave nous and intram uscular 
formulations of peram ivir have confirm ed that parenteral routes of  administration result 
in plasma levels of drug that are as much as 100 times those achieved via the oral route. 
Further details of these studies are provided below and in the Investigator Brochure. 
A phase 2 random
ized, double blind, placeb
o controlled study of two single dose
 
regimens (150mg or 300m g) of intram uscular peramivir in subjects with uncom plicated 
acute influenza infections (study B CX1812-211) was initiated in early 2007 in North 
America and the UK. The study has been extended to sites in Hong Kong, Australia, New 
Zealand and South Africa and is expected 
to complete enrollment in m id-2007.  At a 
scheduled meeting on 21  May 2007, an independ ent data monitoring committee for this 
study com pleted a blinded revi ew of all reported adverse 
events and grade 3 and 4 
clinical laboratory evaluations from the first 135 subjects random ized.  Following this 
blinded saf ety review the DMC provided 
a written reco mmendation that the s
tudy 
continue as planned. 
Because of the previo
us dem onstration of significant an tiviral activ ity, th e strong 
suggestion of clinical efficacy of oral pe
ramivir previously dem onstrated in  acute 
influenza, and the encouraging pharm
acokinetic and prelim inary safety profile of the 
intramuscular formulation of pera mivir demonstrated to date, this phas e 3 study will be 
conducted to evaluate the efficacy and safety profile of intram
uscular peramivir and to  
determine the optimal single dose regimen.  
5.3 
Non-Clinical Experience with Peramivir 
5.3.1 In vitro Assays 
Peramivir is a selective inhibitor of vi
ral neuram inidase, with 50% inhibitory 
concentrations (IC50) for bacterial and m ammalian enzymes of >300µM. 6 In an in vitro 
study, 42 influenza A and 23 influenza B isolates  were collected from untreated subjects 
during the 1999–2000 influenza season in Canada.
7 These isolates were tested for their 
susceptibility to the neuram inidase inhib itors zanam ivir, oseltam ivir carboxylate, and 
peramivir using a chem
iluminescent neuram inidase assay.  Inhibition of Type A 
influenza neuraminidase by peram ivir was appr oximately an order of m agnitude greater 
than inhibition of neuram inidase from  Type B viruses.  IC
50 values for the Type A 
enzymes ranged from <0.1 to 1.4nM, whereas the Type B enzym es ranged from <0.1 to 
11nM, with three out of four values in the 
5- to 11nM range.  Peram ivir was the most 
potent drug against influenza A (H 3N2) viruses with a m ean IC50 of 0.60nM as well as 
most potent  against influenza B with a mean IC50 of 0.87nM.   
In another in vitro  comparison of peram
ivir, oseltam ivir, and zanam ivir, using a 
neuraminidase inhibition assay with influenza A viruses, the m
edian IC 50 of pera mivir 
(approximately 0.34nM) was com
parable to that of
 oseltam ivir (0.45nM) and 
significantly lower than zanam ivir (0.95nM).  F or influenza B virus clinical isolates, the 
IC50 of peramivir (1.36nM) was comparable to that of zanamivir (2.7nM) and lower  than 
that of oseltamivir (8.5nM).8   
The potency of peram
ivir was evaluated ag
ainst five zanam ivir-resistant an d six 
oseltamivir-resistant influenza viruses.9  Peramivir remained a potent inhibitor against all 
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oseltamivir-resistant viruses includi ng the m utations H274Y, R292K, E119V, and 
D198N, with IC 50 values ≤40nM.  Peram ivir also potently inhibited (IC 50 ≤ 26nM) the 
neuraminidase activity of zanamivir-resistant strains, which had the following mutations:  
R292K, E119G, E119A, and E119D.  Howeve
r, one zanam ivir-resistant influenza B 
virus, B/Mem /96, with a m utation R152K isol ated from  cell cultur e, was relatively 
resistant to all neuraminidase inhibitors, including peramivir (IC50 = 400nM). 
5.3.2 Animal Models 
In a m ouse model of influen za infection, a single intram uscular injection of pera mivir 
(10mg/kg) given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain 
resulted in 100% survival in contrast to 100% mortality in a control group injected with 
saline.6 In the sam e mouse m odel, treatm ent of m ice up to 72 hours after influenza
 
infection using peram ivir (20m g/kg) result ed in 100% survival, compared to 100%
 
mortality in the control group injected with vehicle.10 
Peramivir has also dem onstrated activity in animal models utilizing a  clinical H5 N1 
isolate as th e infecting virus strain.   In a mouse model, a single intramuscular dose of 
peramivir (30mg/kg) injected 1 hour after inoculation with the highly pathogenic (H5N1) 
A/Vietnam/1203/04 strain, resulted in a 70% survival rate that wa s similar to that seen in 
mice treated with oseltam ivir given orally at 10m g/kg/day for 5 days
11.  In s imilar 
experiments, mice inoculated with the sam e strain of H5N1 virus tha t were then trea ted 
for up to 8 days with intram
uscular peramivir exhibited 100% survival 12.  This longer 
duration of peram ivir treatment also prevented viral replic ation in the lungs, brain and 
spleen at days 3, 6 and 9 post inoculation. 
5.4 
Previous Phase 3 Clinical Experience with Oral Peramivir 
An oral formulation of peram
ivir has prev iously dem onstrated an tiviral activity and 
preliminary clinical efficacy in ch
allenge studies in hum an volunteers, as well as in 
treatment studies in patients  with u ncomplicated acute  inf luenza inf ections dur ing the 
influenza seasons of 1999-2001.  A Phase 3 
multinational study (B C-01-03) of oral 
peramivir was conducted.  Two dos e regimens of oral peramivir, 800mg QD for 5 days, 
or 800mg QD on Day 1, followed by 400mg QD for 4 days, were compared to a matched 
placebo treatment group.  A total of 1246 subjects  were randomized to treatment at sites 
in the USA, W estern and Eastern Europe, S outh America, Australia and New Zealand.  
As presente d in the  tab le below, th e prim ary end-point of tim e to relief of influenza  
symptoms was not found to be significantly
 different (p=0.17) between the three 
treatment groups.13  A sub-group analysis of the time to relief of symptoms by country or 
region demonstrated marked differences in
 the prim ary endpoint.. In the subset of 
influenza-infected subjects enrolled at  sites in the US, clinically m eaningful differences  
in time to relief of influenza symptoms between the placebo and the two peram ivir arms 
were observed, that just m issed statistical significance (p=0.07).  However, a num ber of 
secondary end-points in this phase 3 study, such as tim e to overall well-being, time to 
normal activity, incidence of infl
uenza rela ted com plications and quantity of viral 
shedding, reached o
r approach ed statistically significant differenced between
 the 
peramivir and placebo treatment groups (p=0.03-0.06). 
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Results of Study BC-01-03 
 
Median Time to Relief of Influenza Symptoms (Hours) 
Dose and Regimen 
Overall Results  (n=1246) 
US Sites (n=206) 
Peramivir 800mg po x 5d 
89.0 
70.8 
Peramivir 800mg po x 1d 
 and          400mg po x 4d 
91.7 
88.8 
Placebo x 5 days 
104.4 
106.8 
p value 
0.17 
0.07 
 
5.5 
Previous Phase 1 Experience with Intramuscular Peramivir 
Two phase one studies evaluating the safety 
and pharmacokinetics of an intram uscular 
formulation of pera mivir have been conduc
ted in a total of 45 he
althy volunteers 
receiving peramivir.  
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability 
of 75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and 
intravenous (i.v.) injections in  a crossover design (9 subjects per group). Peak plasma
 
levels of i.m. pera
mivir generally occurre d within 30 m
inutes fol lowing injection.  
Plasma pharm acokinetic param eters for i.m . peram ivir are summarized  below for the 
three intramuscular single dose regimens evaluated: 
Dose (mg) 
Cmax (ng/mL) 
AUC0-∞ (hr·ng/mL) 
t½a (hr) 
75 i.m. 
4296±812 
11659±1123 
19.8±7.9 
150 i.m. 
7612±884 
23952±3804 
24.3±4.1 
300 i.m. 
15150±2367 
49649±5619 
22.8±2.5 
aterminal half life 
 
In a second phase 1 study, Peram
ivir-Him-06-112, the sam e dose levels of peram ivir 
were adm inistered as single i.m . injections on two consecutive days (6 subjects per 
group). This double-b lind study also includ
ed a placebo  arm . The pharm acokinetic 
parameters of i.m . peramivir following the second day of dosing were consistent with 
those seen following single doses of the drug. 
The observ ations of s afety and  to lerability of i. m. peram ivir in  each  of the 2  phas e 1 
studies were unrem arkable.  No serious ad
verse even ts were repo rted.  The most
 
commonly observed ad verse events or laborato ry abnormalities were h eadache, several 
reports of signs and symptom s of vasovagal reactions following injections, and transient 
increases in creatine kinase.  No consisten t differences in frequency of adverse events 
were observed between the ac tive and placebo treatm ent groups, with the exception that 
CK elevations appeared to be dose rela
ted in the peram ivir treatment groups.  T he 
vasovagal reactions were attri buted to the receipt of rela
tively large volum es of i.m. 
injection (2 injections each of 2mL) in the fasted state. 
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An ongoing phase 2 study, BCX1812-211, is 
a random ized, double-blind placebo- 
controlled study to  evaluate the efficacy and
 safety of two single d
ose reg imens of 
peramivir. Up to 100 subjects per arm  will receive either 150mg or 300mg of peramivir 
or placebo. The prim ary endpoint of the stu
dy is the tim e to alleviation of clinical 
symptoms in adult subjects with u ncomplicated acute influenza.  An independent dat
a 
monitoring comm ittee reviewed grouped blinde d safety data on the first 135 subjects 
randomized.  The study rem ains blinded. The fr equency of vasovagal reactions reported 
as adverse events in this ongoing study is 2/135 (to date) which is lower than that seen in 
the phase 1 volunteer studies. 
5.6 Dose Rationale 
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 
75mg twice daily in adults14.  Oseltamivir was shown to be clinically effective in a Phase 
III study of oral oseltamivir versus placebo in naturally occurring seasonal influenza, and 
these data were sufficient for regulatory approval for marketing of oseltamivir.  At least 
75% of an  oral dose of oseltam
ivir reaches  the sy stemic circu lation as oseltam ivir 
carboxylate. When oseltamivir is adm inistered orally at a dose of 75mg twice daily, the 
serum C max of oseltam ivir carboxylate is approxim ately 348ng/m L and the AUC 0-48 is 
10,876 h·ng/mL. The clinical data indicate that this level of exposure to oseltamivir was 
sufficient to provide clinical improvement in uncomplicated acute influenza.  
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular 
doses of peram ivir are approxim ately 7600ng/mL and 24,000 h·ng/m L for the 150m g 
dose and are approxim ately 15,000ng/m L and 49,000 h·ng/m L for the 300m g dose.  
Previous s tudies hav e assess ed the concen
trations of the neuram
inidase inhibitor 
zanamivir in nasal and pharyngeal secretions after parenteral administration of this drug. .  
Within several hours after ad
ministration, the concentrati
ons in secretions wer
e 
approximately 100-fold lower than in serum or plasma.  In theory, relatively high levels 
of a neuram inidase inh ibitor in  res piratory se cretions ar e desi rable in order to rapidly 
inactivate influenza virus and to delay or 
prevent th e d evelopment of resistan ce in  
infecting virus strains.  Intramuscular doses of peramivir, including doses of 150m g and 
300mg have been shown to be well tolerate
d in previous P hase 1 studies and since no 
identified safety signal has been noted by an  independent data monitoring committee in 
the ongoing Phase 2 study, it is appropriate
 for these two dose regim
ens to undergo 
further evaluation in this Phase 3 study.  
 
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6 STUDY OBJECTIVES 
6.1 
Objectives 
6.1.1 Primary Objective 
The primary objective of this study is to eval uate the efficacy of peram ivir administered 
intramuscularly compared to placebo on th e time to alleviation of  clinical symptoms in 
adult subjects with uncomplicated influenza. 
6.1.2 Secondary Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of peramivir administered intramuscularly; 
2. To evaluate secondary clinical outcomes in response to treatment; 
3. To evaluate changes in
 influenza virus 
titer ( viral sheddi ng) in response to 
treatment; 
4. To assess pharmacoeconomic measures in response to treatment; 
5. To assess changes in influenza viral su
sceptibility to neu raminidase inhibito rs 
following treatment; 
6.2 
Study Endpoints 
6.2.1 Primary Endpoint 
Time to alleviation of clinical symptoms of influenza 
6.2.2 Secondary Endpoint(s) 
Secondary efficacy endpoints will include evaluations in each subject of: 
1. Safety parameters, including: treatment- emergent adverse events (TEAEs) 
and treatment-emergent changes in clinical laboratory tests; 
2. Time to resolution of fever; 
3. Time to resumption of subject’s ability to perform usual activities; 
4. Incidence of influenza related complications 
5. Quantitative change in influenza virus shedding measured by viral titer 
assay (TCID50) and/or by quantitative polymerase chain reaction (PCR) 
assay; 
6. Medical resource utilization (MRU), missed days of work, and impact of 
influenza illness on subject’s work performance and/or productivity. 
6.2.3 Exploratory Endpoint 
An exploratory endpoint will evaluate change in influenza virus susceptibility to 
neuraminidase inhibitors in viral isolates recovered from subjects pre and post treatment. 
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7 STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multinational, random
ized, double-blind study  com paring the efficacy and 
safety of two single dose regim
ens of pera mivir adm inistered intramuscularly versus 
placebo in adults with uncom
plicated acute influenza.  Up
 to 800 subjects will be
 
enrolled in to the s tudy. Each su bject’s as signment to trea tment will be str
atified 
according to a Rapid Antigen Test (RAT) result and current smoking behavior, with 80% 
of subjects centrally random ized via an Inte ractive Voice Response (IVR) system  to one 
of the two active single dose regimens of peramivir (2:2:1 randomization): 
 
Treatment Group 1:  Peramivir 150mg 
maximum n=320 
Treatment Group 2:  Peramivir 300mg 
maximum n=320 
Treatment Group 3:  Placebo 
 
maximum n=160 
 
Previous studies evalu ating the efficacy of 
neuraminidase inh ibitors enro lled su bjects 
with inf luenza-like illness on the basis of presence of 
specific clinical s igns and 
symptoms. These studies were conducted before
 the widespread availability of rapid 
influenza antigen diagnostic test kits (Rapid Antigen Tests-RAT), and typically between 
50-70% of subjects enrolled we re subsequently confirm ed by viral cu lture to  hav e an 
active influ enza infection. The sen sitivity of  comm ercially available RAT kits ranges  
from 62% to 83%, depending 
upon the virus sub-type.
15 In the phase 2 study of 
intramuscular peram ivir (study BCX1812-211) a positive RAT test was required for
 
study entry. It is likely that
 a number of subjects with 
an influenza infection were 
excluded from this study due the sensitivity of this assay. 
 
In this ph ase 3 study a lim ited number of RA T negativ e subjects will be en rolled in 
accordance with the following al gorithm to minimize false negative test results: once an 
individual site has identified 3 RAT positive subjects at screening within a 10 day period, 
indicating influenza activity is present in the site’s vicinity, a RAT negative subject that 
meets the inclusion / ex clusion criteria m ay be enrolled. O ne additional RAT negative 
subject m ay be enro lled there after for each p
receding RAT positive  subjec t th at is  
identified. The RAT result for each subjec
t screen ed will be reco rded on the s tudy 
Interactive Voice Response System (IVRS) to manage this enrollment algorithm.  
 
A baseline nasopharyngeal swab specimen will be sent to the central virology laboratory 
for each RAT negative subject that has been randomized into the study.  These specimens 
will be tested for influenza A and B infection using a PCR assay. The PCR results for 
these specimens will be reported to BioCryst in real time.  The study will close after 
enrollment of at least 500 subjects who have either a positive Influenza A or B RAT at 
screening, or who have a negative RAT at screening but a positive influenza A or B PCR 
assay result from a baseline nasopharyngeal swab. 
 
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Study drug will b e ad ministered as one 2m L intramuscular injection  in each g luteal 
muscle (total of 4mL injected in divided doses). 
At screening, subjects will have an anterior nasal or pharyngeal swab collected for testing 
with a comm ercially available RAT kit for influenza A and B in accordance with the 
RAT manufacturer’s instructions.  If  this test is positive and the subject is enrolled, 
additional s pecimens will be obta ined f or isolation and c ulture of  inf luenza viru s and 
quantitative PCR assay.  If the initial RAT is negative, th e test should be repeated with a  
different commercially available RAT kit. A limited number of RA T negative subjects 
may be enrolled in accordance with the screening algorithm defined above. 
Enrolled subjects will record the following in a Study Diary: 
• 
Oral tem perature m easurements tak en w ith an electronic therm ometer every 12  
hours. W ith the exception of the baseline m
easurement, all tem
perature 
measurements will be obtained
 at leas t 4 hours after, or imm
ediately before, 
administration of oral acetaminophen (paracetamol- provided), aspirin, ibuprofen or 
other NSAID. 
• 
Assessment of seven symptom s of influenza on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, se vere), twice daily (A M, PM) through Day 9, then once 
daily (AM) through Day 14 
• 
Assessment of subject’s ability to perform usual activities, (0–10 on a visual analog 
scale) once daily through Day 14 
• 
Assessment of a subject’s tim e lost from  work or usual activities and productivity 
compared to normal (0-10 on a visual analogue scale) once daily through Day 14 
• 
Doses of antipyretic (e. g. acetaminophen/ paracetamol), expectorant, and/or throat 
lozenges administered each day through Day 14. 
 
Anterior nose (bilateral) and posterior phar ynx specimens (swabs) will be collected at 
Day 1 (pre-treatment) and at Days 3, 5, and 9, for influenza viral culture and quantitative 
PCR assay. In a subset of a m inimum of 200 subjects an addition al viral culture/ P CR 
sample will be collecte d on Day 2. Anterior
 nose (bila teral) and poster ior pha rynx 
specimens (swabs) will be collected  at Days 1, 3, 5, and 9 f or all subjects, and on Day 2 
in the subset of 200 subjects, to assess 
for potential changes 
in influenza viral 
susceptibility to neuraminidase inhibitors in response to treatment. 
At selected sites a separate sub-study will be conducted to collect limited PK samples for 
the purpose of conducting an exposure-respo
nse analysis.  This sub-study will be 
conducted under a separate sub-study protocol, BCX1812-311PK. 
8 SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1.1 Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in this study: 
1. Male and female subjects age ≥18 years 
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a 
commercially available test kit on an adequate specimen collected from an 
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anterior nasal or pharyngeal swab, in accordance with the manufacturer’s 
instructions.  A negative initial RAT should be repeated with a second 
commercially available RAT kit. A limited number of RAT negative subjects may 
be enrolled in accordance with a defined screening algorithm.. 
3. Presence of fever at time of screening of ≥38.0 C (≥100.4 ºF) taken orally, or 
≥38.5ºC (≥101.2 F) taken rectally. For subjects who test RAT positive at the time 
of screening, a subject self-report of a history of fever or feverishness within the 
24 hours prior to screening will also qualify in the absence of documented fever at 
time of screening.  For subjects who test RAT negative at screening, fever as 
described above must be documented at time of screening. 
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal 
symptoms) of any severity (mild, moderate, or severe) 
5. Presence of at least one constitutional symptom (myalgia [muscle aches], 
headache, feverishness, or fatigue) of any severity (mild, moderate, or severe) 
6. Onset of illness no more than 48 hours before presentation 
7. Females of child-bearing potential must have a negative urine pregnancy test 
(Beta HCG) at screening/baseline AND report one of the following: 
• Be surgically sterile or practice monogamy with a partner who is 
surgically sterile 
• Have been sexually abstinent 4 weeks prior to date of screening evaluation 
and be willing to remain abstinent through 4 weeks after study drug 
administration 
• Use oral contraceptives or other form of hormonal birth control including 
hormonal vaginal rings or transdermal patches and have been using these 
for 3 months prior through 4 weeks after study drug administration 
• Use an intra-uterine device (IUD), or double barrier contraception (such as 
condom or diaphragm with spermicidal gel or foam) as birth control 4 
weeks prior to date of screening through 4 weeks after study drug 
administration 
8. Provide written informed consent 
8.1.2 Exclusion Criteria 
Subjects to whom any of the following criteria apply will be excluded from the study: 
1. Women who are pregnant or breast-feeding 
2. Presence of clinically significant signs of acute respiratory distress 
3. History of severe chronic obstructive pulmonary disease (COPD) or severe 
persistent asthma 
4. History of congestive heart failure requiring daily pharmacotherapy with 
symptoms consistent with New York Heart Association Class IV functional status 
within the past 12 months (section  15.1). 
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5. History of chronic renal impairment requiring hemodialysis or known or 
suspected to have moderate or severe renal impairment (actual or estimated 
creatinine clearance <50 mL/min) 
6. Clinical evidence of active bacterial infection at any body site requiring therapy 
with oral or systemic antibiotics 
7. Presence of immunocompromised status due to chronic illness, previous organ 
transplant, or use of immunosuppressive medical therapy. 
8. Current treatment of active viral hepatitis C 
9. Presence of known  HIV infection, with a CD4 count <350 cell/mm3 
10. Current therapy with oral warfarin or other systemic anticoagulant 
11. Receipt of any doses  of rimantadine, amantadine, zanamivir, or oseltamivir in the  
7 days prior to screening 
12. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the 
previous 21 days 
13. History of alcohol abuse or drug addiction within 1 year prior to admission in the 
study 
14. Participation in a previous study of peramivir as treatment for acute influenza or 
previous participation in this study 
15. Participation in a study of any investigational drug within the last 30 days 
16. Screening ECG which suggests acute ischemia or presence of medically 
significant dysrhythmia. 
8.1.3 Removal of Subjects from Therapy or Assessment 
All subjects are permitted to withdraw from participation in this study at any time and for 
any reason, specified or unspeci fied, and without prejudice.  The Investigator or sponsor 
may terminate the subject’s participation in  the study at any tim e for reasons including 
the following: 
1. Adverse event; 
2. Intercurrent illness; 
3. Non-compliance with study procedures; 
4. Subject’s decision; 
5. Administrative reasons; 
6. Lack of efficacy; 
7. Investigator’s opinion to protect the subject’s best interest. 
Any subject who withdraws because of an adverse event will be followed until the sign(s) 
or symptom(s) that constituted the adverse eve nt has/have resolved o r is dete rmined to 
represent a stable medical condition. 
A subject should be withdrawn fr om the trial if, in the opinion of the Investigator, it is 
medically necessary, or if it is the d esire of the subject. If a subjec t does not return for a 
scheduled visit, every effort  should be m ade to contact the subject and determ
ine the 
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subject’s medical condition.  
In any circum stance, ev ery effort sho uld be m ade to  
document subject outcome, if possible. 
If the sub ject withdraw s consen t, n o furt her evaluations should be perfor med and no 
attempts should be made to collect additional data. 
 
9 TREATMENTS 
9.1 
Treatments Administered 
Peramivir is an investig ational drug.  Peram ivir for intramuscular injection is a small-
volume parenteral and will be supp lied as a 75 mg/mL solution in sodium  citrate/ citric 
acid buffer.  The pH is approximately 3.0. 
A m atched placebo  solution of so dium citrat e/ citric acid  buffer with 1.2% sod
ium 
chloride at a pH of approximately 3.0 will be supplied. 
9.2 
Identity of Investigational Product(s) 
Peramivir and placebo peramivir will be supplied in clear 2mL vials.  An individual study 
drug kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending 
upon the treatment group), 2 syringes and 2 need les in which to draw up the solution for  
intramuscular injection. All m aterials will be  packaged in a labele d box container. All 
study drug kits m ust be stored at 2-8 oC.  Each individual study drug kit will b e labeled 
with some or all of the following information as required by local regulations: 
• Sponsor nam e and contact inform
ation, study protocol num
ber, kit num ber, 
description of the contents of the container, instructions for the preparation of the 
syringe and adm inistration of the study dr ug, conditions f or st orage, statem ent 
regarding the investigationa l (clinical trial) use of the study drug and date for
 
retest or expiry date. 
Each vial of study drug will be labeled with some or all of the following infor mation as 
required by local regulations: 
• Sponsor nam e, study protocol number, desc ription of the contents of the vial, 
instructions for the preparation
 of 
the s yringe, statem ent regarding the 
investigational (clinical trial) use of the study drug and lot number. 
9.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be centrally randomized in a ratio of 2:2:1 to one of three treatment groups: 
single dos e peramivir 1 50mg, single dose pera mivir 300mg or placeb o, in acco rdance 
with a computer-generated random ization schedule prepared by a non-study statistician.  
Subjects will be s tratified acco rding to the  result of a RAT test and curren
t sm oking 
behavior.  Once a subject is eligible for randomization, he/she wi ll be assigned a study 
drug kit nu mber that will be obta ined by stu dy staf f f rom the study  inter active voice  
response system (IVRS).  Once a study drug kit nu mber has been assigned to a subject, it 
cannot be reassigned to any other subject.   
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9.4 
Study Medication Accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study 
drugs received from  the sponsor, issued to th
e subject or directly adm inistered to the  
subject (including date and time), and any drug accidentally destroyed.  The sponsor will 
supply a specific dru
g-accountability form .  At the en
d of the study, information
 
describing study drug s upplies (e.g., lot num bers) and disp osition of s upplies for each 
subject must be provided, signed by the Invest
igator or designee, and colle cted by the 
study monitor.  If any errors or irregularities in any shipment of study m edication to the 
site are discovered at any time, the Project Manager must be contacted immediately. 
At the end of the study, all 
medication not dispensed or administered and packaging 
materials will be collected with supervision of the monitor and returned to the sponsor or 
destroyed on site as dictated by the appropr
iate Standard Operating P rocedure at the 
participating institution. 
9.5 
Blinding/Unblinding of Treatments 
This is a double-blind study.  The treatment group assignment will not be known by the 
study subjects, the investigator , the clinical staff, the CRO  or Sponsor staff during the 
conduct of the study. 
Section  11.2.4 provides inform ation regarding the process for unblinding the treatment 
assignment, if necessary, in the event of an SAE. 
9.6 
Prior and Concomitant Therapies 
All m edications, by any route of adm
inistration, used during this study m
ust be 
documented on the Case Report Form  (CRF).  Prescription as well  as non-prescription 
medications should be recorded. Medication us ed for the treatm ent of influenza-related 
symptoms will be captured by the subject in the diary card provided by BioCryst. 
9.7 
Overdose and Toxicity Management 
To date there is no experience  with overdose of in tramuscular or intravenous peramivir.  
If overdose occurs, subjects should receive indicated supportive therapy and evaluation of 
hematologic and clinical chem istry laboratory tests should be conducted.  The effec t of 
hemodialysis on elimination of peramivir is unknown. 
9.8 
Dose Interruption 
As this is a study of a single injection of 
peramivir or placebo, guidelines for treatm ent 
interruption for drug related SAEs or toxicities are not applicable. 
 
10 STUDY CONDUCT 
A study schedule of evaluations is presented in 
Figure 1 .  A detailed lis
t of  the 
evaluations is also provided in the following sections. 
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10.1  Evaluations 
All subjects enrolled in this study will undergo the following evaluations: 
10.1.1 Medical History 
Medical history, influenza va
ccination s tatus within  th e previous 12 m
onths and 
demographic data (including smoking behavior) will be recorded at Screening/Baseline. 
10.1.2 Rapid Antigen Test for Influenza 
At Screening/Baseline, a commercially available, rapid antigen tes t (RAT) for influenza 
A and B will be performed on an adequate specimen collected by swabbing the anterior 
nose or pharynx, in accordance with the RAT 
manufacturer’ instructions.  A negative 
initial RAT should be repeated with a different commercially available RAT kit.  Refer to 
the Study Manual f or instructions regarding the use of the 
RAT kits provided for this 
study.  Sites m ay use the kits provided 
by the Sponsor or any other commercially 
approved RAT available at their site to document a confirmed influenza infection.  
A lim ited num ber of  RAT negativ e subje cts will be  enr olled in a ccordance with the  
following algorithm: Once an ind ividual site has identified 3 RAT positive sub jects at 
screening within a 10 day period,  indicating that influenza activity is present in the site’s 
vicinity, a RAT negative subject that m
eets the inclus ion/ exclus ion criteria m ay be  
enrolled. O ne additional RAT negative subj
ect m ay be enrolled th
ereafter for each 
preceding RAT positive subject that is iden
tified. The RAT result for each subject 
screened will be record ed on the s tudy Inte ractive Voice response (IVR) system to 
manage this enrollment algorithm.  
 
10.1.3 Physical Examination and Influenza-related Complications Assessments 
The Investigator will perform  a physical ex amination at S creening/Baseline.  Subject’s 
weight will be recorded at Screening/Baseline. 
Study personnel will be provided with an influenza-related complications (IRC) checklist 
in the CRF to evalua te the subject for the presence of clinical signs and /or symptoms of 
the following influenza-related complications: sinusitis, otitis, bronchitis and pneumonia.  
At each follow up assessm
ent a t argeted physical exam ination will be conducted to 
record the presence of influenza related complications. If the investigator determines that 
the subject experiences (or is presumed to experience) an IRC as noted above, he/she will 
record that assessm ent on the  IR
C CRF pa ge and any m edication used to treat the 
condition will be recorded on the concom
itant m edication page.  Such inform
ation 
describing IRC signs and/or sym ptoms should not be reported as adverse events. Any 
injection site reactions noted will be recorded in the CRFs as adverse events. 
10.1.4 Vital Signs 
Vital signs evaluations will in clude blood press ure, pulse rate , and resp iration rate. The  
investigator will record or al body tem perature at baseline.  Thereafter the subject will 
record oral temperature twice daily in the study diary card. 
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following 
the study drug injection on Day 1, then once da ily on Days 2 (for those subjects who are 
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seen on day 2), 3, 5, 9, and 14. 
10.1.5 Electrocardiogram Measurements 
A 12-lead elec trocardiogram (ECG) will b e obtained at Screen ing/ Baselin e. I f this  
baseline ECG is interpreted by the conductin
g physician as m eeting the exclusionary 
criteria listed in section 8.1.2 the subject will no t be enrolled in this study.  If the ECG is 
interpreted as being abnorm al and does not m eet the exclusionary criteria (e.g. acute 
ischemia, medically significant dysrhythmia) th en this subject m ay be enrolled, taking 
into con sideration th e subjec t’s m edical history. Appropriate follow-up evaluations, 
including but not limited to repeat ECGs, should be completed at subsequent study visits 
as directed by the investigator. 
10.1.6 Clinical Chemistry Profiles 
Clinical ch emistry pro files will include a C
hemistry 20 panel (
includes sod ium, 
potassium, chloride, total CO 2 [bicarbonate], creatinine, glucose, urea nitrogen, album in, 
total calcium
, total m
agnesium, phosphor
us, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate am
inotransferase (AST), total bilirubin,
 d irect 
bilirubin, lactate dehydrogenase [LDH], total protein, total creatine kinase, and uric acid) 
Blood samples for clinical chem istry profiles will be collected at Screen ing/Baseline, and on 
Days 3, 5 and 14. 
10.1.7 Hematology Profiles 
Hematology will include complete blood count (CBC) with differential. 
Blood samples for he matology profiles will be  collected at Screening/Baseline, and on 
Days 3, Days 5 and 14. 
10.1.8 Serology for Influenza  
Paired blood samples for determination of antibody to influenza A and  B (serology) will 
be obtained with the clinical  laboratory tests at Screenin g/Enrollment and at Day 14. 
These specimens will be stored at the central laboratory and will be analyzed if needed to 
confirm the diagnosis of influenza. 
10.1.9 Urinalysis and Evaluation of Protein in Urine 
Urinalysis will in clude dipstick tests for protein, glucose, ketones, blood, urobilinogen, 
nitrite, pH, and spec
ific gr avity a nd m icroscopic evaluation for R
BCs and WBCs.  
Samples for urinalysis will be collected at Screening/Baseline, and on Days 3, 5, and 14. 
10.1.10Urine Pregnancy Test 
Females of childbearing potential will be ev aluated for pregnancy at Screening/Baseline 
and Day 14 using a urine pregnancy test. 
10.1.11 Samples for Virologic Laboratory Assessments 
An adequate spec imen will b e co llected by sw abbing the anter ior nos e (bila teral) and 
posterior pharynx for virologic laboratory a ssessments including culture for the isolation 
of influenza virus and/or quantitative PCR assa y at Screening/Baseline, and at Days 3, 5, 
and 9.  In a subset of a m inimum of 200 subjects an additio nal sample will be taken at  
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Day 2. Refer to the L
aboratory Manual for instructions re garding the processing and 
shipment of these specimens. 
10.1.12 Subject Self Assessments 
Subject self assessments will be performed beginning pre-dose on Day 1 and recorde d in 
the subject’s Study Diary including the following: 
• Oral temperature measurements with an electronic thermometer (provided by the 
Sponsor for the study) every 12 hours.  With the exception of the baseline 
measurement, all temperature measurements will be obtained at least 4 hours after, or 
immediately before, administration of oral acetaminophen (paracetamol, provided) 
aspirin, ibuprofen or other NSAID. The times of each temperature determination will 
be recorded in the Study Diary.  The baseline temperature will be recorded at the 
screening/Day 1 visit prior to dosing, regardless of whether the subject had recently 
taken an anti-pyretic; the time of anti-pyretic use pre-treatment will be recorded in the 
CRF, if applicable. 
• Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, 
myalgia [muscle aches], headache, feverishness, and fatigue) on a 4-point severity 
scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on 
Day 1 and through Day 9, then once daily through Day 14. 
• Assessment of the subject’s ability to perform usual activities using a 0–10 visual 
analogue scale once daily through Day 14. 
• Assessment of the subject’s time lost from work or usual activities and productivity 
compared to normal using a 0-10 visual analogue scale once daily through Day 14. 
The subject’s diary card will be reviewed by study staff at each visit for completion of the 
record of all required ite ms, with particular emphasis on alleviation of symptoms as well 
as relapse of sym ptoms.  Relapse is defined as the recurrence of at leas t one respiratory 
symptom and one constitutiona l sy mptom (both greater th an m ild in severity) f or 24 
hours and the presence of fever (unless influenc ed by antipyretic use).  Relapse can only 
occur after the subject has m et the endpoint cr iteria for alleviation of symptoms.  Study 
staff will not attem pt to ask subjec ts to retrospectively complete missing diary card data 
for any scheduled assessm ents that have not b een com pleted prio r to  the c linic visit.  
Study staff should, however, rem
ind the subject  to com plete the diary card at all
 
scheduled times. 
10.1.13 Concomitant Medications 
All concom itant m edications used during 
this study, with the exception of those 
medications taken for symptomatic relief of influenza symptoms, which will be reco rded 
by the subject in their diary card, must be documented on the Case Report Form (CRF).  
10.1.14 Adverse Events 
AEs will be assess ed from the tim e of ad ministration of stu dy medication through the 
final study visit. 
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10.1.15 Single Pharmacokinetic Exposure Sample 
On study day 3 a single PK sample will be drawn in concert with the day 3 safety clinical 
laboratory blood draw. This sample will be 
sent for subsequent analys
is of the 
concentration of peramivir at this time point.  Data f rom this sing le PK sample will b e 
combined with data from  the PK s ub-study (BCX1812-311PK) to perfor m an exposure-
response analysis.  This analysis will be described as part of the sub-study analysis plan.. 
 
10.2 Screening  
10.2.1 Informed Consent 
The nature and purpose of the study and the expectations of a participating subject will be 
described to potential study subjects , their que stions will be answered, and the subjects 
will th en b e asked to sign an inf
ormed c onsent docum ent.  Study s ubjects will then 
undergo the screening evaluation as noted in Section  10.2.2 
10.2.2 Screening/Baseline Evaluation and Enrollment 
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or 
in the subject’s hom e, in which case all ev aluations must be conducted by appropriately 
trained and qualified staff. 
Clinical laboratory assessm
ents perform ed at Screenin
g are 
for the purpose of 
establishing a baseline.  Subjects m ay be enrolled and receive treatm ent with study drug 
prior to r eceiving re sults of  the laboratory a ssessments (with the ex ception of  urine 
pregnancy test result, which must be known). 
Eligible sub jects will be enrolled and ra
ndomized to blin ded study treatm ent.  The 
randomization will include stratification by RA T status and current s moking behavior.  
The Investigator will prepare a request for blinded study drug assignment which includes 
the subject’s screening number.  The Investigator or designee at the clinical study center 
will contact the central randomization Interactive Voice System (IVRS call center).  The 
IVRS call center will advise the study center of the investigational study drug kit number 
that is assigned to that subject at enrollment. 
Subjects that are d etermined to be ineligible will be advi sed accordingly, and the reason 
for ineligibility will b e discussed.  If  desired by the subjec t the reason  for ineligibility 
may be pr ovided/discussed with their hea
lth-care provider by the Investigator or 
designee.  
Ineligible subjects who have been screen
ed for the study will also be entered on
 the  
IVRS.  For such subjects, the screening num
ber assigned, subject’s date of birth and a 
reason for ineligibility will be entered on to th e IVRS.  All ineligible subjects must be 
entered onto the IVRS within 24 hours of screening, to assis t with surve illance 
analysis during the course of the study. 
  
10.3 Treatment Period—Study Day 1 
Day 1 represents the only day of study dr
ug dosing.  Study drug adm inistration should 
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occur as soon as possible following inform
ed consent, screening and random
ization.  
Therefore, it is expec ted that the da te of Screening/ Baseline and Day 1 will usua lly be 
the same date.  
10.3.1 Pre-dose Evaluations 
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the 
subject shall complete the record of these assessments in their Study Diary prior to 
dosing.  The subject will be counseled regarding the expectations for recording these 
assessments through Day 14. 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral 
temperature) and a 12 lead ECG will be obtained prior to dosing. At Hour 0, the blinded 
study drug will be administered intramuscularly (one injection in the left gluteal muscle, 
and one injection in the right gluteal muscle within a period of ≤ 10 minutes.).  The 
calendar date and 24-hour clock time of the first and second injections will be recorded. 
The following evaluations will be performed post-dose on Study Day 1: 
• Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral 
temperature) at 15 minutes after the study drug administration 
• Record any concomitant medications 
• Record any AEs 
10.4 Post-Treatment Assessment Period 
10.4.1 Days 2, 3, 5, 9 and 14 
Study evaluations will be perform ed on Days  2 [subset], 3, 5, 9 and 14 in accordance 
with the schedule of evaluations (Figure 1). 
Visits may be conducted in the investigator’s o ffice or clinic, or in the subject’s home, in 
which case all evaluations must be conducted by appropriately trained and qualified staff. 
The Day 2 assessm ent will be con ducted in pe rson only f or the subse t of subjects who 
will provide additional Day 2 viro logy samples. For all o ther study subjects, study staff 
will attempt to contact the subjects on Day 2 by telephon e to confirm  their com pliance 
with completion of the Subject Self  Assessments, to note any concom itant medications 
and adverse events.  Any adverse events repo
rted by the subject during this telephone 
contact will be recorded on the adverse event form and verified during the visit on day 3. 
At each v isit it is im portant that the sub ject’s Study Diar y record be rev iewed for 
completion of daily Subject Self Assessm
ents.  The subjects should be counseled as
 
necessary regarding self assessments and Study Diary record requirements.  The subject’s 
diary card will be reviewed by study staff for alleviation of symptoms as well as relapse 
of symptoms.  Relapse is defined as the r ecurrence of at least one resp iratory symptom 
and one constitutional symptom (both greater than mild in severity) for 24 hours an d the 
presence of fever (unless influenced by antipyretic use).  Relapse can only occur after the 
subject has met the endpoint criteria for alleviation of symptoms. 
Day 3: 
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The results of  the CK assay a t Da y 3 will no t be m ade available to  investiga tors, to 
BioCryst or to any study personnel unless the C K result at Day 3 is ≥ 2000 IU/mL.  A 
single PK sample will be drawn as part of the safety clinical laboratory study on Day 3. 
Day 14: 
If a subject does not have resolution of all 
influenza-related sym ptoms (defined as a 
patient-recorded sym ptom score of  m oderate [ 2] or seve re [ 3]), the investigato r will 
schedule a follow-up assessm ent with the pati ent at Day 21 and, if required, Day 28. 
 
These follow-up assessm ents m ay be conduc ted in person or by telephone at the 
investigator’s discr etion. The subjec ts will no t be required to continu e to reco rd da ily 
symptom sc ores, but w ill report th ese sco res to the inv estigator on Day 21 and, if 
required, on Day 28. No protocol-m andated follow up will occur after Day 28.  Further 
management of the subject will be in acco
rdance with  the investigator’s stan
dard 
practice. 
 
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Figure 1 
Study Measurements and Visit Schedule 
 
Treatment 
Period 
                                                Assessment Day                                     End of Study 
                                                                                                            Early Withdrawal 
 
Screening 1 
(Baseline) 
Day 11 
Day 22 
Day 3 
Day 5 (±1 day) 
Day 9 (±3 day) 
Day 14 (±3 day) 8 
Informed Consent 
X 
 
 
 
 
 
 
Rapid Antigen test for Influenza A & B 
X 
 
 
 
 
 
 
Medical History/Physical Exam3 
X 
 
 
 
 
 
 
Influenza-related complications checklist3 
X 
 
X 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Clinical Chemistries4 
X 
 
 
X 
X 
 
X 
Hematology4 
X 
 
 
X 
X 
 
X 
Exposure Pharmacokinetic Sample 
 
 
 
X4 
 
 
 
Serology (serum) Sample 
X 
 
 
 
 
 
X 
Urinalysis4 
X 
 
 
X 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
ECG6 
X 
 
 
 
 
 
 
Sample (nasophar
yngeal swab) for
 
Influenza Virus  Culture/ PCR assay and 
for resistance studies 
 
X 
X 
X 
X 
X 
 
Study Drug Administration 
 
X 
 
 
 
 
 
Subject Diary Review7 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on subsequent study days may occur in subject’s home by 
the investigator (all visits) or appropriately trained study center staff (Day 2, 3, 5, 9 visits). 
2  Day 2 visit required only for a subset of subjects for whom additional Day 2 virology sample is required.  For all other subjects, Day 2 will be a telephone contact with the subject to ensure 
compliance with diary card completion, concomitant medication and adverse event review. 
3  Medical history and physical exam at screening to include weight, and smoking behavior.  Targeted physical examinations will be performed to complete the influenza-related complications 
checklist by the appropriate medical personnel at appropriate visits. 
4  Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline.  Subject may be enrolled and begin treatment with study drug prior to receiving results. 
On Day 3 an extra tube will be included with the safety blood sample for evaluation of peramivir concentrations. 
5  Vital sign measures will include blood pressure, pulse rate and respiration rate.  Vital signs will be recorded at Screening, pre-dose and at 15 min following the study drug administration on 
Day 1, then once on remaining days as stipulated. The investigator will record oral temperature at baseline.  Thereafter the subject will report oral temperature measurements twice daily in 
the Study Diary 
6  If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study.  If the ECG is 
interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, medically significant dysrhythmia) then this subject may be enrolled, taking into consideration 
the subject’s medical history. Appropriate follow-up evaluations, including but not limited to repeat ECGs, should be completed at subsequent study visits as directed by the investigator. 
7  Subjects record symptom assessment in Study  Diary, twice dail y, beginning pr e-dose on Day 1 thr ough Day 9, then once daily  through Day 14;  subjects record ability  to perform  usual 
activities once daily, beginning pre-dose on Day 1 through Day 14.  Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events 
8   For any subject with unresolved influenza symptoms(moderate or severe) or unresolved adverse events, a follow up assessment (in person or by phone) will be scheduled at Day 21 and Day 
28 if required 
 
BioCryst Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
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11 ADVERSE EVENT MANAGEMENT 
11.1 Definitions 
11.1.1 Adverse Event 
An AE is any untoward m
edical 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, sym ptom, syndrome, or illness that dev elops or 
worsens during the clinical st
udy.  Clinically relevant ab
normal results of diagnostic 
procedures including abnorm
al laborator y findings (e.g., requ
iring unscheduled 
diagnostic procedures or treatm ent measures, or resulting in withdrawal from  the study)  
are considered to be AEs. 
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2). 
Surgical procedures are not AEs but m ay constitute  therapeutic m easures 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 m
easures perm itted by the 
clinical study protocol and the conditions(s) leading to these measures are not AEs, if the 
condition(s) was (were) known befo re the start of study treatm ent.  In the latter case the 
condition should be reported as medical history. 
Assessment of seven influenza sym ptoms (cough, sore throat, nasal obstruction, m yalgia 
[muscle aches], headache, f everishness, and f atigue) will be  documented in a subject’s  
study diary  and analy zed as a m
easure of  efficacy of the study treatm
ent. These  
symptoms will not b e reported as AEs unless the sym ptom(s) worsen to the exte nt that 
the outcome fulfils the def inition of an SAE, which then must be recorded as such  (see 
Section  11.1.2).  Likewise, a RAT for influenza is 
required at screening in order to 
determine eligibility for the study, and therefore a positive RAT is not considered an AE.    
11.1.2 Serious Adverse Event 
A SAE is an adverse event that results in any of the following outcomes: 
• Death 
• Is life-threatening (subject is at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe) 
• Requires in-subject hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (i.e., there is a substantial 
disruption of a person’s ability to carry out normal life functions) 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
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Important medical events that may not result in death, are no t life-threatening, or do not 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they m
ay j eopardize the subject or m
ay r equire m edical or surgical 
intervention to prevent one of  the outcom es listed in this definition.  E xamples of such 
events include allergic bronchospasm requiri
ng intensive treatm ent in an e mergency 
room or at hom
e, blood dyscrasias or c
onvulsions that do not
 result in subject 
hospitalization, or the development of drug dependency or drug abuse. 
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events 
Reports of AEs are to be collected from the time of study drug administration through the 
follow-up period ending on Day 28.  The Invest igator or de signee must completely and 
promptly record each AE on the appropriate 
CRF.  The Investig ator should attem pt, if 
possible, to establish a diagnosis based on th e presenting signs and symptom s.  In such 
cases, the diagnosis should be docum
ented as the A
E and not the individual
 
sign/symptom.  If a clear diagnosis cannot be established, each si gn and symptom must 
be recorded individually. 
The Investigator should attem pt to follo w all unresolved AEs and/or SAEs observed 
during the study until they are reso lved, or for 30 days after th e subject’s last study visit, 
whichever comes first. 
11.2.1 Definition of Severity 
All AEs will be as sessed (graded ) f or severity and class ified into on e of  f our clearly 
defined categories as follows: 
• Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; 
no intervention required.  The AE does not interfere with the 
participant’s normal functioning level.  It may be an annoyance. 
• Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in 
activity; no or minimal intervention required.  The AE produces 
some impairment of functioning, but it is not hazardous to 
health.  It is uncomfortable or an embarrassment. 
• Severe: 
(Grade 3): Symptom results in significant limitation in activity; 
medical intervention may be required.  The AE produces 
significant impairment of functioning or incapacitation. 
• Life-threatening: (Grade 4): Extreme limitation in activity, significant assistance 
required; significant medical intervention or therapy required; 
hospitalization. 
11.2.2 Definition of Relationship to Study Drug 
The blinded Principal Investigator must rev iew each AE and m ake the determ ination of 
relationship to study drug using the following guidelines: 
Not Related: 
The event can be readily explained by other factors such as the 
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subject’s underlying m edical c ondition, concom itant therapy, or 
accident, an d no tem poral relati onship ex ists b etween the study 
drug and the event. 
Unlikely: 
The event d oes not follow a reason able tem poral sequ ence from 
drug adm inistration and is read
ily explained by the subject’s 
clinical state or by other m
odes of therapy  adm inistered to the  
subject. 
Possibly Related: 
There is so me tem poral relationship between the event an
d th e 
administration of the study drug a
nd the event is unlikely to be 
explained by the subject’s m edical condition, other therapies, or 
accident. 
Probably Related: 
The event follows a reasonable tem
poral sequence from drug 
administration, abates upon discontinuation of the drug, and cannot 
be reasonably explained by th
e known characteristics of the 
subject’s clinical state. 
Definitely Related: The event follows a reason
able tem poral sequen ce from 
administration of the m edication, follows a known or suspected 
response pattern to the m edication, is confirm ed by im provement 
upon stopping the m edication (dec hallenge), and reappears upon 
repeated exposure (rechallenge, 
if rechallenge is m
edically 
appropriate). 
11.2.3 Reporting Serious Adverse Events 
Any SAE must be reported to BioCryst
 or its designee within 24 hours of the 
Investigator’s recognition of the SAE by fi
rst notifying the Medical Monitor at the 
number listed below: 
Telephone: 
Europe: +44 1628 548000;  North America: 1-888-724-4908 
Facsimile: 
Europe: +44 1628 540028;  North America: 1-888-887-8097  
           or 1-609-734-9208  
 
The site is required to fax a completed SAE Report Form (provided as a separate report 
form) within 24 hours.  All additional follow-up evaluations of the SAE must be reported 
and sent by facsimile to BioCryst or its designee as soon as they are available. 
The Principal Investigator or designee at each site is respons ible for submitting the IND 
safety report (initial a
nd follow -up) or other safety inform
ation (e.g., revised 
Investigator’s Brochure) to
 the Institutional Review 
Board/Independent Ethics 
Committee (IRB/IEC) and for retaining a copy in their files. 
If the Inv estigator becomes aware of any SA E occurring within 30 days after a s ubject 
has com pleted or withdrawn from  t he study, he or she should notify BioCryst or its 
designee.   
Any SAEs considered possibly related to treatment will be reported to the FDA and other 
Regulatory Competent Authorities as applicab le via the MedW atch reporting system i n 
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accordance with FDA and other ap plicable regulations. However, the Investig ator is not 
obligated to actively seek reports of AEs in former study participants. 
While pregnancy is not considered an AE, a ll cases of fetal drug exposure via parent as 
study participant (see S ection 4.4) are to be 
reported immediately to  BioCryst or its 
designee.  Inform ation rela ted to the pregnancy m
ust be given on a “Pregnancy 
Confirmation and Outcome” form that will be provided by the Sponsor or its designee. 
11.2.4 Emergency Procedures 
In the even t of an SAE, the Principal Inve
stigator m ay request the unblinding of  the  
treatment assignm ent for the subject affected
.  If tim
e allows (i.e., if appropriate 
treatment for the SAE is not im peded), the Principal Investigator wi ll first consult with 
the Med ical Monito r r egarding the  need to  unblind the treatm ent assignm ent for the  
subject.  At all times, the clinical well-being of any subject outweighs the need to consult 
with the Medical Monitor. 
The Principal Investigator m
ay contact th e IVRS central random
ization center and 
request the unblinding of the treatm
ent assi gnment that corresponds to the affected 
subject.  Th e IVRS center will record the na me of the Investigator  making the request, 
the date and time of the request, the reason for the request, the subject number and study 
drug kit number, and whether the Medical M
onitor was consulted prior to the request 
being made.  The Sponsor will be informed within 24 hours if unblinding occurred. 
 
12 STATISTICAL METHODS 
Descriptive statistical methods will be used to summ arize the data from this study, with 
hypothesis testing perform ed for the prim
ary and other selected efficacy endpoints. 
 
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 da ta.  The term “treatm ent group” refers to 
randomized treatment assignment:  peramivir 150 mg, peramivir 300 mg, or placebo.  All 
data collected during the study wi ll be included in data listin gs.  Unless otherwise noted, 
the data will be sorted first by treatm ent assignment, subject num ber, and then by date 
within each subject number.   
Unless specified otherwise, all statistical testing will be two-sided and will be performed 
using a significance (alpha) level of 0.05. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
12.1 Data Collection Methods 
The data will be reco rded on the CRF appr oved by BioCryst. The Investigator must 
submit a completed CRF for each subject who signs an inform
ed consent form (ICF), 
regardless of duration.  All documentation supporting the CRF data, such as laboratory or 
hospital records, must be readily available to verify entries in the CRF. 
Documents (including laborator y reports, hospital records s
ubsequent to SAEs, etc.) 
transmitted to BioCryst should not carry the s
ubject’s name.  This will help to  ensure 
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subject confidentiality. 
The Investigator m ust consult the “CRF
 Com pletion Manual” for com
prehensive 
instruction for completion of the CRF. 
12.2 Statistical Analysis Plan 
A statistical analysis plan (SAP) will be cre ated prior to the review of  any data.  This 
document will provide a m ore technical and detailed description of the proposed data 
analysis methods and procedures. 
12.3 Sample Size Estimates 
From published resu lts, it is exp ected that th e median time to a lleviation of symptoms 
will be between 103.3-116 hours  for subjects receiving p lacebo. 16 , 1 7  For sam ple size 
calculations the best placebo respon se (103.3 hours) will p rovide the most conserv ative 
estimate of an observed hazard ratio. Additionally, it is expected that the median time to 
alleviation for the lowes t dose peramivir arm will be 69.9 h ours, yielding a hazard ratio  
of 0.68.  Using these assum
ptions, a sa mple size of 200 infected subjects per active
 
treatment group and 100 infected subjects in th e placebo group is sufficient to provide at 
least 80% power to detect a hazard ratio of 0.68 usi ng a log-rank statistic and α = 0.025 
(SAS version 9.1.3; tota l accrual time 7 months; total enrollment time 6 months). Up to 
800 subjects will b e enrolled to achieve the target num ber of at least 5 00 subjects with  
diagnostic evidence (RAT or PCR) of an 
acute influenza infection (200 per active 
treatment; 100 receiving placebo) as described in section  12.4.2. 
12.4 Analysis Populations 
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected 
(ITTI), and safety populations. 
12.4.1 Intent-To-Treat Population 
The ITT population will include all subject
s who are random ized.  Subjects will be 
analyzed in the treatment group to which they were randomized.  The ITT population will 
be used for analyses of accountability and demographics. 
12.4.2 Intent-To-Treat Infected Population 
The ITTI po pulation will include all subj ects who are rando mized, received study d rug, 
and have proven influenza by any one of the fo llowing: culture, PCR, or paired serology 
showing ≥ 4-fold increase in antibody to influe
nza A or B, and received study drug. 
 
Subjects will be an alyzed accord ing to the treatment random ized.  If a discrepancy is 
noted in the final database for any subject, such that the drug differs from the randomized 
treatment assignm ent, efficacy analyses m ay be repeated with the su
bjects analy zed 
according to the treatm ent received.  The 
ITTI population will be used for prim
ary 
analyses of efficacy. 
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12.4.3 Safety Population 
The safety population will include all subjects who received study drug.  Subjects will be 
analyzed according to the treatm ent received.  This population will be used for all safety 
analyses. 
12.5 Interim and End of Study Analyses 
Interim Analysis 
An independent DMC will review  safety data on an ongoing basi s.  Safety analyses will 
be presented in a manner consistent with the presentations intended for the final analysis. 
End of Study Analysis 
A final analysis is planned after the last su bject completes or discontinues the study, and 
the resulting clinical database has been cleaned, quality checked, and locked. 
12.6 Efficacy Analyses 
12.6.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time 
from injection of study drug to the start of th e time period when a subject has Alleviation 
of Symptoms.  A subject has Alleviation of 
Symptoms if all of  the seven symptoms of 
influenza (nasal congestion, so re throat, cough, aches and pains, fatigue (tiredness), 
headache, feeling feverish) assessed on his/he
r subject diary are eith
er absent o r are 
present at no m ore than m ild severity leve l and at this status for at least 21.5 hours (24 
hours - 10%). 
Descriptive statistics for the prim ary effi cacy endpoint will be tabulated by treatment 
group.  Alleviation of sym
ptoms will be d etermined by assessm ent of sym ptoms as 
reported on  each  subject’s  diary  card.   T ime to alle viation of sym ptoms will b e 
summarized overall and for i
ndividual sym ptoms for each treatm ent group.  Overall 
treatment dif ferences will be assess ed using a Cox Regression m
odel with ef fects f or 
RAT result at screening, current smoking behavior, treatment group, and influenza season 
at randomization (if necessary).  Subjects who do not experience alleviation of symptoms 
will be censored at the date of their last non-missing post-baseline assessment.  Pairwise 
differences in tim e to alleviation of sy
mptoms am ong the treatm ent groups will be 
evaluated using contrast statem ents from the final Cox m odel. In orde r to m aintain the 
overall type I error in the presence of the planned comparisons between the two peramivir 
treatments and placebo, a Bonfe rroni correction will be app lied to the p rimary efficacy 
endpoint analysis.  P -values for the planne d com parisons of each peram ivir arm  to 
placebo will be adjusted via a Bonferroni corr ection (i.e., if the unadjusted p-value for an 
active com parison versus place bo, p, is less th an 0.05, then p
a=p*number of planned 
comparisons=p*2; otherwise, p
a=p).  Superiority of peram
ivir to placebo will be
 
established if the adjusted p-value is less than or equal to 0.05. 
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12.6.2 Secondary Efficacy Endpoints 
All secondary endpoints will be summ
arized using descriptive statistics by treatm
ent 
group and study day/time, if appropriate.  St atistical comparisons for each endpoint will 
be constructed without adjustment for multiple endpoints. 
The reduction in viral shedding will be assessed as the change in viral titers defined as the 
time-weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) 
and will be summarized  for each treatm ent group.  The tim e-weighted average change 
from baseline will be calculated on a by-subject basis through Day 9 using the trapezoidal 
rule with a ll available post-bas eline on-tre atment data (d ata af ter initia tion of  study 
treatment) minus the baseline value.  Specifically, the time-weighted area under the curve 
for time a (ta) to time b (tb) is given by the formula  
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
, 
where 
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
 and ti represents the date of the ith viral titer 
assessment and y i represents the log10 value of the i th viral titer as sessment. If there is a 
baseline value and only one follow-up value, y
i then the tim e-weighted change from 
baseline is defined as the difference between y i and baseline.  If there is a baselin e value 
and no follow-up value, the subject is exclude d from analysis.  The differences between 
each of the peramivir treatment groups and placebo will be evaluated using a van Elteren 
Test ad justing for RAT result at screen
ing, current sm oking be havior and influenza 
season at randomization (if necessary).   Analyses of the PCR results will be analy zed in 
a similar manner. 
Subject’s ability to perform usual activities as determined from the visual analog scale 
will be summarized by study visit day and treatment group.  Differences between the 
treatment groups will be assessed using the van Elteren Test adjusting for smoking 
behavior and influenza season at randomization (if necessary).  The time (days) to 
resumption of a subject’s ability to perform usual activities (i.e., subject scores ability to 
perform usual activities as 10) will be estimated using the method of Kaplan-Meier.  
Differences between each of the peramivir treatment groups and placebo will be assessed 
using the log rank statistic adjusting for RAT result at screening, current smoking 
behavior and influenza season at randomization (if necessary).  Subjects who do not 
return to the pre-study level of performance of usual activities will be censored at the 
time of their last non-missing post-baseline visual analog scale value. 
Subject’s oral tem perature will be summ
arized by study visit and treatm
ent group.  
Differences between the treatment groups will be assessed using the Wilcoxon Rank Sum 
Test con trolling for RAT resu lt at screen ing, current sm oking behavior and influenza  
season at randomization (if necessary).  A subject has Resolution of Fever if he/she has a 
temperature < 37.2°C (99.0°F) and no antipyretic medications have been taken for at least 
12 hours.  The tim e to resolution of fever will be estimated using the method of Ka plan-
Meier using temperature and sym ptom relief medication information obtained from the  
subject diary data.  Difference between the tr eatment groups will be assessed using the 
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log rank sta tistic controlling for RAT result a t screening, current sm oking behavior and 
influenza season at randomization (if necessary).  Subjects who do not have resolution of 
fever will be censored at the tim
e of their last non- missing post-baseline tem perature 
assessment. 
The MRU, MRU-related direct co sts, and indirect co sts attributable to days m issed of 
work and work productivity and/or perform ance losses will be summ arized by treatment 
group.  Differences between each of the peramivir treatment groups and placebo group 
will be evaluated using both param etric and/or non-parametric tests, as appropriate.   If 
necessary, bootstrapping techniques will be used to calculate confidence intervals around 
the incremental differences in costs.   
12.6.3 Exploratory Endpoint 
Genotypic (including Hem agglutinin and Neurom inidase), phenotypic, viral culture and 
PCR data will be lis ted for each sub ject.  These listings will be constructed in a m anner 
consistent with the F
DA June 2006 Guidance Docum
ent:“Guidance for Subm itting 
Influenza R esistance D ata”.18  Ad ditionally, the num ber and percen tage of  genotypic 
changes from wild-type a mino acid will be summarized separately for treatm ent group, 
protein type, and study visit. 
12.7 Safety Analyses 
AEs will be m apped to a MedDRA-pref erred term and system organ classification.  The 
occurrence of TEAEs will be  summarized by treatment group using MedDRA-preferred 
terms, system organ classifications, and severity.  If a subject experiences multiple events 
that m ap to a s ingle p referred term, the grea test severity and st rongest Investigator 
assessment of relation to study d
rug will be assigned to  the preferred term  for the 
appropriate sum maries.  All AEs will be li
sted f or individual subje cts 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 s igns and clinic al laboratory results will be presented by 
study visit.  Laboratory abnorm alities will be graded according to the DAIDS Table for  
Grading Adverse Events for Adults and Pedi atrics (Publish Date: December 2004).  The 
number and percentage of subjects experien
cing treatm ent-emergent graded toxicities  
will be summarized by treatment group. Laborator y toxicity shifts from baseline to Day 
3, Day 5, and Day 14 will be summarized by treatment group. 
Abnormal physical exam ination findings wi ll be presented by treatm
ent group.  The 
number and percent of subjects experiencing each abnormal physical examination finding 
will be included. 
Concomitant medications will be co ded using the WHO dictionary.  The se data will be  
summarized by treatment group. 
Subject disposition will be presented for a
ll s ubjects.  The num ber of subjects who 
completed the study and discontinued from  the study will be provided.   The reasons for  
early discontinuation also will be presented. 
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12.8 Sub-Study and Pharmacokinetic Analysis 
The sub-study to exam ine exposure respons e, along with the corresponding single PK 
samples collected on all subjects on study day 
3 will be co mpleted as part of the sub-
study. All s tatistical m ethods will be outlin ed as part of the sub-stu
dy protocol and 
exposure-response analysis plan. All sub-study analyses will be reported in a separate 
sub-study report. 
12.9 General Issues for Statistical Analysis 
12.9.1 Multiple Comparisons and Multiplicity 
In order to m aintain the overall typ e I e rror in the presen ce of the plann ed comparisons 
between the two peram
ivir treatm ents and pl acebo, a Bonferroni correction will be
 
applied to the prim ary efficacy end point an alysis.  No oth er ad justments for m ultiple 
comparisons are planned. 
12.9.2 Covariates 
Primary and secondary efficacy analyses will 
be adjusted for RAT result at screen ing, 
current smoking behavior and influenza season at randomization (if necessary).  
12.9.3 Planned Sub-Groups 
The prim ary efficacy endpoint will be summ
arized separately by stratification group 
(current sm oking behavior [sm oker or non-smoker] and RAT result at screening 
[negative or positive]) and by viral subtype using descriptive statistics by treatment group 
and study day, if appropriate.  No formal statistical testing will be utilized. 
Additional analyses m ay be perform ed by count ry, if necessary, for subm ission to local 
regulatory authorities. 
12.9.4 Missing Data 
Every effort will be m ade to obtain  required data at each s cheduled evaluation from all 
subjects who have been random ized.  No attemp t will be m ade retrospectively to obtain 
missing subject reported data (including in
fluenza symptom severity assessm
ents, 
temperature, ability to perf orm usual activi ties, m issed days of work and im
pact of 
influenza on subject’s work perform
ance and/or productivity) 
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 obt ain all da ta, it m ay be necessary to im pute 
missing data.   
 
In assessing  the p rimary efficacy endpoint, fo r subjects w ho withdraw or who d o no t 
experience allev iation of sym ptoms, m issing data will be 
censored using the date of 
subject’s last non-m issing assessment of infl uenza symptoms.  Missing assessm ents of 
influenza symptoms conservatively will be im puted as h aving severity above absen t or 
mild (as f ailures).  For the subjec t diary data,  the f ollowing data con ventions will be  
utilized.  Missing diary com pletion will be imputed as 11:59 for diary entries designated 
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as m orning and 23:59 for evening and daily 
reported v alues.  Entr ies with va lues 
exceeding the 24-hour clock will b e set to 23:59 of the day recorded.  Select explo ratory 
sensitivity analyses m ay be conducted to ascert ain the effect, if any, of these m
ethods.  
These sensitivity analy ses are further de
scribed in the SAP.  Secondary efficacy 
endpoints with tim e to event da ta will be censored using the date of subject’s last non-
missing assessment of the given endpoint. 
 
13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 Regulatory Authority Approvals 
This study  will be conducted in
 com pliance with th e protoco l; GCPs, including  
International Conference on Harmonization (ICH) of Te
chnical Requirem ents for 
Registration of Pharm
aceuticals for Hu
man Use G
uidelines; FDA regulatory
 
requirements and in accordance with the ethical principles of the Declaration of Helsinki.  
In addition, all applicable loca l laws and regu latory requirements relevant to the use of 
new therapeutic agents in the countries involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB)/ Independent E thics Committee (IEC) annually or  more frequently 
if requested by the IRB/ IEC.  A final s
tudy notification will also be forwarded to the 
IRB/IEC af ter the study  is com pleted or in the event of
 prem ature ter mination of the  
study in accordance with the appl icable regulations.  Copies of  all contact with the IRB/ 
IEC should be m aintained in the study docum ents file.  Copies of clinical study status 
reports (including termination) should be provided to BioCryst. 
13.1.2 Ethics Committee Approvals 
Before initiation of the study at each invest
igational site, the pr otocol, the inform ed 
consent form, the subject inform ation sheet, and any other relevant  study documentation 
will be sub mitted to th e appropriate IRB/IE C.  W ritten approval of th e study m ust be 
obtained before the study center can be initiated or the investigational medicinal product 
is re leased to the Inv
estigator.  A ny necessa ry extension s or renew als of  IRB/IEC 
approval must be obtained, in particular, for changes to the study such as modification of 
the pro tocol, the inf ormed consent f orm, th e written inform ation provided to subjects 
and/or other procedures. 
The Investigator will report promptly to 
the IRB/IEC any new inform
ation that m ay 
adversely affect the safety of the subjects or  the conduct of the study.   On completion of 
the study, the Investigator will prov ide the IRB/IEC with a report of the outcom e of the 
study. 
13.1.3 Subject Informed Consent 
Signed info rmed consent m ust be obtained  from each subject p rior to  performing any 
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study-related procedures.  E
ach subject should be given both verbal and w
ritten 
information describing the nature and durati
on of the clinical st
udy.  The inf ormed 
consent process should take place u nder conditions where the subject h as adequate time 
to consider the risks and bene
fits associated with his/her 
participation in  the study.  
Subjects will not be screened or treated 
until the subjec t has signed an approved ICF 
written in a language in which the subject is fluent. 
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.   
The informed consent should be in acco
rdance with the curren
t revision o f the 
Declaration of Helsinki, current ICH and GCP guidelines, and BioCryst policy. 
The Investigator must explain to potential subjects or their legal representatives the aims, 
methods, reasonably anticipated benefits, a
nd potential hazards of the trial and any 
discomfort it may entail.  Subjects will be informed that they are free not to participate in 
the trial and that they may withdraw consent to participate at any time.  They will be told 
that refusal to participate in the study will not prejudice future treatment.  They will a lso 
be told  tha t their recor ds m ay be exam ined by com petent autho rities and au thorized 
persons but that pe rsonal information will be tr eated as strictly confidential and will not 
be publicly available.  Subjects must be given the opportunity to ask questions.  After this 
explanation and before entry in to the trial, consent should be appropriately recorded by 
means of the subject’s dated signature.  The subject shoul d receive a signed and dated 
copy of the ICF.  The original  signed infor med consent should  be retained in the study 
files.  The Investigator shall maintain a log of all subjects who sign the ICF and indicate 
if the subject was enrolled into the study or reason for non-enrollment. 
13.1.4 Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
13.1.5 Investigator Reporting Requirements 
The Investigator will provide  tim ely repo rts regard ing s afety to his /her IRB/IE C as 
required. 
13.2 Study Monitoring 
During trial conduct, BioCryst or its  designee will conduct period ic monitoring visits to 
ensure that the protocol and GCPs a re being followed.  The monitors may review source 
documents to conf irm that th e data recorded on CRFs is accurate.   The investigator and 
institution will allow BioCryst m
onitors or  its des ignees and app ropriate regulatory  
authorities direct access to source documents to perform this verification. 
13.3 Quality Assurance 
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by BioCryst, 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 a udits or inspections and that sufficient tim e is devoted to 
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the process. 
13.4 Study Termination and Site Closure 
BioCryst reserves the right to
 disc ontinue the  tr ial prio r to inc lusion of  the in tended 
number of subjects but intends only to exer
cise this r ight f or valid scientif ic or 
administrative reasons.   After such a deci
sion, the Investigator must contact all 
participating subjects immediately after notification.  As directed by BioCryst, all study 
materials must be collected a nd all case report forms completed to the greatest extent 
possible. 
13.5 Records Retention 
To enable evaluations and/or
 audits from
 regulatory au
thorities o r BioCryst,  the  
Investigator agrees to k eep records,  includi ng the iden tity of  all p articipating sub jects 
(sufficient inf ormation to link re
cords, case report forms and hospital records), all 
original signed inform ed consent form s, copies of all case report form
s and detailed 
records of treatm ent disposition.  The reco
rds should be retained by the Investigator 
according to local regulations or as specified in the Clinical Trial Agreem ent, whichever 
is longer. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the study 
records m ay be transferred to an
 acceptab le designee, such as another investigato
r, 
another institution, or to BioCryst.  The I
nvestigator m ust obtain BioCryst’s written 
permission before disposing of any records. 
13.6 Study Organization 
13.6.1 Data Monitoring Committee 
BioCryst will a ssemble an indep endent Data M onitoring C ommittee ( DMC) to as sess 
safety parameters of the trial on a period ic, ongoing basis while the tr ial is in prog ress. 
The comm ittee will include a s tatistician and th ree phys icians, tw o of whom  will be  
Infectious Disease specialists. Full detail s of the com position of the D MC and how the 
DMC is to operate will be described in a separate DMC charter. 
13.7 Confidentiality of Information 
BioCryst affirms the subject’s right to prot ection against invasion of privacy.  Only a 
subject id entification n umber, initials and /or date of birth will id
entify subject data 
retrieved by BioCryst .  However, in com pliance with federal regulations, BioCryst
 
requires the investigato r to p ermit BioCryst ’s representatives and,  when neces sary, 
representatives of the FDA or 
other regu latory authoritie s to review and/or copy any 
medical records relevant to the study. 
BioCryst will ensure that the use and disclosur e of protected health information obtained 
during a research study com plies with the HIPAA Privacy Rule.  Th e Rule pro vides 
federal protection for the privacy of prot
ected health inf ormation by im plementing 
standards to  protec t an d guard ag ainst the m isuse of  ind ividually id entifiable h ealth 
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information of subj
ects 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 us e or disclosure of an indi vidual's protected 
health information.  A valid au thorization must meet the implem entation specifications 
under the HIPAA Pri
vacy Rule.  Authorizat
ion m ay be com bined in the Inform
ed 
Consent docum ent (approved by the IRB/IE
C) or it may be a separate docum
ent, 
(approved by the IRB/IEC) or provided by the Investigator or Sponsor (without IRB/IEC 
approval).  It is the responsibility of the 
investigator and institution to obtain such 
waiver/authorization in  writing  f rom the appr opriate ind ividual. HIPAA authoriz ations 
are required for U.S. sites only. 
13.8 Study Publication 
All data generated from this study are the propert y of BioCryst and shall be held in strict 
confidence along with all inform
ation furnis hed 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.   W ritten perm ission to the 
Investigator will be contingen t on the review by BioCryst of  the statistical ana lysis and 
manuscript and will provide fo r nondisclosure of BioCryst confidential or proprietary 
information.  In all case s, the partie s agree to s ubmit all m anuscripts or abstracts to all 
other par ties 30 days prior to su
bmission.  This will e
nable all parties to pr
otect 
proprietary information and to provide comme nts based on infor mation that may not yet 
be available to other parties. 
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14 REFERENCES 
 
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282. 
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality 
associated with influenza and respiratory syncytial virus in the United States. JAMA 
2003;289(2):179–186. 
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment 
on influenza-related lower respiratory tract complications and hospitalizations. Arch 
Intern Med 2003;163(14):1667–1672. 
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral 
neuraminidase inhibitor oseltamivir in experimental human influenza: randomized 
controlled trials for prevention and treatment. JAMA 1999;282(13):1240–1246. 
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant 
influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 
2004;364(9436):759–765. 
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-
influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. 
Antimicrob Agents Chemother 2001;45(4):1162–1167. 
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus 
isolates to different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147. 
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, 
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and 
neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 
2001;45(12):3403–3408. 
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine 
combinations exert additive and synergistic anti-influenza virus effects in MDCK 
cells. Antimicrob Agents Chemother 2004;48(12):4855–4863. 
10. BioCryst Pharmaceuticals. Unpublished data. 
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. 
Injectable peramivir promotes survival in mice and ferrets infected with highly 
pathogenic avian influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San 
Francisco 
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA. 
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival 
against lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32 
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03. 
14. Tamiflu® Package Insert.  Roche Pharmaceuticals. Rev. December 2005. 
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product 
information sheets 
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16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the 
oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 
283(8): 1016-1024. 
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of 
oseltamivir in treatment of influenza: a randomised controlled trial. Lancet 2000; 
355(9218): 1845-1850. 
18. US Department of Health and Human Services, Food and Drug Administration 
Center for Drug Evaluation and Reserach (CDER). Attachment to Guidance on 
Antiviral Product Development- Conducting and Submitting Virology Studies to the 
Agency: Guidance for Submitting Influenza Resistance Data.  
http://www.fda.gov/cder/guidance/7070fnlFLU.htm  
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15 APPENDICES 
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina 
 
NYHA Functional Classification of Heart Failure 
 
Class I 
No symptoms.  Ordinary physical activity such as walking and climbing 
stairs does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary  physical activity.  W alking or climbing stairs 
rapidly; walking uphill; walking or st air climbing after meals, in cold 
weather, in wind, or when under em otional stress causes undue fatigue 
or dyspnea. 
Class III 
Symptoms with less than ordinary 
physical activity.  W alking one to 
two blocks on the level and clim bing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at res t.  Inab ility to carry on any ph ysical activity without 
fatigue or dyspnea. 
 
NYHA Functional Classification of Angina 
 
Class I 
Angina only with unusually strenuous activity. 
Class II 
Angina with slightly m ore prolonged or slightly more vigorous activity 
than usual. 
Class III 
Angina with usual daily activity. 
Class IV 
Angina at rest. 
 
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208


 
 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-311 
IND No. 76,350 
 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE 
INFLUENZA 
THE IMPROVE 1 STUDY 
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy) 
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza 
Protocol Date: Version1.0: 04 September 2007 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35244, USA 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
 
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals, 
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to 
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information 
contained herein should be disclosed without prior written approval. 
CONFIDENTIAL 
 
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1 TITLE PAGE 
 
Protocol Number: 
BCX1812-311 
Study Title: 
A phase 3 m
ulticenter, random ized, double-blind, 
placebo-controlled s tudy to evaluate th e effic acy and 
safety of  intram uscular peram ivir in subjec
ts with 
uncomplicated acute influenza 
IND Number: 
76, 350 
Investigational Product: 
Peramivir (BCX1812) 
Indication Studied: 
Uncomplicated acute influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35233 
Development Phase: 
3 
Sponsor Medical 
Officer: 
W. James Alexander, M.D., M.P.H. 
Senior Vice President, Clinical Development  
Chief Medical Officer 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
Email Address: jalexander@biocryst.com  
Compliance Statement: 
This study will be conducted in accordance with the 
ethical principles that have their origin in the 
Declaration of Helsinki and clinical research guidelines 
established by the Code of Federal Regulations (Title 
21, CFR Parts 50, 56, and 312) and ICH Guidelines. 
Essential study documents will be archived in 
accordance with applicable regulations. 
Final Protocol Date: 
Version 1.0: 04 September 2007 
Amendment(s) Date(s): 
None 
 
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1.2 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3 m
ulticenter, random ized, double-blind, placebo-
controlled study to evaluate the efficacy and safety
 of 
intramuscular peram ivir in subj ects with uncom plicated acute 
influenza 
 
 
 
 
 
I have caref ully read th is protoco l 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 
Protocol No. 
BCX1812-311 
Protocol Title: 
A Phase 3, Multicenter, Random
ized, Double-Blind, 
Placebo-Controlled Stu dy to Evaluate the Efficacy an
d 
Safety of Intram
uscular Peram ivir in Subjects with 
Uncomplicated Acute Influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
Investigators/Study 
Sites: 
Multinational 
Development Phase: 
3 
Objectives: 
Primary: 
To evaluate the efficacy of peram
ivir adm inistered 
intramuscularly com pared to p
lacebo on th
e tim e to 
alleviation of  clinica l sym ptoms in adult sub
jects with 
uncomplicated acute influenza. 
Secondary: 
1. To evalua te the saf ety and tolera bility of  pe ramivir 
administered intramuscularly; 
2. To evaluate seconda ry clinical outcom es in response to 
treatment; 
3. To evaluate changes in in
fluenza virus titer (viral 
shedding) in response to treatment;  
4. To assess p harmacoeconomic m easures in resp onse to  
treatment  
5. To assess c hanges in inf luenza vir al suscep tibility to 
neuraminidase inhibitors following treatment  
 
Number of Subjects: 
Total enrollm ent: up t o 800 subjects random
ized (160 
subjects in the placebo treatment group, 320 subjects in the 
peramivir 150mg treatment group and 320 subjects in the 
peramivir 300m g treatm ent group). The study will close 
after enrollment of at least 500 subjects who have either a 
positive Influenza A or B antigen te st (Rapid Antigen Test 
– RAT) at  screening, or who ha
ve a negative RAT at 
screening but a positive influenza A or B PCR a ssay result 
from a baseline nasopharyngeal swab. 
 
Study Design: 
This is a multinational, random
ized, double-blind study  
comparing the efficacy  and safety  of two single dos
e 
regimens of peramivir administered intramuscularly versus 
placebo in adults with uncom
plicated acute influenza.   
Each subjec t’s ass ignment to trea tment will be stra tified 
according to the Rapid Antigen Test (RAT) result at 
screening and current sm
oking be havior, with 80% of 
subjects ce ntrally rand omized to one of
 the two activ
e 
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BioCryst Pharmaceuticals, Inc. 
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single dose regimens of peramivir (2:2:1 randomization) 
 
Treatment Group 1:  Peramivir 150mg 
Treatment Group 2:  Peramivir 300mg 
Treatment Group 3:  Placebo 
 
Enrollment of subjects into the RAT negative s tratum will 
be permitted at individual sites that have identified 3 RAT 
positive su bjects a t s creening within a  10 d ay per iod, 
indicating activity of influenza in the site ’s vicinity. After 
identification of 3 RAT positive subjects within 10 days, a 
site m ay enroll 1 RAT negative s
ubject tha t f ulfills the  
inclusion/ exclusion criteria. One additional RAT negative 
subject may be enrolled thereafter for each preceding RAT 
positive subject that is identified. 
 
Study drug will be adm inistered as one 2mL intramuscular 
injection in each glu teal muscle (total of 4m L injected in 
divided doses). 
 
Subjects eligible for s creening will have an anterior nasal 
or pharyngeal swab collected
 for t esting by RAT for
 
influenza A and B, in accordan ce with the co mmercially 
available RAT kit instructi
ons.  I f the in itial RAT is  
negative, th e te st shou ld be  repeated with a differen
t 
commercially availab le RAT kit. Subjects m
eeting the 
inclusion/ exclusion criteria may be enrolled into the study. 
 
All enrolled subjects will record the following in a Study 
Diary: 
• Oral temperature measurements taken with an electronic 
thermometer every 12 hours. W ith the exception of the 
baseline m easurement, all tem perature m easurements 
will be ob tained at least 4 hours after, or imm ediately 
before, adm
inistration of oral acetaminophen
 
(paracetamol), aspirin, ibuprofen or other NSAID. 
• Assessment of severity of each  of s even  sym ptoms of 
influenza on a 4-point scale (0, absent; 1, m
ild; 2, 
moderate; 3, severe) twice daily (AM, PM) through Day 
9 following treatm ent, then once daily (AM) through 
Day 14 
• Assessment of  subjec t’s ability  to p
erform usual 
activities, (rated as 0–10 on a visual analog scale) once 
daily through Day 14 
• Assessment of subject’s tim e lost from  work or usual 
activities and productivity compared to normal (rated as 
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0-10 on a visual analog scal e) once daily through Day 
14 
• Doses of antipyretic, expe
ctorant, and/ or t hroat 
lozenges taken for symptomatic relief each day through 
Day 14 
 
Anterior nose (bilateral) and posterior pharynx specim ens 
(swabs) will be collected at Day 1 (pre-treatm
ent) and at 
Days 3, 5, and 9, for quantitative virologic assessments.  In 
a subset of  a m inimum of 200 subjects, an additional 
virology sample will b e co llected on day 2. Specim
ens 
from all subjects yielding influenza virus will also be 
assessed for susceptibility to neuraminidase inhibitors (Day 
1 and last specimen yielding positive result). 
 
All virolog ic ass essments will b e p erformed by a c entral 
laboratory.  
 
At the study day 3 visit, when all subjects are evaluated for 
safety and a blood draw is com
pleted for clinical 
laboratory investigations, a single pharm
acokinetic (PK) 
sample will also be  drawn. This sin gle PK sam ple will b e 
analyzed for plasm a concentrations of peram ivir (ng/mL) 
and evaluated in an exposure response analysis. 
 
At selected sites a separate sub-s tudy will be conducted to 
collect limited PK sam ples for the purpose of conducting 
an exposure-respons e analysis.  T
his sub-stud y will be 
conducted under a separate protocol, BCX1812-311PK. 
 
Study Population:   
Male and fem ale subjects, 18 y ears of age and older, with 
symptoms consisten t with a diagnosis of uncomplicated 
acute influenza infectio n may be screened for e nrollment.  
Subject eligibility will be dependent on the presence of two 
or more symptoms consistent with acute inf luenza as well 
as the results obtained f rom a rapid antigen test (RAT) for 
influenza A and B at screening. 
 
Inclusion Criteria: 
1. Male and non-pregnant female subjects age ≥18 years 
2. A positive Influenza A or B Rapid Antigen Test (RAT) 
performed with a commercially available test kit on an 
adequate specimen collected from an anterior nasal or 
pharyngeal swab, in accordance with the 
manufacturer’s instructions.  A negative initial RAT 
should be repeated with a different commercially 
available RAT kit. A limited number of RAT negative 
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subjects may be enrolled in accordance with a defined 
screening algorithm. 
3. Presence of fever at time of screening of ≥38.0 ºC 
(≥100.4 ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken 
rectally. For subjects with a positive RAT at the time of 
screening, a subject self-report of a history of fever or 
feverishness within the 24 hours prior to screening will 
also qualify for enrollment in the absence of 
documented fever at time of screening.  For subjects 
with no positive RAT  at screening, fever as defined  
above must be documented at time of screening 
4. Presence of at least one respiratory symptom (cough, 
sore throat, or nasal symptoms) of any severity (mild, 
moderate, or severe) 
5. Presence of at least one constitutional symptom 
(myalgia [muscle aches], headache, feverishness, or 
fatigue) of any severity (mild, moderate, or severe) 
6. Onset of symptoms no more than 48 hours before 
presentation for screening 
7. Written informed consent 
 
Exclusion Criteria: 
1. Women who are pregnant or breast-feeding 
2. Presence of clinically significant signs of acute 
respiratory distress 
3. History of severe  chronic obstructive pulmonary 
disease (COPD) or  severe persistent asthma 
4. History of congestive heart failure requiring daily 
pharmacotherapy with symptoms consistent with New 
York Heart Association Class IV functional status 
within the past 12 months 
5. Screening ECG which suggests acute ischemia or 
presence of medically significant dysrhythmia. 
6. History of chronic renal impairment requiring 
hemodialysis and/or known or suspected to have 
moderate or severe renal impairment (actual or 
estimated creatinine clearance <50 mL/min) 
7. Current clinical evidence of active bacterial infection at 
any body site that requires therapy with oral or 
systemic antibiotics 
8. Presence of immunocompromised status due to chronic 
illness, previous organ transplant, or use of 
immunosuppressive medical therapy 
9. Current treatment for active viral hepatitis C 
10. Presence of known HIV infection  with a CD4 count 
<350 cell/mm3 
11. Current therapy with oral warfarin or other systemic 
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anticoagulant 
12. Receipt of any doses of  rimantadine, amantadine, 
zanamivir, or oseltamivir in the 7 days prior to 
screening 
13. Immunized against influenza with live attenuated virus 
vaccine (FluMist®) in the previous 21 days 
14. History of alcohol abuse or drug addiction within 1 
year prior to admission in the study 
15. Participation in a previous study of peramivir as 
treatment for acute influenza or previous participation 
in this study 
16. Participation in a study of any investigational drug 
within the last 30 days 
 
Study Endpoints: 
Primary Endpoint: 
Clinical: 
Time to alleviation of clinical symptoms of influenza 
Secondary 
Endpoint(s): 
Safety 
Incidence of treatm
ent-emergent adverse events and
 
treatment-emergent changes in  clinical laboratory tests 
 
Clinical: 
Time to resum ption of subjec t’s ab ility to perf orm usual 
activities 
Time to resolution of fever 
Incidence of influenza related complications 
 
Virologic: 
Quantitative change in influenza virus shedding, measured 
by viral titer assay (TCID
50) and/or by quantitative 
polymerase chain reaction (PCR) assay  
 
Pharmacoeconomic: 
Medical resource utilization (M RU), missed days of work, 
and im pact of inf
luenza illn ess on subject’s work 
performance and/or productivity. 
 
Exploratory 
Endpoint: 
Viral Susceptibility: 
Change in influenza virus susceptibility to neu raminidase 
inhibitors 
 
Investigational Product, 
Dose, and Mode of 
Administration:   
Peramivir (BCX-1812), 75m g/mL or placebo (buffered 
diluent), 2mL per injection, ad ministered intramuscularly 
in the gluteal muscle, bilaterally. 
 
Duration of Treatment: 
Following treatment on day 1, study duration for individual 
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subjects is expected to  be  up to 14 days (including all 
visits). 
 
Statistical Methods: 
Descriptive statistical methods  will be used to summ arize 
the data from this study, with statistical testing utilized for 
the p rimary and secondary efficacy endpoints. Unless 
otherwise n oted, a ll s tatistical testing will be  two-sided, 
and will be performed using a significance (alpha) level of 
0.05. For assessment of the prim ary efficacy endpoint, th e 
overall sig nificance level 
will be m
aintained by a 
Bonferroni adjustm ent fo r the planned com
parisons 
between the two active trea
tment groups and placebo. 
 
Detailed sta tistical pro cedures will be provided  in a f ull 
statistical analysis plan (SAP) completed prior to database 
lock and study unblinding. 
 
Sample Size: 
From previous studies of neuram
inidase treatm ent of 
uncomplicated influenza it is expected that the median time 
to alleviation of symptoms will be 103.3 hours for subjects 
receiving placebo.  Addition ally, it is expected that the 
median time to alleviation for the low dose peram ivir arm 
will be 69.9  hours, yielding a hazard ratio of 0. 68.  Using 
these assumptions, a sample si ze of 200 influenza-infected 
subjects per active treatm
ent group and 100 infected 
subjects in the placebo  group (a total of 500 influenza-
infected su bjects) is s ufficient to  provide at least 80% 
power to detect a hazard ratio of 0.68 using a log-rank 
statistic and  α = 0.025 (SAS version 9.1.3; total accrual 
time 7 months; total enrollment time 6 months).  Up to 800 
subjects will be enrolled to ach ieve the target number of at 
least 500 subjects with  diagnostic evidence (R AT or PCR) 
of an acute influenza infection. 
 
Efficacy:  
The intent-to-treat infected  population will include all 
subjects who are random ized, received study drug, and 
have proven influenza by any one of the following: 
primary viral culture, PCR, or  paired serology showing ≥ 
4-fold increase in antibody to
 influenza A or B.  The 
primary efficacy v ariable is th e tim e to alleviation of 
symptoms, defined as the time from injection of study drug 
to the start of the tim
e period when each
 of seven
 
symptoms of influenza are either absent or are present at 
no more than mild severity level and remain at no worse 
than this severity status for a 24 hour period. 
 
Descriptive statistics for the primary efficacy variable will 
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be tabulated by treatm ent group.  Alleviation of sym ptoms 
will be determined by assessment of symptoms as reported 
on each su bject’s diary card.  Tim
e to alle viation of 
symptoms will b e sum marized for each  treatm ent group.  
Treatment dif ference will be
 as sessed us ing a Cox 
Regression model with effects for RAT result at screening, 
current smoking behavior, tr eatment group, and influenza 
season at random ization.  Pa irwise com parisons between  
each active group and placebo will be constructed from the 
Cox Regression m odel.  Subj ects who do not experience 
alleviation of  sym ptoms will be c ensored a t the date of  
their last non-m issing assessment.  Tim e to resum ption of 
usual activities and tim
e to resolution of
 f ever will be  
analyzed in a similar manner.   
 
Changes in viral titer s will be compared using the van 
Elteren sta tistic con trolling f or RAT result at screen
ing, 
current smoking behavior 
and influenza season at 
randomization.  Analyses of other continuous endpoints 
will be analyzed in a similar manner. 
 
Safety: 
Safety analyses will b e presen ted f or all sub jects in the  
safety population, defined as all randomized subjects who 
receive at least one dose of study drug.  Adverse events 
will be m apped to a Medica l Dictiona ry f or Regulatory 
Activities (MedDRA) preferred term
 and system  organ 
classification.   
The occurrence of treatm
ent-emergent AEs will be 
summarized using preferre
d term
s, system organ 
classifications, and severit
y.  Separate summ
aries of 
treatment-emergent SAEs and treatm
ent-emergent AEs  
that are related to study m edication will be generated.  All 
AEs will be listed f
or individua l subjec ts sho wing both 
verbatim and preferred terms.   
 
Descriptive summaries of vital signs and quantitative 
clinical laboratory changes will be presented by study visit.  
Frequency and percentages 
of subjects with abnorm
al 
laboratory test r esults will be su mmarized b y toxic ity 
grade.   
 
Concomitant m edications w ill be m
apped to a W
HO 
preferred term and drug classification.  The num
ber and 
percent of subjects taking concomitant medications will be 
summarized using preferred terms and drug classifications.  
The num ber and percent of subjects experiencing each 
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abnormal physical examination finding will be presented.  
 
The number and percent of s ubjects discontinuing study as 
well as the reasons for discontinuation will be summarized 
by treatment group.   
 
Protocol Date 
Version 1.0: 04 September 2007 
 
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3 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.................................................................................. 13 
3.1 
LIST OF FIGURES................................................................................................ 15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................... 16 
5 
INTRODUCTION ............................................................................................ 18 
5.1 
BACKGROUND.................................................................................................... 18 
5.2 
RATIONALE FOR STUDY..................................................................................... 18 
5.3 
NON-CLINICAL EXPERIENCE WITH PERAMIVIR.................................................. 19 
5.3.1 In vitro Assays .............................................................................................. 19 
5.3.2 Animal Models.............................................................................................. 20 
5.4 
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR.................. 20 
5.5 
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR................ 21 
5.6 DOSE RATIONALE .................................................................................................... 22 
6 
STUDY OBJECTIVES..................................................................................... 23 
6.1 
OBJECTIVES ....................................................................................................... 23 
6.1.1 Primary Objective......................................................................................... 23 
6.1.2 Secondary Objective(s)................................................................................. 23 
6.2 
STUDY ENDPOINTS............................................................................................. 23 
6.2.1 Primary Endpoint.......................................................................................... 23 
6.2.2 Secondary Endpoint(s).................................................................................. 23 
6.2.3 Exploratory Endpoint.................................................................................... 23 
7 
STUDY DESIGN ............................................................................................. 24 
7.1 
OVERALL STUDY DESIGN AND PLAN ................................................................. 24 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS.................................... 25 
8.1.1 Inclusion Criteria .......................................................................................... 25 
8.1.2 Exclusion Criteria ......................................................................................... 26 
8.1.3 Removal of Subjects from Therapy or Assessment...................................... 27 
9 
TREATMENTS................................................................................................ 28 
9.1 
TREATMENTS ADMINISTERED............................................................................ 28 
9.2 
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .................................................... 28 
9.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................. 28 
9.4 
STUDY MEDICATION ACCOUNTABILITY............................................................. 29 
9.5 
BLINDING/UNBLINDING OF TREATMENTS.......................................................... 29 
9.6 
PRIOR AND CONCOMITANT THERAPIES.............................................................. 29 
9.7 
OVERDOSE AND TOXICITY MANAGEMENT......................................................... 29 
9.8 
DOSE INTERRUPTION.......................................................................................... 29 
10 
STUDY CONDUCT......................................................................................... 30 
10.1 
EVALUATIONS.................................................................................................... 30 
10.1.1 
Medical History ........................................................................................ 30 
10.1.2 
Rapid Antigen Test for Influenza ............................................................. 30 
10.1.3 
Physical Examination and Influenza-related Complications Assessments30 
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10.1.4 
Vital Signs................................................................................................. 31 
10.1.5 
Electrocardiogram Measurements ............................................................ 31 
10.1.6 
Clinical Chemistry Profiles....................................................................... 31 
10.1.7 
Hematology Profiles ................................................................................. 31 
10.1.8 
Serology for Influenza .............................................................................. 31 
10.1.9 
Urinalysis and Evaluation of Protein in Urine.......................................... 31 
10.1.10 Urine Pregnancy Test................................................................................ 32 
10.1.11 Samples for Virologic Laboratory Assessments....................................... 32 
10.1.12 Subject Self Assessments.......................................................................... 32 
10.1.13 Concomitant Medications......................................................................... 33 
10.1.14 Adverse Events ......................................................................................... 33 
10.1.15 Single Pharmacokinetic Exposure Sample ............................................... 33 
10.2 
SCREENING ........................................................................................................ 33 
10.2.1 
Informed Consent...................................................................................... 33 
10.2.2 
Screening/Baseline Evaluation and Enrollment........................................ 33 
10.3 
TREATMENT PERIOD—STUDY DAY 1................................................................ 34 
10.3.1 
Pre-dose Evaluations................................................................................. 34 
10.4 
POST-TREATMENT ASSESSMENT PERIOD........................................................... 34 
10.4.1 
Days 2, 3, 5, 9 and 14................................................................................ 34 
10.4.2 
Adverse Events Reported at Post-treatment Visits................................... 35 
11 
ADVERSE EVENT MANAGEMENT............................................................ 38 
11.1 
DEFINITIONS ...................................................................................................... 38 
11.1.1 
Adverse Event........................................................................................... 38 
11.1.2 
Serious Adverse Event.............................................................................. 38 
11.2 
METHOD, FREQUENCY, AND TIME PERIOD F OR DETECTING ADVERSE EVENTS 
AND REPORTING SERIOUS ADVERSE EVENTS..................................................... 39 
11.2.1 
Definition of Severity ............................................................................... 39 
11.2.2 
Definition of Relationship to Study Drug................................................. 39 
11.2.3 
Reporting Serious Adverse Events ........................................................... 40 
11.2.4 
Emergency Procedures.............................................................................. 41 
12 
STATISTICAL METHODS............................................................................. 41 
12.1 
DATA COLLECTION METHODS........................................................................... 41 
12.2 
STATISTICAL ANALYSIS PLAN ........................................................................... 42 
12.3 
SAMPLE SIZE ESTIMATES................................................................................... 42 
12.4 
ANALYSIS POPULATIONS ................................................................................... 42 
12.4.1 
Intent-To-Treat Population ....................................................................... 42 
12.4.2 
Intent-To-Treat Infected Population ......................................................... 42 
12.4.3 
Safety Population...................................................................................... 43 
12.5 
INTERIM AND END OF STUDY ANALYSES........................................................... 43 
12.6 
EFFICACY ANALYSES......................................................................................... 43 
12.6.1 
Primary Efficacy Endpoint ....................................................................... 43 
12.6.2 
Secondary Efficacy Endpoints.................................................................. 44 
12.6.3 
Exploratory Endpoint................................................................................ 45 
12.7 
SAFETY ANALYSES ............................................................................................ 45 
12.8 
SUB-STUDY AND PHARMACOKINETIC ANALYSIS............................................... 46 
12.9 
GENERAL ISSUES FOR STATISTICAL ANALYSIS .................................................. 46 
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12.9.1 
Multiple Comparisons and Multiplicity.................................................... 46 
12.9.2 
Covariates ................................................................................................. 46 
12.9.3 
Planned Sub-Groups ................................................................................. 46 
12.9.4 
Missing Data............................................................................................. 46 
13 
STUDY ADMINISTRATION ......................................................................... 47 
13.1 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................. 47 
13.1.1 
Regulatory Authority Approvals............................................................... 47 
13.1.2 
Ethics Committee Approvals.................................................................... 47 
13.1.3 
Subject Informed Consent......................................................................... 47 
13.1.4 
Payment to Subjects.................................................................................. 48 
13.1.5 
Investigator Reporting Requirements ....................................................... 48 
13.2 
STUDY MONITORING.......................................................................................... 48 
13.3 
QUALITY ASSURANCE........................................................................................ 48 
13.4 
STUDY TERMINATION AND SITE CLOSURE......................................................... 49 
13.5 
RECORDS RETENTION ........................................................................................ 49 
13.6 
STUDY ORGANIZATION...................................................................................... 49 
13.6.1 
Data Monitoring Committee..................................................................... 49 
13.7 
CONFIDENTIALITY OF INFORMATION ................................................................. 49 
13.8 
STUDY PUBLICATION ......................................................................................... 50 
14 
REFERENCES ................................................................................................. 51 
15 
APPENDICES .................................................................................................. 53 
15.1 
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA
.......................................................................................................................... 53 
 
3.1 
 List of Figures 
Figure 1 
Study Measurements and Visit Schedule...................................................... 37 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE  
adverse event 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the curve 
AUC0–72 
area under the curve from time 0 to 72 hours 
AUC0–∞ 
area under the curve extrapolated from time 0 to infinity 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
Cmax  
maximum plasma concentration 
CK 
creatine kinase 
CNS  
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
GCP  
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IC50  
median inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
influenza related complications  
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IUD 
intrauterine device 
IVRS 
interactive voice response system 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
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RAT 
Rapid Antigen Test 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2  
elimination half-life 
t1/2 λz 
terminal half-life 
TCID50 
time weighted change
 f rom baseline in log
10 tissue -culture 
infective dose50 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to attain maximum plasma concentration 
UPEP 
urine protein electrophoresis 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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5 INTRODUCTION 
5.1 
Background 
Influenza v irus is a m ember of the orthomyxovirus fam ily and cau ses an acu te v iral 
disease of the respiratory tract.  Typical influenza illness is characterized by abrupt onset 
of fever, headache, myalgia, sore throat, and nonproductive cough.1  The illness is usually 
self-limiting, with relief of symptoms occurring within 5 to 7 days.  Nevertheless, it is an 
important disease for several reasons, 
including ease of comm
unicability, short 
incubation time, rapid rate of viral mutation, morbidity with resultant loss of productivity, 
risk of com plicating conditions, and increased risk of death, pa rticularly in the e lderly.  
During 19 of the 23 influenza seasons
 between 1972/1973 a nd 1994/1995, estim ated 
influenza-associated deaths in the U nited States ranged from approxim ately 25 to m ore 
than 150 per 100,000 persons above 65 years of age, accounting for more than 90% of the 
deaths attributed to pneumonia and influenza.2 
Presently, o nly a few m easures are availab le that can red uce th e im pact of influenza: 
active immunoprophylaxis with an inactivat
ed or live attenu
ated vaccine and 
chemoprophylaxis or therapy with an influe nza-specific antiviral drug.  Neuram inidase 
inhibitors are the current m
ainstay of an tiviral treatm ent for influenza. Mark
eted 
neuraminidase inhib itors inc lude zanam ivir (Relenza ®, GlaxoSm ithKline) an d 
oseltamivir (Tamiflu®, Roche-Gilead) , an oral prodrug of the activ e agent, oseltamivir 
carboxylate.  Influenza neuram inidase is a surface glycoprotei n that cleaves sialic acid 
residues from glycoproteins and glycolipids.  The enzyme is responsible for the release of 
new viral p articles from infected cells and 
may also ass ist in the sp reading of virus  
through the mucus within the respiratory tract.  The neuraminidase inhibitors represent an 
important advance in the treatment of influenza with respect to activity against influenza 
A and B viruses, with p roven therapeutic value in reduc ing influenza lower resp iratory 
complications,3 and lower rates of antiviral drug resistance4. 
The use of curren tly av ailable neu raminidase inhibitors has been  lim ited by concerns  
including, the degree of effectiv eness, the requirement for an inhaler device (zanamivir), 
and the em ergence of resistant influenza vi rus variants in som e treated populations. 5 In 
addition, there are risks of bronchospasm
 w ith zanam ivir; and gastrointestinal side 
effects, with oseltamivir. 
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to 
the armamentarium of drugs for the treatment of influenza infections due to its potential 
for parenteral administration and lower frequency of dosing. 
5.2 
Rationale for Study 
An oral formulation of peram ivir has previously been evaluated in a f ull range of safety, 
tolerability, pharmacokinetic, and efficacy studies.  In  a m ultinational phase 3  clinical 
trial conducted in 1999-2001, oral peram
ivir de monstrated antiviral activity against 
influenza A  and B inf
ections, and  im provement in the r
elief of  clin ical sym ptoms.  
Because of the lim ited bioavailability of peramivir following oral administration (<5%), 
it was de termined that the paren teral route of  administration is m ore appropriate for the 
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delivery of peram ivir.  Subsequent phase 
1 studies of intrave nous and intram uscular 
formulations of peram ivir have confirm ed that parenteral routes of  administration result 
in plasma levels of drug that are as much as 100 times those achieved via the oral route. 
Further details of these studies are provided below and in the Investigator Brochure. 
A phase 2 random
ized, double blind, placeb
o controlled study of two single dose
 
regimens (150mg or 300m g) of intram uscular peramivir in subjects with uncom plicated 
acute influenza infections (study B CX1812-211) was initiated in early 2007 in North 
America and the UK. The study has been extended to sites in Hong Kong, Australia, New 
Zealand and South Africa and is expected 
to complete enrollment in m id-2007.  At a 
scheduled meeting on 21  May 2007, an independ ent data monitoring committee for this 
study com pleted a blinded revi ew of all reported adverse 
events and grade 3 and 4 
clinical laboratory evaluations from the first 135 subjects random ized.  Following this 
blinded saf ety review the DMC provided 
a written reco mmendation that the s
tudy 
continue as planned. 
Because of the previo
us dem onstration of significant an tiviral activ ity, th e strong 
suggestion of clinical efficacy of oral pe
ramivir previously dem onstrated in  acute 
influenza, and the encouraging pharm
acokinetic and prelim inary safety profile of the 
intramuscular formulation of pera mivir demonstrated to date, this phas e 3 study will be 
conducted to evaluate the efficacy and safety profile of intram
uscular peramivir and to  
determine the optimal single dose regimen.  
5.3 
Non-Clinical Experience with Peramivir 
5.3.1 In vitro Assays 
Peramivir is a selective inhibitor of vi
ral neuram inidase, with 50% inhibitory 
concentrations (IC50) for bacterial and m ammalian enzymes of >300µM. 6 In an in vitro 
study, 42 influenza A and 23 influenza B isolates  were collected from untreated subjects 
during the 1999–2000 influenza season in Canada.
7 These isolates were tested for their 
susceptibility to the neuram inidase inhib itors zanam ivir, oseltam ivir carboxylate, and 
peramivir using a chem
iluminescent neuram inidase assay.  Inhibition of Type A 
influenza neuraminidase by peram ivir was appr oximately an order of m agnitude greater 
than inhibition of neuram inidase from  Type B viruses.  IC
50 values for the Type A 
enzymes ranged from <0.1 to 1.4nM, whereas the Type B enzym es ranged from <0.1 to 
11nM, with three out of four values in the 
5- to 11nM range.  Peram ivir was the most 
potent drug against influenza A (H 3N2) viruses with a m ean IC50 of 0.60nM as well as 
most potent  against influenza B with a mean IC50 of 0.87nM.   
In another in vitro  comparison of peram
ivir, oseltam ivir, and zanam ivir, using a 
neuraminidase inhibition assay with influenza A viruses, the m
edian IC 50 of pera mivir 
(approximately 0.34nM) was com
parable to that of
 oseltam ivir (0.45nM) and 
significantly lower than zanam ivir (0.95nM).  F or influenza B virus clinical isolates, the 
IC50 of peramivir (1.36nM) was comparable to that of zanamivir (2.7nM) and lower  than 
that of oseltamivir (8.5nM).8   
The potency of peram
ivir was evaluated ag
ainst five zanam ivir-resistant an d six 
oseltamivir-resistant influenza viruses.9  Peramivir remained a potent inhibitor against all 
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oseltamivir-resistant viruses includi ng the m utations H274Y, R292K, E119V, and 
D198N, with IC 50 values ≤40nM.  Peram ivir also potently inhibited (IC 50 ≤ 26nM) the 
neuraminidase activity of zanamivir-resistant strains, which had the following mutations:  
R292K, E119G, E119A, and E119D.  Howeve
r, one zanam ivir-resistant influenza B 
virus, B/Mem /96, with a m utation R152K isol ated from  cell cultur e, was relatively 
resistant to all neuraminidase inhibitors, including peramivir (IC50 = 400nM). 
5.3.2 Animal Models 
In a m ouse model of influen za infection, a single intram uscular injection of pera mivir 
(10mg/kg) given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain 
resulted in 100% survival in contrast to 100% mortality in a control group injected with 
saline.6 In the sam e mouse m odel, treatm ent of m ice up to 72 hours after influenza
 
infection using peram ivir (20m g/kg) result ed in 100% survival, compared to 100%
 
mortality in the control group injected with vehicle.10 
Peramivir has also dem onstrated activity in animal models utilizing a  clinical H5 N1 
isolate as th e infecting virus strain.   In a mouse model, a single intramuscular dose of 
peramivir (30mg/kg) injected 1 hour after inoculation with the highly pathogenic (H5N1) 
A/Vietnam/1203/04 strain, resulted in a 70% survival rate that wa s similar to that seen in 
mice treated with oseltam ivir given orally at 10m g/kg/day for 5 days
11.  In s imilar 
experiments, mice inoculated with the sam e strain of H5N1 virus tha t were then trea ted 
for up to 8 days with intram
uscular peramivir exhibited 100% survival 12.  This longer 
duration of peram ivir treatment also prevented viral replic ation in the lungs, brain and 
spleen at days 3, 6 and 9 post inoculation. 
5.4 
Previous Phase 3 Clinical Experience with Oral Peramivir 
An oral formulation of peram
ivir has prev iously dem onstrated an tiviral activity and 
preliminary clinical efficacy in ch
allenge studies in hum an volunteers, as well as in 
treatment studies in patients  with u ncomplicated acute  inf luenza inf ections dur ing the 
influenza seasons of 1999-2001.  A Phase 3 
multinational study (B C-01-03) of oral 
peramivir was conducted.  Two dos e regimens of oral peramivir, 800mg QD for 5 days, 
or 800mg QD on Day 1, followed by 400mg QD for 4 days, were compared to a matched 
placebo treatment group.  A total of 1246 subjects  were randomized to treatment at sites 
in the USA, W estern and Eastern Europe, S outh America, Australia and New Zealand.  
As presente d in the  tab le below, th e prim ary end-point of tim e to relief of influenza  
symptoms was not found to be significantly
 different (p=0.17) between the three 
treatment groups.13  A sub-group analysis of the time to relief of symptoms by country or 
region demonstrated marked differences in
 the prim ary endpoint.. In the subset of 
influenza-infected subjects enrolled at  sites in the US, clinically m eaningful differences  
in time to relief of influenza symptoms between the placebo and the two peram ivir arms 
were observed, that just m issed statistical significance (p=0.07).  However, a num ber of 
secondary end-points in this phase 3 study, such as tim e to overall well-being, time to 
normal activity, incidence of infl
uenza rela ted com plications and quantity of viral 
shedding, reached o
r approach ed statistically significant differenced between
 the 
peramivir and placebo treatment groups (p=0.03-0.06). 
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Results of Study BC-01-03 
 
Median Time to Relief of Influenza Symptoms (Hours) 
Dose and Regimen 
Overall Results  (n=1246) 
US Sites (n=206) 
Peramivir 800mg po x 5d 
89.0 
70.8 
Peramivir 800mg po x 1d 
 and          400mg po x 4d 
91.7 
88.8 
Placebo x 5 days 
104.4 
106.8 
p value 
0.17 
0.07 
 
5.5 
Previous Phase 1 Experience with Intramuscular Peramivir 
Two phase one studies evaluating the safety 
and pharmacokinetics of an intram uscular 
formulation of pera mivir have been conduc
ted in a total of 45 he
althy volunteers 
receiving peramivir.  
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability 
of 75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and 
intravenous (i.v.) injections in  a crossover design (9 subjects per group). Peak plasma
 
levels of i.m. pera
mivir generally occurre d within 30 m
inutes fol lowing injection.  
Plasma pharm acokinetic param eters for i.m . peram ivir are summarized  below for the 
three intramuscular single dose regimens evaluated: 
Dose (mg) 
Cmax (ng/mL) 
AUC0-∞ (hr·ng/mL) 
t½a (hr) 
75 i.m. 
4296±812 
11659±1123 
19.8±7.9 
150 i.m. 
7612±884 
23952±3804 
24.3±4.1 
300 i.m. 
15150±2367 
49649±5619 
22.8±2.5 
aterminal half life 
 
In a second phase 1 study, Peram
ivir-Him-06-112, the sam e dose levels of peram ivir 
were adm inistered as single i.m . injections on two consecutive days (6 subjects per 
group). This double-b lind study also includ
ed a placebo  arm . The pharm acokinetic 
parameters of i.m . peramivir following the second day of dosing were consistent with 
those seen following single doses of the drug. 
The observ ations of s afety and  to lerability of i. m. peram ivir in  each  of the 2  phas e 1 
studies were unrem arkable.  No serious ad
verse even ts were repo rted.  The most
 
commonly observed ad verse events or laborato ry abnormalities were h eadache, several 
reports of signs and symptom s of vasovagal reactions following injections, and transient 
increases in creatine kinase.  No consisten t differences in frequency of adverse events 
were observed between the ac tive and placebo treatm ent groups, with the exception that 
CK elevations appeared to be dose rela
ted in the peram ivir treatment groups.  T he 
vasovagal reactions were attri buted to the receipt of rela
tively large volum es of i.m. 
injection (2 injections each of 2mL) in the fasted state. 
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An ongoing phase 2 study, BCX1812-211, is 
a random ized, double-blind placebo- 
controlled study to  evaluate the efficacy and
 safety of two single d
ose reg imens of 
peramivir. Up to 100 subjects per arm  will receive either 150mg or 300mg of peramivir 
or placebo. The prim ary endpoint of the stu
dy is the tim e to alleviation of clinical 
symptoms in adult subjects with u ncomplicated acute influenza.  An independent dat
a 
monitoring comm ittee reviewed grouped blinde d safety data on the first 135 subjects 
randomized.  The study rem ains blinded. The fr equency of vasovagal reactions reported 
as adverse events in this ongoing study is 2/135 (to date) which is lower than that seen in 
the phase 1 volunteer studies. 
5.6 Dose Rationale 
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 
75mg twice daily in adults14.  Oseltamivir was shown to be clinically effective in a Phase 
III study of oral oseltamivir versus placebo in naturally occurring seasonal influenza, and 
these data were sufficient for regulatory approval for marketing of oseltamivir.  At least 
75% of an  oral dose of oseltam
ivir reaches  the sy stemic circu lation as oseltam ivir 
carboxylate. When oseltamivir is adm inistered orally at a dose of 75mg twice daily, the 
serum C max of oseltam ivir carboxylate is approxim ately 348ng/m L and the AUC 0-48 is 
10,876 h·ng/mL. The clinical data indicate that this level of exposure to oseltamivir was 
sufficient to provide clinical improvement in uncomplicated acute influenza.  
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular 
doses of peram ivir are approxim ately 7600ng/mL and 24,000 h·ng/m L for the 150m g 
dose and are approxim ately 15,000ng/m L and 49,000 h·ng/m L for the 300m g dose.  
Previous s tudies hav e assess ed the concen
trations of the neuram
inidase inhibitor 
zanamivir in nasal and pharyngeal secretions after parenteral administration of this drug. .  
Within several hours after ad
ministration, the concentrati
ons in secretions wer
e 
approximately 100-fold lower than in serum or plasma.  In theory, relatively high levels 
of a neuram inidase inh ibitor in  res piratory se cretions ar e desi rable in order to rapidly 
inactivate influenza virus and to delay or 
prevent th e d evelopment of resistan ce in  
infecting virus strains.  Intramuscular doses of peramivir, including doses of 150m g and 
300mg have been shown to be well tolerate
d in previous P hase 1 studies and since no 
identified safety signal has been noted by an  independent data monitoring committee in 
the ongoing Phase 2 study, it is appropriate
 for these two dose regim
ens to undergo 
further evaluation in this Phase 3 study.  
 
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6 STUDY OBJECTIVES 
6.1 
Objectives 
6.1.1 Primary Objective 
The primary objective of this study is to eval uate the efficacy of peram ivir administered 
intramuscularly compared to placebo on th e time to alleviation of  clinical symptoms in 
adult subjects with uncomplicated influenza. 
6.1.2 Secondary Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of peramivir administered intramuscularly; 
2. To evaluate secondary clinical outcomes in response to treatment; 
3. To evaluate changes in
 influenza virus 
titer ( viral sheddi ng) in response to 
treatment; 
4. To assess pharmacoeconomic measures in response to treatment; 
5. To assess changes in influenza viral su
sceptibility to neu raminidase inhibito rs 
following treatment; 
6.2 
Study Endpoints 
6.2.1 Primary Endpoint 
Time to alleviation of clinical symptoms of influenza 
6.2.2 Secondary Endpoint(s) 
Secondary efficacy endpoints will include evaluations in each subject of: 
1. Safety parameters, including: treatment- emergent adverse events (TEAEs) 
and treatment-emergent changes in clinical laboratory tests; 
2. Time to resolution of fever; 
3. Time to resumption of subject’s ability to perform usual activities; 
4. Incidence of influenza related complications 
5. Quantitative change in influenza virus shedding measured by viral titer 
assay (TCID50) and/or by quantitative polymerase chain reaction (PCR) 
assay; 
6. Medical resource utilization (MRU), missed days of work, and impact of 
influenza illness on subject’s work performance and/or productivity. 
6.2.3 Exploratory Endpoint 
An exploratory endpoint will evaluate change in influenza virus susceptibility to 
neuraminidase inhibitors in viral isolates recovered from subjects pre and post treatment. 
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7 STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multinational, random
ized, double-blind study  com paring the efficacy and 
safety of two single dose regim
ens of pera mivir adm inistered intramuscularly versus 
placebo in adults with uncom
plicated acute influenza.  Up
 to 800 subjects will be
 
enrolled in to the s tudy. Each su bject’s as signment to trea tment will be str
atified 
according to a Rapid Antigen Test (RAT) result and current smoking behavior, with 80% 
of subjects centrally random ized via an Inte ractive Voice Response (IVR) system  to one 
of the two active single dose regimens of peramivir (2:2:1 randomization): 
 
Treatment Group 1:  Peramivir 150mg 
maximum n=320 
Treatment Group 2:  Peramivir 300mg 
maximum n=320 
Treatment Group 3:  Placebo 
 
maximum n=160 
 
Previous studies evalu ating the efficacy of 
neuraminidase inh ibitors enro lled su bjects 
with inf luenza-like illness on the basis of presence of 
specific clinical signs and 
symptoms. These studies were conducted before
 the widespread availability of rapid 
influenza antigen diagnostic test kits (Rapid Antigen Tests-RAT), and typically between 
50-70% of subjects enrolled we re subsequently confirm ed by viral cu lture to  hav e an 
active influ enza infection. The sen sitivity of  comm ercially available RAT kits ranges  
from 62% to 83%, depending 
upon the virus sub-type.
15 In the phase 2 study of 
intramuscular peram ivir (study BCX1812-211) a positive RAT test was required for
 
study entry. It is likely that
 a number of subjects with 
an influenza infection were 
excluded from this study due the sensitivity of this assay. 
 
In this ph ase 3 study a lim ited number of RA T negativ e subjects will be en rolled in 
accordance with the following al gorithm to minimize false negative test results: once an 
individual site has identified 3 RAT positive subjects at screening within a 10 day period, 
indicating influenza activity is present in the site’s vicinity, a RAT negative subject that 
meets the inclusion / ex clusion criteria m ay be enrolled. O ne additional RAT negative 
subject m ay be enro lled there after for each p
receding RAT positive  subjec t th at is  
identified. The RAT result for each subjec
t screen ed will be reco rded on the s tudy 
Interactive Voice Response System (IVRS) to manage this enrollment algorithm.  
 
A baseline nasopharyngeal swab specimen will be sent to the central virology laboratory 
for each RAT negative subject that has been randomized into the study.  These specimens 
will be tested for influenza A and B infection using a PCR assay. The PCR results for 
these specimens will be reported to BioCryst in real time.  The study will close after 
enrollment of at least 500 subjects who have either a positive Influenza A or B RAT at 
screening, or who have a negative RAT at screening but a positive influenza A or B PCR 
assay result from a baseline nasopharyngeal swab. 
 
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Study drug will b e ad ministered as one 2m L intramuscular injection  in each g luteal 
muscle (total of 4mL injected in divided doses). 
At screening, subjects will have an anterior nasal or pharyngeal swab collected for testing 
with a comm ercially available RAT kit for influenza A and B in accordance with the 
RAT manufacturer’s instructions.  If  this test is positive and the subject is enrolled, 
additional s pecimens will be obta ined f or isolation and c ulture of  inf luenza viru s and 
quantitative PCR assay.  If the initial RAT is negative, th e test should be repeated with a  
different commercially available RAT kit. A limited number of RA T negative subjects 
may be enrolled in accordance with the screening algorithm defined above. 
Enrolled subjects will record the following in a Study Diary: 
• 
Oral tem perature m easurements tak en w ith an electronic therm ometer every 12  
hours. W ith the exception of the baseline m
easurement, all tem
perature 
measurements will be obtained
 at leas t 4 hours after, or imm
ediately before, 
administration of oral acetaminophen (paracetamol- provided), aspirin, ibuprofen or 
other NSAID. 
• 
Assessment of seven symptom s of influenza on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, se vere), twice daily (A M, PM) through Day 9, then once 
daily (AM) through Day 14 
• 
Assessment of subject’s ability to perform usual activities, (0–10 on a visual analog 
scale) once daily through Day 14 
• 
Assessment of a subject’s tim e lost from  work or usual activities and productivity 
compared to normal (0-10 on a visual analogue scale) once daily through Day 14 
• 
Doses of antipyretic (e. g. acetaminophen/ paracetamol), expectorant, and/or throat 
lozenges administered each day through Day 14. 
 
Anterior nose (bilateral) and posterior phar ynx specimens (swabs) will be collected at 
Day 1 (pre-treatment) and at Days 3, 5, and 9, for influenza viral culture and quantitative 
PCR assay. In a subset of a m inimum of 200 subjects an addition al viral culture/ P CR 
sample will be collecte d on Day 2. Anterior
 nose (bila teral) and poster ior pha rynx 
specimens (swabs) will be collected  at Days 1, 3, 5, and 9 f or all subjects, and on Day 2 
in the subset of 200 subjects, to assess 
for potential changes 
in influenza viral 
susceptibility to neuraminidase inhibitors in response to treatment. 
At selected sites a separate sub-study will be conducted to collect limited PK samples for 
the purpose of conducting an exposure-respo
nse analysis.  This sub-study will be 
conducted under a separate sub-study protocol, BCX1812-311PK. 
8 SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1.1 Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in this study: 
1. Male and female subjects age ≥18 years 
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a 
commercially available test kit on an adequate specimen collected from an 
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anterior nasal or pharyngeal swab, in accordance with the manufacturer’s 
instructions.  A negative initial RAT should be repeated with a second 
commercially available RAT kit. A limited number of RAT negative subjects may 
be enrolled in accordance with a defined screening algorithm.. 
3. Presence of fever at time of screening of ≥38.0 C (≥100.4 ºF) taken orally, or 
≥38.5ºC (≥101.2 F) taken rectally. For subjects who test RAT positive at the time 
of screening, a subject self-report of a history of fever or feverishness within the 
24 hours prior to screening will also qualify in the absence of documented fever at 
time of screening.  For subjects who test RAT negative at screening, fever as 
described above must be documented at time of screening. 
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal 
symptoms) of any severity (mild, moderate, or severe) 
5. Presence of at least one constitutional symptom (myalgia [muscle aches], 
headache, feverishness, or fatigue) of any severity (mild, moderate, or severe) 
6. Onset of illness no more than 48 hours before presentation 
7. Females of child-bearing potential must have a negative urine pregnancy test 
(Beta HCG) at screening/baseline AND report one of the following: 
• Be surgically sterile or practice monogamy with a partner who is 
surgically sterile 
• Have been sexually abstinent 4 weeks prior to date of screening evaluation 
and be willing to remain abstinent through 4 weeks after study drug 
administration 
• Use oral contraceptives or other form of hormonal birth control including 
hormonal vaginal rings or transdermal patches and have been using these 
for 3 months prior through 4 weeks after study drug administration 
• Use an intra-uterine device (IUD), or double barrier contraception (such as 
condom or diaphragm with spermicidal gel or foam) as birth control 4 
weeks prior to date of screening through 4 weeks after study drug 
administration 
8. Provide written informed consent 
8.1.2 Exclusion Criteria 
Subjects to whom any of the following criteria apply will be excluded from the study: 
1. Women who are pregnant or breast-feeding 
2. Presence of clinically significant signs of acute respiratory distress 
3. History of severe chronic obstructive pulmonary disease (COPD) or severe 
persistent asthma 
4. History of congestive heart failure requiring daily pharmacotherapy with 
symptoms consistent with New York Heart Association Class IV functional status 
within the past 12 months (section  15.1). 
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5. Screening ECG which suggests acute ischemia or presence of medically 
significant dysrhythmia.  
6. History of chronic renal impairment requiring hemodialysis or known or 
suspected to have moderate or severe renal impairment (actual or estimated 
creatinine clearance <50 mL/min) 
7. Clinical evidence of active bacterial infection at any body site requiring therapy 
with oral or systemic antibiotics 
8. Presence of immunocompromised status due to chronic illness, previous organ 
transplant, or use of immunosuppressive medical therapy. 
9. Current treatment of active viral hepatitis C 
10. Presence of known  HIV infection, with a CD4 count <350 cell/mm3 
11. Current therapy with oral warfarin or other systemic anticoagulant 
12. Receipt of any doses  of rimantadine, amantadine, zanamivir, or oseltamivir in the  
7 days prior to screening 
13. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the 
previous 21 days 
14. History of alcohol abuse or drug addiction within 1 year prior to admission in the 
study 
15. Participation in a previous study of peramivir as treatment for acute influenza or 
previous participation in this study 
16. Participation in a study of any investigational drug within the last 30 days 
8.1.3 Removal of Subjects from Therapy or Assessment 
All subjects are permitted to withdraw from participation in this study at any time and for 
any reason, specified or unspeci fied, and without prejudice.  The Investigator or sponsor 
may terminate the subject’s participation in  the study at any tim e for reasons including 
the following: 
1. Adverse event; 
2. Intercurrent illness; 
3. Non-compliance with study procedures; 
4. Subject’s decision; 
5. Administrative reasons; 
6. Lack of efficacy; 
7. Investigator’s opinion to protect the subject’s best interest. 
Any subject who withdraws because of an adverse event will be followed until the sign(s) 
or symptom(s) that constituted the adverse eve nt has/have resolved o r is dete rmined to 
represent a stable medical condition. 
A subject should be withdrawn fr om the trial if, in the opinion of the Investigator, it is 
medically necessary, or if it is the d esire of the subject. If a subjec t does not return for a 
scheduled visit, every effort  should be m ade to contact the subject and determ
ine the 
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subject’s medical condition.  
In any circum stance, ev ery effort sho uld be m ade to  
document subject outcome, if possible. 
If the sub ject withdraw s consen t, n o furt her evaluations should be perfor med and no 
attempts should be made to collect additional data. 
 
9 TREATMENTS 
9.1 
Treatments Administered 
Peramivir is an investig ational drug.  Peram ivir for intramuscular injection is a small-
volume parenteral and will be supp lied as a 75 mg/mL solution in sodium  citrate/ citric 
acid buffer.  The pH is approximately 3.0. 
A m atched placebo  solution of so dium citrat e/ citric acid  buffer with 1.2% sod
ium 
chloride at a pH of approximately 3.0 will be supplied. 
9.2 
Identity of Investigational Product(s) 
Peramivir and placebo peramivir will be supplied in clear 2mL vials.  An individual study 
drug kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending 
upon the treatment group), 2 syringes and 2 need les in which to draw up the solution for  
intramuscular injection. All m aterials will be  packaged in a labele d box container. All 
study drug kits m ust be stored at 2-8 oC.  Each individual study drug kit will b e labeled 
with some or all of the following information as required by local regulations: 
• Sponsor nam e and contact inform
ation, study protocol num
ber, kit num ber, 
description of the contents of the container, instructions for the preparation of the 
syringe and adm inistration of the study dr ug, conditions f or st orage, statem ent 
regarding the investigationa l (clinical trial) use of the study drug and date for
 
retest or expiry date. 
Each vial of study drug will be labeled with some or all of the following infor mation as 
required by local regulations: 
• Sponsor nam e, study protocol number, desc ription of the contents of the vial, 
instructions for the preparation
 of 
the s yringe, statem ent regarding the 
investigational (clinical trial) use of the study drug and lot number. 
9.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be centrally randomized in a ratio of 2:2:1 to one of three treatment groups: 
single dos e peramivir 1 50mg, single dose pera mivir 300mg or placeb o, in acco rdance 
with a computer-generated random ization schedule prepared by a non-study statistician.  
Subjects will be s tratified acco rding to the  result of a RAT test and curren
t sm oking 
behavior.  Once a subject is eligible for randomization, he/she wi ll be assigned a study 
drug kit nu mber that will be obta ined by stu dy staf f f rom the study  inter active voice  
response system (IVRS).  Once a study drug kit nu mber has been assigned to a subject, it 
cannot be reassigned to any other subject.   
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9.4 
Study Medication Accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study 
drugs received from  the sponsor, issued to th
e subject or directly adm inistered to the  
subject (including date and time), and any drug accidentally destroyed.  The sponsor will 
supply a specific dru
g-accountability form .  At the en
d of the study, information
 
describing study drug s upplies (e.g., lot num bers) and disp osition of s upplies for each 
subject must be provided, signed by the Invest
igator or designee, and collected by  the 
study monitor.  If any errors or irregularities in any shipment of study m edication to the 
site are discovered at any time, the Project Manager must be contacted immediately. 
At the end of the study, all 
medication not dispensed or administered and packaging 
materials will be collected with supervision of the monitor and returned to the sponsor or 
destroyed on site as dictated by the appropr
iate Standard Operating P rocedure at the 
participating institution. 
9.5 
Blinding/Unblinding of Treatments 
This is a double-blind study.  The treatment group assignment will not be known by the 
study subjects, the investigator , the clinical staff, the CRO  or Sponsor staff during the 
conduct of the study. 
Section  11.2.4 provides inform ation regarding the process for unblinding the treatment 
assignment, if necessary, in the event of an SAE. 
9.6 
Prior and Concomitant Therapies 
All m edications, by any route of adm
inistration, used during this study m
ust be 
documented on the Case Report Form  (CRF).  Prescription as well  as non-prescription 
medications should be recorded. Medication us ed for the treatm ent of influenza-related 
symptoms will be captured by the subject in the diary card provided by BioCryst. 
9.7 
Overdose and Toxicity Management 
To date there is no experience  with overdose of in tramuscular or intravenous peramivir.  
If overdose occurs, subjects should receive indicated supportive therapy and evaluation of 
hematologic and clinical chem istry laboratory tests should be conducted.  The effec t of 
hemodialysis on elimination of peramivir is unknown. 
9.8 
Dose Interruption 
As this is a study of a single injection of 
peramivir or placebo, guidelines for treatm ent 
interruption for drug related SAEs or toxicities are not applicable. 
 
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10 STUDY CONDUCT 
A study schedule of evaluations is presented in 
Figure 1 .  A detailed lis
t of  the 
evaluations is also provided in the following sections. 
10.1  Evaluations 
All subjects enrolled in this study will undergo the following evaluations: 
10.1.1 Medical History 
Medical history, influenza va
ccination s tatus within  th e previous 12 m
onths and 
demographic data (including smoking behavior) will be recorded at Screening/Baseline. 
10.1.2 Rapid Antigen Test for Influenza 
At Screening/Baseline, a commercially available, rapid antigen tes t (RAT) for influenza 
A and B will be performed on an adequate specimen collected by swabbing the anterior 
nose or pharynx, in accordance with the RAT 
manufacturer’ instructions.  A negative 
initial RAT should be repeated with a different commercially available RAT kit.  Refer to 
the Study Manual f or instructions regarding the use of the 
RAT kits provided for this 
study.  Sites m ay use the kits provided 
by the Sponsor or any other commercially 
approved RAT available at their site to document a confirmed influenza infection.  
A lim ited num ber of  RAT negativ e subje cts will be  enr olled in a ccordance with the  
following algorithm: Once an ind ividual site has identified 3 RAT positive sub jects at 
screening within a 10 day period,  indicating that influenza activity is present in the site’s 
vicinity, a RAT negative subject that m
eets the inclus ion/ exclus ion criteria m ay be  
enrolled. O ne additional RAT negative subj
ect m ay be enrolled th
ereafter for each 
preceding RAT positive subject that is iden
tified. The RAT result for each subject 
screened will be record ed on the s tudy Inte ractive Voice response (IVR) system to 
manage this enrollment algorithm.  
 
10.1.3 Physical Examination and Influenza-related Complications Assessments 
The Investigator will perform  a physical ex amination at S creening/Baseline.  Subject’s 
weight will be recorded at Screening/Baseline. 
Study personnel will be provided with an influenza-related complications (IRC) checklist 
in the CRF to evalua te the subject for the presence of clinical signs and /or symptoms of 
the following influenza-related complications: sinusitis, otitis, bronchitis and pneumonia.  
At each follow up assessm
ent a t argeted physical exam ination will be conducted to 
record the presence of influenza related complications. If the investigator determines that 
the subject experiences (or is presumed to experience) an IRC as noted above, he/she will 
record that assessm ent on the  IR
C CRF pa ge and any m edication used to treat the 
condition will be reco rded on the concom itant medication page.  The investigato r will 
promptly provide appropriate treatm
ent fo r any suspected or proven IRC, as such 
treatment will not affect the efficacy assessments. Such information describing IRC signs 
and/or symptoms should not be reported as adverse events. Any inj ection site reactions  
noted will be recorded in the CRFs as adverse events. 
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10.1.4 Vital Signs 
Vital signs evaluations will in clude blood press ure, pulse rate , and resp iration rate. The  
investigator will record or al body tem perature at baseline.  Thereafter the subject will 
record oral temperature twice daily in the study diary card. 
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following 
the study drug injection on Day 1, then once da ily on Days 2 (for those subjects who are 
seen on day 2), 3, 5, 9, and 14. 
10.1.5 Electrocardiogram Measurements 
A 12-lead elec trocardiogram (ECG) will be
 obtained a t Screen ing/ Baseline.  The 
principal investigator will be re sponsible for interpretation of the Screening ECG. This 
interpretation may be performed by the investigator or he/she may delegate this action to 
another physician and the investigator wi
ll acknowledge the interp
retation.  If this
 
baseline ECG is interpreted as meeting the exclusionary criteria listed in section 8.1.2 the 
subject will not be enrolled in this study.  If the ECG is interpreted as being abnormal but 
does not meet the exclusionary criteria, 
the subject m ay be enrolled unless other 
exclusion criteria apply.  The principal investigator is responsible to ensure that such an 
enrolled subject be inform ed of the nature  of the abnorm al ECG and that any m edically 
indicated repeat ECG examinations and/or referral of the subject for further evaluation is 
made either during subject' s participation in  the study or imm ediately after the subject' s 
discharge from the study.  
10.1.6 Clinical Chemistry Profiles 
Clinical ch emistry pro files will include a C
hemistry 20 panel (
includes sod ium, 
potassium, chloride, total CO 2 [bicarbonate], creatinine, glucose, urea nitrogen, album in, 
total calcium
, total m
agnesium, phosphor
us, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate am
inotransferase (AST), total bilirubin,
 d irect 
bilirubin, lactate dehydrogenase [LDH], total protein, total creatine kinase, and uric acid) 
Blood samples for clinical chem istry profiles will be collected at Screen ing/Baseline, and on 
Days 3, 5 and 14. 
10.1.7 Hematology Profiles 
Hematology will include complete blood count (CBC) with differential. 
Blood samples for he matology profiles will be  collected at Screening/Baseline, and on 
Days 3, Days 5 and 14. 
10.1.8 Serology for Influenza  
Paired blood samples for determination of antibody to influenza A and  B (serology) will 
be obtained with the clinical  laboratory tests at Screenin g/Enrollment and at Day 14. 
These specimens will be stored at the central laboratory and will be analyzed if needed to 
confirm the diagnosis of influenza. 
10.1.9 Urinalysis and Evaluation of Protein in Urine 
Urinalysis will in clude dipstick tests for protein, glucose, ketones, blood, urobilinogen, 
nitrite, pH, and spec
ific gr avity a nd m icroscopic evaluation for R
BCs and WBCs.  
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Samples for urinalysis will be collected at Screening/Baseline, and on Days 3, 5, and 14. 
10.1.10Urine Pregnancy Test 
Females of childbearing potential will be ev aluated for pregnancy at Screening/Baseline 
and Day 14 using a urine pregnancy test. 
10.1.11 Samples for Virologic Laboratory Assessments 
An adequate spec imen will b e co llected by sw abbing the anter ior nos e (bila teral) and 
posterior pharynx for virologic laboratory a ssessments including culture for the isolation 
of influenza virus and/or quantitative PCR assa y at Screening/Baseline, and at Days 3, 5, 
and 9.  In a subset of a m inimum of 200 subjects an additio nal sample will be taken at  
Day 2. Refer to the L
aboratory Manual for instructions re garding the processing and 
shipment of these specimens. 
10.1.12 Subject Self Assessments 
Subject self assessments will be performed beginning pre-dose on Day 1 and recorde d in 
the subject’s Study Diary including the following: 
• Oral temperature measurements with an electronic thermometer (provided by the 
Sponsor for the study) every 12 hours.  With the exception of the baseline 
measurement, all temperature measurements will be obtained at least 4 hours after, or 
immediately before, administration of oral acetaminophen (paracetamol, provided) 
aspirin, ibuprofen or other NSAID. The times of each temperature determination will 
be recorded in the Study Diary.  The baseline temperature will be recorded at the 
screening/Day 1 visit prior to dosing, regardless of whether the subject had recently 
taken an anti-pyretic; the time of anti-pyretic use pre-treatment will be recorded in the 
CRF, if applicable. 
• Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, 
myalgia [muscle aches], headache, feverishness, and fatigue) on a 4-point severity 
scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on 
Day 1 and through Day 9, then once daily through Day 14. 
• Assessment of the subject’s ability to perform usual activities using a 0–10 visual 
analogue scale once daily through Day 14. 
• Assessment of the subject’s time lost from work or usual activities and productivity 
compared to normal using a 0-10 visual analogue scale once daily through Day 14. 
The subject’s diary card will be reviewed by study staff at each visit for completion of the 
record of all required ite ms, with particular emphasis on alleviation of symptoms as well 
as relapse of sym ptoms.  Relapse is defined as the recurrence of at leas t one respiratory 
symptom and one constitutiona l sy mptom (both greater th an m ild in severity) f or 24 
hours and the presence of fever (unless influenc ed by antipyretic use).  Relapse can only 
occur after the subject has m et the endpoint cr iteria for alleviation of symptoms.  Study 
staff will not attem pt to ask subjec ts to retrospectively complete missing diary card data 
for any scheduled assessm ents that have not b een com pleted prio r to  the c linic visit.  
Study staff should, however, rem
ind the subject  to com plete the diary card at all
 
scheduled times. 
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10.1.13 Concomitant Medications 
All concom itant m edications used during 
this study, with the exception of those 
medications taken for symptomatic relief of influenza symptoms, which will be reco rded 
by the subject in their diary card, must be documented on the Case Report Form (CRF).  
10.1.14 Adverse Events 
AEs will be assess ed from the tim e of ad ministration of stu dy medication through the 
final study visit. 
10.1.15 Single Pharmacokinetic Exposure Sample 
On study day 3 a single PK sample will be drawn in concert with the day 3 safety clinical 
laboratory blood draw. This sample will be 
sent for subsequent analys
is of the 
concentration of peramivir at this time point.  Data f rom this sing le PK sample will b e 
combined with data from  the PK s ub-study (BCX1812-311PK) to perfor m an exposure-
response analysis.  This analysis will be described as part of the sub-study analysis plan.. 
 
10.2 Screening  
10.2.1 Informed Consent 
The nature and purpose of the study and the expectations of a participating subject will be 
described to potential study subjects , their que stions will be answered, and the subjects 
will th en b e asked to sign an inf
ormed c onsent docum ent.  Study s ubjects will then 
undergo the screening evaluation as noted in Section  10.2.2 
10.2.2 Screening/Baseline Evaluation and Enrollment 
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or 
in the subject’s hom e, in which case all ev aluations must be conducted by appropriately 
trained and qualified staff. 
Clinical laboratory assessm
ents perform ed at Screenin
g are 
for the purpose of 
establishing a baseline.  Subjects m ay be enrolled and receive treatm ent with study drug 
prior to r eceiving re sults of  the laboratory a ssessments (with the ex ception of  urine 
pregnancy test result, which must be known). 
Eligible sub jects will be enrolled and ra
ndomized to blin ded study treatm ent.  The 
randomization will include stratification by RA T status and current s moking behavior.  
The Investigator will prepare a request for blinded study drug assignment which includes 
the subject’s screening number.  The Investigator or designee at the clinical study center 
will contact the central randomization Interactive Voice System (IVRS call center).  The 
IVRS call center will advise the study center of the investigational study drug kit number 
that is assigned to that subject at enrollment. 
Subjects that are d etermined to be ineligible will be advi sed accordingly, and the reason 
for ineligibility will b e discussed.  If  desired by the subjec t the reason  for ineligibility 
may be pr ovided/discussed with their hea
lth-care provider by the Investigator or 
designee.  
Ineligible subjects who have been screen
ed for the study will also be entered on
 the  
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IVRS.  For such subjects, the screening num
ber assigned, subject’s date of birth and a 
reason for ineligibility will be entered on to th e IVRS.  All ineligible subjects must be 
entered onto the IVRS within 24 hours of screening, to assis t with surve illance 
analysis during the course of the study. 
  
10.3 Treatment Period—Study Day 1 
Day 1 represents the only day of study dr
ug dosing.  Study drug adm inistration should 
occur as soon as possible following inform
ed consent, screening and random
ization.  
Therefore, it is expec ted that the da te of Screening/ Baseline and Day 1 will usua lly be 
the same date.  
10.3.1 Pre-dose Evaluations 
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the 
subject shall complete the record of these assessments in their Study Diary prior to 
dosing.  The subject will be counseled regarding the expectations for recording these 
assessments through Day 14. 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral 
temperature) and a 12 lead ECG will be obtained prior to dosing. At Hour 0, the blinded 
study drug will be administered intramuscularly (one injection in the left gluteal muscle, 
and one injection in the right gluteal muscle within a period of ≤ 10 minutes.).  The 
calendar date and 24-hour clock time of the first and second injections will be recorded. 
The following evaluations will be performed post-dose on Study Day 1: 
• Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral 
temperature) at 15 minutes after the study drug administration 
• Record any concomitant medications 
• Record any AEs 
10.4 Post-Treatment Assessment Period 
10.4.1 Days 2, 3, 5, 9 and 14 
Study evaluations will be performed on Days 2 [subset of subjects only], 3, 5, 9 and 14 in 
accordance with the schedule of evaluations (Figure 1). Subjects with persistent moderate 
or severe influenza symptoms at day 14 will also complete a Day 21 visit.  
Visits may be conducted in the investigator’s o ffice or clinic, or in the subject’s home, in 
which case all evaluations must be conducted by appropriately trained and qualified staff. 
The Day 2 assessment will be conducted in clinic or by study staff only for the subset o f 
subjects who will provide additional Day 2 virology samples. For all other study subjects, 
study staff will attem pt to contact the subjec ts on Day 2 by telephone to confirm
 their 
compliance with com pletion of the Subject Self  Assessments, to note any concom itant 
medications and adverse events.  A ny adverse events reported by the subject during this 
telephone contact will be recorded on the adverse event form and verified during the visit 
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on day 3. 
At each v isit it is im portant that the sub ject’s Study Diar y record be rev iewed for 
completion of daily Subject Self Assessm
ents.  The subjects should be counseled as
 
necessary regarding self assessments and Study Diary record requirements.  The subject’s 
diary card will be reviewed by study staff for alleviation of symptoms as well as relapse 
of symptoms.  Relapse is defined as the r ecurrence of at least one resp iratory symptom 
and one constitutional symptom (both greater than mild in severity) for 24 hours an d the 
presence of fever (unless influenced by antipyretic use).  Relapse can only occur after the 
subject has met the endpoint criteria for alleviation of symptoms. 
Day 3: 
The results of  the serum CK result obtained a
t Day 3 will not be m
ade available  to  
investigators, to BioCryst or to any study personnel, unless the CK result at Day 3 is 
≥ 
2000 IU/mL.  A single PK sa mple will be obt ained on Day 3 at the sam e time as the 
clinical laboratory blood specimen is obtained.  
Day 14: 
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven  
symptoms assessed) of either m oderate or se vere intensity at th e Day 14 visit th en the 
subject must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required 
at day 28 (± 3 days)  If a subject reports m oderate or severe influenza symptoms then the 
investigator will record the intensity of each of the influenza symptoms on a visit specific 
CRF page at the day 21 and day 28 visits. A
fter day 14 the subjec t will not re cord 
symptoms in a diary. 
Day 21 (if applicable): 
The day 21 visit is to  be completed only if the subject reports sym ptoms of influenza of 
moderate or severe intensity at day 14. The investigator will  make a clinical judgment as 
to the appropriate medical course of action for such subjects at the Day 2 1 visit and such 
action(s) will be re corded on the Day 21 CRF page. The investigator will re
call the  
subject for a further study visit at day 28 (± 3 days) if m oderate or severe symptom(s) of 
influenza persist at Day 21.  
Day 28 (if applicable): 
The day 28 visit is to  be completed only if the subject reports sym ptoms of influenza of 
moderate or severe intensity at day 21. The investigator will  make a clinical judgment as 
to the appropriate m edical course of action 
for such subjects at this visit and such 
action(s) will be recorded on the Da y 28 CR F page. No further follow-up visits beyond 
day 28 are to be form ally scheduled unless in  the clinical judgm ent of the investigator 
further follow-up is required. The investigat
or will use his/her 
clinical judgm ent to 
manage the subject, referring the subject, if appropriate, for further care. 
10.4.2 Adverse Events Reported at Post-treatment Visits 
In this stud y, symptoms of influenza will be considered separately from adverse e vents 
reported during the post-treatment period. Accordingly, adverse events that have onset in 
the post-treatment period will be assessed and followed as specified in 11.2. Specifically, 
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the inves tigator shou ld attem pt to f ollow all unresolved AEs and/or SAEs observed 
during the study until they are resolved, or ar e judged medically stable, or are otherwise 
medically explained. 
 
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Figure 1 
Study Measurements and Visit Schedule 
 
Treatment 
Period 
                                                Assessment Day                                     End of Study 
                                                                                                            Early Withdrawal 
 
Screening 1 
(Baseline) 
Day 11 
Day 22 
Day 3 
Day 5 (±1 day) 
Day 9 (±3 day) 
Day 14 (±3 day) 8 
Informed Consent 
X 
 
 
 
 
 
 
Rapid Antigen test for Influenza A & B 
X 
 
 
 
 
 
 
Medical History/Physical Exam3 
X 
 
 
 
 
 
 
Influenza-related complications checklist3 
X 
 
X 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Clinical Chemistries4 
X 
 
 
X 
X 
 
X 
Hematology4 
X 
 
 
X 
X 
 
X 
Exposure Pharmacokinetic Sample 
 
 
 
X4 
 
 
 
Serology (serum) Sample 
X 
 
 
 
 
 
X 
Urinalysis4 
X 
 
 
X 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
ECG6 
X 
 
 
 
 
 
 
Sample (nasopharyngeal swab) for 
Influenza Virus Culture/ PCR assay and 
for resistance studies 
 
X 
X 
X 
X 
X 
 
Study Drug Administration 
 
X 
 
 
 
 
 
Subject Diary Review7 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on subsequent study days may occur in subject’s home by 
the investigator (all visits) or appropriately trained study center staff (Day 2, 3, 5, 9 visits). 
2  Day 2 visit required only for a subset of subjects for whom additional Day 2 virology sample is required.  For all other subjects, Day 2 will be a telephone contact with the subject to ensure 
compliance with diary card completion, concomitant medication and adverse event review. 
3  Medical history and physical exam at screening to include weight, and smoking behavior.  Targeted physical examinations will be performed to complete the influenza-related complications 
checklist by the appropriate medical personnel at appropriate visits. 
4  Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline.  Subject may be enrolled and begin treatment with study drug prior to receiving results. 
On Day 3 an extra tube will be included with the safety blood sample for evaluation of peramivir concentrations. 
5  Vital sign measures will include blood pressure, pulse rate and respiration rate.  Vital signs will be recorded at Screening, pre-dose and at 15 min following the study drug administration on 
Day 1, then once on remaining days as stipulated. The investigator will record oral temperature at baseline.  Thereafter the subject will report oral temperature measurements twice daily in 
the Study Diary 
6  If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study.  If the ECG is 
interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, medically significant dysrhythmia) then this subject may be enrolled If the conditions 
highlighted in section 10.1.5 are met for the subject. 
7  Subjects record symptom assessment in Study  Diary, twice dail y, beginning pr e-dose on Day 1 through Day 9, then once daily  through Day 1 4;  subjects record  ability to perform usual 
activities once daily, beginning pre-dose on Day 1 through Day 14.  Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events 
8   For any subjec t with unresolved moderate or severe intensity influenza sym ptoms a follow up assess ment will be schedul ed at Day  21 ( ± 3 day s) and Day  28 (± 3 day s) if r equired
(See Section 10.4.1).  
 
BioCryst Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
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11 ADVERSE EVENT MANAGEMENT 
11.1 Definitions 
11.1.1 Adverse Event 
An AE is any untoward m
edical 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, sym ptom, syndrome, or illness that dev elops or 
worsens during the clinical st
udy.  Clinically relevant ab
normal results of diagnostic 
procedures including abnorm
al laborator y findings (e.g., requ
iring unscheduled 
diagnostic procedures or treatm ent measures, or resulting in withdrawal from  the study)  
are considered to be AEs. 
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2). 
Surgical procedures are not AEs but m ay constitute therapeutic m easures 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 m
easures perm itted by the 
clinical study protocol and the conditions(s) leading to these measures are not AEs, if the 
condition(s) was (were) known befo re the start of study treatm ent.  In the latter case the 
condition should be reported as medical history. 
Assessment of seven influenza sym ptoms (cough, sore throat, nasal obstruction, m yalgia 
[muscle aches], headache, f everishness, and f atigue) will be  documented in a subject’s  
study diary  and analy zed as a m
easure of  efficacy of the study treatm
ent. These  
symptoms will not b e reported as AEs unless the sym ptom(s) worsen to the exte nt that 
the outcome fulfils the def inition of an SAE, which then must be recorded as such  (see 
Section  11.1.2).  Likewise, a RAT for influenza is 
required at screening in order to 
determine eligibility for the study, and therefore a positive RAT is not considered an AE.    
11.1.2 Serious Adverse Event 
A SAE is an adverse event that results in any of the following outcomes: 
• Death 
• Is life-threatening (subject is at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe) 
• Requires in-subject hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (i.e., there is a substantial 
disruption of a person’s ability to carry out normal life functions) 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
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Important medical events that may not result in death, are no t life-threatening, or do not 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they m
ay j eopardize the subject or m
ay r equire m edical or surgical 
intervention to prevent one of  the outcom es listed in this definition.  E xamples of such 
events include allergic bronchospasm requiri
ng intensive treatm ent in an e mergency 
room or at hom
e, blood dyscrasias or c
onvulsions that do not
 result in subject 
hospitalization, or the development of drug dependency or drug abuse. 
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and 
Reporting Serious Adverse Events 
Reports of AEs are to be collected from the time of study drug administration through the 
follow-up period ending on Day 14.  The Invest igator or de signee must completely and 
promptly record each AE on the appropriate 
CRF.  The Investig ator should attem pt, if 
possible, to establish a diagnosis based on th e presenting signs and symptom s.  In such 
cases, the diagnosis should be docum
ented as the A
E and not the individual
 
sign/symptom.  If a clear diagnosis cannot be established, each si gn and symptom must 
be recorded individually. 
The Investigator should attem pt to follo w all unresolved AEs and/or SAEs observed 
during the study until they are resolved, or ar e judged medically stable, or are otherwise 
medically explained. 
11.2.1 Definition of Severity 
All AEs will be as sessed (graded ) f or severity and class ified into on e of  f our clearly 
defined categories as follows: 
• Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; 
no intervention required.  The AE does not interfere with the 
participant’s normal functioning level.  It may be an annoyance. 
• Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in 
activity; no or minimal intervention required.  The AE produces 
some impairment of functioning, but it is not hazardous to 
health.  It is uncomfortable or an embarrassment. 
• Severe: 
(Grade 3): Symptom results in significant limitation in activity; 
medical intervention may be required.  The AE produces 
significant impairment of functioning or incapacitation. 
• Life-threatening: (Grade 4): Extreme limitation in activity, significant assistance 
required; significant medical intervention or therapy required; 
hospitalization. 
11.2.2 Definition of Relationship to Study Drug 
The blinded Principal Investigator must rev iew each AE and m ake the determ ination of 
relationship to study drug using the following guidelines: 
Not Related: 
The event can be readily explained by other factors such as the 
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subject’s underlying m edical c ondition, concom itant therapy, or 
accident, an d no tem poral relati onship ex ists b etween the study 
drug and the event. 
Unlikely: 
The event d oes not follow a reason able tem poral sequ ence from 
drug adm inistration and is read
ily explained by the subject’s 
clinical state or by other m
odes of therapy  adm inistered to the  
subject. 
Possibly Related: 
There is so me tem poral relationship between the event an
d th e 
administration of the study drug a
nd the event is unlikely to be 
explained by the subject’s m edical condition, other therapies, or 
accident. 
Probably Related: 
The event follows a reasonable tem
poral sequence from drug 
administration, abates upon discontinuation of the drug, and cannot 
be reasonably explained by th
e known characteristics of the 
subject’s clinical state. 
Definitely Related: The event follows a reason
able tem poral sequen ce from 
administration of the m edication, follows a known or suspected 
response pattern to the m edication, is confirm ed by im provement 
upon stopping the m edication (dec hallenge), and reappears upon 
repeated exposure (rechallenge, 
if rechallenge is m
edically 
appropriate). 
11.2.3 Reporting Serious Adverse Events 
Any SAE must be reported to BioCryst
 or its designee within 24 hours of the 
Investigator’s recognition of the SAE by fi
rst notifying the Medical Monitor at the 
number listed below: 
Telephone: 
Europe: +44 1628 548000;  North America: 1-888-724-4908 
Facsimile: 
Europe: +44 1628 540028;  North America: 1-888-887-8097  
           or 1-609-734-9208  
 
The site is required to fax a completed SAE Report Form (provided as a separate report 
form) within 24 hours.  All additional follow-up evaluations of the SAE must be reported 
and sent by facsimile to BioCryst or its designee as soon as they are available. 
The Principal Investigator or designee at each site is respons ible for submitting the IND 
safety report (initial a
nd follow -up) or other safety inform
ation (e.g., revised 
Investigator’s Brochure) to
 the Institutional Review 
Board/Independent Ethics 
Committee (IRB/IEC) and for retaining a copy in their files. 
If the Inv estigator becomes aware of any SA E occurring within 30 days after a s ubject 
has com pleted or withdrawn from  t he study, he or she should notify BioCryst or its 
designee.   
Any SAEs considered possibly related to treatment will be reported to the FDA and other 
Regulatory Competent Authorities as applicab le via the MedW atch reporting system i n 
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accordance with FDA and other ap plicable regulations. However, the Investig ator is not 
obligated to actively seek reports of AEs in former study participants. 
While pregnancy is not considered an AE, a ll cases of fetal drug exposure via parent as 
study participant (see S ection 4.4) are to be 
reported immediately to  BioCryst or its 
designee.  Inform ation rela ted to the pregnancy m
ust be given on a “Pregnancy 
Confirmation and Outcome” form that will be provided by the Sponsor or its designee. 
11.2.4 Emergency Procedures 
In the even t of an SAE, the Principal Inve
stigator m ay request the unblinding of  the  
treatment assignm ent for the subject affected
.  If tim
e allows (i.e., if appropriate 
treatment for the SAE is not im peded), the Principal Investigator wi ll first consult with 
the Med ical Monito r r egarding the  need to  unblind the treatm ent assignm ent for the  
subject.  At all times, the clinical well-being of any subject outweighs the need to consult 
with the Medical Monitor. 
The Principal Investigator m
ay contact th e IVRS central random
ization center and 
request the unblinding of the treatm
ent assi gnment that corresponds to the affected 
subject.  Th e IVRS center will record the na me of the Investigator  making the request, 
the date and time of the request, the reason for the request, the subject number and study 
drug kit number, and whether the Medical M
onitor was consulted prior to the request 
being made.  The Sponsor will be informed within 24 hours if unblinding occurred. 
 
12 STATISTICAL METHODS 
Descriptive statistical methods will be used to summ arize the data from this study, with 
hypothesis testing perform ed for the prim
ary and other selected efficacy endpoints. 
 
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 da ta.  The term “treatm ent group” refers to 
randomized treatment assignment:  peramivir 150 mg, peramivir 300 mg, or placebo.  All 
data collected during the study wi ll be included in data listin gs.  Unless otherwise noted, 
the data will be sorted first by treatm ent assignment, subject num ber, and then by date 
within each subject number.   
Unless specified otherwise, all statistical testing will be two-sided and will be performed 
using a significance (alpha) level of 0.05. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
12.1 Data Collection Methods 
The data will be reco rded on the CRF appr oved by BioCryst. The Investigator must 
submit a completed CRF for each subject who signs an inform
ed consent form (ICF), 
regardless of duration.  All documentation supporting the CRF data, such as laboratory or 
hospital records, must be readily available to verify entries in the CRF. 
Documents (including laborator y reports, hospital records s
ubsequent to SAEs, etc.) 
transmitted to BioCryst should not carry the s
ubject’s name.  This will help to  ensure 
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subject confidentiality. 
12.2 Statistical Analysis Plan 
A statistical analysis plan (SAP) will be cre ated prior to the review of  any data.  This 
document will provide a m ore technical and detailed description of the proposed data 
analysis methods and procedures. 
12.3 Sample Size Estimates 
From published resu lts, it is exp ected that th e median time to a lleviation of symptoms 
will be between 103.3-116 hours  for subjects receiving p lacebo. 16 , 1 7  For sam ple size 
calculations the best placebo respon se (103.3 hours) will p rovide the most conserv ative 
estimate of an observed hazard ratio. Additionally, it is expected that the median time to 
alleviation for the lowes t dose peramivir arm will be 69.9 h ours, yielding a hazard ratio  
of 0.68.  Using these assum
ptions, a sa mple size of 200 infected subjects per active
 
treatment group and 100 infected subjects in th e placebo group is sufficient to provide at 
least 80% power to detect a hazard ratio of 0.68 usi ng a log-rank statistic and α = 0.025 
(SAS version 9.1.3; tota l accrual time 7 months; total enrollment time 6 months). Up to 
800 subjects will b e enrolled to achieve the target num ber of at least 5 00 subjects with  
diagnostic evidence (RAT or PCR) of an 
acute influenza infection (200 per active 
treatment; 100 receiving placebo) as described in section  12.4.2. 
12.4 Analysis Populations 
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected 
(ITTI), and safety populations. 
12.4.1 Intent-To-Treat Population 
The ITT population will include all subject
s who are random ized.  Subjects will be 
analyzed in the treatment group to which they were randomized.  The ITT population will 
be used for analyses of accountability and demographics. 
12.4.2 Intent-To-Treat Infected Population 
The ITTI po pulation will include all subj ects who are rando mized, received study d rug, 
and have proven influenza by any one of the fo llowing: culture, PCR, or paired serology 
showing ≥ 4-fold increase in antibody to influe
nza A or B, and received study drug. 
 
Subjects will be an alyzed accord ing to the treatment random ized.  If a discrepancy is 
noted in the final database for any subject, such that the drug differs from the randomized 
treatment assignm ent, efficacy analyses m ay be repeated with the su
bjects analy zed 
according to the treatm ent received.  The 
ITTI population will be used for prim
ary 
analyses of efficacy. 
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12.4.3 Safety Population 
The safety population will include all subjects who received study drug.  Subjects will be 
analyzed according to the treatm ent received.  This population will be used for all safety 
analyses. 
12.5 Interim and End of Study Analyses 
Interim Analysis 
An independent DMC will review  safety data on an ongoing basi s.  Safety analyses will 
be presented in a manner consistent with the presentations intended for the final analysis. 
End of Study Analysis 
A final analysis is planned after the last su bject completes or discontinues the study, and 
the resulting clinical database has been cleaned, quality checked, and locked. 
12.6 Efficacy Analyses 
12.6.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time 
from injection of study drug to the start of th e time period when a subject has Alleviation 
of Symptoms.  A subject has Alleviation of 
Symptoms if all of  the seven symptoms of 
influenza (nasal congestion, so re throat, cough, aches and pains, fatigue (tiredness), 
headache, feeling feverish) assessed on his/he
r subject diary are eith
er absent o r are 
present at no m ore than m ild severity leve l and at this status for at least 21.5 hours (24 
hours - 10%). 
Descriptive statistics for the prim ary effi cacy endpoint will be tabulated by treatment 
group.  Alleviation of sym
ptoms will be d etermined by assessm ent of sym ptoms as 
reported on  each  subject’s  diary  card.   T ime to alle viation of sym ptoms will b e 
summarized overall and for i
ndividual sym ptoms for each treatm ent group.  Overall 
treatment dif ferences will be assess ed using a Cox Regression m
odel with ef fects f or 
RAT result at screening, current smoking behavior, treatment group, and influenza season 
at randomization (if necessary).  Subjects who do not experience alleviation of symptoms 
will be censored at the date of their last non-missing post-baseline assessment.  Pairwise 
differences in tim e to alleviation of sy
mptoms am ong the treatm ent groups will be 
evaluated using contrast statem ents from the final Cox m odel. In orde r to m aintain the 
overall type I error in the presence of the planned comparisons between the two peramivir 
treatments and placebo, a Bonfe rroni correction will be app lied to the p rimary efficacy 
endpoint analysis.  P -values for the planne d com parisons of each peram ivir arm  to 
placebo will be adjusted via a Bonferroni corr ection (i.e., if the unadjusted p-value for an 
active com parison versus place bo, p, is less th an 0.05, then p
a=p*number of planned 
comparisons=p*2; otherwise, p
a=p).  Superiority of peram
ivir to placebo will be
 
established if the adjusted p-value is less than or equal to 0.05. 
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12.6.2 Secondary Efficacy Endpoints 
All secondary endpoints will be summ
arized using descriptive statistics by treatm
ent 
group and study day/time, if appropriate.  St atistical comparisons for each endpoint will 
be constructed without adjustment for multiple endpoints. 
The reduction in viral shedding will be assessed as the change in viral titers defined as the 
time-weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) 
and will be summarized  for each treatm ent group.  The tim e-weighted average change 
from baseline will be calculated on a by-subject basis through Day 9 using the trapezoidal 
rule with a ll available post-bas eline on-tre atment data (d ata af ter initia tion of  study 
treatment) minus the baseline value.  Specifically, the time-weighted area under the curve 
for time a (ta) to time b (tb) is given by the formula  
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
, 
where 
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
 and ti represents the date of the ith viral titer 
assessment and y i represents the log10 value of the i th viral titer as sessment. If there is a 
baseline value and only one follow-up value, y
i then the tim e-weighted change from 
baseline is defined as the difference between y i and baseline.  If there is a baselin e value 
and no follow-up value, the subject is exclude d from analysis.  The differences between 
each of the peramivir treatment groups and placebo will be evaluated using a van Elteren 
Test ad justing for RAT result at screen
ing, current sm oking be havior and influenza 
season at randomization (if necessary).   Analyses of the PCR results will be analy zed in 
a similar manner. 
Subject’s ability to perform usual activities as determined from the visual analog scale 
will be summarized by study visit day and treatment group.  Differences between the 
treatment groups will be assessed using the van Elteren Test adjusting for smoking 
behavior and influenza season at randomization (if necessary).  The time (days) to 
resumption of a subject’s ability to perform usual activities (i.e., subject scores ability to 
perform usual activities as 10) will be estimated using the method of Kaplan-Meier.  
Differences between each of the peramivir treatment groups and placebo will be assessed 
using the log rank statistic adjusting for RAT result at screening, current smoking 
behavior and influenza season at randomization (if necessary).  Subjects who do not 
return to the pre-study level of performance of usual activities will be censored at the 
time of their last non-missing post-baseline visual analog scale value. 
Subject’s oral tem perature will be summ
arized by study visit and treatm
ent group.  
Differences between the treatment groups will be assessed using the Wilcoxon Rank Sum 
Test con trolling for RAT resu lt at screen ing, current sm oking behavior and influenza  
season at randomization (if necessary).  A subject has Resolution of Fever if he/she has a 
temperature < 37.2°C (99.0°F) and no antipyretic medications have been taken for at least 
12 hours.  The tim e to resolution of fever will be estimated using the method of Ka plan-
Meier using temperature and sym ptom relief medication information obtained from the  
subject diary data.  Difference between the tr eatment groups will be assessed using the 
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log rank sta tistic controlling for RAT result a t screening, current sm oking behavior and 
influenza season at randomization (if necessary).  Subjects who do not have resolution of 
fever will be censored at the tim
e of their last non- missing post-baseline tem perature 
assessment. 
The MRU, MRU-related direct co sts, and indirect co sts attributable to days m issed of 
work and work productivity and/or perform ance losses will be summ arized by treatment 
group.  Differences between each of the peramivir treatment groups and placebo group 
will be evaluated using both param etric and/or non-parametric tests, as appropriate.   If 
necessary, bootstrapping techniques will be used to calculate confidence intervals around 
the incremental differences in costs.   
12.6.3 Exploratory Endpoint 
Genotypic (including Hem agglutinin and Neurom inidase), phenotypic, viral culture and 
PCR data will be lis ted for each sub ject.  These listings will be constructed in a m anner 
consistent with the F
DA June 2006 Guidance Docum
ent:“Guidance for Subm itting 
Influenza R esistance D ata”.18  Ad ditionally, the num ber and percen tage of  genotypic 
changes from wild-type a mino acid will be summarized separately for treatm ent group, 
protein type, and study visit. 
12.7 Safety Analyses 
AEs will be m apped to a MedDRA-pref erred term and system organ classification.  The 
occurrence of TEAEs will be  summarized by treatment group using MedDRA-preferred 
terms, system organ classifications, and severity.  If a subject experiences multiple events 
that m ap to a s ingle p referred term, the grea test severity and st rongest Investigator 
assessment of relation to study d
rug will be assigned to  the preferred term  for the 
appropriate sum maries.  All AEs will be li
sted f or individual subje cts 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 s igns and clinic al laboratory results will be presented by 
study visit.  Laboratory abnorm alities will be graded according to the DAIDS Table for  
Grading Adverse Events for Adults and Pedi atrics (Publish Date: December 2004).  The 
number and percentage of subjects experien
cing treatm ent-emergent graded toxicities  
will be summarized by treatment group. Laborator y toxicity shifts from baseline to Day 
3, Day 5, and Day 14 will be summarized by treatment group. 
Abnormal physical exam ination findings wi ll be presented by treatm
ent group.  The 
number and percent of subjects experiencing each abnormal physical examination finding 
will be included. 
Concomitant medications will be co ded using the WHO dictionary.  The se data will be  
summarized by treatment group. 
Subject disposition will be presented for a
ll s ubjects.  The num ber of subjects who 
completed the study and discontinued from  the study will be provided.   The reasons for  
early discontinuation also will be presented. 
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12.8 Sub-Study and Pharmacokinetic Analysis 
The sub-study to exam ine exposure respons e, along with the corresponding single PK 
samples collected on all subjects on study day 
3 will be co mpleted as part of the sub-
study. All s tatistical m ethods will be outlin ed as part of the sub-stu
dy protocol and 
exposure-response analysis plan. All sub-study analyses will be reported in a separate 
sub-study report. 
12.9 General Issues for Statistical Analysis 
12.9.1 Multiple Comparisons and Multiplicity 
In order to m aintain the overall typ e I e rror in the presen ce of the plann ed comparisons 
between the two peram
ivir treatm ents and pl acebo, a Bonferroni correction will be
 
applied to the prim ary efficacy end point an alysis.  No oth er ad justments for m ultiple 
comparisons are planned. 
12.9.2 Covariates 
Primary and secondary efficacy analyses will 
be adjusted for RAT result at screen ing, 
current smoking behavior and influenza season at randomization (if necessary).  
12.9.3 Planned Sub-Groups 
The prim ary efficacy endpoint will be summ
arized separately by stratification group 
(current sm oking behavior [sm oker or non-smoker] and RAT result at screening 
[negative or positive]) and by viral subtype using descriptive statistics by treatment group 
and study day, if appropriate.  No formal statistical testing will be utilized. 
Additional analyses m ay be perform ed by count ry, if necessary, for subm ission to local 
regulatory authorities. 
12.9.4 Missing Data 
Every effort will be m ade to obtain  required data at each s cheduled evaluation from all 
subjects who have been random ized.  No attemp t will be m ade retrospectively to obtain 
missing subject reported data (including in
fluenza symptom severity assessm
ents, 
temperature, ability to perf orm usual activi ties, m issed days of work and im
pact of 
influenza on subject’s work perform
ance and/or productivity) 
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 obt ain all da ta, it m ay be necessary to im pute 
missing data.   
 
In assessing  the p rimary efficacy endpoint, fo r subjects w ho withdraw or who d o no t 
experience allev iation of sym ptoms, m issing data will be 
censored using the date of 
subject’s last non-m issing assessment of infl uenza symptoms.  Missing assessm ents of 
influenza symptoms conservatively will be im puted as h aving severity above absen t or 
mild (as f ailures).  For the subjec t diary data,  the f ollowing data con ventions will be  
utilized.  Missing diary com pletion will be imputed as 11:59 for diary entries designated 
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as m orning and 23:59 for evening and daily 
reported v alues.  Entr ies with va lues 
exceeding the 24-hour clock will b e set to 23:59 of the day recorded.  Select explo ratory 
sensitivity analyses m ay be conducted to ascert ain the effect, if any, of these m
ethods.  
These sensitivity analy ses are further de
scribed in the SAP.  Secondary efficacy 
endpoints with tim e to event da ta will be censored using the date of subject’s last non-
missing assessment of the given endpoint. 
 
13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 Regulatory Authority Approvals 
This study  will be conducted in
 com pliance with th e protoco l; GCPs, including  
International Conference on Harmonization (ICH) of Te
chnical Requirem ents for 
Registration of Pharm
aceuticals for Hu
man Use G
uidelines; FDA regulatory
 
requirements and in accordance with the ethical principles of the Declaration of Helsinki.  
In addition, all applicable loca l laws and regu latory requirements relevant to the use of 
new therapeutic agents in the countries involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB)/ Independent E thics Committee (IEC) annually or  more frequently 
if requested by the IRB/ IEC.  A final s
tudy notification will also be forwarded to the 
IRB/IEC af ter the study  is com pleted or in the event of
 prem ature ter mination of the  
study in accordance with the appl icable regulations.  Copies of  all contact with the IRB/ 
IEC should be m aintained in the study docum ents file.  Copies of clinical study status 
reports (including termination) should be provided to BioCryst. 
13.1.2 Ethics Committee Approvals 
Before initiation of the study at each invest
igational site, the pr otocol, the inform ed 
consent form, the subject inform ation sheet, and any other relevant  study documentation 
will be sub mitted to th e appropriate IRB/IE C.  W ritten approval of th e study m ust be 
obtained before the study center can be initiated or the investigational medicinal product 
is re leased to the Inv
estigator.  A ny necessa ry extension s or renew als of  IRB/IEC 
approval must be obtained, in particular, for changes to the study such as modification of 
the pro tocol, the inf ormed consent f orm, th e written inform ation provided to subjects 
and/or other procedures. 
The Investigator will report promptly to 
the IRB/IEC any new inform
ation that m ay 
adversely affect the safety of the subjects or  the conduct of the study.   On completion of 
the study, the Investigator will prov ide the IRB/IEC with a report of the outcom e of the 
study. 
13.1.3 Subject Informed Consent 
Signed info rmed consent m ust be obtained  from each subject p rior to  performing any 
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study-related procedures.  E
ach subject should be given both verbal and w
ritten 
information describing the nature and durati
on of the clinical st
udy.  The inf ormed 
consent process should take place u nder conditions where the subject h as adequate time 
to consider the risks and bene
fits associated with his/her 
participation in  the study.  
Subjects will not be screened or treated 
until the subjec t has signed an approved ICF 
written in a language in which the subject is fluent. 
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.   
The informed consent should be in acco
rdance with the curren
t revision o f the 
Declaration of Helsinki, current ICH and GCP guidelines, and BioCryst policy. 
The Investigator must explain to potential subjects or their legal representatives the aims, 
methods, reasonably anticipated benefits, a
nd potential hazards of the trial and any 
discomfort it may entail.  Subjects will be informed that they are free not to participate in 
the trial and that they may withdraw consent to participate at any time.  They will be told 
that refusal to participate in the study will not prejudice future treatment.  They will a lso 
be told  tha t their recor ds m ay be exam ined by com petent autho rities and au thorized 
persons but that pe rsonal information will be tr eated as strictly confidential and will not 
be publicly available.  Subjects must be given the opportunity to ask questions.  After this 
explanation and before entry in to the trial, consent should be appropriately recorded by 
means of the subject’s dated signature.  The subject shoul d receive a signed and dated 
copy of the ICF.  The original  signed infor med consent should  be retained in the study 
files.  The Investigator shall maintain a log of all subjects who sign the ICF and indicate 
if the subject was enrolled into the study or reason for non-enrollment. 
13.1.4 Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
13.1.5 Investigator Reporting Requirements 
The Investigator will provide  tim ely repo rts regard ing s afety to his /her IRB/IE C as 
required. 
13.2 Study Monitoring 
During trial conduct, BioCryst or its  designee will conduct period ic monitoring visits to 
ensure that the protocol and GCPs a re being followed.  The monitors may review source 
documents to conf irm that th e data recorded on CRFs is accurate.   The investigator and 
institution will allow BioCryst m
onitors or  its des ignees and app ropriate regulatory  
authorities direct access to source documents to perform this verification. 
13.3 Quality Assurance 
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by BioCryst, 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 a udits or inspections and that sufficient tim e is devoted to 
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the process. 
13.4 Study Termination and Site Closure 
BioCryst reserves the right to
 disc ontinue the  tr ial prio r to inc lusion of  the in tended 
number of subjects but intends only to exer
cise this r ight f or valid scientif ic or 
administrative reasons.   After such a deci
sion, the Investigator must contact all 
participating subjects immediately after notification.  As directed by BioCryst, all study 
materials must be collected a nd all case report forms completed to the greatest extent 
possible. 
13.5 Records Retention 
To enable evaluations and/or
 audits from
 regulatory au
thorities o r BioCryst,  the  
Investigator agrees to k eep records,  includi ng the iden tity of  all p articipating sub jects 
(sufficient inf ormation to link re
cords, case report forms and hospital records), all 
original signed inform ed consent form s, copies of all case report form
s and detailed 
records of treatm ent disposition.  The reco
rds should be retained by the Investigator 
according to local regulations or as specified in the Clinical Trial Agreem ent, whichever 
is longer. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the study 
records m ay be transferred to an
 acceptab le designee, such as another investigato
r, 
another institution, or to BioCryst.  The I
nvestigator m ust obtain BioCryst’s written 
permission before disposing of any records. 
13.6 Study Organization 
13.6.1 Data Monitoring Committee 
BioCryst will a ssemble an indep endent Data M onitoring C ommittee ( DMC) to as sess 
safety parameters of the trial on a period ic, ongoing basis while the tr ial is in prog ress. 
The comm ittee will include a s tatistician and th ree phys icians, tw o of whom  will be  
Infectious Disease specialists. Full detail s of the com position of the D MC and how the 
DMC is to operate will be described in a separate DMC charter. 
13.7 Confidentiality of Information 
BioCryst affirms the subject’s right to prot ection against invasion of privacy.  Only a 
subject id entification n umber, initials and /or date of birth will id
entify subject data 
retrieved by BioCryst .  However, in com pliance with federal regulations, BioCryst
 
requires the investigato r to p ermit BioCryst ’s representatives and,  when neces sary, 
representatives of the FDA or 
other regu latory authoritie s to review and/or copy any 
medical records relevant to the study. 
BioCryst will ensure that the use and disclosur e of protected health information obtained 
during a research study com plies with the HIPAA Privacy Rule.  Th e Rule pro vides 
federal protection for the privacy of prot
ected health inf ormation by im plementing 
standards to  protec t an d guard ag ainst the m isuse of  ind ividually id entifiable h ealth 
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information of subj
ects 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 us e or disclosure of an indi vidual's protected 
health information.  A valid au thorization must meet the implem entation specifications 
under the HIPAA Pri
vacy Rule.  Authorizat
ion m ay be com bined in the Inform
ed 
Consent docum ent (approved by the IRB/IE
C) or it may be a separate docum
ent, 
(approved by the IRB/IEC) or provided by the Investigator or Sponsor (without IRB/IEC 
approval).  It is the responsibility of the 
investigator and institution to obtain such 
waiver/authorization in  writing  f rom the appr opriate ind ividual. HIPAA authoriz ations 
are required for U.S. sites only. 
13.8 Study Publication 
All data generated from this study are the propert y of BioCryst and shall be held in strict 
confidence along with all inform
ation furnis hed 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.   W ritten perm ission to the 
Investigator will be contingen t on the review by BioCryst of  the statistical ana lysis and 
manuscript and will provide fo r nondisclosure of BioCryst confidential or proprietary 
information.  In all case s, the partie s agree to s ubmit all m anuscripts or abstracts to all 
other par ties 30 days prior to su
bmission.  This will e
nable all parties to pr
otect 
proprietary information and to provide comme nts based on infor mation that may not yet 
be available to other parties. 
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14 REFERENCES 
 
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282. 
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality 
associated with influenza and respiratory syncytial virus in the United States. JAMA 
2003;289(2):179–186. 
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment 
on influenza-related lower respiratory tract complications and hospitalizations. Arch 
Intern Med 2003;163(14):1667–1672. 
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral 
neuraminidase inhibitor oseltamivir in experimental human influenza: randomized 
controlled trials for prevention and treatment. JAMA 1999;282(13):1240–1246. 
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant 
influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 
2004;364(9436):759–765. 
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-
influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. 
Antimicrob Agents Chemother 2001;45(4):1162–1167. 
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus 
isolates to different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147. 
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, 
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and 
neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 
2001;45(12):3403–3408. 
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine 
combinations exert additive and synergistic anti-influenza virus effects in MDCK 
cells. Antimicrob Agents Chemother 2004;48(12):4855–4863. 
10. BioCryst Pharmaceuticals. Unpublished data. 
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. 
Injectable peramivir promotes survival in mice and ferrets infected with highly 
pathogenic avian influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San 
Francisco 
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA. 
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival 
against lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32 
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03. 
14. Tamiflu® Package Insert.  Roche Pharmaceuticals. Rev. December 2005. 
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product 
information sheets 
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16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the 
oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 
283(8): 1016-1024. 
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of 
oseltamivir in treatment of influenza: a randomised controlled trial. Lancet 2000; 
355(9218): 1845-1850. 
18. US Department of Health and Human Services, Food and Drug Administration 
Center for Drug Evaluation and Reserach (CDER). Attachment to Guidance on 
Antiviral Product Development- Conducting and Submitting Virology Studies to the 
Agency: Guidance for Submitting Influenza Resistance Data.  
http://www.fda.gov/cder/guidance/7070fnlFLU.htm  
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15 APPENDICES 
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina 
 
NYHA Functional Classification of Heart Failure 
 
Class I 
No symptoms.  Ordinary physical activity such as walking and climbing 
stairs does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary  physical activity.  W alking or climbing stairs 
rapidly; walking uphill; walking or st air climbing after meals, in cold 
weather, in wind, or when under em otional stress causes undue fatigue 
or dyspnea. 
Class III 
Symptoms with less than ordinary 
physical activity.  W alking one to 
two blocks on the level and clim bing more than one flight of stairs in 
normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at res t.  Inab ility to carry on any ph ysical activity without 
fatigue or dyspnea. 
 
NYHA Functional Classification of Angina 
 
Class I 
Angina only with unusually strenuous activity. 
Class II 
Angina with slightly m ore prolonged or slightly more vigorous activity 
than usual. 
Class III 
Angina with usual daily activity. 
Class IV 
Angina at rest. 
 
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261


 
 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-311 
IND No. 76,350 
 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE 
INFLUENZA 
THE IMPROVE I STUDY 
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy) 
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza 
Protocol Date(s):  
Version 1.0: 04 September 2007 
Version 2.0: 05 October 2007 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35244, USA 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
 
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals, 
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to 
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information 
contained herein should be disclosed without prior written approval. 
CONFIDENTIAL 
 
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1 
TITLE PAGE 
 
Protocol Number: 
BCX1812-311 
Study Title: 
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza 
IND Number: 
76, 350 
Investigational Product: 
Peramivir (BCX1812) 
Indication Studied: 
Uncomplicated acute influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35233 
Development Phase: 
3 
Sponsor Medical Officer: 
W. James Alexander, M.D., M.P.H. 
Senior Vice President, Clinical Development  
Chief Medical Officer 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
Email Address: jalexander@biocryst.com  
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki 
and clinical research guidelines established by the Code of 
Federal Regulations (Title 21, CFR Parts 50, 56, and 312) 
and ICH Guidelines. Essential study documents will be 
archived in accordance with applicable regulations. 
Final Protocol Date: 
Version 1.0: 04 September 2007 
Amendment(s) Date(s): 
Version 2.0: 05 October 2007 
 
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1.2 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3 multicenter, random ized, double-blind, placebo-controlled 
study to evaluate the effic acy and safety of intramuscular peramivir in 
subjects with uncomplicated acute influenza 
 
I have carefully read this protocol and agree that it contains all of the necessary  information 
required to conduct this study.  I agree to c onduct this study  as described and according t o 
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for  
Good Clinical Practices, and all applicable regulatory requirements. 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
Name (Print) 
 
 
 
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2 
SYNOPSIS 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
Investigators/Study Sites: 
Multinational 
Development Phase: 
3 
Objectives: 
Primary: 
To evaluate the efficacy of peramivir administered 
intramuscularly compared to placebo on the time to alleviation 
of clinical symptoms in adult subjects with uncomplicated acute 
influenza. 
 
Secondary: 
1. 
To evaluate the safety and tolerability of peramivir 
administered intramuscularly 
2. 
To evaluate secondary clinical outcomes in response to 
treatment 
3. 
To evaluate changes in influenza virus titer in 
nasopharyngeal samples (viral shedding) in response to 
treatment 
 
Exploratory: 
1. To assess pharmacoeconomic measures as response to 
treatment  
2. To assess changes in influenza viral susceptibility to 
neuraminidase inhibitors following treatment 
 
Number of Subjects: 
Total enrollment: a total of 750 evaluable subjects will be 
randomized to treatment (150 subjects in the placebo treatment 
group, 300 subjects in the peramivir 150mg treatment group and 
300 subjects in the peramivir 300mg treatment group).  
 
An evaluable subject is one who is randomized, receives study 
drug, and has confirmed acute influenza by primary viral culture 
or PCR. A positive Rapid Antigen Test (RAT) at screening will 
be required for enrollment.  Because results of clinic-based RAT 
tests may not precisely indicate presence of influenza infection, 
it is expected that at least 850 subjects will be randomized to 
treatment to ensure that 750 evaluable subjects are treated. 
 
Study Design: 
This is a multinational, randomized, double-blind study 
comparing the efficacy and safety of two single dose regimens 
of peramivir administered intramuscularly versus placebo in 
adults with uncomplicated acute influenza. 
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Each subject’s assignment to treatment will be stratified 
according to body mass index (BMI). Two BMI strata are 
planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0 
kg/m2). The number of subjects enrolled who have a BMI ≤ 29.9 
kg/m2 (Normal-Overweight) will be at least 75% of the total 
enrollment. The number of subjects enrolled who have a BMI ≥ 
30.0 kg/m2 (Obese) will be ≤ 25% of total enrollment.   
 
All subjects will be centrally randomized to one of three 
treatment groups according to BMI strata in a ratio of 2:2:1 such 
that 80% of subjects are randomized to one of the two single 
dose regimens of peramivir. 
 
Treatment Group 1:  Peramivir 150mg 
Treatment Group 2:  Peramivir 300mg 
Treatment Group 3:  Placebo 
 
Study drug will be administered as bilateral 2mL intramuscular 
injections (total of 4mL injected in equally divided doses). 
Procedures for gluteal intramuscular injection, with a 
recommended needle length appropriate to the physical 
characteristics of the subject, are provided in the study drug 
administration manual. 
 
Subjects eligible for screening will have an anterior nasal swab 
collected for testing by rapid antigen testing (RAT) for influenza 
A and B, in accordance with the commercially available RAT 
kit instructions.  If the initial RAT is negative, the test should be 
repeated within one hour. Subjects meeting the 
inclusion/exclusion criteria may be enrolled into the study. 
 
All enrolled subjects will record the following information in a 
Study Diary: 
• Assessment of the presence and severity of each of seven 
symptoms of influenza on a 4-point scale (0, absent; 1, mild; 
2, moderate; 3, severe) twice daily (AM, PM) through Day 9 
following treatment, then once daily (AM) through Day 14 
• Oral temperature measurements taken with an electronic 
thermometer every 12 hours. With the exception of the 
baseline measurement, all temperature measurements will be 
obtained at least 4 hours after, or immediately before, 
administration of oral acetaminophen (paracetamol) or other 
anti-pyretic medications. 
• Assessment of subject’s time lost from work or usual 
activities and rating of productivity compared to normal 
(rated as 0-10 on a visual analog scale) once daily through 
Day 14 
• Doses of antipyretic, expectorant, and/or throat lozenges 
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taken for symptomatic relief each day through Day 14 
 
Anterior nose (bilateral) and posterior pharynx specimens 
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3, 
5, and 9, for quantitative virologic assessments. Specimens from 
all subjects yielding influenza virus will also be assessed for 
susceptibility to neuraminidase inhibitors (Day 1 and last 
specimen yielding positive result on culture) as well as other 
virologic assessments (e.g. PCR, genotypic testing) 
 
All virologic assessments will be performed by a central 
laboratory.  
 
Two samples for pharmacokinetic (PK) testing for plasma levels 
of peramivir will be obtained from all subjects randomized.  The 
first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second 
PK sample will be obtained at the day 3 visit in all subjects. The 
data from these PK samples will be utilized in a population 
exposure-response analysis. 
 
At selected sites a separate sub-study will be conducted to 
collect additional PK samples between treatment and Day 3 for 
the purpose of conducting a separate exposure-response 
analysis.  This sub-study will be conducted under a separate 
protocol, BCX1812-311PK. 
 
Study Population: 
Male and female subjects, 18 years of age and older, with 
symptoms consistent with a diagnosis of uncomplicated acute 
influenza infection may be screened for enrollment.  Subject 
eligibility will require the presence of two or more symptoms 
consistent with acute influenza as well as positive results 
obtained from a rapid antigen test (RAT) for influenza A or B at 
screening. 
 
Inclusion Criteria: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A or B Rapid Antigen Test (RAT) 
performed with a commercially available test kit on an 
adequate anterior nasal specimen, in accordance with the 
manufacturer’s instructions.  A negative initial RAT should 
be repeated within one-hour.  
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A 
subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for 
enrollment in the absence of documented fever at the time of 
screening.   
4. Presence of at least one respiratory symptom (cough, sore 
throat, or nasal symptoms) of at least moderate severity. 
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5. Presence of at least one constitutional symptom (myalgia 
[aches and pains], headache, feverishness, or fatigue) of at 
least moderate severity.  
6. Onset of symptoms no more than 48 hours before 
presentation for screening. 
7. Written informed consent. 
 
Exclusion Criteria: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory 
distress. 
3. History of severe chronic obstructive pulmonary disease 
(COPD) or severe persistent asthma. 
4. History of congestive heart failure requiring daily 
pharmacotherapy with symptoms consistent with New York 
Heart Association Class III or IV functional status within the 
past 12 months. 
5. Screening ECG which suggests acute ischemia or presence 
of medically significant dysrhythmia. 
6. History of chronic renal impairment requiring hemodialysis 
and/or known or suspected to have moderate or severe renal 
impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or 
symptoms consistent with otitis, bronchitis, sinusitis and/or 
pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic 
illness, previous organ transplant, or use of 
immunosuppressive medical therapy which would include 
oral or systemic treatment with > 10 mg prednisone or 
equivalent on a daily basis within 30 days of screening. 
10. Currently receiving treatment for viral hepatitis B or viral 
hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 
cell/mm3. 
12. Current therapy with oral warfarin or other systemic 
anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, 
or oseltamivir in the 7 days prior to screening. 
14. Immunized against influenza with live attenuated virus 
vaccine (FluMist®) in the previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine 
within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 
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14 days. 
17. History of alcohol abuse or drug addiction within 1 year 
prior to admission in the study. 
18. Participation in a previous study of intramuscular or 
intravenous peramivir or previous participation in this study 
19. Participation in a study of any investigational drug or device 
within the last 30 days. 
 
Study Endpoints: 
Primary Endpoint: 
Clinical: 
Time to alleviation of clinical symptoms of influenza. 
 
Secondary Endpoint(s): 
Safety: 
Incidence of treatment-emergent adverse events and treatment-
emergent changes in  clinical laboratory tests. 
 
Clinical: 
Time to resolution of fever. 
Incidence of influenza related complications. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
viral titer assay (TCID50). 
 
Exploratory Endpoint(s): 
Pharmacoeconomic: 
Medical resource utilization (MRU), missed days of work, and 
impact of influenza illness on subject’s work performance 
and/or productivity. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
PCR. 
Change in influenza virus susceptibility to neuraminidase 
inhibitors. 
 
Investigational Product, Dose, and Mode of Administration: 
Peramivir (BCX-1812), 75mg/mL, 2mL per injection, administered as bilateral injections. 
Reference Therapy, Dose, and Mode of Administration: 
Matching Placebo (buffered diluent), 2mL per injection administered as bilateral injections. 
Duration of Treatment: 
Following treatment on day 1, study duration for all subjects is 
expected to be up to 14 days (including all visits). Presence of 
unresolved adverse events and/or treatment-emergent laboratory 
findings at the Day 14 visit, or persistent or recurrent symptoms 
of influenza (of the seven symptoms assessed) of either 
moderate or severe intensity at the Day 14 visit, will require 
additional follow up. 
Statistical Methods: 
Study Hypothesis: 
The null hypothesis (H0) for this study is that the time to 
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alleviation of influenza symptoms is the same for subjects 
treated with placebo and for subjects treated with peramivir 
150mg (H01) or peramivir 300mg (H02). 
 
The alternative hypothesis (H1) is that subjects treated with 
peramivir 150mg (H11) or peramivir 300mg (H12) have an 
improvement in time to alleviation of influenza symptoms over 
those treated with placebo. 
 
Sample Size: 
From preliminary results of a phase 2 study evaluating peramivir 
treatment of uncomplicated influenza, it is expected that the 
median time to alleviation of symptoms will be 137.0 hours  
(95% CI: 115.9, 165.8) for subjects receiving placebo 
treatment.  Additionally, it is expected that the median time to 
alleviation for the 150 mg dose peramivir arm will be reduced 
by 30% compared to placebo (see table below) yielding a hazard 
ratio of 0.70.  
 
Median Time To Alleviation of Symptoms (Hours) 
Placebo 
Peramivir 150mg 
Difference (hours) 
145.0 
101.5 
43.5 
140.0 
98.0 
42.0 
135.0 
94.5 
40.5 
130.0 
91.0 
39.0 
125.0 
87.5 
37.5 
120.0 
84.0 
36.0 
115.0 
80.5 
34.5 
110.0 
77.0 
33.0 
105.0 
73.5 
31.5 
100.0 
70.0 
30.0 
 
Using these assumptions, a sample size of 300 evaluable 
subjects per active treatment group and 150 evaluable subjects 
in the placebo group (a total of 750 evaluable subjects) is 
sufficient to provide at least 90% power to detect a hazard ratio 
of 0.70 using a log-rank statistic and α = 0.025 (SAS version 
9.1.3; total accrual time 7 months; total enrollment time 6 
months). 
Efficacy:  
The intent-to-treat infected population (ITTI) will include all 
subjects who are randomized, received study drug, and have 
confirmed influenza by primary viral culture or PCR.  The 
primary efficacy variable is the time to alleviation of symptoms, 
defined as the time from injection of study drug to the start of 
the time period when each of seven symptoms of influenza are 
either absent or are present at no more than mild severity level 
and remain at no worse than this severity status for a 21.5 hour 
(24 hours – 10%) period. 
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Descriptive statistics for the primary efficacy variable will be 
tabulated by treatment group.  Alleviation of symptoms will be 
determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be 
summarized for each treatment group.  Treatment difference will 
be assessed using a Cox Regression model with effects for BMI 
at screening, influenza type by PCR at screening, treatment 
group, and, if necessary, influenza season at randomization.  
Pairwise comparisons between each active group and placebo 
will be constructed from the Cox Regression model.  Subjects 
who do not experience alleviation of symptoms will be censored 
at the date of their last non-missing assessment.  Time to 
resolution of fever will be analyzed in a similar manner.   
 
Efficacy analyses will be repeated for a Per-Protocol Infected 
population (PPI). This population will include those subjects in 
the ITTI population who received an adequate intramuscular 
injection.  Details of this population will be described in the 
statistical analysis plan. The PPI population analysis will be 
used as supportive to the primary analysis with the ITTI. 
 
Changes in influenza virus TCID50 (viral titers from 
nasopharyngeal specimens) will be compared using the van 
Elteren statistic controlling for BMI at screening, influenza type 
by PCR, and, if necessary, for influenza season at 
randomization.  Analyses of other continuous endpoints will be 
analyzed in a similar manner.  
 
The number and percentage of subjects experiencing influenza 
related complications (IRC) will be summarized by 
complication preferred term and treatment group.  The 
difference between the treatment groups will be assessed using a 
logistic regression model with factors for treatment group, BMI 
at screening, influenza type by PCR, and influenza season at 
randomization (if necessary).  Pairwise differences between the 
treatment groups will be evaluated using contrasts from the final 
logistic regression model. 
 
Safety: 
Safety analyses will be presented for all subjects in the safety 
population, defined as all randomized subjects who receive at 
least one dose of study drug.  Adverse events will be mapped to 
a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification.   
 
The occurrence of treatment-emergent AEs will be summarized 
using preferred terms, system organ classifications, and severity.  
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be 
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generated.  All AEs will be listed for individual subjects 
showing both verbatim and preferred terms.   
 
Descriptive summaries of vital signs and quantitative clinical 
laboratory changes will be presented by study visit.  Frequency 
and percentages of subjects with abnormal laboratory test results 
will be summarized by toxicity grade.   
 
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 each abnormal physical 
examination finding will be presented.  
 
The number and percent of subjects discontinuing study as well 
as the reasons for discontinuation will be summarized by 
treatment group. 
 
Date of Protocol: 
Version 1.0: 04-September-2007 
Amendment (Dates): 
Version 2.0: 05-October-2007 
 
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3 
TABLE OF CONTENTS 
1 TITLE 
PAGE .................................................................................................................2 
1.1 P
ROTOCOL APPROVAL SIGNATURE PAGE ......................................................................3 
1.2 C
LINICAL STUDY PROTOCOL AGREEMENT ....................................................................4 
2 SYNOPSIS
.....................................................................................................................5 
3 TABLE 
OF CONTENTS .............................................................................................13 
3.1 L
IST OF FIGURES...........................................................................................................15 
3.2 L
IST OF TABLES............................................................................................................15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................16 
5 INTRODUCTION
........................................................................................................18 
5.1 B
ACKGROUND...............................................................................................................18 
5.2 R
ATIONALE FOR STUDY................................................................................................18 
5.3 N
ON-CLINICAL EXPERIENCE WITH PERAMIVIR............................................................19 
5.3.1 
In vitro Assays..........................................................................................................19 
5.3.2 Anim
al Models.........................................................................................................19 
5.4 P
REVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................20 
5.5 P
REVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR ........................20 
5.6 P
HASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR..........................................21 
5.7 DOSE RATIONALE ................................................................................................................23 
6 STUDY 
OBJECTIVES ................................................................................................24 
6.1 O
BJECTIVES ..................................................................................................................24 
6.1.1 Prim
ary Objective ....................................................................................................24 
6.1.2 Secondary
 Objective(s) ............................................................................................24 
6.1.3 Explorator
y Objective(s)..........................................................................................24 
6.2 S
TUDY ENDPOINTS .......................................................................................................24 
6.2.1 Prim
ary Endpoint .....................................................................................................24 
6.2.2 Secondary
 Endpoint(s).............................................................................................24 
6.2.3 Explorator
y Endpoints .............................................................................................25 
7 STUDY 
DESIGN.........................................................................................................25 
7.1 O
VERALL STUDY DESIGN AND PLAN ...........................................................................25 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS................................................26 
8.1.1 Inclusion 
Criteria......................................................................................................26 
8.1.2 Exclusion 
Criteria.....................................................................................................27 
8.1.3 
Removal of Subjects from Therapy or Assessment .................................................27 
9 TREATMENTS
............................................................................................................28 
9.1 T
REATMENTS ADMINISTERED ......................................................................................28 
9.2 I
DENTITY OF INVESTIGATIONAL PRODUCT(S)..............................................................28 
9.3 M
ETHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................29 
9.4 S
TUDY MEDICATION ACCOUNTABILITY ......................................................................29 
9.5 B
LINDING/UNBLINDING OF TREATMENTS....................................................................29 
9.6 P
RIOR AND CONCOMITANT THERAPIES........................................................................30 
9.7 O
VERDOSE AND TOXICITY MANAGEMENT...................................................................30 
9.8 D
OSE INTERRUPTION ....................................................................................................30 
10 STUDY 
CONDUCT ....................................................................................................30 
10.1 E
VALUATIONS...............................................................................................................30 
10.1.1 Medical 
History ...................................................................................................30 
10.1.2 
Rapid Antigen Test for Influenza ........................................................................30 
10.1.3 
Physical Examination and Influenza-related Complications Assessments..........31 
10.1.4 Vital 
Signs ...........................................................................................................31 
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10.1.5 Electrocardiogram
 Measurements .......................................................................31 
10.1.6 Clinical 
Laboratories............................................................................................31 
10.1.7 
Urine Pregnancy Test...........................................................................................32 
10.1.8 Serology
 for Influenza .........................................................................................32 
10.1.9 
Samples for Virologic Laboratory Assessments..................................................32 
10.1.10 
Subject Self Assessments.....................................................................................32 
10.1.11 Concom
itant Medications....................................................................................33 
10.1.12 Adverse 
Events ....................................................................................................33 
10.1.13 
Pharmacokinetic Exposure Samples....................................................................33 
10.2 S
CREENING PERIOD ......................................................................................................33 
10.2.1 Inform
ed Consent ................................................................................................33 
10.2.2 
Screening/Baseline Evaluation and Enrollment...................................................33 
10.3 T
REATMENT PERIOD—STUDY DAY 1 ..........................................................................34 
10.3.1 Pre-dose 
Evaluations-Study Day 1 ......................................................................34 
10.3.2 Post-dose 
Evaluations-Study Day 1.....................................................................34 
10.4 P
OST-TREATMENT ASSESSMENT PERIOD.....................................................................35 
10.4.1 
Days 2, 3, 5, 9 and 14 ..........................................................................................35 
10.4.2 
Adverse Events Reported at Post-treatment Visits ..............................................36 
11 
ADVERSE EVENT MANAGEMENT........................................................................39 
11.1 D
EFINITIONS .................................................................................................................39 
11.1.1 Adverse 
Event......................................................................................................39 
11.1.2 
Serious Adverse Event.........................................................................................39 
11.2 M
ETHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND  
REPORTING SERIOUS ADVERSE EVENTS ......................................................................40 
11.2.1 Definition 
of Severity ..........................................................................................40 
11.2.2 
Definition of Relationship to Study Drug............................................................41 
11.2.3 
Reporting Serious Adverse Events ......................................................................41 
11.2.4 E
mergency Procedures ........................................................................................42 
12 STATISTICAL 
METHODS ........................................................................................42 
12.1 D
ATA COLLECTION METHODS .....................................................................................42 
12.2 S
TATISTICAL ANALYSIS PLAN......................................................................................43 
12.3 S
TUDY HYPOTHESIS .....................................................................................................43 
12.4 S
AMPLE SIZE ESTIMATES .............................................................................................43 
12.5 A
NALYSIS POPULATIONS..............................................................................................44 
12.6 I
NTERIM AND END OF STUDY ANALYSES.....................................................................45 
12.7 E
FFICACY ANALYSES ...................................................................................................45 
12.7.1 
Primary Efficacy Endpoint ..................................................................................45 
12.7.2 
Secondary Efficacy Endpoints.............................................................................45 
12.7.3 Explorator
y Endpoint...........................................................................................46 
12.8 S
AFETY ANALYSES.......................................................................................................47 
12.9 S
UB-STUDY AND PHARMACOKINETIC ANALYSIS.........................................................47 
12.10 G
ENERAL ISSUES FOR STATISTICAL ANALYSIS............................................................47 
12.10.1 
Multiple Comparisons and Multiplicity...............................................................47 
12.10.2 Covariates
............................................................................................................48 
12.10.3 Planned 
Sub-Groups ............................................................................................48 
12.10.4 Missing 
Data........................................................................................................48 
13 STUDY 
ADMINISTRATION.....................................................................................48 
13.1 R
EGULATORY AND ETHICAL CONSIDERATIONS...........................................................48 
13.1.1 
Regulatory Authority Approvals .........................................................................48 
13.1.2 
Ethics Committee Approvals...............................................................................49 
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13.1.3 
Subject Informed Consent ...................................................................................49 
13.1.4 
Payment to Subjects.............................................................................................50 
13.1.5 Investigator 
Reporting Requirements ..................................................................50 
13.2 S
TUDY MONITORING ....................................................................................................50 
13.3 Q
UALITY ASSURANCE ..................................................................................................50 
13.4 S
TUDY TERMINATION AND SITE CLOSURE...................................................................50 
13.5 R
ECORDS RETENTION...................................................................................................50 
13.6 S
TUDY ORGANIZATION.................................................................................................51 
13.6.1 
Data Monitoring Committee................................................................................51 
13.7 C
ONFIDENTIALITY OF INFORMATION ...........................................................................51 
13.8 S
TUDY PUBLICATION....................................................................................................51 
14 REFERENCES
.............................................................................................................52 
15 APPENDICE
S..............................................................................................................54 
15.1 NYHA
 FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA......54 
15.2 C
RITERIA FOR SEVERE COPD AND SEVERE ASTHMA..................................................55 
 
3.1 
 List of Figures 
Figure 1 
Study Measurements and Visit Schedule.................................................................37 
 
3.2 
List of Tables 
Table 1 
Results of study BC-01-03.......................................................................................20 
Table 2 
Pharmacokinetic parameters from study Him-06-111. ............................................21 
Table 3 
Summary of Efficacy from BCX1812-211. .............................................................22 
Table 4 
Summary of Safety from BCX1812-211. ................................................................23 
Table 5 
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio)..........44 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE  
adverse event 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the curve 
AUC0–72 
area under the curve from time 0 to 72 hours 
AUC0–∞ 
area under the curve extrapolated from time 0 to infinity 
BMI 
Body Mass Index in kg/m2 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CIOMS 
Council for International Organizations of Medical sciences 
Cmax  
maximum plasma concentration 
CK 
creatine kinase 
CNS  
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
GCP  
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IC50  
median inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
influenza related complications  
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IUD 
intrauterine device 
IVRS 
interactive voice response system 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
RAT 
Rapid Antigen Test 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SD 
standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Event 
t1/2  
elimination half-life 
t1/2 λz 
terminal half-life 
TCID50 
tissue-culture infective dose50 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to attain maximum plasma concentration 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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5 
INTRODUCTION 
5.1 
Background 
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the 
respiratory tract.  Typical influenza illness is characterized by abrupt onset of fever, headache, 
myalgia, sore throat, and nonproductive cough.1  The illness is usually self-limiting, with relief of 
symptoms occurring within 5 to 7 days.  Nevertheless, it is an important disease for several 
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation, 
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk 
of death, particularly in the elderly.  During 19 of the 23 influenza seasons between 1972/1973 
and 1994/1995, estimated influenza-associated deaths in the United States ranged from 
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for 
more than 90% of the deaths attributed to pneumonia and influenza.2 
Presently, only a few measures are available that can reduce the impact of influenza: active 
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or 
therapy with an influenza-specific antiviral drug.  Neuraminidase inhibitors are the current 
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include 
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral 
prodrug of the active agent, oseltamivir carboxylate.  Influenza neuraminidase is a surface 
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids.  The enzyme 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.  The neuraminidase inhibitors 
represent an important advance in the treatment of influenza with respect to activity against 
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory 
complications,3 and lower rates of antiviral drug resistance4. 
The use of currently available neuraminidase inhibitors has been limited by concerns including, 
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence 
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of 
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir. 
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the 
armamentarium of drugs for the treatment of influenza infections due to its potential for 
parenteral administration and lower frequency of dosing. 
5.2 
Rationale for Study 
An oral formulation of peramivir has previously been evaluated in a full range of safety, 
tolerability, pharmacokinetic, and efficacy studies.  In a multinational phase 3 clinical trial 
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B 
infections, and improvement in the relief of clinical symptoms.  Because of the limited 
bioavailability of peramivir following oral administration (<5%), it was determined that the 
parenteral route of administration is more appropriate for the delivery of peramivir.  Subsequent 
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that 
parenteral routes of administration result in plasma levels of drug that are as much as 100 times 
those achieved via the oral route. Further details of these studies are provided below and in the 
Investigator Brochure. 
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Because of the previous demonstration of significant antiviral activity, the strong suggestion of 
clinical efficacy of oral peramivir previously demonstrated in acute influenza, and the 
encouraging pharmacokinetic and preliminary safety profile of the intramuscular formulation of 
peramivir demonstrated to date, this phase 3 study will be conducted to evaluate the efficacy and 
safety profile of intramuscular peramivir and to determine the optimal single dose regimen.  
5.3 
Non-Clinical Experience with Peramivir 
5.3.1 
In vitro Assays 
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations 
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and 
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza 
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase 
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent 
neuraminidase assay.  Inhibition of Type A influenza neuraminidase by peramivir was 
approximately an order of magnitude greater than inhibition of neuraminidase from Type B 
viruses.  IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B 
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.  
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of 
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.   
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase 
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM) 
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).  
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to 
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8   
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9  Peramivir remained a potent inhibitor against all oseltamivir-resistant 
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.  
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant 
strains, which had the following mutations:  R292K, E119G, E119A, and E119D.  However, one 
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell 
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 = 
400nM). 
5.3.2 
Animal Models 
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg) 
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100% 
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse 
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg) 
resulted in 100% survival, compared to 100% mortality in the control group injected with 
vehicle.10 
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the 
infecting virus strain.  In a mouse model, a single intramuscular dose of peramivir (30mg/kg) 
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain, 
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given 
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orally at 10mg/kg/day for 5 days11.  In similar experiments, mice inoculated with the same strain 
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited 
100% survival12.  This longer duration of peramivir treatment also prevented viral replication in 
the lungs, brain and spleen at days 3, 6 and 9 post inoculation. 
5.4 
Previous Phase 3 Clinical Experience with Oral Peramivir 
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary 
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in 
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001.  A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted.  Two dose 
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg 
QD for 4 days, were compared to a matched placebo treatment group.  A total of 1246 subjects 
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America, 
Australia and New Zealand.  As presented in the Table 1 below, the primary end-point of time to 
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be 
significantly different (p=0.17) between the three treatment groups.13  A sub-group analysis of the 
time to relief of symptoms by country or region demonstrated marked differences in the primary 
endpoint.. In the subset of influenza-infected subjects enrolled at  sites in the US, clinically 
meaningful differences in time to relief of influenza symptoms between the placebo and the two 
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.  
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral 
shedding, achieved or approached statistically significant differences between the peramivir and 
placebo treatment groups (p=0.03-0.06). 
Table 1 
Results of study BC-01-03 
 
 
Median Time to Relief of Influenza Symptoms (Hours) 
Dose and Regimen 
Overall Results 
(n=694) 
US Sites 
(n=198) 
Peramivir 800mg po x 5d 
89.0 
70.8 
Peramivir 800mg po x 1d 
 and          400mg po x 4d 
91.7 
88.8 
Placebo x 5 days 
104.4 
106.8 
p value 
0.17 
0.07 
 
5.5 
Previous Phase 1 Experience with Intramuscular Peramivir 
Two phase 1studies evaluating the safety and pharmacokinetics of an intramuscular formulation 
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir.  
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of 
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and 
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of 
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i.m. peramivir generally occurred within 30 minutes following injection.  Plasma 
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three 
intramuscular single dose regimens evaluated. 
Table 2 
Pharmacokinetic parameters from study Him-06-111. 
 
Dose (mg) 
Cmax (ng/mL) 
AUC0-∞ (hr·ng/mL) 
t½a (hr) 
75 i.m. 
4296 ± 812 
11659 ± 1123 
19.8 ± 7.9 
150 i.m. 
7612 ± 884 
23952 ± 3804 
24.3 ± 4.1 
300 i.m. 
15150 ± 2367 
49649 ± 5619 
22.8 ± 2.5 
aterminal half life 
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were 
administered as single i.m. injections on two consecutive days (6 subjects per group). This 
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m. 
peramivir following the second day of dosing were consistent with those seen following single 
doses of the drug. 
The observations of safety and tolerability of i.m. peramivir in each of the 2 phase 1 studies were 
unremarkable.  No serious adverse events were reported.  The most commonly observed adverse 
events or laboratory abnormalities were headache, several reports of signs and symptoms of 
vasovagal reactions following injections, and transient increases in creatine kinase.  No consistent 
differences in frequency of adverse events were observed between the active and placebo 
treatment groups, with the exception that CK elevations appeared to be dose related in the 
peramivir treatment groups.  The vasovagal reactions were attributed to the receipt of relatively 
large volumes of i.m. injection (2 injections each of 2mL) in the fasted state. 
5.6 
Phase 2 Experience with Intramuscular Peramivir 
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of 
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to 
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to 
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical 
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the 
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve 
statistical significance in the pre-planned ITTI study population (Table 3). Based on pre-planned 
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not 
receive an adequate intramuscular injection.  
In phase 1 studies (Hi
m-06-111 and Him-06-112) of i.m . per amivir, significant increases in 
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who 
received active study drug or placebo. CK is a well established marker of muscle damage, and it 
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection. 
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not 
observed in a majority of subjects.  In the phase 1 studies study drug was administered with a 1½ 
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inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with 
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed 
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle 
used for injection failed to penetrate muscle and deliver intramuscular study medication in many 
subjects. 
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was 
observed over baseline. Within this adequate intramuscular injection sub-group, notable 
improvements in the time to alleviation of symptoms were observed for both peramivir dose 
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg 
treatment (Table 3).  These efficacy data support the further development of peramivir as a single 
dose, intramuscular treatment for acute influenza. 
Table 3 
Summary of Efficacy from BCX1812-211. 
 
 
Placebo 
Peramivir 
150mg 
Peramivir 
300mg 
Intent-to-Treat Infected Population1 (n=313) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=107 
137.0 
115.9-163.8 
n=104 
114.1 
95.2-145.5 
22.9 
n=102 
115.9 
77.8-136.6
21.1 
Adequate Injection Population2 (n=101) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=40 
152.2 
103.8-183.9 
n=32 
107.6 
76.8-175.1 
44.6 
n=29 
87.4 
40.8-163.8
64.8 
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at 
baseline/screening visit. 
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue, 
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study 
visit. 
An independent data monitoring committee reviewed grouped blinded safety data throughout 
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and 
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC. 
The three treatment groups were similar with respect to the frequency and severity of adverse 
events. Two serious adverse events were reported in the study, and neither was considered by the 
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study 
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death) 
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There 
were no meaningful differences among the three treatment groups with respect to the frequency 
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities, 
together with a list of the most frequently reported adverse events, is presented in Table 4. 
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Table 4 
Summary of Safety from BCX1812-211. 
 
Safety Parameters 
Placebo 
(N=114) 
Peramivir 150 mg 
(N=113) 
Peramivir 300 mg 
(N=115) 
Any Clinical Adverse Event 
49 (43%) 
43 (38%) 
44 (38%) 
Any Graded Laboratory Toxicity 
99 (87%) 
93 (82%) 
92 (80%) 
Any Serious Adverse Event 
1 (<1%) 
0 
1 (<1%) 
Most Frequent Adverse Events 
Assessed as Study Drug-Related 
    Diarrhea 
    Nausea 
    Vasovagal Reaction 
 
 
5 (4%) 
7 (6%) 
4 (4%) 
 
 
5 (4%) 
7 (6%) 
2 (2%) 
 
 
6 (5%) 
9 (8%) 
0 
 
5.7 Dose Rationale 
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg 
twice daily in adults14.  Oseltamivir was shown to be clinically effective in a phase 3 study of oral 
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were 
sufficient for regulatory approval for marketing of oseltamivir.  At least 75% of an oral dose of 
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is 
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is 
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this 
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated 
acute influenza.  
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of 
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are 
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose.  Previous studies have 
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal 
secretions after parenteral administration of this drug. .  Within several hours after administration, 
the concentrations in secretions were approximately 100-fold lower than in serum or plasma.  In 
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in 
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in 
infecting virus strains.  Intramuscular doses of peramivir, including doses of 150mg and 300mg 
have been shown to be well tolerated in previous Phase 1 studies.  In the completed Phase 2 
study, both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns 
were apparent. Therefore, it is appropriate for these two dose regimens to undergo further 
evaluation in this Phase 3 study.  
 
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6 
STUDY OBJECTIVES 
6.1 
Objectives 
6.1.1 
Primary Objective 
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the 
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza. 
6.1.2 
Secondary Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of peramivir administered intramuscularly, 
2. To evaluate secondary clinical outcomes in response to treatment, 
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in 
response to treatment. 
6.1.3 
Exploratory Objective(s) 
The following exploratory objectives have been identified for this study. 
1. To assess pharmacoeconomic measures as response to treatment. 
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following 
treatment. 
6.2 
Study Endpoints 
6.2.1 
Primary Endpoint 
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza for each 
subject. 
6.2.2 
Secondary Endpoint(s) 
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of: 
Safety: 
Incidence of treatment-emergent adverse events and treatment-emergent changes 
in clinical laboratory tests. 
Clinical:  
Time to resolution of fever; Incidence of influenza related complications. 
Virologic: 
Quantitative change in influenza virus shedding, measured by viral titer assay 
(TCID50). 
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6.2.3 
Exploratory Endpoints 
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also 
be assessed and include: 
Pharmacoeconomic:  
Medical resource utilization (MRU), missed days of work, and impact of 
influenza illness on subject’s work performance and/or productivity. 
Virologic: 
Quantitative change in influenza virus shedding, measured by PCR; 
Change in influenza virus susceptibility to neuraminidase inhibitors. 
 
7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multinational, randomized, double-blind study comparing the efficacy and safety of two 
single dose regimens of peramivir administered intramuscularly versus placebo in adults with 
uncomplicated acute influenza. 
Each subject’s assignment to treatment will be stratified according to body mass index (BMI). 
Two BMI strata are planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0 kg/m2). The 
number of subjects enrolled who have a BMI ≤ 29.9 kg/m2 (Normal-Overweight) will be at least 
75% of the total enrollment. The number of subjects enrolled who have a BMI ≥ 30.0 kg/m2 
(Obese) will be ≤ 25% of total enrollment.  All subjects will be centrally randomized to one of 
three treatment groups in a ratio of 2:2:1 such that 80% of subjects are randomized to one of the 
two single dose regimens of peramivir. 
Treatment Group 1:  Peramivir 150mg 
Treatment Group 2:  Peramivir 300mg 
Treatment Group 3:  Placebo 
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected 
in equally divided doses). Procedures for intramuscular injection, with a recommended needle 
length appropriate to the physical characteristics of the subject, are provided in the study drug 
administration manual. 
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for 
influenza A and B, in accordance with the commercially available RAT kit instructions.  If the 
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the 
inclusion/ exclusion criteria may be enrolled into the study. 
All enrolled subjects will record the following information in a Study Diary.  
• 
Assessment of the presence and severity of each of seven symptoms of influenza on a 
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through 
Day 9 following treatment, then once daily (AM) through Day 14. 
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• 
Oral temperature measurements will be taken with an electronic thermometer every 12 
hours. With the exception of the baseline measurement, all temperature measurements 
will be obtained at least 4 hours after, or immediately before, administration of oral 
acetaminophen (paracetamol) or other antipyretic medication. 
• 
Assessment of subject’s time lost from work or usual activities and rating of productivity 
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14 
• 
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief 
each day through Day 14 
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments.  Specimens from all 
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase 
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic 
assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a 
central laboratory.  
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained 
from all subjects randomized.  The first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second PK sample will be obtained at the 
day 3 visit in all subjects. The data from these PK samples will be utilized in a population 
exposure-response analysis. 
At selected sites a separate sub-study will be conducted to collect additional PK samples between 
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis.  This 
sub-study will be conducted under a separate protocol, BCX1812-311PK.  Study drug will be 
administered as bilateral 2mL intramuscular injections (total of 4mL injected in divided doses). 
Procedures for intramuscular injection, with a recommended needle length appropriate to the size 
and weight of the subject, are provided in the study drug administration manual. 
 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1.1 
Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in this study: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A or B Rapid Antigen Test (RAT) performed with a commercially 
available test kit on an adequate anterior nasal specimen, in accordance with the 
manufacturer’s instructions.  A negative initial RAT should be repeated within one hour.  
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC 
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for enrollment in the absence of 
documented fever at the time of screening.   
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of 
at least moderate severity. 
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5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache, 
feverishness, or fatigue) of at least moderate severity. 
6. Onset of symptoms no more than 48 hours before presentation for screening. 
7. Written informed consent. 
8.1.2 
Exclusion Criteria 
Subjects to whom any of the following criteria apply will be excluded from the study: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory distress 
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent 
asthma. (See Section  15.2). 
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms 
consistent with New York Heart Association Class III or IV functional status within the 
past 12 months. (See Section  15.1). 
5. Screening ECG which suggests acute ischemia or presence of medically significant 
dysrhythmia. 
6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to 
have moderate or severe renal impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis, 
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic illness, previous organ transplant, 
or use of immunosuppressive medical therapy which would include oral or systemic 
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of 
screening. 
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 cell/mm3. 
12. Current therapy with oral warfarin or other systemic anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days 
prior to screening. 
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the 
previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 14 days. 
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study. 
18. Participation in a previous study of intramuscular or intravenous peramivir or previous 
participation in this study. 
19. Participation in a study of any investigational drug or device within the last 30 days. 
8.1.3 
Removal of Subjects from Therapy or Assessment 
All subjects are permitted to withdraw fro m participation in this  study at any ti me and for any  
reason, specified or 
unspecified, and without prejudice.  T he Investigator  or sp onsor m ay 
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terminate the subject’s participation in the study at any time for reasons including the following: 
1. Adverse event; 
2. Intercurrent illness; 
3. Non-compliance with study procedures; 
4. Subject’s decision; 
5. Administrative reasons; 
6. Lack of efficacy; 
7. Investigator’s opinion to protect the subject’s best interest. 
Any subject who withdraws because of an adve
rse event will be followe d until the sign(s) or 
symptom(s) that constituted the adverse event has/ha ve resolved or is determ ined to represent a 
stable medical condition. 
A subject should be with drawn from the trial if, in the opinion of the Investigator, it is medically 
necessary, or if it is the desire of the subject. 
If a subject does not return for a scheduled visit, 
every effort should be made to contact the subject and determine the subject’s medical condition.  
In any circumstance, every effort should be made to document subject outcome, if possible. 
If the subject withdraws consent, no fu rther ev aluations should b e perfo rmed and no attempts 
should be made to collect additional data. 
 
9 
TREATMENTS 
9.1 
Treatments Administered 
Peramivir is an investigational drug.  Peramivir for intramuscular injection is a small-volume 
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer.  The 
pH is approximately 3.0. 
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a 
pH of approximately 3.0 will be supplied. 
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF. 
Procedures for intramuscular injection, with a recommended needle length appropriate to the 
physical characteristics of the subject, are provided in the study drug administration manual. 
9.2 
Identity of Investigational Product(s) 
Peramivir and placebo peramivir will be supplied in clear 2mL vials.  An individual study drug 
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the 
treatment group), 2 syringes and 2 needles in which to draw up the solution for intramuscular 
injection. All materials will be packaged in a labeled box container. All study drug kits must be 
stored at 2-8oC.   
Each individual study drug kit will be labeled with some or all of the following information as 
required by local regulations: 
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• 
Sponsor name and contact information, study protocol number, kit number, description of 
the contents of the container, instructions for the preparation of the syringe and 
administration of the study drug, conditions for storage, statement regarding the 
investigational (clinical trial) use of the study drug and date for retest or expiry date. 
Each vial of study drug will be labeled with some or all of the following information as required 
by local regulations: 
• 
Sponsor name, study protocol number, description of the contents of the vial, instructions 
for the preparation of the syringe, statement regarding the investigational (clinical trial) 
use of the study drug and lot number. 
9.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be centrally randomized according to BMI strata in a ratio of 2:2:1 to one of three 
treatment groups: single dose peramivir 150mg, single dose peramivir 300mg or placebo, in 
accordance with a computer-generated randomization schedule prepared by a non-study 
statistician. Eighty percent (80%) of subjects will be randomized to treatment with one of the two 
single dose regimens of peramivir, 20% will be randomized to treatment with placebo. 
Each subject’s assignment to treatment will be stratified according to body mass index (BMI). 
Two BMI strata are planned: Normal-Overweight (≤ 29.9 kg/m2), and Obese (≥ 30.0 kg/m2). The 
number of subjects enrolled who have a BMI ≤ 29.9 kg/m2 (Normal-Overweight) will be at least 
75% of the total enrollment. The number of subjects enrolled who have a BMI ≥ 30.0 kg/m2 
(Obese) will be ≤ 25% of total enrollment.   
Once a subject is eligible for randomization, he/she will be assigned a study drug kit number that 
will be obtained by study staff from the study interactive voice response system (IVRS).  Once a 
study drug kit number has been assigned to a subject, it cannot be reassigned to any other subject.   
9.4 
Study Medication Accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs 
received from the sponsor, issued to the subject or directly administered to the subject (including 
date and time), and any drug accidentally destroyed.  The sponsor will supply a specific drug-
accountability form.  At the end of the study, information describing study drug supplies (e.g., lot 
numbers) and disposition of supplies for each subject must be provided, signed by the 
Investigator or designee, and collected by the study monitor.  If any errors or irregularities in any 
shipment of study medication to the site are discovered at any time, the Project Manager must be 
contacted immediately. 
At the end of the study, all medication not dispensed or administered and 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 at the participating institution. 
9.5 
Blinding/Unblinding of Treatments 
This is a double-blind study.  The treatment group assignment will not be known by the study 
subjects, the investigator, the clinical staff, the CRO or Sponsor staff during the conduct of the 
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study. 
Section  11.2.4 provides information regarding the process for unblinding the treatment 
assignment, if necessary, in the event of an SAE. 
9.6 
Prior and Concomitant Therapies 
All medications, by any route of administration, used during this study must be documented on 
the Case Report Form (CRF).  Prescription as well as non-prescription medications should be 
recorded. Medication used for the treatment of influenza-related symptoms will be captured by 
the subject in the diary card provided by BioCryst. 
9.7 
Overdose and Toxicity Management 
To date there is no experience with overdose of intramuscular or intravenous peramivir.  If 
overdose occurs, subjects should receive indicated supportive therapy and evaluation of 
hematologic and clinical chemistry laboratory tests should be conducted.  The effect of 
hemodialysis on elimination of peramivir is unknown. 
9.8 
Dose Interruption 
As this is a study of a single injection of peramivir or placebo, guidelines for treatment 
interruption for drug related SAEs or toxicities are not applicable. 
 
10 STUDY CONDUCT 
A study schedule of evaluations is presented in Figure 1.  A detailed list of the evaluations an 
visits is also provided in the following sections. 
10.1 Evaluations 
All subjects enrolled in this study will undergo the following evaluations: 
10.1.1 Medical History 
Medical history, influenza vaccination status within the previous 12 months and demographic 
data (including smoking behavior) will be recorded at Screening/Baseline. 
10.1.2 Rapid Antigen Test for Influenza 
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A and B 
will be performed on an adequate specimen collected by swabbing the anterior nose in 
accordance with the RAT manufacturer’ instructions.  A negative initial RAT should be repeated 
within one hour.  Refer to the Study Manual for instructions regarding the use of the RAT kits 
provided for this study.  Sites may use the kits provided by the Sponsor or any other 
commercially approved RAT available at their site to document a confirmed influenza infection.  
 
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10.1.3 Physical Examination and Influenza-related Complications Assessments 
The Investigator will perform a physical examination at Screening/Baseline.  Subject’s height and 
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF. 
Study personnel will be provided with an influenza-related complications (IRC) checklist in the 
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following 
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects 
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia 
at screening are not eligible for enrollment in this study (See Section  8.1.2: exclusion criteria 
number 8). 
A targeted physical examination will be conducted at each visit to record the presence/absence of 
influenza related complications (IRC). If the investigator determines that the subject experiences 
(or is presumed to experience) an IRC as noted above, he/she will record that assessment on the 
IRC CRF page and any medication used to treat the condition will be recorded on the 
concomitant medication page.  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 adverse events. Any injection site reactions noted will be recorded in the CRFs 
as adverse events. 
10.1.4 Vital Signs 
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The 
investigator will record oral body temperature at baseline. Thereafter the subject will record oral 
temperature twice daily in the study diary card. 
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the 
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14. 
10.1.5 Electrocardiogram Measurements 
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal 
investigator will be responsible for interpretation of the Screening ECG. This interpretation may 
be performed by the investigator or he/she may delegate this action to another physician and the 
investigator will acknowledge the interpretation.  If this baseline ECG is interpreted as meeting 
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study.  If the 
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may 
be enrolled unless other exclusion criteria apply.  The principal investigator is responsible to 
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any 
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation 
is made either during subject's participation in the study or immediately after the subject's 
discharge from the study.  
10.1.6 Clinical Laboratories 
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). 
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Hematology will include complete blood count (CBC) with differential. 
Urinalysis will include dipstick tests for protein, glucose, ketones, blood, urobilinogen, nitrite, 
pH, and specific gravity and microscopic evaluation for RBCs and WBCs. 
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at 
Screening/Baseline, and on Days 3, 5 and 14.  
10.1.7 Urine Pregnancy Test 
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day 
14 using a urine pregnancy test. 
10.1.8 Serology for Influenza  
Paired blood samples for determination of antibody to influenza A and B (serology) will be 
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These 
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the 
diagnosis of influenza. 
10.1.9 Samples for Virologic Laboratory Assessments 
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior 
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus 
and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9.  Refer to the 
Laboratory Manual for instructions regarding the processing and shipment of these specimens. 
10.1.10  Subject Self Assessments 
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the 
subject’s Study Diary including the following: 
• 
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for 
the study) every 12 hours.  With the exception of the baseline measurement, all temperature 
measurements will be obtained at least 4 hours after, or immediately before, administration of 
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of 
each temperature determination will be recorded in the Study Diary.  The baseline 
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of 
whether the subject had recently taken an anti-pyretic; the time of anti-pyretic use pre-
treatment will be recorded in the CRF, if applicable. 
• 
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia 
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9, 
then once daily through Day 14. 
• 
Assessment of the subject’s time lost from work or usual activities and productivity compared 
to normal using a 0-10 visual analogue scale once daily through Day 14. 
The subject’s diary card will be reviewed by study staff at each visit for completion of the record 
of all required items, with particular emphasis on alleviation of symptoms as well as relapse of 
symptoms.  Relapse is defined as the recurrence of at least one respiratory symptom and one 
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever 
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(unless influenced by antipyretic use).  Relapse can only occur after the subject has met the 
endpoint criteria for alleviation of symptoms.  Study staff will not attempt to ask subjects to 
retrospectively complete missing diary card data for any scheduled assessments that have not 
been completed prior to the clinic visit.  Study staff should, however, remind the subject to 
complete the diary card at all scheduled times. 
10.1.11  Concomitant Medications 
All concomitant medications used during this study, with the exception of those medications 
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in 
their diary card, must be documented on the Case Report Form (CRF).  
10.1.12  Adverse Events 
AEs will be assessed from the time of administration of study medication through the final study 
visit. 
10.1.13  Pharmacokinetic Exposure Samples 
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels. 
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug 
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all 
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical 
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample 
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population 
exposure response analysis. 
At selected sites a separate sub-study will also be conducted to collect additional PK samples for 
the purpose of conducting an exposure-response analysis.  This sub-study will be conducted 
under a separate protocol, BCX1812-311PK.  Data from these two PK samples in all subjects will 
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based 
exposure-response analysis.  This analysis will be described as part of the sub-study analysis plan.  
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions 
provided regarding the processing and shipment of these PK samples. 
 
10.2 Screening Period 
10.2.1 Informed Consent 
The nature and purpose of the study and the expectations of a participating subject will be 
described to potential study subjects, their questions will be answered, and the subjects will then 
be asked to sign an informed consent document.  Study subjects will then undergo the screening 
evaluation as noted in Section  10.2.2 
10.2.2 Screening/Baseline Evaluation and Enrollment 
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the 
subject’s home, in which case all evaluations must be conducted by appropriately trained and 
qualified staff. 
Clinical laboratory assessments performed at Screening are for the purpose of establishing a 
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baseline.  Subjects may be enrolled and receive treatment with study drug prior to receiving 
results of the laboratory assessments (with the exception of urine pregnancy test result, which 
must be known). 
Eligible subjects will be enrolled and randomized to blinded study treatment.  The randomization 
will be stratified by BMI: Normal-Overweight (BMI ≤ 29.9 kg/m2) and Obese (BMI ≥ 30.0 
kg/m2).  The Investigator will prepare a request for blinded study drug assignment which includes 
the subject’s screening number.  The Investigator or designee at the clinical study center will 
contact the central randomization Interactive Voice System (IVRS call center).  The IVRS call 
center will advise the study center of the investigational study drug kit number that is assigned to 
that subject at enrollment. 
Subjects that are determined to be ineligible will be advised accordingly, and the reason for 
ineligibility will be discussed.  If desired by the subject the reason for ineligibility may be 
provided and/or discussed with their health-care provider by the Investigator or designee.  
Ineligible subjects who have been screened for the study will also be entered on the IVRS.  For 
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility 
will be entered on to the IVRS.  All ineligible subjects must be entered onto the IVRS within 
24 hours of screening, to assist with surveillance analysis during the course of the study. 
10.3 Treatment Period—Study Day 1 
Day 1 represents the only day of study drug dosing.  Study drug administration should occur as 
soon as possible following informed consent, screening and randomization.  Therefore, it is 
expected that the date of Screening/ Baseline and Day 1 will usually be the same date.  
10.3.1 Pre-dose Evaluations-Study Day 1 
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject 
shall complete the record of these assessments in their Study Diary prior to dosing.  The subject 
will be counseled regarding the expectations for recording these assessments through Day 14. 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a 
12 lead ECG will be obtained prior to dosing.  
10.3.2 Post-dose Evaluations-Study Day 1 
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a 
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second 
injections will be recorded. The gluteal site of injection and the syringe needle length are also to 
be recorded in the subjects CRF.  Sites are instructed to follow procedures for intramuscular 
injection, with a recommended needle length appropriate to the physical characteristics of the 
subject, provided in the study drug administration manual.  
The following evaluations will be performed post-dose on Study Day 1: 
• 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15 
minutes following the second intramuscular injection of blinded study drug; record the exact 
24-hour clock time of the vital sign measurements in the subjects CRF. 
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• 
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection 
of blinded study drug; record the exact 24-hour clock time of the blood draw. 
• 
Record any concomitant medications. 
• 
Record any AEs. 
10.4 Post-Treatment Assessment Period 
10.4.1 Days 2, 3, 5, 9 and 14 
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of 
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14 
will also complete a Day 21 visit, and if required a Day 28 visit.  
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which 
case all evaluations must be conducted by appropriately trained and qualified staff. 
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance 
with completion of the Subject Self Assessments, to note any concomitant medications and 
adverse events.  Any adverse events reported by the subject during this telephone contact will be 
recorded on the adverse event form and verified during the visit on day 3. 
At each visit it is important that the subject’s Study Diary record be reviewed for completion of 
daily Subject Self Assessments.  The subjects should be counseled as necessary regarding self 
assessments and Study Diary record requirements.  The subject’s diary card will be reviewed by 
study staff for alleviation of symptoms as well as relapse of symptoms.  Relapse is defined as the 
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than 
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).  
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms. 
Day 3: 
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical 
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be 
recorded in the subjects CRF.  
Day 14: 
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven 
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject 
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3 
days)  If a subject reports moderate or severe influenza symptoms then the investigator will 
record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21 
and day 28 visits. After day 14 the subject will not record symptoms in a diary. 
Day 21 (if applicable): 
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded 
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on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28 
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.  
Day 28 (if applicable): 
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at this visit and such action(s) will be recorded on the 
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless 
in the clinical judgment of the investigator further follow-up is required. The investigator will use 
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further 
medical care. 
10.4.2 Adverse Events Reported at Post-treatment Visits 
In this study, symptoms of influenza will be considered separately from adverse events reported 
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, 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. 
 
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Figure 1 
Study Measurements and Visit Schedule 
 
Treatment 
Period 
Assessment Day 
End of Study 
Early Withdrawal 
Assessments 
Screening 1
(Baseline) 
Day 11 
Day 22 
Day 3 
Day 5 
(±1 day) 
Day 9 
(±3 day) 
Day 14 
(±3 day) 8 
Informed Consent 
X 
 
 
 
 
 
 
Rapid Antigen test for 
Influenza A & B 
X 
 
 
 
 
 
 
Medical History/Physical Exam 
X 
 
 
 
 
 
 
Influenza-related complications 
checklist3 
X 
 
 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Clinical Chemistries4 
X 
 
 
X 
X 
 
X 
Hematology4 
X 
 
 
X 
X 
 
X 
Exposure Pharmacokinetic Sample 
 
X 
 
X4 
 
 
 
Serology (serum) Sample 
X 
 
 
 
 
 
X 
Urinalysis4 
X 
 
 
X 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
ECG6 
X 
 
 
 
 
 
 
Sample (nasopharyngeal swab) for 
Influenza Virus Culture/ PCR assay 
and for resistance studies 
 
X 
 
X 
X 
X 
 
Study Drug Administration 
 
X 
 
 
 
 
 
Subject Diary Review7 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Study Measurements and Visit Schedule Figure Legend on Next Page 
 
BioCryst Pharmaceuticals, Inc. 
 
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Study Measurements and Visit Schedule Figure Legend 
 
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on 
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9 
visits). 
2  Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse 
event review. 
3  A targeted physical examination will be conducted at each visit to record the presence/absence of influenza related complications. 
4  Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline.  Subject may be enrolled and begin 
treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second treatment 
administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second PK sample for 
evaluation of peramivir concentrations. 
5  Vital sign measures will include blood pressure, pulse rate and respiration rate.  Vital signs will be recorded at Screening, pre-dose and at 
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral 
temperature at baseline.  Thereafter the subject will report oral temperature measurements twice daily in the Study Diary 
6  If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will 
not be enrolled in this study.  If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, 
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7  Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through 
Day 14.  Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.  
Subjects record oral temperature twice daily throughout as well as all concomitant medication and adverse events. 
8   For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (± 
3 days) and Day 28 (± 3 days) if required  (See Section 10.4.1).  
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11 ADVERSE EVENT MANAGEMENT 
11.1 Definitions 
11.1.1 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. 
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2). 
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 seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches 
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and 
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as 
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE, 
which then must be recorded as such (see Section  11.1.2).  Likewise, a RAT for influenza is 
required at screening in order to determine eligibility for the study, and therefore a positive RAT 
is not considered an AE.    
11.1.2 Serious Adverse Event 
A SAE is an adverse event that results in any of the following outcomes: 
• 
Death 
• 
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe) 
• 
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption 
of a person’s ability to carry out normal life functions) 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event 
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 
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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. 
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to 
competent authorities where this type of reporting is required (e.g. European Union Directives). 
See section 11.2.3. 
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting 
Serious Adverse Events 
Reports of AEs are to be collected from the time of study drug administration through the 
follow-up period ending on Day 14.  The Investigator or designee must completely and promptly 
record each AE on the appropriate CRF.  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. 
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. 
11.2.1 Definition of Severity 
All AEs will be assessed (graded) for severity and classified into one of four clearly defined 
categories as follows: 
• 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required.  The AE does not interfere with the participant’s 
normal functioning level.  It may be an annoyance. 
• 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; 
no or minimal intervention required.  The AE produces some 
impairment of functioning, but it is not hazardous to health.  It is 
uncomfortable or an embarrassment. 
• 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; 
medical intervention may be required.  The AE produces significant 
impairment of functioning or incapacitation. 
• 
Life-threatening: 
(Grade 4): Extreme limitation in activity, significant assistance 
required; significant medical intervention or therapy required; 
hospitalization. 
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11.2.2 Definition of Relationship to Study Drug 
The blinded Principal Investigator 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). 
11.2.3 Reporting Serious Adverse Events 
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to 
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first 
notifying the Medical Monitor at the number listed below: 
Telephone: 
Europe: +44 1628 548000;  
North America: 1-888-724-4908 
Facsimile: 
Europe: +44 1628 540028;  
North America: 1-888-887-8097  
 
 
 
 
 
 
 
          or 1-609-734-9208 
In addition to the telephone numbers listed above, local country-specific toll free numbers may be 
provided within the study reference manual. 
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report 
form) within 24 hours.  All additional follow-up evaluations of the SAE / SUSAR must be 
reported and sent by facsimile to BioCryst or its designee as soon as they are available. 
The Principal Investigator or designee at each site is responsible for submitting the IND safety 
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy 
in their files. 
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject 
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.   
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and 
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting 
system in accordance with FDA and other applicable regulations. However, the Investigator is not 
obligated to actively seek reports of AEs in former study participants. 
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study 
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.  
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome” 
form that will be provided by the Sponsor or its designee. 
11.2.4 Emergency Procedures 
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the 
treatment assignment for the subject affected.  If time allows (i.e., if appropriate treatment for the 
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor 
regarding the need to unblind the treatment assignment for the subject.  At all times, the clinical 
well-being of any subject outweighs the need to consult with the Medical Monitor. 
The Principal Investigator may contact the IVRS central randomization center and request the 
unblinding of the treatment assignment that corresponds to the affected subject.  The IVRS center 
will record the name of the Investigator making the request, the date and time of the request, the 
subject number and date of birth.  The Sponsor will be informed within 24 hours if unblinding 
occurred. 
12 STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary and other selected efficacy endpoints.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation (SD), minimum, and maximum for continuous data and frequencies and 
percentages for categorical data.  The term “treatment group” refers to randomized treatment 
assignment: peramivir 150 mg, peramivir 300 mg, or placebo.  All data collected during the study 
will be included in data listings.  Unless otherwise noted, the data will be sorted first by treatment 
assignment, subject number, and then by date within each subject number.   
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
12.1 Data Collection Methods 
The data will be recorded on the CRF approved by BioCryst. The Investigator must submit a 
completed CRF for each subject who signs an informed consent form (ICF), regardless of 
duration.  All documentation supporting the CRF data, such as laboratory or hospital records, 
must be readily available to verify entries in the CRF. 
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted 
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to BioCryst should not carry the subject’s name.  This will help to ensure subject confidentiality. 
12.2 Statistical Analysis Plan 
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. 
12.3 Study Hypothesis 
The primary hypothesis for evaluating the primary objective may be stated as follows: 
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for 
subjects treated with placebo and for subjects treated with peramivir 150mg (H01) or peramivir 
300mg (H02). 
 
The alternative hypothesis (H1) is that subjects treated with peramivir 150mg (H11) or peramivir 
300mg (H12) have an improvement in time to alleviation of influenza symptoms over those 
treated with placebo. 
12.4 Sample Size Estimates 
A total of 750 evaluable subjects randomized in a 2:2:1 (300 subjects treated with peramivir 
150mg: 300 subjects treated with peramivir 300 mg: 150 subjects treated with placebo) are 
estimated for this phase 3 study.  Because results of clinic-based RAT tests may not precisely 
indicate presence of influenza infection, it is expected that at least 850 subjects will be 
randomized to treatment to ensure that 750 evaluable subjects are treated. 
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated 
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95% 
CI: 115.9, 165.8) for subjects receiving placebo treatment.  Additionally, it is expected that the 
median time to alleviation for the 150 mg dose peramivir arm will be reduced by 30% compared 
to placebo (Table 5) yielding a hazard ratio of 0.70.  
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Table 5 
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio). 
 
Median Time To Alleviation of Symptoms (Hours) 
Placebo 
Peramivir 150mg 
Difference (hours) 
145.0 
101.5 
43.5 
140.0 
98.0 
42.0 
135.0 
94.5 
40.5 
130.0 
91.0 
39.0 
125.0 
87.5 
37.5 
120.0 
84.0 
36.0 
115.0 
80.5 
34.5 
110.0 
77.0 
33.0 
105.0 
73.5 
31.5 
100.0 
70.0 
30.0 
Using these assumptions, a sample size of 300 evaluable subjects per active treatment group and 
150 evaluable subjects in the placebo group (a total of 750 evaluable subjects) is sufficient to 
provide at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and 
α = 0.025 (SAS version 9.1.3; total accrual time 7 months; total enrollment time 6 months). 
12.5 Analysis Populations 
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI), 
per-protocol infected (PPI), and safety populations. 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.  
Subjects will be analyzed in the treatment group to which they were 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 
randomized, received study drug, and have confirmed influenza by culture or PCR.  Subjects will 
be analyzed according to the treatment randomized.  If a discrepancy is noted in the final database 
for any subject, such that the drug differs from the randomized treatment assignment, efficacy 
analyses may be repeated with the subjects analyzed according to the treatment received.  The 
ITTI population will be used for primary analyses of efficacy. 
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who 
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection 
will be further described in the SAP. The PPI population will be used as supportive of the primary 
analyses for efficacy completed with the ITTI population. 
Safety Population: The safety population will include all subjects who received study drug.  
Subjects will be analyzed according to the treatment received.  This population will be used for 
all safety analyses. 
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12.6 Interim and End of Study Analyses 
Interim Analysis 
An independent DMC will review safety data on an ongoing basis.  Safety analyses will be 
presented in a manner consistent with the presentations intended for the final analysis. 
End of Study Analysis 
A final analysis is planned after the last subject completes or discontinues the study, and the 
resulting clinical database has been cleaned, quality checked, and locked. 
12.7 Efficacy Analyses 
12.7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to alleviation of symptoms, defined as the time from 
injection of study drug to the start of the time period when a subject has Alleviation of 
Symptoms.  A subject has Alleviation of Symptoms if all of the seven symptoms of influenza 
(nasal congestion, sore throat, cough, aches and pains, fatigue (tiredness), headache, feeling 
feverish) assessed on his/her subject diary are either absent or are present at no more than mild 
severity level and at this status for at least 21.5 hours (24 hours - 10%). 
Descriptive statistics for the primary efficacy endpoint will be tabulated by treatment group.  
Alleviation of symptoms will be determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be summarized overall and for 
individual symptoms for each treatment group.  Overall treatment differences will be assessed 
using a Cox Regression model with effects for BMI at screening, influenza type by PCR, 
treatment group, and influenza season at randomization (if necessary).  Subjects who do not 
experience alleviation of symptoms will be censored at the date of their last non-missing post-
baseline assessment.  Pairwise differences in time to alleviation of symptoms among the 
treatment groups will be evaluated using contrast statements from the final Cox model. In order to 
maintain the overall type I error in the presence of the planned comparisons between the two 
peramivir treatments and placebo, a Bonferroni correction will be applied to the primary efficacy 
endpoint analysis.  P-values for the planned comparisons of each peramivir arm to placebo will be 
adjusted via a Bonferroni correction (i.e., if the unadjusted p-value for an active comparison 
versus placebo, p, is less than 0.05, then pa=p*number of planned comparisons=p*2; otherwise, 
pa=p).  Superiority of peramivir to placebo will be established if the adjusted p-value is less than 
or equal to 0.05. 
12.7.2 Secondary Efficacy Endpoints 
All secondary endpoints will be summarized using descriptive statistics by treatment group, and 
study day/time, if appropriate.  Statistical comparisons for each endpoint will be constructed 
without adjustment for multiple endpoints. 
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be 
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summarized for each treatment group.  The time-weighted average change from baseline will be 
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available post-
baseline on-treatment data (data after initiation of study treatment) minus the baseline value.  
Specifically, the time-weighted area under the curve for time a (ta) to time b (tb) is given by the 
formula  
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
, 
where 
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
 and ti represents the date of the ith viral titer 
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline 
value and only one follow-up value, yi then the time-weighted change from baseline is defined as 
the difference between yi and baseline.  If there is a baseline value and no follow-up value, the 
subject is excluded from analysis.  The differences between each of the peramivir treatment 
groups and placebo will be evaluated using a van Elteren Test adjusting for BMI at screening, 
influenza type by PCR, and influenza season at randomization (if necessary).   Analyses of the 
PCR results will be analyzed in a similar manner. 
Subject’s oral temperature will be summarized by study visit and treatment group.  Differences 
between the treatment groups will be assessed using the Wilcoxon Rank Sum Test controlling for 
BMI at screening, influenza type by PCR, and influenza season at randomization (if necessary).  
A subject has Resolution of Fever if he/she has a temperature < 37.2°C (99.0°F) and no 
antipyretic medications have been taken for at least 12 hours.  The time to resolution of fever will 
be estimated using the method of Kaplan-Meier using temperature and symptom relief medication 
information obtained from the subject diary data.  Difference between the treatment groups will 
be assessed using the log rank statistic controlling for BMI at screening, influenza type by PCR, 
and influenza season at randomization (if necessary).  Subjects who do not have resolution of 
fever will be censored at the time of their last non-missing post-baseline temperature assessment. 
The number and percentage of subjects experiencing influenza related complications will be 
summarized by complication preferred term and treatment group.  The difference between the 
treatment groups will be assessed a logistic regression model with factors for treatment group, 
BMI at screening, influenza type by PCR, and influenza season at randomization (if necessary).  
Pairwise differences between the treatment groups will be evaluated using contrasts from the final 
logistic regression model. 
12.7.3 Exploratory Endpoint 
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and 
work productivity and/or performance losses will be summarized by treatment group and BMI.  
Methods for describing differences between treatment groups will be presented in the SAP. 
Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data 
will be listed for each subject.  These listings will be constructed in a manner consistent with the 
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18  
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be 
summarized separately for treatment group, protein type, and study visit. 
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12.8 Safety Analyses 
AEs will be mapped to a MedDRA-preferred term and system organ classification.  The 
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms, 
system organ classifications, and severity.  If a subject experiences multiple events that map to a 
single preferred term, the greatest severity and strongest Investigator assessment of relation to 
study drug will be assigned to the preferred term for the appropriate summaries.  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 study 
visit.  Laboratory abnormalities will be graded according to the DAIDS Table for Grading 
Adverse Events for Adults and Pediatrics (Publish Date: December 2004).  The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by 
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be 
summarized by treatment group. 
Abnormal physical examination findings will be presented by treatment group.  The number and 
percent of subjects experiencing each abnormal physical examination finding will be included. 
Concomitant medications will be coded using the WHO dictionary.  These data will be 
summarized by treatment group. 
Subject disposition will be presented for all subjects.  The number of subjects who completed the 
study and discontinued from the study will be provided.  The reasons for early discontinuation 
also will be presented. 
12.9 Sub-Study and Pharmacokinetic Analysis 
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine 
exposure response will be conducted at selected sites. The data from the sub-study will be 
combined with the two PK samples (collected on all subjects at 30-60 minutes following 
administration of study drug and on study day 3) to perform a population exposure-response 
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All 
statistical methods will be outlined as part of the sub-study protocol and exposure-response 
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained 
in this study and a companion study BCX1812-312, will be reported in a separate sub-study 
report. 
12.10 
General Issues for Statistical Analysis 
12.10.1 
Multiple Comparisons and Multiplicity 
In order to maintain the overall type I error in the presence of the planned comparisons between 
the two peramivir treatments and placebo, a Bonferroni correction will be applied to the primary 
efficacy endpoint analysis.  No other adjustments for multiple comparisons are planned. 
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12.10.2 
Covariates 
Primary and secondary efficacy analyses will be adjusted for BMI at screening, influenza type by 
PCR, and influenza season at randomization (if necessary).  
12.10.3 
Planned Sub-Groups 
The primary efficacy endpoint will be summarized separately by BMI, influenza season at 
randomization (if necessary), and by viral subtype by PCR using descriptive statistics by 
treatment group and study day, if appropriate.  No formal statistical testing will be utilized. 
Additional analyses may be performed by country, if necessary, for submission to local 
regulatory authorities. 
12.10.4 
Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized.  No attempt will be made retrospectively to obtain missing subject 
reported data (including influenza symptom severity assessments, temperature, ability to perform 
usual activities, missed days of work and impact of influenza on subject’s work performance 
and/or productivity) 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.   
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience 
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms.  Missing assessments of influenza symptoms 
conservatively will be imputed as having severity above absent or mild (as failures).  For the 
subject diary data, the following data conventions will be utilized.  Missing diary completion 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 set to 23:59 of the day 
recorded.  Select exploratory sensitivity analyses may be conducted to ascertain the effect, if any, 
of these methods.  These sensitivity analyses are further described in the SAP.  Secondary 
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint. 
 
13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; 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 
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and regulatory requirements relevant to the use of new therapeutic agents in the countries 
involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if 
requested by the IRB/ IEC.  A final study notification will also be forwarded to the IRB/IEC after 
the study is completed or in the event of premature termination of the study in accordance with 
the applicable regulations.  Copies of all contact with the IRB/ IEC should be maintained in the 
study documents file.  Copies of clinical study status reports (including termination) should be 
provided to BioCryst. 
13.1.2 Ethics Committee Approvals 
Before initiation of the study at each investigational site, the protocol, the informed consent form, 
the subject information sheet, and any other relevant study documentation will be submitted to 
the appropriate IRB/IEC.  Written approval of the study must be obtained before the study center 
can be initiated or the investigational medicinal product is released to the Investigator.  Any 
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for 
changes to the study such as modification of the protocol, the informed consent form, the written 
information provided to subjects and/or other procedures. 
The Investigator will report promptly to the IRB/IEC 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/IEC with a report of the outcome of the study. 
13.1.3 Subject Informed Consent 
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures.  Each subject should be given both verbal and written information describing 
the nature and duration of the clinical study.  The informed consent process should take place 
under conditions where the subject has adequate time to consider the risks and benefits associated 
with his/her participation in the study.  Subjects will not be screened or treated until the subject 
has signed an approved ICF written in a language in which the subject is fluent. 
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.  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 or their legal representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it 
may entail.  Subjects will be informed that they are free not to participate in the trial and that they 
may withdraw consent to participate at any time.  They will be told that refusal to participate in 
the study will not prejudice future treatment.  They will also be told that their records may be 
examined by competent authorities and authorized persons but that personal information will be 
treated as strictly confidential and will not be publicly available.  Subjects must be given the 
opportunity to ask questions.  After this explanation and before entry into the trial, consent should 
be appropriately recorded by means of the subject’s dated signature.  The subject should receive a 
signed and dated copy of the ICF.  The original signed informed consent should be retained in the 
study files.  The Investigator shall maintain a log of all subjects who sign the ICF and indicate if 
the subject was enrolled into the study or reason for non-enrollment. 
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13.1.4 Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
13.1.5 Investigator Reporting Requirements 
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required. 
13.2 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 institution will allow 
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
13.3 Quality Assurance 
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by BioCryst, 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. 
13.4 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. 
13.5 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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13.6 Study Organization 
13.6.1 Data Monitoring Committee 
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety 
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee 
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical 
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate 
will be described in a separate DMC charter. 
13.7 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 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/IEC) or it may be a separate 
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without 
IRB/IEC approval).  It is the responsibility of the investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are 
required for U.S. sites only. 
13.8 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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14 REFERENCES 
 
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282. 
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with 
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186. 
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on 
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 
2003;163(14):1667–1672. 
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase 
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for 
prevention and treatment. JAMA 1999;282(13):1240–1246. 
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza 
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765. 
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza 
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents 
Chemother 2001;45(4):1162–1167. 
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to 
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147. 
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, 
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase 
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408. 
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine 
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. 
Antimicrob Agents Chemother 2004;48(12):4855–4863. 
10. BioCryst Pharmaceuticals. Unpublished data. 
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable 
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian 
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco 
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA. 
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against 
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32 
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03. 
14. Tamiflu® Package Insert.  Roche Pharmaceuticals. Rev. December 2005. 
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product 
information sheets 
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024. 
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in 
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850. 
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18. US Department of Health and Human Services, Food and Drug Administration Center for 
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product 
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for 
Submitting Influenza Resistance Data.  http://www.fda.gov/cder/guidance/7070fnlFLU.htm  
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15 APPENDICES 
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina 
 
NYHA Functional Classification of Heart Failure 
 
Class I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs 
does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly; 
walking uphill; walking or stair climbing after meals, in cold weather, in wind, 
or when under emotional stress causes undue fatigue or dyspnea. 
Class III 
Symptoms w ith less than ordinary phy
sical activity.  Walking one to two 
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al 
conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or 
dyspnea. 
 
NYHA Functional Classification of Angina 
 
Class I 
Angina only with unusually strenuous activity. 
Class II 
Angina with slightl y more prolonged o r slightly more vigorous activit y than 
usual. 
Class III 
Angina with usual daily activity. 
Class IV 
Angina at rest. 
 
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15.2 Criteria for Severe COPD and Severe Asthma 
The following guidelines are provided to assist in the evaluation of subjects who have a medical 
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe 
COPD or severe persistent Asthma are to be excluded from this study. (See section  8.1.2, 
exclusion criteria number 3). 
Classification of Asthma from National Asthma and Education and Prevention Program 
 
 
 
For Adults and Children (> 5 yrs) who 
can use a spirometer or peak flow meter 
Classification 
Days with 
Symptoms 
Nights with 
Symptoms 
FEV1 or PEF 
% Predicted Normal 
PEF Variability 
(%) 
Severe persistent 
Continual 
Frequent 
≤ 60 
> 30 
Moderate Persistent 
Daily 
> 1/ week 
> 60 - < 80 
> 30 
Mild Persistent 
> 2 / week 
but < 1 
times / day 
> 2/ month 
≥ 80 
20 – 30 
Mild Intermittent 
≤ 2 / week 
< 2 / month 
≥ 80 
< 20 
FEV1: percentage predicted value for forced expiratory volume in 1 second. 
PEF: percentage of personal best for peak expiratory flow. 
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, 
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007 
 
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1 
(GOLD Criteria) 
Stage 
Characteristics 
Mild COPD 
FEV1/FVC < 70% 
FEV1 ≥ 80% predicted 
Moderate COPD 
FEV1/FVC < 70% 
50 % ≤ FEV1 < 80% predicted 
Severe COPD 
FEV1/FVC < 70% 
30 % ≤ FEV1 < 50% predicted 
Very Severe COPD 
FEV1/FVC < 70% 
FEV1 < 30% predicted or FEV1 < 50% 
predicted plus chronic respiratory failure 
FEV1: percentage predicted value for forced expiratory volume in one second. 
FVC: forced vital capacity 
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555. 
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316


 
 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-311 
IND No. 76,350 
 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE 
INFLUENZA 
THE IMPROVE I STUDY 
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy) 
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza 
Protocol Date(s):  
Version 1.0: 04 September 2007 
Version 2.0: 05 October 2007 
Version 3.0 20 November 2007 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35244, USA 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
 
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals, 
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to 
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information 
contained herein should be disclosed without prior written approval. 
CONFIDENTIAL 
 
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1 
TITLE PAGE 
 
Protocol Number: 
BCX1812-311 
Study Title: 
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza. 
IND Number: 
76, 350 
Investigational Product: 
Peramivir (BCX1812) 
Indication Studied: 
Uncomplicated acute influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35233 
Development Phase: 
3 
Sponsor Medical Officer: 
W. James Alexander, M.D., M.P.H. 
Senior Vice President, Clinical Development  
Chief Medical Officer 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
Email Address: jalexander@biocryst.com  
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki 
and clinical research guidelines established by the Code of 
Federal Regulations (Title 21, CFR Parts 50, 56, and 312) 
and ICH Guidelines. Essential study documents will be 
archived in accordance with applicable regulations. 
Final Protocol Date: 
Version 1.0: 04 September 2007 
Amendment(s) Date(s): 
Version 2.0: 05 October 2007 
Version 3.0: 20 November 2007 
 
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1.2 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3 multicenter, random ized, double-blind, placebo-controlled 
study to evaluate the effic acy and safety of intramuscular peramivir in 
subjects with uncomplicated acute influenza 
 
I have carefully read this protocol and agree that it contains all of the necessary  information 
required to conduct this study.  I agree to c onduct this study  as described and according t o 
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for  
Good Clinical Practices, and all applicable regulatory requirements. 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
Name (Print) 
 
 
 
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2 
SYNOPSIS 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza. 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
Investigators/Study Sites: 
Multinational 
Development Phase: 
3 
Objectives: 
Primary: 
To evaluate the efficacy of peramivir administered 
intramuscularly compared to placebo on the time to alleviation 
of clinical symptoms in adult subjects with uncomplicated acute 
influenza A. 
 
Secondary: 
1. 
To evaluate the safety and tolerability of peramivir 
administered intramuscularly 
2. 
To evaluate secondary clinical outcomes in response to 
treatment 
3. 
To evaluate changes in influenza virus titer in 
nasopharyngeal samples (viral shedding) in response to 
treatment 
 
Exploratory: 
1. To assess pharmacoeconomic measures as response to 
treatment  
2. To assess changes in influenza viral susceptibility to 
neuraminidase inhibitors following treatment 
 
Number of Subjects: 
Total enrollment: up to a total of 750 evaluable subjects will be 
randomized to treatment (150 subjects in the placebo treatment 
group, 300 subjects in the peramivir 300mg treatment group and 
300 subjects in the peramivir 600mg treatment group).  
 
An evaluable subject is one who is randomized, receives study 
drug, and has confirmed acute influenza A by primary viral 
culture or PCR. A positive Rapid Antigen Test (RAT) for 
influenza A at screening will be required for enrollment.  
Because results of clinic-based RAT tests may not precisely 
indicate presence of influenza infection, it is expected that at 
least 850 subjects will be randomized to treatment to ensure that 
750 evaluable subjects are treated. 
 
Study Design: 
This is a multinational, randomized, double-blind study 
comparing the efficacy and safety of two single dose regimens 
of peramivir administered intramuscularly versus placebo in 
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adults with uncomplicated acute influenza. 
 
Each subject’s assignment to treatment will be stratified 
according to smoking status. 
 
All subjects will be centrally randomized to one of three 
treatment groups according to smoking status strata in a ratio of 
2:2:1 such that 80% of subjects are randomized to one of the two 
single dose regimens of peramivir. 
 
Treatment Group 1:  Peramivir 300mg 
Treatment Group 2:  Peramivir 600mg 
Treatment Group 3:  Placebo 
 
Study drug will be administered as bilateral 4mL intramuscular 
injections (total of 8mL injected in equally divided doses). 
Procedures for gluteal intramuscular injection, with a 
recommended needle length appropriate to the physical 
characteristics of the subject, are provided in the study drug 
administration manual. 
 
Subjects eligible for screening will have an anterior nasal swab 
collected for testing by rapid antigen testing (RAT) for influenza 
A, in accordance with the commercially available RAT kit 
instructions.  If the initial RAT is negative, the test should be 
repeated within one hour. Subjects meeting the 
inclusion/exclusion criteria may be enrolled into the study. 
 
All enrolled subjects will record the following information in a 
Study Diary: 
• Assessment of the presence and severity of each of seven 
symptoms of influenza on a 4-point scale (0, absent; 1, mild; 
2, moderate; 3, severe) twice daily (AM, PM) through Day 9 
following treatment, then once daily (AM) through Day 14 
• Oral temperature measurements taken with an electronic 
thermometer every 12 hours. With the exception of the 
baseline measurement, all temperature measurements will be 
obtained at least 4 hours after, or immediately before, 
administration of oral acetaminophen (paracetamol) or other 
anti-pyretic medications. 
• Assessment of subject’s time lost from work or usual 
activities and rating of productivity compared to normal 
(rated as 0-10 on a visual analog scale) once daily through 
Day 14 
• Doses of antipyretic, expectorant, and/or throat lozenges 
taken for symptomatic relief each day through Day 14 
 
Anterior nose (bilateral) and posterior pharynx specimens 
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3, 
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5, and 9, for quantitative virologic assessments. Specimens from 
all subjects yielding influenza virus will also be assessed for 
susceptibility to neuraminidase inhibitors (Day 1 and last 
specimen yielding positive result on culture) as well as other 
virologic assessments (e.g. PCR, genotypic testing) 
 
All virologic assessments will be performed by a central 
laboratory.  
 
Two samples for pharmacokinetic (PK) testing for plasma levels 
of peramivir will be obtained from all subjects randomized.  The 
first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second 
PK sample will be obtained at the day 3 visit in all subjects. The 
data from these PK samples will be utilized in a population 
exposure-response analysis. 
 
At selected sites a separate sub-study will be conducted to 
collect additional PK samples between treatment and Day 3 for 
the purpose of conducting a separate exposure-response 
analysis.  This sub-study will be conducted under a separate 
protocol, BCX1812-311PK. 
 
Study Population: 
Male and female subjects, 18 years of age and older, with 
symptoms consistent with a diagnosis of uncomplicated acute 
influenza infection may be screened for enrollment.  Subject 
eligibility will require the presence of two or more symptoms of 
at least moderate severity consistent with acute influenza as well 
as positive results obtained from a rapid antigen test (RAT) for 
influenza A at screening. 
 
Inclusion Criteria: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A Rapid Antigen Test (RAT) 
performed with a commercially available test kit on an 
adequate anterior nasal specimen, in accordance with the 
manufacturer’s instructions.  A negative initial RAT should 
be repeated within one-hour. Subjects with a positive 
influenza B or mixed A and B RAT will be excluded. 
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A 
subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for 
enrollment in the absence of documented fever at the time of 
screening.   
4. Presence of at least one respiratory symptom (cough, sore 
throat, or nasal symptoms) of at least moderate severity. 
5. Presence of at least one constitutional symptom (myalgia 
[aches and pains], headache, feverishness, or fatigue) of at 
least moderate severity.  
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6. Onset of symptoms no more than 48 hours before 
presentation for screening. 
7. Written informed consent. 
 
Exclusion Criteria: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory 
distress. 
3. History of severe chronic obstructive pulmonary disease 
(COPD) or severe persistent asthma. 
4. History of congestive heart failure requiring daily 
pharmacotherapy with symptoms consistent with New York 
Heart Association Class III or IV functional status within the 
past 12 months. 
5. Screening ECG which suggests acute ischemia or presence 
of medically significant dysrhythmia. 
6. History of chronic renal impairment requiring hemodialysis 
and/or known or suspected to have moderate or severe renal 
impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or 
symptoms consistent with otitis, bronchitis, sinusitis and/or 
pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic 
illness, previous organ transplant, or use of 
immunosuppressive medical therapy which would include 
oral or systemic treatment with > 10 mg prednisone or 
equivalent on a daily basis within 30 days of screening. 
10. Currently receiving treatment for viral hepatitis B or viral 
hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 
cell/mm3. 
12. Current therapy with oral warfarin or other systemic 
anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, 
or oseltamivir in the 7 days prior to screening. 
14. Immunized against influenza with live attenuated virus 
vaccine (FluMist®) in the previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine 
within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 
14 days. 
17. History of alcohol abuse or drug addiction within 1 year 
prior to admission in the study. 
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18. Participation in a previous study of intramuscular or 
intravenous peramivir or previous participation in this study 
19. Participation in a study of any investigational drug or device 
within the last 30 days. 
 
Study Endpoints: 
Primary Endpoint: 
Clinical: 
Time to alleviation of clinical symptoms of influenza. 
 
Secondary Endpoint(s): 
Safety: 
Incidence of treatment-emergent adverse events and treatment-
emergent changes in  clinical laboratory tests. 
 
Clinical: 
Time to resolution of fever. 
Incidence of influenza related complications. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
viral titer assay (TCID50). 
 
Exploratory Endpoint(s): 
Pharmacoeconomic: 
Medical resource utilization (MRU), missed days of work, and 
impact of influenza illness on subject’s work performance 
and/or productivity. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
PCR. 
Change in influenza virus susceptibility to neuraminidase 
inhibitors. 
 
Investigational Product, Dose, and Mode of Administration: 
Peramivir (BCX-1812), 7 5mg/mL, 4mL (300m g) per injection, adm inistered as bilateral 
injections. 
Reference Therapy, Dose, and Mode of Administration: 
Matching Placebo (buffered diluent), 4mL per injection administered as bilateral injections. 
Duration of Treatment: 
Following treatment on day 1, study duration for all subjects is 
expected to be up to 14 days (including all visits). Presence of 
unresolved adverse events and/or treatment-emergent laboratory 
findings at the Day 14 visit, or persistent or recurrent symptoms 
of influenza (of the seven symptoms assessed) of either 
moderate or severe intensity at the Day 14 visit, will require 
additional follow up. 
Statistical Methods: 
Study Hypothesis: 
The null hypothesis (H0) for this study is that the time to 
alleviation of influenza symptoms is the same for subjects 
treated with placebo and for subjects treated with peramivir 
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300mg (H01) or peramivir 600mg (H02). 
 
The alternative hypothesis (H1) is that subjects treated with 
peramivir 300mg (H11) or peramivir 600mg (H12) have an 
improvement in time to alleviation of influenza symptoms over 
those treated with placebo. 
 
Sample Size: 
From preliminary results of a phase 2 study evaluating peramivir 
treatment of uncomplicated influenza, it is expected that the 
median time to alleviation of symptoms will be 137.0 hours  
(95% CI: 115.9, 165.8) for subjects receiving placebo 
treatment.  Additionally, it is expected that the median time to 
alleviation for the 150 mg dose peramivir arm will be reduced 
by 30% compared to placebo (see table below) yielding a hazard 
ratio of 0.70.  
 
Median Time To Alleviation of Symptoms (Hours) 
Placebo 
Peramivir 150mg 
Difference (hours) 
145.0 
101.5 
43.5 
140.0 
98.0 
42.0 
135.0 
94.5 
40.5 
130.0 
91.0 
39.0 
125.0 
87.5 
37.5 
120.0 
84.0 
36.0 
115.0 
80.5 
34.5 
110.0 
77.0 
33.0 
105.0 
73.5 
31.5 
100.0 
70.0 
30.0 
 
Using these assumptions, a sample size of 300 evaluable 
subjects per active treatment group and 150 evaluable subjects 
in the placebo group (a total of 750 evaluable subjects) is 
sufficient to provide at least 90% power to detect a hazard ratio 
of 0.70 using a log-rank statistic and α = 0.025 (SAS version 
9.1.3; total accrual time 7 months; total enrollment time 6 
months). 
Efficacy:  
The intent-to-treat infected population (ITTI) will include all 
subjects who are randomized, received study drug, and have 
confirmed influenza A by primary viral culture or PCR.  The 
primary efficacy variable is the time to alleviation of symptoms, 
defined as the time from injection of study drug to the start of 
the time period when each of seven symptoms of influenza are 
either absent or are present at no more than mild severity level 
and remain at no worse than this severity status for a 21.5 hour 
(24 hours – 10%) period. 
 
Descriptive statistics for the primary efficacy variable will be 
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tabulated by treatment group.  Alleviation of symptoms will be 
determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be 
summarized for each treatment group.  Treatment differences 
between each active group and placebo will be assessed using a 
Wilcoxon-Gehan statistic stratified by smoking status at 
screening.  Subjects who do not experience alleviation of 
symptoms will be censored at the date of their last non-missing 
assessment.  The overall significance level will be maintained by 
utilization of Hochberg’s method for the planned comparisons 
between the two active treatments and placebo. Time to 
resolution of fever will be analyzed in a similar manner without 
the adjustment for multiple comparisons.   
 
Efficacy analyses will be repeated for a Per-Protocol Infected 
population (PPI). This population will include those subjects in 
the ITTI population who received an adequate intramuscular 
injection.  Details of this population will be described in the 
statistical analysis plan. The PPI population analysis will be 
used as supportive to the primary analysis with the ITTI. 
 
Changes in influenza virus TCID50 (viral titers from 
nasopharyngeal specimens) will be compared using the van 
Elteren statistic controlling for smoking status at screening.  
Analyses of other continuous endpoints will be analyzed in a 
similar manner.  
 
The number and percentage of subjects experiencing influenza 
related complications (IRC) will be summarized by 
complication preferred term and treatment group.  The 
difference between the treatment groups will be assessed using a 
logistic regression model with factors for treatment group and 
smoking status at screening.  Pairwise differences between the 
treatment groups will be evaluated using contrasts from the final 
logistic regression model. 
 
Safety: 
Safety analyses will be presented for all subjects in the safety 
population, defined as all randomized subjects who receive at 
least one dose of study drug.  Adverse events will be mapped to 
a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification.   
 
The occurrence of treatment-emergent AEs will be summarized 
using preferred terms, system organ classifications, and severity.  
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be 
generated.  All AEs will be listed for individual subjects 
showing both verbatim and preferred terms.   
 
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Descriptive summaries of vital signs and quantitative clinical 
laboratory changes will be presented by study visit.  Frequency 
and percentages of subjects with abnormal laboratory test results 
will be summarized by toxicity grade.   
 
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 each abnormal physical 
examination finding will be presented.  
 
The number and percent of subjects discontinuing study as well 
as the reasons for discontinuation will be summarized by 
treatment group. 
 
Date of Protocol: 
Version 1.0: 04-September-2007 
Amendment (Dates): 
Version 2.0: 05-October-2007 
Version 3.0: 20-November-2007 
 
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3 
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...........................................................................................................13 
3.1 
LIST OF FIGURES .........................................................................................................................15 
3.2 
LIST OF TABLES ..........................................................................................................................15 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................................16 
5 
INTRODUCTION......................................................................................................................18 
5.1 
BACKGROUND.............................................................................................................................18 
5.2 
RATIONALE FOR STUDY ..............................................................................................................18 
5.3 
NON-CLINICAL EXPERIENCE WITH PERAMIVIR...........................................................................19 
5.3.1 
In vitro Assays.......................................................................................................................19 
5.3.2 
Animal Models......................................................................................................................19 
5.4 
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................................20 
5.5 
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR.........................................20 
5.6 
PHASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR .........................................................22 
5.7 DOSE RATIONALE................................................................................................................................25 
6 
STUDY OBJECTIVES..............................................................................................................26 
6.1 
OBJECTIVES ................................................................................................................................26 
6.1.1 
Primary Objective..................................................................................................................26 
6.1.2 
Secondary Objective(s) .........................................................................................................26 
6.1.3 
Exploratory Objective(s) .......................................................................................................26 
6.2 
STUDY ENDPOINTS......................................................................................................................26 
6.2.1 
Primary Endpoint...................................................................................................................26 
6.2.2 
Secondary Endpoint(s) ..........................................................................................................26 
6.2.3 
Exploratory Endpoints...........................................................................................................27 
7 
STUDY DESIGN.......................................................................................................................27 
7.1 
OVERALL STUDY DESIGN AND PLAN ..........................................................................................27 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................................28 
8.1.1 
Inclusion Criteria...................................................................................................................28 
8.1.2 
Exclusion Criteria..................................................................................................................29 
8.1.3 
Removal of Subjects from Therapy or Assessment...............................................................30 
9 
TREATMENTS .........................................................................................................................30 
9.1 
TREATMENTS ADMINISTERED.....................................................................................................30 
9.2 
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .............................................................................30 
9.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................31 
9.4 
STUDY MEDICATION ACCOUNTABILITY......................................................................................31 
9.5 
BLINDING/UNBLINDING OF TREATMENTS...................................................................................31 
9.6 
PRIOR AND CONCOMITANT THERAPIES.......................................................................................32 
9.7 
OVERDOSE AND TOXICITY MANAGEMENT..................................................................................32 
9.8 
DOSE INTERRUPTION...................................................................................................................32 
10 
STUDY CONDUCT..................................................................................................................32 
10.1 
EVALUATIONS.............................................................................................................................32 
10.1.1 
Informed Consent .............................................................................................................32 
10.1.2 
Medical History ................................................................................................................32 
10.1.3 
Rapid Antigen Test for Influenza .....................................................................................32 
10.1.4 
Physical Examination and Influenza-related Complications Assessments .......................33 
10.1.5 
Vital Signs ........................................................................................................................33 
10.1.6 
Electrocardiogram Measurements ....................................................................................33 
10.1.7 
Clinical Laboratories ........................................................................................................33 
10.1.8 
Urine Pregnancy Test .......................................................................................................34 
10.1.9 
Serology for Influenza ......................................................................................................34 
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10.1.10 
Samples for Virologic Laboratory Assessments...............................................................34 
10.1.11 
Subject Self Assessments..................................................................................................34 
10.1.12 
Concomitant Medications.................................................................................................35 
10.1.13 
Adverse Events.................................................................................................................35 
10.1.14 
Pharmacokinetic Exposure Samples.................................................................................35 
10.2 
SCREENING PERIOD.....................................................................................................................35 
10.2.1 
Informed Consent .............................................................................................................35 
10.2.2 
Screening/Baseline Evaluation and Enrollment................................................................35 
10.3 
TREATMENT PERIOD—STUDY DAY 1 .........................................................................................36 
10.3.1 
Pre-dose Evaluations-Study Day 1 ...................................................................................36 
10.3.2 
Post-dose Evaluations-Study Day 1..................................................................................36 
10.4 
POST-TREATMENT ASSESSMENT PERIOD....................................................................................37 
10.4.1 
Days 2, 3, 5, 9 and 14 .......................................................................................................37 
10.4.2 
Adverse Events Reported at Post-treatment Visits ...........................................................38 
11 
ADVERSE EVENT MANAGEMENT......................................................................................41 
11.1 
DEFINITIONS ...............................................................................................................................41 
11.1.1 
Adverse Event...................................................................................................................41 
11.1.2 
Serious Adverse Event......................................................................................................41 
11.2 
METHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND REPORTING 
SERIOUS ADVERSE EVENTS ........................................................................................................42 
11.2.1 
Definition of Severity .......................................................................................................42 
11.2.2 
Definition of Relationship to Study Drug.........................................................................43 
11.2.3 
Reporting Serious Adverse Events ...................................................................................43 
11.2.4 
Emergency Procedures .....................................................................................................44 
12 
STATISTICAL METHODS ......................................................................................................44 
12.1 
DATA COLLECTION METHODS ....................................................................................................44 
12.2 
STATISTICAL ANALYSIS PLAN ....................................................................................................45 
12.3 
STUDY HYPOTHESIS....................................................................................................................45 
12.4 
SAMPLE SIZE ESTIMATES............................................................................................................45 
12.5 
ANALYSIS POPULATIONS ............................................................................................................46 
12.6 
INTERIM AND END OF STUDY ANALYSES....................................................................................47 
12.7 
EFFICACY ANALYSES..................................................................................................................47 
12.7.1 
Primary Efficacy Endpoint ...............................................................................................47 
12.7.2 
Secondary Efficacy Endpoints..........................................................................................47 
12.7.3 
Exploratory Endpoints......................................................................................................48 
12.8 
SAFETY ANALYSES .....................................................................................................................48 
12.9 
SUB-STUDY AND PHARMACOKINETIC ANALYSIS........................................................................49 
12.10 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ...........................................................................49 
12.10.1 
Multiple Comparisons and Multiplicity............................................................................49 
12.10.2 
Covariates.........................................................................................................................49 
12.10.3 
Planned Sub-Groups.........................................................................................................49 
12.10.4 
Missing Data.....................................................................................................................50 
13 
STUDY ADMINISTRATION...................................................................................................50 
13.1 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................................................50 
13.1.1 
Regulatory Authority Approvals.......................................................................................50 
13.1.2 
Ethics Committee Approvals............................................................................................51 
13.1.3 
Subject Informed Consent ................................................................................................51 
13.1.4 
Payment to Subjects..........................................................................................................51 
13.1.5 
Investigator Reporting Requirements ...............................................................................51 
13.2 
STUDY MONITORING...................................................................................................................52 
13.3 
QUALITY ASSURANCE.................................................................................................................52 
13.4 
STUDY TERMINATION AND SITE CLOSURE..................................................................................52 
13.5 
RECORDS RETENTION .................................................................................................................52 
13.6 
STUDY ORGANIZATION...............................................................................................................52 
13.6.1 
Data Monitoring Committee.............................................................................................52 
13.7 
CONFIDENTIALITY OF INFORMATION ..........................................................................................53 
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13.8 
STUDY PUBLICATION ..................................................................................................................53 
14 
REFERENCES...........................................................................................................................54 
15 
APPENDICES ...........................................................................................................................56 
15.1 
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA ......................56 
15.2 
CRITERIA FOR SEVERE COPD AND SEVERE ASTHMA .................................................................57 
 
3.1 
 List of Figures 
Figure 1 
Study Measurements and Visit Schedule.................................................................39 
 
3.2 
List of Tables 
Table 1 
Results of study BC-01-03.......................................................................................20 
Table 2 
Pharmacokinetic parameters from study Him-06-111. ............................................21 
Table 3 
Summary of Efficacy from BCX1812-211. .............................................................24 
Table 4 
Summary of Safety from BCX1812-211. ................................................................25 
Table 5 
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio)..........46 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE  
adverse event 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the curve 
AUC0–72 
area under the curve from time 0 to 72 hours 
AUC0–∞ 
area under the curve extrapolated from time 0 to infinity 
BMI 
Body Mass Index in kg/m2 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CIOMS 
Council for International Organizations of Medical sciences 
Cmax  
maximum plasma concentration 
CK 
creatine kinase 
CNS  
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
GCP  
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IC50  
median inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
influenza related complications  
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected 
IUD 
intrauterine device 
IVRS 
interactive voice response system 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
RAT 
Rapid Antigen Test 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SD 
standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Event 
t1/2  
elimination half-life 
t1/2 λz 
terminal half-life 
TCID50 
tissue-culture infective dose50 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to attain maximum plasma concentration 
UPEP 
Urine protein electrophoresis 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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5 
INTRODUCTION 
5.1 
Background 
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the 
respiratory tract.  Typical influenza illness is characterized by abrupt onset of fever, headache, 
myalgia, sore throat, and nonproductive cough.1  The illness is usually self-limiting, with relief of 
symptoms occurring within 5 to 7 days.  Nevertheless, it is an important disease for several 
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation, 
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk 
of death, particularly in the elderly.  During 19 of the 23 influenza seasons between 1972/1973 
and 1994/1995, estimated influenza-associated deaths in the United States ranged from 
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for 
more than 90% of the deaths attributed to pneumonia and influenza.2 
Presently, only a few measures are available that can reduce the impact of influenza: active 
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or 
therapy with an influenza-specific antiviral drug.  Neuraminidase inhibitors are the current 
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include 
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral 
prodrug of the active agent, oseltamivir carboxylate.  Influenza neuraminidase is a surface 
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids.  The enzyme 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.  The neuraminidase inhibitors 
represent an important advance in the treatment of influenza with respect to activity against 
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory 
complications,3 and lower rates of antiviral drug resistance4. 
The use of currently available neuraminidase inhibitors has been limited by concerns including, 
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence 
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of 
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir. 
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the 
armamentarium of drugs for the treatment of influenza infections due to its potential for 
parenteral administration and lower frequency of dosing. 
5.2 
Rationale for Study 
An oral formulation of peramivir has previously been evaluated in a full range of safety, 
tolerability, pharmacokinetic, and efficacy studies.  In a multinational phase 3 clinical trial 
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B 
infections, and improvement in the relief of clinical symptoms.  Because of the limited 
bioavailability of peramivir following oral administration (<5%), it was determined that the 
parenteral route of administration is more appropriate for the delivery of peramivir.  Subsequent 
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that 
parenteral routes of administration result in plasma levels of drug that are as much as 100 times 
those achieved via the oral route. In a phase 2 study of intramuscular peramivir in subjects with 
acute uncomplicated influenza, subjects who received a single injection of 150mg or 300mg 
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peramivir had clinically meaningful reductions in the time to alleviation of symptoms of 
influenza, compared to subjects who received a placebo injection. Further details of these studies 
are provided below and in the Investigator Brochure. 
Because of the previous demonstration of clinical efficacy of intramuscular peramivir in acute 
influenza in the phase 2 study, and the encouraging pharmacokinetic and preliminary safety 
profile of the intramuscular formulation of peramivir demonstrated to date, this phase 3 study will 
be conducted to evaluate the efficacy and safety profile of intramuscular peramivir and to 
determine the optimal single dose regimen.  
5.3 
Non-Clinical Experience with Peramivir 
5.3.1 
In vitro Assays 
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations 
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and 
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza 
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase 
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent 
neuraminidase assay.  Inhibition of Type A influenza neuraminidase by peramivir was 
approximately an order of magnitude greater than inhibition of neuraminidase from Type B 
viruses.  IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B 
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.  
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of 
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.   
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase 
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM) 
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).  
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to 
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8   
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9  Peramivir remained a potent inhibitor against all oseltamivir-resistant 
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.  
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant 
strains, which had the following mutations:  R292K, E119G, E119A, and E119D.  However, one 
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell 
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 = 
400nM). 
5.3.2 
Animal Models 
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg) 
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100% 
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse 
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg) 
resulted in 100% survival, compared to 100% mortality in the control group injected with 
vehicle.10 
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the 
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infecting virus strain.  In a mouse model, a single intramuscular dose of peramivir (30mg/kg) 
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain, 
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given 
orally at 10mg/kg/day for 5 days11.  In similar experiments, mice inoculated with the same strain 
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited 
100% survival12.  This longer duration of peramivir treatment also prevented viral replication in 
the lungs, brain and spleen at days 3, 6 and 9 post inoculation. 
5.4 
Previous Phase 3 Clinical Experience with Oral Peramivir 
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary 
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in 
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001.  A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted.  Two dose 
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg 
QD for 4 days, were compared to a matched placebo treatment group.  A total of 1246 subjects 
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America, 
Australia and New Zealand.  As presented in the Table 1 below, the primary end-point of time to 
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be 
significantly different (p=0.17) between the three treatment groups.13  A sub-group analysis of the 
time to relief of symptoms by country or region demonstrated marked differences in the primary 
endpoint.. In the subset of influenza-infected subjects enrolled at  sites in the US, clinically 
meaningful differences in time to relief of influenza symptoms between the placebo and the two 
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.  
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral 
shedding, achieved or approached statistically significant differences between the peramivir and 
placebo treatment groups (p=0.03-0.06). 
Table 1 
Results of study BC-01-03 
 
 
Median Time to Relief of Influenza Symptoms (Hours) 
Dose and Regimen 
Overall Results 
(n=694) 
US Sites 
(n=198) 
Peramivir 800mg po x 5d 
89.0 
70.8 
Peramivir 800mg po x 1d 
 and          400mg po x 4d 
91.7 
88.8 
Placebo x 5 days 
104.4 
106.8 
p value 
0.17 
0.07 
 
5.5 
Previous Phase 1 Experience with Intramuscular Peramivir 
Two phase 1studies evaluating the safety and pharmacokinetics of an intramuscular formulation 
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir. An 
additional phase 1 study has recently been initiated to evaluate the pharmacokinetics and 
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tolerability of higher single doses (up to 600 mg) of intramuscular peramivir. 
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of 
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and 
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of 
i.m. peramivir generally occurred within 30 minutes following injection.  Plasma 
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three 
intramuscular single dose regimens evaluated. 
Table 2 
Pharmacokinetic parameters from study Him-06-111. 
 
Dose (mg) 
Cmax (ng/mL) 
AUC0-∞ (hr·ng/mL) 
t½a (hr) 
75 i.m. 
4296 ± 812 
11659 ± 1123 
19.8 ± 7.9 
150 i.m. 
7612 ± 884 
23952 ± 3804 
24.3 ± 4.1 
300 i.m. 
15150 ± 2367 
49649 ± 5619 
22.8 ± 2.5 
aterminal half life 
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were 
administered as single i.m. injections on two consecutive days (6 subjects per group). This 
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m. 
peramivir following the second day of dosing were consistent with those seen following single 
doses of the drug. 
An additional phase 1 study, BCX1812- 117, was initiated to evaluate the effect  of needle length 
adjustment according to gender and bod
y m ass index on the pharm acokinetics and s afety of 
peramivir fo llowing vent rogluteal int ramuscular injection, and dors
ogluteal intram uscular 
injection in a subgroup  o f subjects.  Interim  data are available for the first 40 subjects who
 
received single peram ivir doses of 
600 m g, co nsisting of directly
 obse rved tolerabilit y 
assessments, safety  laboratory  studies, reporte d adverse even ts, and pharmacokinetic data.  
Clinical laboratory results obtained 72 hours after dosing showed no abnorm alities with reg ards 
to hematology or urinary analytes and the only chemistry analytes outside normal ranges (CK and 
AST) were related to receipt of intramuscular injection.   
 
A majority of the first 40 subjects treated com plained of acute pain immediately after injection at 
the ventrogluteal site and a num ber of these subj ects reported that the pain w as also assoc iated 
with muscle cramping. Some subjects reported radiation of pain to the lower extremities. In most 
instances, these reactions abated after 15-30 minutes.  
 
This protocol also evaluated the acute tolerab ility of doses of 450 m g and 600 mg of perami vir 
administered at the dors
ogluteal site.  Direct
 observations deter mined that the use of the 
dorsogluteal injection site resulted in an acute tolerability profile of the 600 mg dose of peramivir 
that was i mproved com pared to that observed w
ith ventrogl uteal site injections. However, a 
number of th ese subjects also experienced acute pain and discomfort and some reported muscle 
cramping in the gluteal area which persisted for up to 30 minutes.   
 
In summary, this study confirmed that the intram uscular injection of peram ivir results in acute 
pain and discomfort after gluteal injection in the majority of subjects in whom total doses of up to 
600mg are adm inistered. In some subjects, the ac
ute pain at the injection site 
may also b e 
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associated with muscle cramping.  Based on these findings, the dorsogluteal site will be util ized 
in future trials. 
 
The safety data for i.m. peramivir administered as single doses ranging from 75 mg to 600mg at 
the dorsogluteal injection site in each of the 3 phase 1 studies conducted to date have been 
unremarkable.   No serious adverse events were reported.  The most commonly observed adverse 
events or laboratory abnormalities were injection site pain or discomfort, headache, and transient 
increases in muscle enzymes (CK). There have been several reports of signs and symptoms of 
self-limited vasovagal reactions following injections..  No consistent differences in frequency of 
adverse events or laboratory toxicities were observed between the active and placebo treatment 
groups in the controlled phase 1studies, with the exception that CK elevations appeared to be 
dose related in the peramivir treatment groups.   
5.6 
Phase 2 Experience with Intramuscular Peramivir 
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of 
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to 
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to 
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical 
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the 
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve 
statistical significance in the pre-planned ITTI study population (Table 3).. Based on pre-planned 
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not 
receive an adequate intramuscular injection.  
In phase 1 studies (Hi
m-06-111 and Him-06-112) of i.m . per amivir, significant increases in 
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who 
received active study drug or placebo. CK is a well established marker of muscle damage, and it 
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection. 
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not 
observed in a majority of subjects.  In the phase 1 studies study drug was administered with a 1½ 
inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with 
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed 
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle 
used for injection failed to penetrate muscle and deliver intramuscular study medication in many 
subjects. 
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was 
observed over baseline. Within this adequate intramuscular injection sub-group, notable 
improvements in the time to alleviation of symptoms were observed for both peramivir dose 
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg 
treatment 
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Table 3).  A further sub-group analysis suggested that in subjects with an influenza B infection 
confirmed by PCR a single dose of peramivir had marginal activity (Table 3). These efficacy data 
support the further development of peramivir as a single dose, intramuscular treatment for acute 
influenza. 
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Table 3 
Summary of Efficacy from BCX1812-211. 
 
 
Placebo 
Peramivir 
150mg 
Peramivir 
300mg 
Intent-to-Treat Infected Population1 (n=313) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=107 
137.0 
115.9-163.8 
n=104 
114.1 
95.2-145.5 
22.9 
n=102 
115.9 
77.8-136.6
21.1 
Adequate Injection Population2 (n=101) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=40 
152.2 
103.8-183.9 
n=32 
107.6 
76.8-175.1 
44.6 
n=29 
87.4 
40.8-163.8
64.8 
ITTI Influenza A infected population (n=247) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=83 
138.4 
117.0-173.4 
 
n=85 
115.7 
92.2-145.5 
22.7 
n=79 
115.9 
51.1-195.9 
22.5 
ITTI Influenza B infected population (n=66) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=24 
117.1 
100.3-162.3 
n=19 
100.8 
68.2-162.0 
16.3 
n=23 
123.3 
67.5-178.7 
-6.2 
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at 
baseline/screening visit. 
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue, 
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study 
visit. 
An independent data monitoring committee reviewed grouped blinded safety data throughout 
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and 
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC. 
The three treatment groups were similar with respect to the frequency and severity of adverse 
events. Two serious adverse events were reported in the study, and neither was considered by the 
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study 
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death) 
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There 
were no meaningful differences among the three treatment groups with respect to the frequency 
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities, 
together with a list of the most frequently reported adverse events, is presented in Table 4. 
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Table 4 
Summary of Safety from BCX1812-211. 
 
Safety Parameters 
Placebo 
(N=114) 
Peramivir 150 mg 
(N=113) 
Peramivir 300 mg 
(N=115) 
Any Clinical Adverse Event 
49 (43%) 
43 (38%) 
44 (38%) 
Any Graded Laboratory Toxicity 
99 (87%) 
93 (82%) 
92 (80%) 
Any Serious Adverse Event 
1 (<1%) 
0 
1 (<1%) 
Most Frequent Adverse Events 
Assessed as Study Drug-Related 
    Diarrhea 
    Nausea 
    Vasovagal Reaction 
 
 
5 (4%) 
7 (6%) 
4 (4%) 
 
 
5 (4%) 
7 (6%) 
2 (2%) 
 
 
6 (5%) 
9 (8%) 
0 
 
5.7 Dose Rationale 
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg 
twice daily in adults14.  Oseltamivir was shown to be clinically effective in a phase 3 study of oral 
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were 
sufficient for regulatory approval for marketing of oseltamivir.  At least 75% of an oral dose of 
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is 
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is 
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this 
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated 
acute influenza.  
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of 
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are 
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose.  Previous studies have 
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal 
secretions after parenteral administration of this drug. .  Within several hours after administration, 
the concentrations in secretions were approximately 100-fold lower than in serum or plasma.  In 
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in 
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in 
infecting virus strains.  Intramuscular doses of peramivir, including doses of 300mg and 600mg 
have been shown to be well tolerated in previous Phase 1 studies.  In the completed Phase 2 
study, both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns 
were apparent. As evidence of a dose response between the 150mg and 300mg doses was 
observed in the phase 2 study, it is possible that a higher dose of 600mg of peramivir may further 
improve the treatment response observed in study 211.  Therefore, it is appropriate to evaluate 
two dose regimens of 300mg and 600mg to undergo further evaluation in this Phase 3 study.  
 
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6 
STUDY OBJECTIVES 
6.1 
Objectives 
6.1.1 
Primary Objective 
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the 
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza. 
6.1.2 
Secondary Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of peramivir administered intramuscularly, 
2. To evaluate secondary clinical outcomes in response to treatment, 
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in 
response to treatment. 
6.1.3 
Exploratory Objective(s) 
The following exploratory objectives have been identified for this study. 
1. To assess pharmacoeconomic measures as response to treatment. 
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following 
treatment. 
6.2 
Study Endpoints 
6.2.1 
Primary Endpoint 
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza in 
subjects with influenza A. 
6.2.2 
Secondary Endpoint(s) 
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of: 
Safety: 
Incidence of treatment-emergent adverse events and treatment-emergent changes 
in clinical laboratory tests. 
Clinical:  
Time to resolution of fever; Incidence of influenza related complications. 
Virologic: 
Quantitative change in influenza virus shedding, measured by viral titer assay 
(TCID50). 
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6.2.3 
Exploratory Endpoints 
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also 
be assessed and include: 
Pharmacoeconomic:  
Medical resource utilization (MRU), missed days of work, and impact of 
influenza illness on subject’s work performance and/or productivity. 
Virologic: 
Quantitative change in influenza virus shedding, measured by PCR; 
Change in influenza virus susceptibility to neuraminidase inhibitors. 
 
7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multinational, randomized, double-blind study comparing the efficacy and safety of two 
single dose regimens of peramivir administered intramuscularly versus placebo in adults with 
uncomplicated acute influenza. 
Up to a total of 750 evaluable subjects will be randomized to treatment (150 subjects in the 
placebo treatment group, 300 subjects in the peramivir 300mg treatment group and 300 subjects 
in the peramivir 600mg treatment group).  
Each subject’s assignment to treatment will be stratified according to smoking status. All subjects 
will be centrally randomized to one of three treatment groups in a ratio of 2:2:1 such that 80% of 
subjects are randomized to one of the two single dose regimens of peramivir. 
Treatment Group 1:  Peramivir 300mg 
Treatment Group 2:  Peramivir 600mg 
Treatment Group 3:  Placebo 
Study drug will be administered as bilateral 4mL intramuscular injections (total of 8mL injected 
in equally divided doses). Procedures for intramuscular injection, with a recommended needle 
length appropriate to the physical characteristics of the subject, are provided in the study drug 
administration manual. 
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for 
influenza A and B, in accordance with the commercially available RAT kit instructions.  If the 
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the 
inclusion/ exclusion criteria may be enrolled into the study. 
All enrolled subjects will record the following information in a Study Diary.  
• 
Assessment of the presence and severity of each of seven symptoms of influenza on a 
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through 
Day 9 following treatment, then once daily (AM) through Day 14. 
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• 
Oral temperature measurements will be taken with an electronic thermometer every 12 
hours. With the exception of the baseline measurement, all temperature measurements 
will be obtained at least 4 hours after, or immediately before, administration of oral 
acetaminophen (paracetamol) or other antipyretic medication. 
• 
Assessment of subject’s time lost from work or usual activities and rating of productivity 
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14 
• 
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief 
each day through Day 14 
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments.  Specimens from all 
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase 
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic 
assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a 
central laboratory.  
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained 
from all subjects randomized.  The first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second PK sample will be obtained at the 
day 3 visit in all subjects. The data from these PK samples will be utilized in a population 
exposure-response analysis. 
At selected sites a separate sub-study will be conducted to collect additional PK samples between 
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis.  This 
sub-study will be conducted under a separate protocol, BCX1812-311PK.   
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected 
in divided doses). Procedures for intramuscular injection, with a recommended needle length 
appropriate to the size and weight of the subject, are provided in the study drug administration 
manual. 
 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1.1 
Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in this study: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A Rapid Antigen Test (RAT) performed with a commercially 
available test kit on an adequate anterior nasal specimen, in accordance with the 
manufacturer’s instructions.  A negative initial RAT should be repeated within one hour. 
Subjects with a positive influenza B or mixed A and B RAT will be excluded. 
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC 
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for enrollment in the absence of 
documented fever at the time of screening.   
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4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of 
at least moderate severity. 
5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache, 
feverishness, or fatigue) of at least moderate severity. 
6. Onset of symptoms no more than 48 hours before presentation for screening. 
7. Written informed consent. 
8.1.2 
Exclusion Criteria 
Subjects to whom any of the following criteria apply will be excluded from the study: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory distress 
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent 
asthma. (See Section  15.2). 
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms 
consistent with New York Heart Association Class III or IV functional status within the 
past 12 months. (See Section  15.1). 
5. Screening ECG which suggests acute ischemia or presence of medically significant 
dysrhythmia. 
6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to 
have moderate or severe renal impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis, 
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic illness, previous organ transplant, 
or use of immunosuppressive medical therapy which would include oral or systemic 
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of 
screening. 
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 cell/mm3. 
12. Current therapy with oral warfarin or other systemic anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days 
prior to screening. 
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the 
previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 14 days. 
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study. 
18. Participation in a previous study of intramuscular or intravenous peramivir or previous 
participation in this study. 
19. Participation in a study of any investigational drug or device within the last 30 days. 
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8.1.3 
Removal of Subjects from Therapy or Assessment 
All subjects are permitted to withdraw fro m participation in this  study at any ti me and for any  
reason, specified or 
unspecified, and without prejudice.  T he Investigator  or sp onsor m ay 
terminate the subject’s participation in the study at any time for reasons including the following: 
1. Adverse event; 
2. Intercurrent illness; 
3. Non-compliance with study procedures; 
4. Subject’s decision; 
5. Administrative reasons; 
6. Lack of efficacy; 
7. Investigator’s opinion to protect the subject’s best interest. 
Any subject who withdraws because of an adve
rse event will be followe d until the sign(s) or 
symptom(s) that constituted the adverse event has/ha ve resolved or is determ ined to represent a 
stable medical condition. 
A subject should be with drawn from the trial if, in the opinion of the Investigator, it is medically 
necessary, or if it is the desire of the subject. 
If a subject does not return for a scheduled visit, 
every effort should be made to contact the subject and determine the subject’s medical condition.  
In any circumstance, every effort should be made to document subject outcome, if possible. 
If the subject withdraws consent, no fu rther ev aluations should b e perfo rmed and no attempts 
should be made to collect additional data. 
 
9 
TREATMENTS 
9.1 
Treatments Administered 
Peramivir is an investigational drug.  Peramivir for intramuscular injection is a small-volume 
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer.  The 
pH is approximately 3.0. 
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a 
pH of approximately 3.0 will be supplied. 
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF. 
Procedures for intramuscular injection, with a recommended needle length appropriate to the 
physical characteristics of the subject, are provided in the study drug administration manual. 
9.2 
Identity of Investigational Product(s) 
Peramivir and placebo peramivir will be supplied in clear 2mL vials.  An individual study drug 
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the 
treatment group). Syringes and needles will be provided in which to draw up the solution for 
intramuscular injection. All study drug kits must be stored at 2-8oC.   
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Each individual study drug kit will be labeled with some or all of the following information as 
required by local regulations: 
• 
Sponsor name and contact information, study protocol number, kit number, description of 
the contents of the container, instructions for the preparation of the syringe and 
administration of the study drug, conditions for storage, statement regarding the 
investigational (clinical trial) use of the study drug and date for retest or expiry date. 
Each vial of study drug will be labeled with some or all of the following information as required 
by local regulations: 
• 
Sponsor name, study protocol number, description of the contents of the vial, instructions 
for the preparation of the syringe, statement regarding the investigational (clinical trial) 
use of the study drug and lot number. 
9.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be centrally randomized according in a ratio of 2:2:1 to one of three treatment 
groups: single dose peramivir 300mg, single dose peramivir 600mg or placebo, in accordance 
with a computer-generated randomization schedule prepared by a non-study statistician. Eighty 
percent (80%) of subjects will be randomized to treatment with one of the two single dose 
regimens of peramivir, 20% will be randomized to treatment with placebo. 
Each subject’s assignment to treatment will be stratified according to smoking status. 
Once a subject is eligible for randomization, he/she will be assigned two study drug kit numbers 
that will be obtained by study staff from the study interactive voice response system (IVRS).  
Once a study drug kit number has been assigned to a subject, it cannot be reassigned to any other 
subject.   
9.4 
Study Medication Accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs 
received from the sponsor, issued to the subject or directly administered to the subject (including 
date and time), and any drug accidentally destroyed.  The sponsor will supply a specific drug-
accountability form.  At the end of the study, information describing study drug supplies (e.g., lot 
numbers) and disposition of supplies for each subject must be provided, signed by the 
Investigator or designee, and collected by the study monitor.  If any errors or irregularities in any 
shipment of study medication to the site are discovered at any time, the Project Manager must be 
contacted immediately. 
At the end of the study, all medication not dispensed or administered and 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 at the participating institution. 
9.5 
Blinding/Unblinding of Treatments 
This is a double-blind study.  The treatment group assignment will not be known by the study 
subjects, the investigator, the clinical staff, the CRO or Sponsor staff during the conduct of the 
study. 
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Section  11.2.4 provides information regarding the process for unblinding the treatment 
assignment, if necessary, in the event of an SAE. 
9.6 
Prior and Concomitant Therapies 
All medications, by any route of administration, used during this study must be documented on 
the Case Report Form (CRF).  Prescription as well as non-prescription medications should be 
recorded. Medication used for the treatment of influenza-related symptoms will be captured by 
the subject in the diary card provided by BioCryst. 
9.7 
Overdose and Toxicity Management 
To date there is no experience with overdose of intramuscular or intravenous peramivir.  If 
overdose occurs, subjects should receive indicated supportive therapy and evaluation of 
hematologic and clinical chemistry laboratory tests should be conducted.  The effect of 
hemodialysis on elimination of peramivir is unknown. 
9.8 
Dose Interruption 
As this is a study of a single dose of peramivir or placebo, guidelines for treatment interruption 
for drug related SAEs or toxicities are not applicable. 
 
10 STUDY CONDUCT 
A study schedule of evaluations is presented in Figure 1.  A detailed list of the evaluations and 
visits is also provided in the following sections. 
10.1 Evaluations 
All subjects enrolled in this study will undergo the following evaluations: 
10.1.1 Informed Consent 
Prior to any  study-related procedure subjects will be administered informed consent. For further 
discussion of consent see section  10.2.1. 
10.1.2 Medical History 
Medical history, influenza vaccination status within the previous 12 months and demographic 
data (including smoking behavior) will be recorded at Screening/Baseline. 
10.1.3 Rapid Antigen Test for Influenza 
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A will be 
performed on an adequate specimen collected by swabbing the anterior nose in accordance with 
the RAT manufacturer’ instructions.  A negative initial RAT should be repeated within one hour.  
Subjects with a positive influenza B or mixed A and B RAT will be excluded. Refer to the Study 
Manual for instructions regarding the use of the RAT kits provided for this study.  Sites may use 
the kits provided by the Sponsor or any other commercially approved RAT available at their site 
to document a confirmed influenza infection.  
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10.1.4 Physical Examination and Influenza-related Complications Assessments 
The Investigator will perform a physical examination at Screening/Baseline.  Subject’s height and 
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF. 
Study personnel will be provided with an influenza-related complications (IRC) checklist in the 
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following 
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects 
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia 
at screening are not eligible for enrollment in this study (See Section  8.1.2: exclusion criteria 
number 8). 
A targeted physical examination will be conducted at each visit to record the presence/absence of 
influenza related complications (IRC). If the investigator determines that the subject experiences 
(or is presumed to experience) an IRC as noted above, he/she will record that assessment on the 
IRC CRF page and any medication used to treat the condition will be recorded on the 
concomitant medication page.  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 adverse events. Any injection site reactions noted will be recorded in the CRFs 
as adverse events. 
10.1.5 Vital Signs 
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The 
investigator will record oral or rectal body temperature at baseline. Thereafter the subject will 
record oral temperature twice daily in the study diary card. 
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the 
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14. 
10.1.6 Electrocardiogram Measurements 
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal 
investigator will be responsible for interpretation of the Screening ECG. This interpretation may 
be performed by the investigator or he/she may delegate this action to another physician and the 
investigator will acknowledge the interpretation.  If this baseline ECG is interpreted as meeting 
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study.  If the 
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may 
be enrolled unless other exclusion criteria apply.  The principal investigator is responsible to 
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any 
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation 
is made either during subject's participation in the study or immediately after the subject's 
discharge from the study.  
10.1.7 Clinical Laboratories 
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). 
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Hematology will include complete blood count (CBC) with differential. 
Urinalysis will include dipstick tests for protein, glucose, ketones, blood, urobilinogen, nitrite, 
pH, and specific gravity and microscopic evaluation for RBCs and WBCs. For any subject with a 
Day 3 positive test for urine protein by dipstick test of 2+ or higher, who had a Baseline/ Day 1 
protein dipstick of <2+, a 24 hour urine collection for assessment of protein and a simultaneous 
assessment by UPEP on the same specimen will be obtained. 
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at 
Screening/Baseline, and on Days 3, 5 and 14.  
10.1.8 Urine Pregnancy Test 
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day 
14 using a urine pregnancy test. 
10.1.9 Serology for Influenza  
Paired blood samples for determination of antibody to influenza A and B (serology) will be 
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These 
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the 
diagnosis of influenza. 
10.1.10 Samples for Virologic Laboratory Assessments 
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior 
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus 
and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9.  Refer to the 
Laboratory Manual for instructions regarding the processing and shipment of these specimens. 
10.1.11  Subject Self Assessments 
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the 
subject’s Study Diary including the following: 
• 
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for 
the study) every 12 hours.  With the exception of the baseline measurement, all temperature 
measurements will be obtained at least 4 hours after, or immediately before, administration of 
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of 
each temperature determination will be recorded in the Study Diary.  The baseline 
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of 
whether the subject had recently taken an anti-pyretic; the time of anti-pyretic use pre-
treatment will be recorded in the CRF, if applicable. 
• 
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia 
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9, 
then once daily through Day 14. 
• 
Assessment of the subject’s time lost from work or usual activities and productivity compared 
to normal using a 0-10 visual analogue scale once daily through Day 14. 
The subject’s diary card will be reviewed by study staff at each visit for completion of the record 
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of all required items, with particular emphasis on alleviation of symptoms as well as relapse of 
symptoms.  Relapse is defined as the recurrence of at least one respiratory symptom and one 
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever 
(unless influenced by antipyretic use).  Relapse can only occur after the subject has met the 
endpoint criteria for alleviation of symptoms.  Study staff will not attempt to ask subjects to 
retrospectively complete missing diary card data for any scheduled assessments that have not 
been completed prior to the clinic visit.  Study staff should, however, remind the subject to 
complete the diary card at all scheduled times. 
10.1.12  Concomitant Medications 
All concomitant medications used during this study, with the exception of those medications 
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in 
their diary card, must be documented on the Case Report Form (CRF).  
10.1.13  Adverse Events 
AEs will be assessed from the time of administration of study medication through the final study 
visit. 
10.1.14  Pharmacokinetic Exposure Samples 
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels. 
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug 
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all 
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical 
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample 
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population 
exposure response analysis. 
At selected sites a separate sub-study will also be conducted to collect additional PK samples for 
the purpose of conducting an exposure-response analysis.  This sub-study will be conducted 
under a separate protocol, BCX1812-311PK.  Data from these two PK samples in all subjects will 
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based 
exposure-response analysis.  This analysis will be described as part of the sub-study analysis plan.  
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions 
provided regarding the processing and shipment of these PK samples. 
 
10.2 Screening Period 
10.2.1 Informed Consent 
The nature and purpose of the study and the expectations of a participating subject will be 
described to potential study subjects, their questions will be answered, and the subjects will then 
be asked to sign an informed consent document.  Study subjects will then undergo the screening 
evaluation as noted in Section  10.2.2 
10.2.2 Screening/Baseline Evaluation and Enrollment 
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the 
subject’s home, in which case all evaluations must be conducted by appropriately trained and 
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qualified staff. 
Clinical laboratory assessments performed at Screening are for the purpose of establishing a 
baseline.  Subjects may be enrolled and receive treatment with study drug prior to receiving 
results of the laboratory assessments (with the exception of urine pregnancy test result, which 
must be known). 
Eligible subjects will be enrolled and randomized to blinded study treatment.  The randomization 
will be stratified by smoking status.  The Investigator will prepare a request for blinded study 
drug assignment which includes the subject’s screening number.  The Investigator or designee at 
the clinical study center will contact the central randomization Interactive Voice System (IVRS 
call center).  The IVRS call center will advise the study center of the two investigational study 
drug kit numbers that are assigned to that subject at enrollment. 
Subjects that are determined to be ineligible will be advised accordingly, and the reason for 
ineligibility will be discussed.  If desired by the subject the reason for ineligibility may be 
provided and/or discussed with their health-care provider by the Investigator or designee.  
Ineligible subjects who have been screened for the study will also be entered on the IVRS.  For 
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility 
will be entered on to the IVRS.  All ineligible subjects must be entered onto the IVRS within 
24 hours of screening, to assist with surveillance analysis during the course of the study. 
10.3 Treatment Period—Study Day 1 
Day 1 represents the only day of study drug dosing.  Study drug administration should occur as 
soon as possible following informed consent, screening and randomization.  Therefore, it is 
expected that the date of Screening/ Baseline and Day 1 will usually be the same date.  
10.3.1 Pre-dose Evaluations-Study Day 1 
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject 
shall complete the record of these assessments in their Study Diary prior to dosing.  The subject 
will be counseled regarding the expectations for recording these assessments through Day 14. 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a 
12 lead ECG will be obtained prior to dosing.  
A nasopharyngeal swab for influenza culture/ PCR assay will be obtained prior to dosing. 
10.3.2 Post-dose Evaluations-Study Day 1 
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a 
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second 
injections will be recorded. The gluteal site of injection and the syringe needle length are also to 
be recorded in the subjects CRF.  Sites are instructed to follow procedures for intramuscular 
injection, with a recommended needle length appropriate to the physical characteristics of the 
subject, provided in the study drug administration manual.  
The following evaluations will be performed post-dose on Study Day 1: 
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• 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15 
minutes following the second intramuscular injection of blinded study drug; record the exact 
24-hour clock time of the vital sign measurements in the subjects CRF. 
• 
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection 
of blinded study drug; record the exact 24-hour clock time of the blood draw. 
• 
Record any concomitant medications. 
• 
Record any AEs. 
10.4 Post-Treatment Assessment Period 
10.4.1 Days 2, 3, 5, 9 and 14 
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of 
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14 
will also complete a Day 21 visit, and if required a Day 28 visit.  
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which 
case all evaluations must be conducted by appropriately trained and qualified staff. 
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance 
with completion of the Subject Self Assessments, to note any concomitant medications and 
adverse events.  Any adverse events reported by the subject during this telephone contact will be 
recorded on the adverse event form and verified during the visit on day 3. 
For any subject with a Day 3 positive test for urine protein by dipstick test of 2+ or higher, who 
had a Baseline/ Day 1 protein dipstick of <2+, a 24 hour urine collection for assessment of 
protein and a simultaneous assessment by UPEP on the same specimen will be obtained. 
At each visit it is important that the subject’s Study Diary record be reviewed for completion of 
daily Subject Self Assessments.  The subjects should be counseled as necessary regarding self 
assessments and Study Diary record requirements.  The subject’s diary card will be reviewed by 
study staff for alleviation of symptoms as well as relapse of symptoms.  Relapse is defined as the 
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than 
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).  
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms. 
Day 3: 
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical 
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be 
recorded in the subjects CRF.  
Day 14: 
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven 
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject 
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3 
days)  If a subject reports moderate or severe influenza symptoms then the investigator will 
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record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21 
and day 28 visits. After day 14 the subject will not record symptoms in a diary. 
Day 21 (if applicable): 
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded 
on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28 
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.  
Day 28 (if applicable): 
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at this visit and such action(s) will be recorded on the 
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless 
in the clinical judgment of the investigator further follow-up is required. The investigator will use 
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further 
medical care. 
10.4.2 Adverse Events Reported at Post-treatment Visits 
In this study, symptoms of influenza will be considered separately from adverse events reported 
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, 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. 
 
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Figure 1 
Study Measurements and Visit Schedule 
 
Treatment 
Period 
Assessment Day 
End of Study 
Early Withdrawal 
Assessments 
Screening 1
(Baseline) 
Day 11 
Day 22 
Day 3 
Day 5 
(±1 day) 
Day 9 
(±3 day) 
Day 14 
(±3 day) 8 
Informed Consent 
X 
 
 
 
 
 
 
Rapid Antigen test for 
Influenza A  
X 
 
 
 
 
 
 
Medical History/Physical Exam 
X 
 
 
 
 
 
 
Influenza-related complications 
checklist3 
X 
 
 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Clinical Chemistries4 
X 
 
 
X 
X 
 
X 
Hematology4 
X 
 
 
X 
X 
 
X 
Exposure Pharmacokinetic Sample9 
 
X 
 
X4 
 
 
 
Serology (serum) Sample 
X 
 
 
 
 
 
X 
Urinalysis10 
X 
 
 
X4 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
ECG6 
X 
 
 
 
 
 
 
Sample (nasopharyngeal swab) for 
Influenza Virus Culture/ PCR assay 
and for resistance studies 
 
X 
 
X 
X 
X 
 
Study Drug Administration 
 
X 
 
 
 
 
 
Subject Diary Review7 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Study Measurements and Visit Schedule Figure Legend on Next Page 
 
BioCryst Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
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Study Measurements and Visit Schedule Figure Legend 
 
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on 
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9 
visits). 
2  Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse 
event review. 
3  A targeted physical examination will be conducted at each visit to record the presence/absence of influenza related complications. 
4  Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline.  Subject may be enrolled 
and begin treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second 
treatment administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second 
PK sample for evaluation of peramivir concentrations. For any subject with a Day 3 positive test for urine protein by dipstick test of 2+ 
or higher, who had a Baseline/ Day 1 protein dipstick of <2+, a 24 hour urine collection for assessment of protein and a simultaneous 
assessment by UPEP on the same specimen will be obtained. 
5  Vital sign measures will include blood pressure, pulse rate and respiration rate.  Vital signs will be recorded at Screening, pre-dose and at 
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral 
temperature at baseline.  Thereafter the subject will report oral temperature measurements twice daily in the Study Diary 
6  If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will 
not be enrolled in this study.  If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, 
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7  Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through 
Day 14.  Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.  
Subjects record oral temperature twice daily throughout as well as all influenza related medications. 
8   For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (± 
3 days) and Day 28 (± 3 days) if required  (See Section 10.4.1).  
9   A PK sample will be drawn 30-60 minutes following the second treatment injection on Day 1, and on Day 3.. 
10.For any subject with a Day 3 positive test for urine protein by dipstick test of 2+ or higher, who had a Baseline/ Day 1 protein dipstick of 
<2+, a 24 hour urine collection for assessment of protein and a simultaneous assessment by UPEP on the same specimen will be obtained. 
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11 ADVERSE EVENT MANAGEMENT 
11.1 Definitions 
11.1.1 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. 
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2). 
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 seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches 
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and 
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as 
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE, 
which then must be recorded as such (see Section  11.1.2).  Likewise, a RAT for influenza is 
required at screening in order to determine eligibility for the study, and therefore a positive RAT 
is not considered an AE.    
11.1.2 Serious Adverse Event 
A SAE is an adverse event that results in any of the following outcomes: 
• 
Death 
• 
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe) 
• 
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption 
of a person’s ability to carry out normal life functions) 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event 
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 
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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. 
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to 
competent authorities where this type of reporting is required (e.g. European Union Directives). 
See section 11.2.3. 
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting 
Serious Adverse Events 
Reports of AEs are to be collected from the time of study drug administration through the 
follow-up period ending on Day 14.  The Investigator or designee must completely and promptly 
record each AE on the appropriate CRF.  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. 
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. 
11.2.1 Definition of Severity 
All AEs will be assessed (graded) for severity and classified into one of four clearly defined 
categories as follows: 
• 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required.  The AE does not interfere with the participant’s 
normal functioning level.  It may be an annoyance. 
• 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; 
no or minimal intervention required.  The AE produces some 
impairment of functioning, but it is not hazardous to health.  It is 
uncomfortable or an embarrassment. 
• 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; 
medical intervention may be required.  The AE produces significant 
impairment of functioning or incapacitation. 
• 
Life-threatening: 
(Grade 4): Extreme limitation in activity, significant assistance 
required; significant medical intervention or therapy required; 
hospitalization. 
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11.2.2 Definition of Relationship to Study Drug 
The blinded Principal Investigator 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). 
11.2.3 Reporting Serious Adverse Events 
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to 
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first 
notifying the Medical Monitor at the number listed below: 
Telephone: 
Europe: +44 1628 548000;  
North America: 1-888-724-4908 
Facsimile: 
Europe: +44 1628 540028;  
North America: 1-888-887-8097  
 
 
 
 
 
 
 
          or 1-609-734-9208 
In addition to the telephone numbers listed above, local country-specific toll free numbers may be 
provided within the study reference manual. 
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report 
form) within 24 hours.  All additional follow-up evaluations of the SAE / SUSAR must be 
reported and sent by facsimile to BioCryst or its designee as soon as they are available. 
The Principal Investigator or designee at each site is responsible for submitting the IND safety 
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy 
in their files. 
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject 
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.   
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and 
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting 
system in accordance with FDA and other applicable regulations. However, the Investigator is not 
obligated to actively seek reports of AEs in former study participants. 
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study 
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.  
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome” 
form that will be provided by the Sponsor or its designee. 
11.2.4 Emergency Procedures 
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the 
treatment assignment for the subject affected.  If time allows (i.e., if appropriate treatment for the 
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor 
regarding the need to unblind the treatment assignment for the subject.  At all times, the clinical 
well-being of any subject outweighs the need to consult with the Medical Monitor. 
The Principal Investigator may contact the IVRS central randomization center and request the 
unblinding of the treatment assignment that corresponds to the affected subject.  The IVRS center 
will record the name of the Investigator making the request, the date and time of the request, the 
subject number and date of birth.  The Sponsor will be informed within 24 hours if unblinding 
occurred. 
12 STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary and other selected efficacy endpoints.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation (SD), minimum, and maximum for continuous data and frequencies and 
percentages for categorical data.  The term “treatment group” refers to randomized treatment 
assignment: peramivir 300 mg, peramivir 600 mg, or placebo.  All data collected during the study 
will be included in data listings.  Unless otherwise noted, the data will be sorted first by treatment 
assignment, subject number, and then by date within each subject number.   
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
12.1 Data Collection Methods 
The data will be recorded on the CRF approved by BioCryst. The Investigator must submit a 
completed CRF for each subject who signs an informed consent form (ICF), regardless of 
duration.  All documentation supporting the CRF data, such as laboratory or hospital records, 
must be readily available to verify entries in the CRF. 
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted 
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to BioCryst should not carry the subject’s name.  This will help to ensure subject confidentiality. 
12.2 Statistical Analysis Plan 
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. 
12.3 Study Hypothesis 
The primary hypothesis for evaluating the primary objective may be stated as follows: 
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for 
subjects treated with placebo and for subjects treated with peramivir 300mg (H01) or peramivir 
600mg (H02). 
 
The alternative hypothesis (H1) is that subjects treated with peramivir 300mg (H11) or peramivir 
600mg (H12) have an improvement in time to alleviation of influenza symptoms over those 
treated with placebo. 
12.4 Sample Size Estimates 
Up to a total of 750 evaluable subjects randomized in a 2:2:1 (300 subjects treated with peramivir 
300mg: 300 subjects treated with peramivir 600 mg: 150 subjects treated with placebo) are 
estimated for this phase 3 study.  Because results of clinic-based RAT tests may not precisely 
indicate presence of influenza infection, it is expected that at least 850 subjects will be 
randomized to treatment to ensure that 750 evaluable subjects are treated. 
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated 
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95% 
CI: 115.9, 165.8) for subjects receiving placebo treatment.  Additionally, it is expected that the 
median time to alleviation for the 150 mg dose peramivir arm will be reduced by 30% compared 
to placebo (Table 5) yielding a hazard ratio of 0.70.  
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Table 5 
Median time to alleviation of symptoms (30% reduction, 0.70 hazard ratio). 
 
Median Time To Alleviation of Symptoms (Hours) 
Placebo 
Peramivir 150mg 
Difference (hours) 
145.0 
101.5 
43.5 
140.0 
98.0 
42.0 
135.0 
94.5 
40.5 
130.0 
91.0 
39.0 
125.0 
87.5 
37.5 
120.0 
84.0 
36.0 
115.0 
80.5 
34.5 
110.0 
77.0 
33.0 
105.0 
73.5 
31.5 
100.0 
70.0 
30.0 
Using these assumptions, a sample size of 300 evaluable subjects per active treatment group and 
150 evaluable subjects in the placebo group (a total of 750 evaluable subjects) is sufficient to 
provide at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and 
α = 0.025 (SAS version 9.1.3; total accrual time 7 months; total enrollment time 6 months). 
12.5 Analysis Populations 
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI), 
per-protocol infected (PPI), and safety populations. 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.  
Subjects will be analyzed in the treatment group to which they were 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 
randomized, received study drug, and have confirmed influenza A by culture or PCR.  Subjects 
will be analyzed according to the treatment randomized.  If a discrepancy is noted in the final 
database for any subject, such that the drug differs from the randomized treatment assignment, 
efficacy analyses may be repeated with the subjects analyzed according to the treatment received.  
The ITTI population will be used for primary analyses of efficacy. 
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who 
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection 
will be further described in the SAP. The PPI population will be used as supportive of the primary 
analyses for efficacy completed with the ITTI population. 
Safety Population: The safety population will include all subjects who received study drug.  
Subjects will be analyzed according to the treatment received.  This population will be used for 
all safety analyses. 
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12.6 Interim and End of Study Analyses 
Interim Analysis 
An independent DMC will review safety data on an ongoing basis.  Safety analyses will be 
presented in a manner consistent with the presentations intended for the final analysis. 
End of Study Analysis 
A final analysis is planned after the last subject completes or discontinues the study, and the 
resulting clinical database has been cleaned, quality checked, and locked. 
12.7 Efficacy Analyses 
12.7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to alleviation of symptoms of influenza in subjects 
diagnosed with influenza A, defined as the time from injection of study drug to the start of the 
time period when a subject has Alleviation of Symptoms.  A subject has Alleviation of Symptoms 
if all of the seven symptoms of influenza (nasal congestion, sore throat, cough, aches and pains, 
fatigue (tiredness), headache, feeling feverish) assessed on his/her subject diary are either absent 
or are present at no more than mild severity level and at this status for at least 21.5 hours (24 
hours - 10%). 
Descriptive statistics for the primary efficacy variable will be tabulated by treatment group.  
Alleviation of symptoms will be determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be summarized for each treatment 
group.  Treatment comparisons between each active group and placebo will be assessed using a 
Wilcoxon-Gehan19 statistic stratified by smoking status at screening Pairwise comparisons 
between each active group and placebo will be assessed using a Wilcoxon-Gehan test..  Subjects 
who do not experience alleviation of symptoms will be censored at the date of their last non-
missing post-baseline assessment.  For assessment of the primary efficacy endpoint, the overall 
significance level will be maintained by utilization of Hochberg’s20 method for the planned 
comparisons between the two active treatments and placebo. 
12.7.2 Secondary Efficacy Endpoints 
All secondary endpoints will be summarized using descriptive statistics by treatment group, and 
study day/time, if appropriate.  Statistical comparisons for each endpoint will be constructed 
without adjustment for multiple endpoints. 
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be 
summarized for each treatment group.  The time-weighted average change from baseline will be 
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available post-
baseline on-treatment data (data after initiation of study treatment) minus the baseline value.  
Specifically, the time-weighted area under the curve for time a (ta) to time b (tb) is given by the 
formula  
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)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
, 
where 
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
 and ti represents the date of the ith viral titer 
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline 
value and only one follow-up value, yi then the time-weighted change from baseline is defined as 
the difference between yi and baseline.  If there is a baseline value and no follow-up value, the 
subject is excluded from analysis.  The differences between each of the peramivir treatment 
groups and placebo will be evaluated using a van Elteren Test adjusting for smoking status at 
screening. Analyses of the PCR results will be analyzed in a similar manner. 
Subject’s oral temperature will be summarized by study visit and treatment group.  Differences 
between the treatment groups will be assessed using the van Elteren test controlling for smoking 
status at screening. A subject has Resolution of Fever if he/she has a temperature < 37.2°C 
(99.0°F) and no antipyretic medications have been taken for at least 12 hours.  The time to 
resolution of fever will be estimated using the method of Kaplan-Meier using temperature and 
symptom relief medication information obtained from the subject diary data.  Differences 
between the treatment groups will be assessed using the Wilcoxon-Gehan statistic controlling for 
smoking status at screening.  Subjects who do not have resolution of fever will be censored at the 
time of their last non-missing post-baseline temperature assessment. 
The number and percentage of subjects experiencing influenza related complications will be 
summarized by complication preferred term and treatment group.  The difference between the 
treatment groups will be assessed a logistic regression model with factors for treatment group and 
smoking status at screening.  Pairwise differences between the treatment groups will be evaluated 
using contrasts from the final logistic regression model. 
12.7.3 Exploratory Endpoints 
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and 
work productivity and/or performance losses will be summarized by treatment group and 
smoking status.  Methods for describing differences between treatment groups will be presented 
in the SAP. 
Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data 
will be listed for each subject.  These listings will be constructed in a manner consistent with the 
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18  
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be 
summarized separately for treatment group, protein type, and study visit. 
12.8 Safety Analyses 
AEs will be mapped to a MedDRA-preferred term and system organ classification.  The 
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms, 
system organ classifications, and severity.  If a subject experiences multiple events that map to a 
single preferred term, the greatest severity and strongest Investigator assessment of relation to 
study drug will be assigned to the preferred term for the appropriate summaries.  All AEs will be 
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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 study 
visit.  Laboratory abnormalities will be graded according to the DAIDS Table for Grading 
Adverse Events for Adults and Pediatrics (Publish Date: December 2004).  The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by 
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be 
summarized by treatment group. 
Abnormal physical examination findings will be presented by treatment group.  The number and 
percent of subjects experiencing each abnormal physical examination finding will be included. 
Concomitant medications will be coded using the WHO dictionary.  These data will be 
summarized by treatment group. 
Subject disposition will be presented for all subjects.  The number of subjects who completed the 
study and discontinued from the study will be provided.  The reasons for early discontinuation 
also will be presented. 
12.9 Sub-Study and Pharmacokinetic Analysis 
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine 
exposure response will be conducted at selected sites. The data from the sub-study will be 
combined with the two PK samples (collected on all subjects at 30-60 minutes following 
administration of study drug and on study day 3) to perform a population exposure-response 
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All 
statistical methods will be outlined as part of the sub-study protocol and exposure-response 
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained 
in this study and a companion study BCX1812-312, will be reported in a separate sub-study 
report. 
12.10 
General Issues for Statistical Analysis 
12.10.1 
Multiple Comparisons and Multiplicity 
In order to maintain the overall type I error in the presence of the planned comparisons between 
the two peramivir treatments and placebo, Hochberg’s method will be applied to the primary 
efficacy endpoint analysis.  No other adjustments for multiple comparisons are planned. 
12.10.2 
Covariates 
Primary and secondary efficacy analyses will be adjusted for smoking status at screening.  
12.10.3 
Planned Sub-Groups 
The primary efficacy endpoint will be summarized separately by smoking status at screening 
using descriptive statistics by treatment group and study day, if appropriate.  No formal statistical 
testing will be utilized. 
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Additional analyses may be performed by country, if necessary, for submission to local 
regulatory authorities. 
12.10.4 
Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized.  No attempt will be made retrospectively to obtain missing subject 
reported data (including influenza symptom severity assessments, temperature, ability to perform 
usual activities, missed days of work and impact of influenza on subject’s work performance 
and/or productivity) 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.   
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience 
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms.  Missing assessments of influenza symptoms 
conservatively will be imputed as having severity above absent or mild (as failures).  For the 
subject diary data, the following data conventions will be utilized.  Missing diary completion will 
be imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily 
reported values.  Select exploratory sensitivity analyses may be conducted to ascertain the effect, 
if any, of these methods.  These sensitivity analyses are further described in the SAP.  Secondary 
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint. 
 
13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; GCPs, including International 
Conference on Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in accordance 
with the ethical principles of the Declaration of Helsinki.  In addition, all applicable local laws 
and regulatory requirements relevant to the use of new therapeutic agents in the countries 
involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if 
requested by the IRB/ IEC.  A final study notification will also be forwarded to the IRB/IEC after 
the study is completed or in the event of premature termination of the study in accordance with 
the applicable regulations.  Copies of all contact with the IRB/ IEC should be maintained in the 
study documents file.  Copies of clinical study status reports (including termination) should be 
provided to BioCryst. 
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13.1.2 Ethics Committee Approvals 
Before initiation of the study at each investigational site, the protocol, the informed consent form, 
the subject information sheet, and any other relevant study documentation will be submitted to 
the appropriate IRB/IEC.  Written approval of the study must be obtained before the study center 
can be initiated or the investigational medicinal product is released to the Investigator.  Any 
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for 
changes to the study such as modification of the protocol, the informed consent form, the written 
information provided to subjects and/or other procedures. 
The Investigator will report promptly to the IRB/IEC 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/IEC with a report of the outcome of the study. 
13.1.3 Subject Informed Consent 
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures.  Each subject should be given both verbal and written information describing 
the nature and duration of the clinical study.  The informed consent process should take place 
under conditions where the subject has adequate time to consider the risks and benefits associated 
with his/her participation in the study.  Subjects will not be screened or treated until the subject 
has signed an approved ICF written in a language in which the subject is fluent. 
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.  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 or their legal representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it 
may entail.  Subjects will be informed that they are free not to participate in the trial and that they 
may withdraw consent to participate at any time.  They will be told that refusal to participate in 
the study will not prejudice future treatment.  They will also be told that their records may be 
examined by competent authorities and authorized persons but that personal information will be 
treated as strictly confidential and will not be publicly available.  Subjects must be given the 
opportunity to ask questions.  After this explanation and before entry into the trial, consent should 
be appropriately recorded by means of the subject’s dated signature.  The subject should receive a 
signed and dated copy of the ICF.  The original signed informed consent should be retained in the 
study files.  The Investigator shall maintain a log of all subjects who sign the ICF and indicate if 
the subject was enrolled into the study or reason for non-enrollment. 
13.1.4 Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
13.1.5 Investigator Reporting Requirements 
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required. 
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13.2 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 institution will allow 
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
13.3 Quality Assurance 
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by BioCryst, 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. 
13.4 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. 
13.5 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. 
13.6 Study Organization 
13.6.1 Data Monitoring Committee 
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety 
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee 
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical 
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate 
will be described in a separate DMC charter. 
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13.7 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 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/IEC) or it may be a separate 
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without 
IRB/IEC approval).  It is the responsibility of the investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are 
required for U.S. sites only. 
13.8 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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14 REFERENCES 
 
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282. 
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with 
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186. 
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on 
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 
2003;163(14):1667–1672. 
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase 
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for 
prevention and treatment. JAMA 1999;282(13):1240–1246. 
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza 
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765. 
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza 
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents 
Chemother 2001;45(4):1162–1167. 
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to 
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147. 
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, 
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase 
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408. 
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine 
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. 
Antimicrob Agents Chemother 2004;48(12):4855–4863. 
10. BioCryst Pharmaceuticals. Unpublished data. 
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable 
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian 
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco 
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA. 
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against 
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32 
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03. 
14. Tamiflu® Package Insert.  Roche Pharmaceuticals. Rev. December 2005. 
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product 
information sheets 
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024. 
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in 
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850. 
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18. US Department of Health and Human Services, Food and Drug Administration Center for 
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product 
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for 
Submitting Influenza Resistance Data.  http://www.fda.gov/cder/guidance/7070fnlFLU.htm  
19. Gehan EA (1965): A generalized Wilcoxon test 
for co mparing arbitrarily  singl y censored 
samples. Biometrika 52:203-223 
20. Hochberg, Y. A sharper Bonferroni pr ocedure for multiple tests of significance. Biometrika.  
1988;75:800-2 
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15 APPENDICES 
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina 
 
NYHA Functional Classification of Heart Failure 
 
Class I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs 
does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly; 
walking uphill; walking or stair climbing after meals, in cold weather, in wind, 
or when under emotional stress causes undue fatigue or dyspnea. 
Class III 
Symptoms w ith less than ordinary phy
sical activity.  Walking one to two 
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al 
conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or 
dyspnea. 
 
NYHA Functional Classification of Angina 
 
Class I 
Angina only with unusually strenuous activity. 
Class II 
Angina with slightl y more prolonged o r slightly more vigorous activit y than 
usual. 
Class III 
Angina with usual daily activity. 
Class IV 
Angina at rest. 
 
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15.2 Criteria for Severe COPD and Severe Asthma 
The following guidelines are provided to assist in the evaluation of subjects who have a medical 
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe 
COPD or severe persistent Asthma are to be excluded from this study. (See section  8.1.2, 
exclusion criteria number 3). 
Classification of Asthma from National Asthma and Education and Prevention Program 
 
 
 
For Adults and Children (> 5 yrs) who 
can use a spirometer or peak flow meter 
Classification 
Days with 
Symptoms 
Nights with 
Symptoms 
FEV1 or PEF 
% Predicted Normal 
PEF Variability 
(%) 
Severe persistent 
Continual 
Frequent 
≤ 60 
> 30 
Moderate Persistent 
Daily 
> 1/ week 
> 60 - < 80 
> 30 
Mild Persistent 
> 2 / week 
but < 1 
times / day 
> 2/ month 
≥ 80 
20 – 30 
Mild Intermittent 
≤ 2 / week 
< 2 / month 
≥ 80 
< 20 
FEV1: percentage predicted value for forced expiratory volume in 1 second. 
PEF: percentage of personal best for peak expiratory flow. 
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, 
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007 
 
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1 
(GOLD Criteria) 
Stage 
Characteristics 
Mild COPD 
FEV1/FVC < 70% 
FEV1 ≥ 80% predicted 
Moderate COPD 
FEV1/FVC < 70% 
50 % ≤ FEV1 < 80% predicted 
Severe COPD 
FEV1/FVC < 70% 
30 % ≤ FEV1 < 50% predicted 
Very Severe COPD 
FEV1/FVC < 70% 
FEV1 < 30% predicted or FEV1 < 50% 
predicted plus chronic respiratory failure 
FEV1: percentage predicted value for forced expiratory volume in one second. 
FVC: forced vital capacity 
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555. 
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373


 
 
CLINICAL STUDY PROTOCOL 
Protocol No. BCX1812-311 
IND No. 76,350 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAMUSCULAR PERAMIVIR IN SUBJECTS WITH UNCOMPLICATED ACUTE 
INFLUENZA 
THE IMPROVE I STUDY 
(IntraMuscular Peramivir for the Relief Of symptoms and Virologic Efficacy) 
Short title: Intramuscular Peramivir for the Treatment of Uncomplicated Influenza 
Protocol Date(s):  
Version 1.0: 04 September 2007 
Version 2.0: 05 October 2007 
Version 3.0: 20 November 2007 
Version 4.0: 18 December 2007 
 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35244, USA 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
 
The document contains trade secrets and proprietary information of BioCryst Pharmaceuticals, 
Inc. This information is confidential property of BioCryst Pharmaceuticals, Inc., and is subject to 
confidentiality agreements entered into with BioCryst Pharmaceuticals, Inc. No information 
contained herein should be disclosed without prior written approval. 
CONFIDENTIAL 
 
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1 
TITLE PAGE 
 
Protocol Number: 
BCX1812-311 
Study Title: 
A phase 3 multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza. 
IND Number: 
76, 350 
Investigational Product: 
Peramivir (BCX1812) 
Indication Studied: 
Uncomplicated acute influenza 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
2190 Parkway Lake Drive 
Birmingham, AL 35233 
Development Phase: 
3 
Sponsor Medical Officer: 
W. James Alexander, M.D., M.P.H. 
Senior Vice President, Clinical Development  
Chief Medical Officer 
Phone: +1 919 859 1302 
Fax: +1 919 851 1416 
Email Address: jalexander@biocryst.com  
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki 
and clinical research guidelines established by the Code of 
Federal Regulations (Title 21, CFR Parts 50, 56, and 312) 
and ICH Guidelines. Essential study documents will be 
archived in accordance with applicable regulations. 
Final Protocol Date: 
Version 1.0: 04 September 2007 
Amendment(s) Date(s): 
Version 2.0: 05 October 2007 
Version 3.0: 20 November 2007 
Version 4.0: 18 December 2007 
 
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1.2 
Clinical Study Protocol Agreement 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3 multicenter, random ized, double-blind, placebo-controlled 
study to evaluate the effic acy and safety of intramuscular peramivir in 
subjects with uncomplicated acute influenza 
 
I have carefully read this protocol and agree that it contains all of the necessary  information 
required to conduct this study.  I agree to c onduct this study  as described and according t o 
the Decl aration of Helsinki, Internationa l Conference on Har monization Guidelines for  
Good Clinical Practices, and all applicable regulatory requirements. 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
Name (Print) 
 
 
 
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2 
SYNOPSIS 
 
Protocol No. 
BCX1812-311 
Protocol Title: 
A phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
intramuscular peramivir in subjects with uncomplicated acute 
influenza. 
Sponsor: 
BioCryst Pharmaceuticals, Inc. 
Investigators/Study Sites: 
Multinational 
Development Phase: 
3 
Objectives: 
Primary: 
To evaluate the efficacy of peramivir administered 
intramuscularly compared to placebo on the time to alleviation 
of clinical symptoms in adult subjects with uncomplicated acute 
influenza. 
 
Secondary: 
1. 
To evaluate the safety and tolerability of peramivir 
administered intramuscularly 
2. 
To evaluate secondary clinical outcomes in response to 
treatment 
3. 
To evaluate changes in influenza virus titer in 
nasopharyngeal samples (viral shedding) in response to 
treatment 
 
Exploratory: 
1. To assess pharmacoeconomic measures as response to 
treatment  
2. To assess changes in influenza viral susceptibility to 
neuraminidase inhibitors following treatment 
 
Number of Subjects: 
Total enrollment: approximately 600 subjects will be 
randomized.  Subjects will be allocated to treatment using a 2:1 
randomization schema.  
 
An evaluable subject is one who is randomized, receives study 
drug, and has confirmed acute influenza A or B by primary viral 
culture or PCR. A positive Rapid Antigen Test (RAT) for 
influenza A and B at screening will be required for enrollment.  
Because results of clinic-based RAT tests may not precisely 
indicate presence of influenza infection, it is expected that 
approximately 600 subjects will be randomized to treatment to 
ensure enrollment of approximately 450 subjects that are 
positive for influenza A. 
 
Study Design: 
This is a multinational, randomized, double-blind study 
comparing the efficacy and safety of a 300 mg dose of peramivir 
administered intramuscularly versus placebo in adults with 
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uncomplicated acute influenza.  All subjects will be centrally 
randomized to treatment with 300 mg of peramivir or placebo in 
a ratio of 2:1, and will be stratified according to smoking status 
and RAT test for influenza A or B.  
 
Study drug will be administered as bilateral 2mL intramuscular 
injections (total of 4mL injected in equally divided doses). 
Procedures for gluteal intramuscular injection, with a 
recommended needle length appropriate to the physical 
characteristics of the subject, are provided in the study drug 
administration manual. 
 
Subjects eligible for screening will have an anterior nasal swab 
collected for testing by rapid antigen testing (RAT) for influenza 
A and B in accordance with the commercially available RAT kit 
instructions.  If the initial RAT is negative, the test should be 
repeated within one hour. Subjects meeting the 
inclusion/exclusion criteria may be enrolled into the study. 
 
All enrolled subjects will record the following information in a 
Study Diary: 
 
• Assessment of the presence and severity of each of seven 
symptoms of influenza on a 4-point scale (0, absent; 1, mild; 
2, moderate; 3, severe) twice daily (AM, PM) through Day 9 
following treatment, then once daily (AM) through Day 14. 
• Oral temperature measurements taken with an electronic 
thermometer every 12 hours. With the exception of the 
baseline measurement, all temperature measurements will be 
obtained at least 4 hours after, or immediately before, 
administration of oral acetaminophen (Tylenol or 
paracetamol) or other anti-pyretic medications. 
• Assessment of subject’s time lost from work or usual 
activities and rating of productivity compared to normal 
(rated as 0-10 on a visual analog scale) once daily through 
Day 14. 
• Doses of antipyretic, expectorant, and/or throat lozenges 
taken for symptomatic relief each day through Day 14. 
 
Anterior nose (bilateral) and posterior pharynx specimens 
(swabs) will be collected at Day 1 (pre-treatment) and at Days 3, 
5, and 9, for quantitative virologic assessments. Specimens from 
all subjects yielding influenza virus will also be assessed for 
susceptibility to neuraminidase inhibitors (Day 1 and last 
specimen yielding positive result on culture) as well as other 
virologic assessments (e.g. PCR, genotypic testing). All 
virologic assessments will be performed by a central laboratory. 
 
Two samples for pharmacokinetic (PK) testing for plasma levels 
of peramivir will be obtained from all subjects randomized.  The 
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first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second 
PK sample will be obtained at the day 3 visit in all subjects. The 
data from these PK samples will be utilized in a population 
exposure-response analysis. 
 
At selected sites a separate sub-study will be conducted to 
collect additional PK samples between treatment and Day 3 for 
the purpose of conducting a separate exposure-response 
analysis.  This sub-study will be conducted under a separate 
protocol, BCX1812-311PK. 
 
Study Population: 
Male and female subjects, 18 years of age and older, with 
symptoms consistent with a diagnosis of uncomplicated acute 
influenza infection may be screened for enrollment.  Subject 
eligibility will require the presence of two or more symptoms of 
at least moderate severity consistent with acute influenza as well 
as positive results obtained from a rapid antigen test (RAT) for 
influenza A and/or B at screening. 
 
Inclusion Criteria: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A and/or B Rapid Antigen Test (RAT) 
performed with a commercially available test kit on an 
adequate anterior nasal specimen, in accordance with the 
manufacturer’s instructions.  A negative initial RAT should 
be repeated within one-hour.  
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 
ºF) taken orally, or ≥38.5 ºC (≥101.2 ºF) taken rectally. A 
subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for 
enrollment in the absence of documented fever at the time of 
screening.   
4. Presence of at least one respiratory symptom (cough, sore 
throat, or nasal symptoms) of at least moderate severity. 
5. Presence of at least one constitutional symptom (myalgia 
[aches and pains], headache, feverishness, or fatigue) of at 
least moderate severity.  
6. Onset of symptoms no more than 48 hours before 
presentation for screening. 
7. Written informed consent. 
 
Exclusion Criteria: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory 
distress. 
3. History of severe chronic obstructive pulmonary disease 
(COPD) or severe persistent asthma (See section  15.2). 
4. History of congestive heart failure requiring daily 
pharmacotherapy with symptoms consistent with New York 
Heart Association Class III or IV functional status within the 
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past 12 months. 
5. Screening ECG which suggests acute ischemia or presence 
of medically significant dysrhythmia. 
6. History of chronic renal impairment requiring hemodialysis 
and/or known or suspected to have moderate or severe renal 
impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or 
symptoms consistent with otitis, bronchitis, sinusitis and/or 
pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic 
illness, previous organ transplant, or use of 
immunosuppressive medical therapy which would include 
oral or systemic treatment with > 10 mg prednisone or 
equivalent on a daily basis within 30 days of screening. 
10. Currently receiving treatment for viral hepatitis B or viral 
hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 
cell/mm3. 
12. Current therapy with oral warfarin or other systemic 
anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, 
or oseltamivir in the 7 days prior to screening. 
14. Immunized against influenza with live attenuated virus 
vaccine (FluMist®) in the previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine 
within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 
14 days. 
17. History of alcohol abuse or drug addiction within 1 year 
prior to admission in the study. 
18. Participation in a previous study of intramuscular or 
intravenous peramivir or previous participation in this study. 
19. Participation in a study of any investigational drug or device 
within the last 30 days. 
 
Study Endpoints: 
Primary Endpoint: 
Clinical: 
Time to alleviation of clinical symptoms of influenza. 
 
Secondary Endpoint(s): 
Safety: 
Incidence of treatment-emergent adverse events and treatment-
emergent changes in clinical laboratory tests. 
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Clinical: 
Time to resolution of fever. 
Incidence of influenza related complications. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
viral titer assay (TCID50). 
 
Exploratory Endpoint(s): 
Pharmacoeconomic: 
Medical resource utilization (MRU), missed days of work, and 
impact of influenza illness on subject’s work performance 
and/or productivity. 
 
Virologic: 
Quantitative change in influenza virus shedding, measured by 
PCR. 
Change in influenza virus susceptibility to neuraminidase 
inhibitors. 
 
Investigational Product, Dose, and Mode of Administration: 
Peramivir (BCX-1812), 75mg/mL, 2mL (150mg) per injection, administered as bilateral 
intramuscular injections. 
Reference Therapy, Dose, and Mode of Administration: 
Matching Placebo (buffered diluent), 2mL per injection administered as bilateral intramuscular 
injections. 
Duration of Treatment: 
Following treatment on day 1, study duration for all subjects is 
expected to be up to 14 days (including all visits). Presence of 
unresolved adverse events and/or treatment-emergent laboratory 
findings at the Day 14 visit, or persistent or recurrent symptoms 
of influenza (of the seven symptoms assessed) of either 
moderate or severe intensity at the Day 14 visit, will require 
additional follow up. 
Statistical Methods: 
Study Hypothesis: 
The null hypothesis (H0) for this study is that the time to 
alleviation of influenza symptoms is the same for subjects 
treated with placebo and for subjects treated with peramivir 
300mg. 
 
The alternative hypothesis (H1) is that subjects treated with 
peramivir 300mg have an improvement in time to alleviation of 
influenza symptoms over those treated with placebo. 
 
Sample Size: 
From preliminary results of a phase 2 study evaluating peramivir 
treatment of uncomplicated influenza, it is expected that the 
median time to alleviation of symptoms will be 137.0 hours 
(95% CI: 115.9, 165.8) for subjects receiving placebo treatment. 
Additionally, it is expected that the median time to alleviation 
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for the 300 mg dose peramivir arm will be reduced by 30% 
compared to placebo yielding a hazard ratio of 0.70.  Data from 
the phase 2 study suggested that the activity of peramivir against 
influenza B was limited. Therefore, this study will be sized to 
ensure that a minimum number of influenza A subjects is 
enrolled to achieve study power. 
 
Using these assumptions, a sample size of 450 evaluable 
subjects with influenza A (300 in the 300 mg treatment group 
and 150 evaluable subjects in the placebo group) is sufficient to 
provide at least 90% power to detect a hazard ratio of 0.70 using 
a log-rank statistic and α = 0.05 (SAS version 9.1.3; total 
accrual time 7 months; total enrollment time 6 months). 
Efficacy:  
The primary efficacy analysis will be completed with the intent-
to-treat infected population (ITTI). The ITTI population will 
include all subjects who are randomized, received study drug, 
and have confirmed influenza A and/or B by primary viral 
culture or PCR.  The primary efficacy variable is the time to 
alleviation of symptoms, defined as the time from injection of 
study drug to the start of the time period when each of seven 
symptoms of influenza are either absent or are present at no 
more than mild severity level and remain at no worse than this 
severity status for a 21.5 hour (24 hours – 10%) period.  
 
Descriptive statistics for the primary efficacy variable will be 
tabulated by treatment group.  Alleviation of symptoms will be 
determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be 
summarized for each treatment group.  Treatment differences 
between the 300 mg peramivir dose and placebo will be assessed 
using a Wilcoxon-Gehan statistic stratified by smoking status 
and positive PCR or viral culture for influenza A or B at 
screening.  Subjects who do not experience alleviation of 
symptoms will be censored at the date of their last non-missing 
assessment.  
 
Efficacy analyses will be repeated for Intent To Treat Infected 
with influenza A (ITTI-A) population and Per-Protocol Infected 
population (PPI). The ITTI-A population includes all subjects 
who are randomized, received study drug, and have confirmed 
influenza A by primary viral culture or PCR.  The PPI 
population will include those subjects in the ITTI population 
who received an adequate intramuscular injection.  Details of 
this population will be described in the statistical analysis plan.  
 
Changes in influenza virus TCID50 (viral titers from 
nasopharyngeal specimens) will be compared using the van 
Elteren statistic controlling for smoking status and positive PCR 
or viral culture for influenza A or B at screening.  Analyses of 
other continuous endpoints will be analyzed in a similar manner. 
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The number and percentage of subjects experiencing influenza 
related complications (IRC) will be summarized by 
complication preferred term and treatment group.  The 
difference between the treatment groups (300 mg peramivir and 
placebo) will be assessed using a Cochran-Mantel-Haenszel 
(CMH) test statistic controlling for smoking status, and positive 
PCR or viral culture for influenza A or B at screening.  
 
Safety: 
Safety analyses will be presented for all subjects in the safety 
population, defined as all randomized subjects who receive at 
least one dose of study drug.  Adverse events will be mapped to 
a Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and system organ classification.   
 
The occurrence of treatment-emergent AEs will be summarized 
using preferred terms, system organ classifications, and severity.  
Separate summaries of treatment-emergent SAEs and treatment-
emergent AEs that are related to study medication will be 
generated.  All AEs will be listed for individual subjects 
showing both verbatim and preferred terms.   
 
Descriptive summaries of vital signs and quantitative clinical 
laboratory changes will be presented by study visit.  Frequency 
and percentages of subjects with abnormal laboratory test results 
will be summarized by toxicity grade.   
 
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 each abnormal physical 
examination finding will be presented.  
 
The number and percent of subjects discontinuing study as well 
as the reasons for discontinuation will be summarized by 
treatment group. 
 
Date of Protocol: 
Version 1.0: 04-September-2007 
Amendment (Dates): 
Version 2.0: 05-October-2007 
Version 3.0: 20-November-2007 
Version 4.0: 18-December-2007 
 
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3 
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...........................................................................................................12 
3.1 
LIST OF FIGURES .........................................................................................................................14 
3.2 
LIST OF TABLES ..........................................................................................................................14 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................................15 
5 
INTRODUCTION......................................................................................................................17 
5.1 
BACKGROUND.............................................................................................................................17 
5.2 
RATIONALE FOR STUDY ..............................................................................................................17 
5.3 
NON-CLINICAL EXPERIENCE WITH PERAMIVIR...........................................................................18 
5.3.1 
In vitro Assays.......................................................................................................................18 
5.3.2 
Animal Models......................................................................................................................18 
5.4 
PREVIOUS PHASE 3 CLINICAL EXPERIENCE WITH ORAL PERAMIVIR...........................................19 
5.5 
PREVIOUS PHASE 1 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR.........................................19 
5.6 
PHASE 2 EXPERIENCE WITH INTRAMUSCULAR PERAMIVIR .........................................................21 
5.7 DOSE RATIONALE................................................................................................................................23 
6 
STUDY OBJECTIVES..............................................................................................................24 
6.1 
OBJECTIVES ................................................................................................................................24 
6.1.1 
Primary Objective..................................................................................................................24 
6.1.2 
Secondary Objective(s) .........................................................................................................24 
6.1.3 
Exploratory Objective(s) .......................................................................................................24 
6.2 
STUDY ENDPOINTS......................................................................................................................24 
6.2.1 
Primary Endpoint...................................................................................................................24 
6.2.2 
Secondary Endpoint(s) ..........................................................................................................24 
6.2.3 
Exploratory Endpoints...........................................................................................................24 
7 
STUDY DESIGN.......................................................................................................................25 
7.1 
OVERALL STUDY DESIGN AND PLAN ..........................................................................................25 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................................26 
8.1.1 
Inclusion Criteria...................................................................................................................26 
8.1.2 
Exclusion Criteria..................................................................................................................26 
8.1.3 
Removal of Subjects from Therapy or Assessment...............................................................27 
9 
TREATMENTS .........................................................................................................................28 
9.1 
TREATMENTS ADMINISTERED.....................................................................................................28 
9.2 
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .............................................................................28 
9.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................28 
9.4 
STUDY MEDICATION ACCOUNTABILITY......................................................................................29 
9.5 
BLINDING/UNBLINDING OF TREATMENTS...................................................................................29 
9.6 
PRIOR AND CONCOMITANT THERAPIES.......................................................................................29 
9.7 
OVERDOSE AND TOXICITY MANAGEMENT..................................................................................29 
9.8 
DOSE INTERRUPTION...................................................................................................................29 
10 
STUDY CONDUCT..................................................................................................................30 
10.1 
EVALUATIONS.............................................................................................................................30 
10.1.1 
Informed Consent .............................................................................................................30 
10.1.2 
Medical History ................................................................................................................30 
10.1.3 
Rapid Antigen Test for Influenza .....................................................................................30 
10.1.4 
Physical Examination and Influenza-related Complications Assessments .......................30 
10.1.5 
Vital Signs ........................................................................................................................30 
10.1.6 
Electrocardiogram Measurements ....................................................................................31 
10.1.7 
Clinical Laboratories ........................................................................................................31 
10.1.8 
Urine Pregnancy Test .......................................................................................................31 
10.1.9 
Serology for Influenza ......................................................................................................31 
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10.1.10 
Samples for Virologic Laboratory Assessments...............................................................31 
10.1.11 
Subject Self Assessments..................................................................................................32 
10.1.12 
Concomitant Medications.................................................................................................32 
10.1.13 
Adverse Events.................................................................................................................32 
10.1.14 
Pharmacokinetic Exposure Samples.................................................................................32 
10.2 
SCREENING PERIOD.....................................................................................................................33 
10.2.1 
Informed Consent .............................................................................................................33 
10.2.2 
Screening/Baseline Evaluation and Enrollment................................................................33 
10.3 
TREATMENT PERIOD—STUDY DAY 1 .........................................................................................33 
10.3.1 
Pre-dose Evaluations-Study Day 1 ...................................................................................34 
10.3.2 
Post-dose Evaluations-Study Day 1..................................................................................34 
10.4 
POST-TREATMENT ASSESSMENT PERIOD....................................................................................34 
10.4.1 
Days 2, 3, 5, 9 and 14 .......................................................................................................34 
10.4.2 
Adverse Events Reported at Post-treatment Visits ...........................................................35 
11 
ADVERSE EVENT MANAGEMENT......................................................................................38 
11.1 
DEFINITIONS ...............................................................................................................................38 
11.1.1 
Adverse Event...................................................................................................................38 
11.1.2 
Serious Adverse Event......................................................................................................38 
11.2 
METHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING ADVERSE EVENTS AND REPORTING 
SERIOUS ADVERSE EVENTS ........................................................................................................39 
11.2.1 
Definition of Severity .......................................................................................................39 
11.2.2 
Definition of Relationship to Study Drug.........................................................................40 
11.2.3 
Reporting Serious Adverse Events ...................................................................................40 
11.2.4 
Emergency Procedures .....................................................................................................41 
12 
STATISTICAL METHODS ......................................................................................................41 
12.1 
DATA COLLECTION METHODS ....................................................................................................41 
12.2 
STATISTICAL ANALYSIS PLAN ....................................................................................................42 
12.3 
STUDY HYPOTHESIS....................................................................................................................42 
12.4 
SAMPLE SIZE ESTIMATES............................................................................................................42 
12.5 
ANALYSIS POPULATIONS ............................................................................................................42 
12.6 
INTERIM AND END OF STUDY ANALYSES....................................................................................43 
12.7 
EFFICACY ANALYSES..................................................................................................................43 
12.7.1 
Primary Efficacy Endpoint ...............................................................................................43 
12.7.2 
Secondary Efficacy Endpoints..........................................................................................44 
12.7.3 
Exploratory Endpoints......................................................................................................44 
12.8 
SAFETY ANALYSES .....................................................................................................................45 
12.9 
SUB-STUDY AND PHARMACOKINETIC ANALYSIS........................................................................45 
12.10 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ...........................................................................46 
12.10.1 
Multiple Comparisons and Multiplicity............................................................................46 
12.10.2 
Covariates.........................................................................................................................46 
12.10.3 
Planned Sub-Groups .........................................................................................................46 
12.10.4 
Missing Data.....................................................................................................................46 
13 
STUDY ADMINISTRATION...................................................................................................47 
13.1 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................................................47 
13.1.1 
Regulatory Authority Approvals.......................................................................................47 
13.1.2 
Ethics Committee Approvals............................................................................................47 
13.1.3 
Subject Informed Consent ................................................................................................47 
13.1.4 
Payment to Subjects..........................................................................................................48 
13.1.5 
Investigator Reporting Requirements ...............................................................................48 
13.2 
STUDY MONITORING...................................................................................................................48 
13.3 
QUALITY ASSURANCE.................................................................................................................48 
13.4 
STUDY TERMINATION AND SITE CLOSURE..................................................................................48 
13.5 
RECORDS RETENTION .................................................................................................................49 
13.6 
STUDY ORGANIZATION...............................................................................................................49 
13.6.1 
Data Monitoring Committee.............................................................................................49 
13.7 
CONFIDENTIALITY OF INFORMATION ..........................................................................................49 
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13.8 
STUDY PUBLICATION ..................................................................................................................49 
14 
REFERENCES...........................................................................................................................51 
15 
APPENDICES ...........................................................................................................................53 
15.1 
NYHA FUNCTIONAL CLASSIFICATION CRITERIA: HEART FAILURE AND ANGINA ......................53 
15.2 
CRITERIA FOR SEVERE COPD AND SEVERE ASTHMA .................................................................54 
 
3.1 
 List of Figures 
Figure 1 
Study Measurements and Visit Schedule.................................................................36 
 
3.2 
List of Tables 
Table 1 
Results of study BC-01-03.......................................................................................19 
Table 2 
Pharmacokinetic parameters from study Him-06-111. ............................................20 
Table 3 
Summary of Efficacy from BCX1812-211. .............................................................22 
Table 4 
Summary of Safety from BCX1812-211. ................................................................23 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE  
adverse event 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the curve 
AUC0–72 
area under the curve from time 0 to 72 hours 
AUC0–∞ 
area under the curve extrapolated from time 0 to infinity 
BMI 
Body Mass Index in kg/m2 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CIOMS 
Council for International Organizations of Medical sciences 
Cmax  
maximum plasma concentration 
CK 
creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CNS  
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
GCP  
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IC50  
median inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
influenza related complications  
ITT 
intent-to-treat 
ITTI 
intent-to-treat infected (Includes ITTI and ITTI-A) 
IUD 
intrauterine device 
IVRS 
interactive voice response system 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NSAID 
non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
PPI 
per-protocol infected 
RAT 
Rapid Antigen Test 
RBC 
red blood cell 
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SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Event 
t1/2  
elimination half-life 
t1/2 λz 
terminal half-life 
TCID50 
tissue-culture infective dose50 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to attain maximum plasma concentration 
UPEP 
Urine protein electrophoresis 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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5 
INTRODUCTION 
5.1 
Background 
Influenza virus is a member of the orthomyxovirus family and causes an acute viral disease of the 
respiratory tract.  Typical influenza illness is characterized by abrupt onset of fever, headache, 
myalgia, sore throat, and nonproductive cough.1  The illness is usually self-limiting, with relief of 
symptoms occurring within 5 to 7 days.  Nevertheless, it is an important disease for several 
reasons, including ease of communicability, short incubation time, rapid rate of viral mutation, 
morbidity with resultant loss of productivity, risk of complicating conditions, and increased risk 
of death, particularly in the elderly.  During 19 of the 23 influenza seasons between 1972/1973 
and 1994/1995, estimated influenza-associated deaths in the United States ranged from 
approximately 25 to more than 150 per 100,000 persons above 65 years of age, accounting for 
more than 90% of the deaths attributed to pneumonia and influenza.2 
Presently, only a few measures are available that can reduce the impact of influenza: active 
immunoprophylaxis with an inactivated or live attenuated vaccine and chemoprophylaxis or 
therapy with an influenza-specific antiviral drug.  Neuraminidase inhibitors are the current 
mainstay of antiviral treatment for influenza. Marketed neuraminidase inhibitors include 
zanamivir (Relenza®, GlaxoSmithKline) and oseltamivir (Tamiflu®, Roche-Gilead), an oral 
prodrug of the active agent, oseltamivir carboxylate.  Influenza neuraminidase is a surface 
glycoprotein that cleaves sialic acid residues from glycoproteins and glycolipids.  The enzyme 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.  The neuraminidase inhibitors 
represent an important advance in the treatment of influenza with respect to activity against 
influenza A and B viruses, with proven therapeutic value in reducing influenza lower respiratory 
complications,3 and lower rates of antiviral drug resistance4. 
The use of currently available neuraminidase inhibitors has been limited by concerns including, 
the degree of effectiveness, the requirement for an inhaler device (zanamivir), and the emergence 
of resistant influenza virus variants in some treated populations.5 In addition, there are risks of 
bronchospasm with zanamivir; and gastrointestinal side effects, with oseltamivir. 
Peramivir is a neuraminidase inhibitor that represents a potentially promising addition to the 
armamentarium of drugs for the treatment of influenza infections due to its potential for 
parenteral administration and lower frequency of dosing. 
5.2 
Rationale for Study 
An oral formulation of peramivir has previously been evaluated in a full range of safety, 
tolerability, pharmacokinetic, and efficacy studies.  In a multinational phase 3 clinical trial 
conducted in 1999-2001, oral peramivir demonstrated antiviral activity against influenza A and B 
infections, and improvement in the relief of clinical symptoms.  Because of the limited 
bioavailability of peramivir following oral administration (<5%), it was determined that the 
parenteral route of administration is more appropriate for the delivery of peramivir.  Subsequent 
phase 1 studies of intravenous and intramuscular formulations of peramivir have confirmed that 
parenteral routes of administration result in plasma levels of drug that are as much as 100 times 
those achieved via the oral route. In a phase 2 study of intramuscular peramivir in subjects with 
acute uncomplicated influenza, subjects who received a single injection of 150mg or 300mg 
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peramivir had clinically meaningful reductions in the time to alleviation of symptoms of 
influenza, compared to subjects who received a placebo injection. Further details of these studies 
are provided below and in the Investigator Brochure. 
Because of the previous demonstration of clinical efficacy of intramuscular peramivir in acute 
influenza in the phase 2 study, and the encouraging pharmacokinetic and preliminary safety 
profile of the intramuscular formulation of peramivir demonstrated to date, this phase 3 study will 
be conducted to evaluate the efficacy and safety profile of an intramuscular 300 mg peramivir 
dose compared to placebo.  
5.3 
Non-Clinical Experience with Peramivir 
5.3.1 
In vitro Assays 
Peramivir is a selective inhibitor of viral neuraminidase, with 50% inhibitory concentrations 
(IC50) for bacterial and mammalian enzymes of >300µM.6 In an in vitro study, 42 influenza A and 
23 influenza B isolates were collected from untreated subjects during the 1999–2000 influenza 
season in Canada.7 These isolates were tested for their susceptibility to the neuraminidase 
inhibitors zanamivir, oseltamivir carboxylate, and peramivir using a chemiluminescent 
neuraminidase assay.  Inhibition of Type A influenza neuraminidase by peramivir was 
approximately an order of magnitude greater than inhibition of neuraminidase from Type B 
viruses.  IC50 values for the Type A enzymes ranged from <0.1 to 1.4nM, whereas the Type B 
enzymes ranged from <0.1 to 11nM, with three out of four values in the 5- to 11nM range.  
Peramivir was the most potent drug against influenza A (H3N2) viruses with a mean IC50 of 
0.60nM as well as most potent against influenza B with a mean IC50 of 0.87nM.   
In another in vitro comparison of peramivir, oseltamivir, and zanamivir, using a neuraminidase 
inhibition assay with influenza A viruses, the median IC50 of peramivir (approximately 0.34nM) 
was comparable to that of oseltamivir (0.45nM) and significantly lower than zanamivir (0.95nM).  
For influenza B virus clinical isolates, the median IC50 of peramivir (1.36nM) was comparable to 
that of zanamivir (2.7nM) and lower than that of oseltamivir (8.5nM).8   
The potency of peramivir was evaluated against five zanamivir-resistant and six oseltamivir-
resistant influenza viruses.9  Peramivir remained a potent inhibitor against all oseltamivir-resistant 
viruses including the mutations H274Y, R292K, E119V, and D198N, with IC50 values ≤40nM.  
Peramivir also potently inhibited (IC50 ≤ 26nM) the neuraminidase activity of zanamivir-resistant 
strains, which had the following mutations:  R292K, E119G, E119A, and E119D.  However, one 
zanamivir-resistant influenza B virus, B/Mem/96, with a mutation R152K isolated from cell 
culture, was relatively resistant to all neuraminidase inhibitors, including peramivir (IC50 = 
400nM). 
5.3.2 
Animal Models 
In a mouse model of influenza infection, a single intramuscular injection of peramivir (10mg/kg) 
given 4 hours prior to inoculation with an A/NWS/33 (H1N1) influenza strain resulted in 100% 
survival in contrast to 100% mortality in a control group injected with saline.6 In the same mouse 
model, treatment of mice up to 72 hours after influenza infection using peramivir (20mg/kg) 
resulted in 100% survival, compared to 100% mortality in the control group injected with 
vehicle.10 
Peramivir has also demonstrated activity in animal models utilizing a clinical H5N1 isolate as the 
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infecting virus strain.  In a mouse model, a single intramuscular dose of peramivir (30mg/kg) 
injected 1 hour after inoculation with the highly pathogenic (H5N1) A/Vietnam/1203/04 strain, 
resulted in a 70% survival rate that was similar to that seen in mice treated with oseltamivir given 
orally at 10mg/kg/day for 5 days11.  In similar experiments, mice inoculated with the same strain 
of H5N1 virus that were then treated for up to 8 days with intramuscular peramivir exhibited 
100% survival12.  This longer duration of peramivir treatment also prevented viral replication in 
the lungs, brain and spleen at days 3, 6 and 9 post inoculations. 
5.4 
Previous Phase 3 Clinical Experience with Oral Peramivir 
An oral formulation of peramivir has previously demonstrated antiviral activity and preliminary 
clinical efficacy in challenge studies in human volunteers, as well as in treatment studies in 
patients with uncomplicated acute influenza infections during the influenza seasons of 1999-
2001.  A Phase 3 multinational study (BC-01-03) of oral peramivir was conducted.  Two dose 
regimens of oral peramivir, 800mg QD for 5 days, or 800mg QD on Day 1, followed by 400mg 
QD for 4 days, were compared to a matched placebo treatment group.  A total of 1246 subjects 
were randomized to treatment at sites in the USA, Western and Eastern Europe, South America, 
Australia and New Zealand.  As presented in the Table 1 below, the primary end-point of time to 
relief of influenza symptoms in 694 subjects with confirmed influenza was not found to be 
significantly different (p=0.17) between the three treatment groups.13  A sub-group analysis of the 
time to relief of symptoms by country or region demonstrated marked differences in the primary 
endpoint.. In the subset of influenza-infected subjects enrolled at  sites in the US, clinically 
meaningful differences in time to relief of influenza symptoms between the placebo and the two 
peramivir arms were observed, however statistical significance (p=0.07) was not achieved.  
However, a number of secondary endpoints in this phase 3 study, such as time to overall well-
being, time to normal activity, incidence of influenza related complications and quantity of viral 
shedding, achieved or approached statistically significant differences between the peramivir and 
placebo treatment groups (p=0.03-0.06). 
Table 1 
Results of study BC-01-03 
 
 
Median Time to Relief of Influenza Symptoms (Hours) 
Dose and Regimen 
Overall Results 
(n=694) 
US Sites 
(n=198) 
Peramivir 800mg po x 5d 
89.0 
70.8 
Peramivir 800mg po x 1d 
 and          400mg po x 4d 
91.7 
88.8 
Placebo x 5 days 
104.4 
106.8 
p value 
0.17 
0.07 
 
5.5 
Previous Phase 1 Experience with Intramuscular Peramivir 
Two phase 1 studies evaluating the safety and pharmacokinetics of an intramuscular formulation 
of peramivir have been conducted in a total of 45 healthy volunteers receiving peramivir. An 
additional phase 1 study has recently been initiated to evaluate the pharmacokinetics and 
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tolerability of higher single doses (up to 600 mg) of intramuscular peramivir. 
Study Peramivir-Him-06-111 evaluated the single dose pharmacokinetics and tolerability of 
75mg, 150mg and 300mg doses of peramivir administered as intramuscular (i.m.) and 
intravenous (i.v.) injections in a crossover design (9 subjects per group). Peak plasma levels of 
i.m. peramivir generally occurred within 30 minutes following injection.  Plasma 
pharmacokinetic parameters for i.m. peramivir are summarized in Table 2 below for the three 
intramuscular single dose regimens evaluated. 
Table 2 
Pharmacokinetic parameters from study Him-06-111. 
 
Dose (mg) 
Cmax (ng/mL) 
AUC0-∞ (hr·ng/mL) 
t½a (hr) 
75 i.m. 
4296 ± 812 
11659 ± 1123 
19.8 ± 7.9 
150 i.m. 
7612 ± 884 
23952 ± 3804 
24.3 ± 4.1 
300 i.m. 
15150 ± 2367 
49649 ± 5619 
22.8 ± 2.5 
aterminal half life 
In a second phase 1 study, Peramivir-Him-06-112, the same dose levels of peramivir were 
administered as single i.m. injections on two consecutive days (6 subjects per group). This 
double-blind study also included a placebo arm. The pharmacokinetic parameters of i.m. 
peramivir following the second day of dosing were consistent with those seen following single 
doses of the drug. 
An additional phase 1 study, BCX1812-117, was initiated to evaluate the effect of needle length 
adjustment according to gender and body mass index on the pharmacokinetics and safety of 
peramivir following ventrogluteal intramuscular injection, and dorsogluteal intramuscular 
injection in a subgroup of subjects.  Interim data are available for the first 40 subjects who 
received single peramivir doses of 600 mg, consisting of directly observed tolerability 
assessments, safety laboratory studies, reported adverse events, and pharmacokinetic data.  
Clinical laboratory results obtained 72 hours after dosing showed no abnormalities with regards 
to hematology or urinary analytes and the only chemistry analytes outside normal ranges (CK and 
AST) were related to receipt of intramuscular injection.   
 
A majority of the first 40 subjects treated complained of acute pain immediately after injection at 
the ventrogluteal site and a number of these subjects reported that the pain was also associated 
with muscle cramping. Some subjects reported radiation of pain to the lower extremities. In most 
instances, these reactions abated after 15-30 minutes.  
 
This protocol also evaluated the acute tolerability of doses of 450 mg and 600 mg of peramivir 
administered at the dorsogluteal site.  Direct observations determined that the use of the 
dorsogluteal injection site resulted in an acute tolerability profile of the 600 mg dose of peramivir 
that was improved compared to that observed with ventrogluteal site injections. However, a 
number of these subjects also experienced acute pain and discomfort and some reported muscle 
cramping in the gluteal area which persisted for up to 30 minutes.   
 
In summary, this study confirmed that the intramuscular injection of peramivir results in acute 
pain and discomfort after gluteal injection in the majority of subjects in whom total doses of up to 
600mg are administered. In some subjects, the acute pain at the injection site may also be 
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associated with muscle cramping.  Based on these findings, the dorsogluteal site will be utilized 
in future trials. 
 
The safety data for i.m. peramivir administered as single doses ranging from 75 mg to 600mg at 
the dorsogluteal injection site in each of the 3 phase 1 studies conducted to date have been 
unremarkable.   No serious adverse events were reported.  The most commonly observed adverse 
events or laboratory abnormalities were injection site pain or discomfort, headache, and transient 
increases in muscle enzymes (CK). There have been several reports of signs and symptoms of 
self-limited vasovagal reactions following injections.  No consistent differences in frequency of 
adverse events or laboratory toxicities were observed between the active and placebo treatment 
groups in the controlled phase 1 studies, with the exception that CK elevations appeared to be 
dose related in the peramivir treatment groups.   
5.6 
Phase 2 Experience with Intramuscular Peramivir 
A phase 2 study BCX1812-211 was completed in 2007. This study was a randomized, double-
blind placebo- controlled study to evaluate the efficacy and safety of two single dose regimens of 
peramivir. A total of 344 subjects were enrolled into this study with 115 subjects randomized to 
Placebo; 114 subjects randomized to peramivir 150 mg; and 114 subjects randomized to 
peramivir 300 mg. The primary endpoint of the study was the time to alleviation of clinical 
symptoms in adult subjects with uncomplicated acute influenza. Based on preliminary data, the 
primary endpoint of time to alleviation of clinical symptoms in BCX1812-211 did not achieve 
statistical significance in the pre-planned ITTI study population (Table 3).  Based on pre-planned 
and post hoc analyses, it appeared that a majority of subjects within this phase 2 study did not 
receive an adequate intramuscular injection.  
In phase 1 studies (Him-06-111 and Him-06-112) of i.m. peramivir, significant increases in 
creatine kinase (CK) were observed at Day 3 compared with Baseline (Day 1) in all subjects who 
received active study drug or placebo. CK is a well established marker of muscle damage, and it 
was hypothesized that CK increase may act as a surrogate marker of an adequate i.m. injection. 
Within the phase 2 study, an increase in CK between Baseline (Day 1) and Day 3 was not 
observed in a majority of subjects.  In the phase 1 studies study drug was administered with a 1½ 
inch needle. In the phase 2 study a shorter needle (1 inch) was supplied with the study drug, with 
guidance that a longer needle (1½ inch) should be used for larger subjects. Based on the observed 
lack of CK increases at Day 3 compared to baseline, the Sponsor hypothesized that the needle 
used for injection failed to penetrate muscle and deliver intramuscular study medication in many 
subjects. 
A sub group of subjects was identified in which a Day 3 CK increase of at least 50U/L was 
observed over baseline. Within this adequate intramuscular injection sub-group, notable 
improvements in the time to alleviation of symptoms were observed for both peramivir dose 
groups: 44.6 hours for peramivir 150 mg treatment and 64.8 hours for the peramivir 300 mg 
treatment (Table 3).  A further sub-group analysis suggested that in subjects with an influenza B 
infection confirmed by PCR a single dose of peramivir had limited activity (Table 3). These 
efficacy data support the further development of peramivir as a single dose, intramuscular 
treatment for acute influenza. 
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Table 3 
Summary of Efficacy from BCX1812-211. 
 
 
Placebo 
Peramivir 
150mg 
Peramivir 
300mg 
Intent-to-Treat Infected Population1 (n=313) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=107 
137.0 
115.9-163.8 
n=104 
114.1 
95.2-145.5 
22.9 
n=102 
115.9 
77.8-136.6
21.1 
Adequate Injection Population2 (n=101) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=40 
152.2 
103.8-183.9 
n=32 
107.6 
76.8-175.1 
44.6 
n=29 
87.4 
40.8-163.8
64.8 
ITTI Influenza A infected population (n=247) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=83 
138.4 
117.0-173.4 
 
n=85 
115.7 
92.2-145.5 
22.7 
n=79 
115.9 
51.1-195.9 
22.5 
ITTI Influenza B infected population (n=66) 
Median time to alleviation of symptoms (hrs) 
(95% Confidence Interval) 
Improvement over Placebo (hrs) 
n=24 
117.1 
100.3-162.3 
n=19 
100.8 
68.2-162.0 
16.3 
n=23 
123.3 
67.5-178.7 
-6.2 
1: Intent-to-Treat Infected Population: PCR+ for either Influenza A and/or Influenza B at 
baseline/screening visit. 
2: Adequate Injection Population: ITTI subjects in who study drug reached target muscle tissue, 
as evidenced by an increase in serum CK levels of ≥ 50 U/L over baseline at the Day 3 study 
visit. 
An independent data monitoring committee reviewed grouped blinded safety data throughout 
study BCX1812-211. In the overall safety population (n=342), doses of peramivir 150 mg and 
300 mg were both found to be well tolerated and no safety concerns were identified by the DMC. 
The three treatment groups were similar with respect to the frequency and severity of adverse 
events. Two serious adverse events were reported in the study, and neither was considered by the 
investigator to be related to treatment. One SAE (pyelonephritis) occurred 5-days after study 
treatment in a subject who received placebo, and one SAE (meningitis, resulting in death) 
occurred 10-days after study treatment in a subject who received 300 mg of peramivir. There 
were no meaningful differences among the three treatment groups with respect to the frequency 
or severity of graded laboratory toxicities. A summary of the adverse events and graded toxicities, 
together with a list of the most frequently reported adverse events, is presented in Table 4. 
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Table 4 
Summary of Safety from BCX1812-211. 
 
Safety Parameters 
Placebo 
(n=114) 
Peramivir 150 mg 
(n=113) 
Peramivir 300 mg 
(n=115) 
Any Clinical Adverse Event 
49 (43%) 
43 (38%) 
44 (38%) 
Any Graded Laboratory Toxicity 
99 (87%) 
93 (82%) 
92 (80%) 
Any Serious Adverse Event 
1 (<1%) 
0 
1 (<1%) 
Most Frequent Adverse Events 
Assessed as Study Drug-Related 
    Diarrhea 
    Nausea 
    Vasovagal Reaction 
 
 
5 (4%) 
7 (6%) 
4 (4%) 
 
 
5 (4%) 
7 (6%) 
2 (2%) 
 
 
6 (5%) 
9 (8%) 
0 
 
5.7 Dose Rationale 
Oseltamivir is approved for the treatment of uncomplicated acute influenza at a dosage of 75mg 
twice daily in adults14.  Oseltamivir was shown to be clinically effective in a phase 3 study of oral 
oseltamivir versus placebo in naturally occurring seasonal influenza, and these data were 
sufficient for regulatory approval for marketing of oseltamivir.  At least 75% of an oral dose of 
oseltamivir reaches the systemic circulation as oseltamivir carboxylate. When oseltamivir is 
administered orally at a dose of 75mg twice daily, the serum Cmax of oseltamivir carboxylate is 
approximately 348ng/mL and the AUC0-48 is 10,876 h·ng/mL. The clinical data indicate that this 
level of exposure to oseltamivir was sufficient to provide clinical improvement in uncomplicated 
acute influenza.  
The serum pharmacokinetic data (Cmax and AUC0-∞, respectively) following intramuscular doses of 
peramivir are approximately 7600ng/mL and 24,000 h·ng/mL for the 150mg dose and are 
approximately 15,000ng/mL and 49,000 h·ng/mL for the 300mg dose.  Previous studies have 
assessed the concentrations of the neuraminidase inhibitor zanamivir in nasal and pharyngeal 
secretions after parenteral administration of this drug. .  Within several hours after administration, 
the concentrations in secretions were approximately 100-fold lower than in serum or plasma.  In 
theory, relatively high levels of a neuraminidase inhibitor in respiratory secretions are desirable in 
order to rapidly inactivate influenza virus and to delay or prevent the development of resistance in 
infecting virus strains.  Intramuscular doses of peramivir, including doses of 300mg and 600mg 
have been shown to be tolerated in previous Phase 1 studies.  In the completed Phase 2 study, 
both doses of peramivir (150 mg and 300 mg) were well tolerated and no safety concerns were 
apparent. The evidence of a dose response between the 150mg and 300mg doses observed in 
study BCX1812-211 indicates that the 300 mg dose should be studied further.  The results of 
study BCX1812-211 support advancing the 300 mg dose to undergo further evaluation in this 
Phase 3 study.  
 
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6 
STUDY OBJECTIVES 
6.1 
Objectives 
6.1.1 
Primary Objective 
To evaluate the efficacy of peramivir administered intramuscularly compared to placebo on the 
time to alleviation of clinical symptoms in adult subjects with uncomplicated acute influenza. 
6.1.2 
Secondary Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the safety and tolerability of peramivir administered intramuscularly. 
2. To evaluate secondary clinical outcomes in response to treatment. 
3. To evaluate changes in influenza virus titer in nasopharyngeal samples (viral shedding) in 
response to treatment. 
6.1.3 
Exploratory Objective(s) 
The following exploratory objectives have been identified for this study. 
1. To assess pharmacoeconomic measures as response to treatment. 
2. To assess changes in influenza viral susceptibility to neuraminidase inhibitors following 
treatment. 
6.2 
Study Endpoints 
6.2.1 
Primary Endpoint 
The primary clinical endpoint is the time to alleviation of clinical symptoms of influenza. 
6.2.2 
Secondary Endpoint(s) 
Secondary safety, clinical, and virologic endpoints will include evaluations in each subject of: 
Safety: 
Incidence of treatment-emergent adverse events and treatment-emergent changes 
in clinical laboratory tests. 
Clinical:  
Time to resolution of fever; Incidence of influenza related complications. 
Virologic: 
Quantitative change in influenza virus shedding, measured by viral titer assay 
(TCID50). 
6.2.3 
Exploratory Endpoints 
Pharmacoeconomic and virologic evaluations in each subject for exploratory endpoints will also 
be assessed and include: 
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Pharmacoeconomic:  
Medical resource utilization (MRU), missed days of work, and impact of 
influenza illness on subject’s work performance and/or productivity. 
Virologic: 
Quantitative change in influenza virus shedding, measured by PCR; 
Change in influenza virus susceptibility to neuraminidase inhibitors. 
 
7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a multinational, randomized, double-blind study comparing the efficacy and safety of a 
300 mg dose of peramivir administered intramuscularly versus placebo in adults with 
uncomplicated acute influenza.  Approximately 600 subjects will be randomized to treatment to 
ensure enrollment of approximately 450 subjects that are positive for influenza A.  All subjects 
will be centrally randomized to 300 mg of peramivir or placebo in a ratio of 2:1 and will be 
stratified according to smoking status and RAT test for influenza A or B. 
Study drug will be administered as bilateral 2mL intramuscular injections (total of 4mL injected 
in equally divided doses). Procedures for intramuscular injection, with a recommended needle 
length appropriate to the physical characteristics of the subject, are provided in the study drug 
administration manual. 
Subjects eligible for screening will have an anterior nasal swab collected for testing by RAT for 
influenza A and B, in accordance with the commercially available RAT kit instructions.  If the 
initial RAT is negative, the test should be repeated within one hour. Subjects meeting the 
inclusion/ exclusion criteria may be enrolled into the study. 
All enrolled subjects will record the following information in a Study Diary.  
• 
Assessment of the presence and severity of each of seven symptoms of influenza on a 
4-point scale (0, absent; 1, mild; 2, moderate; 3, severe) twice daily (AM, PM) through 
Day 9 following treatment, then once daily (AM) through Day 14. 
• 
Oral temperature measurements will be taken with an electronic thermometer every 12 
hours. With the exception of the baseline measurement, all temperature measurements 
will be obtained at least 4 hours after, or immediately before, administration of oral 
acetaminophen (paracetamol) or other antipyretic medication. 
• 
Assessment of subject’s time lost from work or usual activities and rating of productivity 
compared to normal (rated as 0-10 on a visual analog scale) once daily through Day 14 
• 
Doses of antipy retic, expectorant, and/or th roat lozenges taken for s ymptomatic relief 
each day through Day 14 
Anterior nose (bilateral) and posterior pharynx specimens (swabs) will be collected at Day 1 (pre-
treatment) and at Days 3, 5, and 9, for quantitative virologic assessments.  Specimens from all 
subjects yielding influenza virus will also be assessed for susceptibility to neuraminidase 
inhibitors (Day 1 and last specimen yielding positive result) as well as other virologic 
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assessments (e.g. PCR, genotypic testing). All virologic assessments will be performed by a 
central laboratory.  
Two samples for pharmacokinetic (PK) testing for plasma levels of peramivir will be obtained 
from all subjects randomized.  The first PK sample will be obtained between 30 and 60 minutes 
following study drug administration in all subjects. The second PK sample will be obtained at the 
day 3 visit in all subjects. The data from these PK samples will be utilized in a population 
exposure-response analysis. 
At selected sites a separate sub-study will be conducted to collect additional PK samples between 
treatment and Day 3 for the purpose of conducting a separate exposure-response analysis.  This 
sub-study will be conducted under a separate protocol, BCX1812-311PK.   
8 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1.1 
Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in this study: 
1. Male and non-pregnant female subjects age ≥18 years. 
2. A positive Influenza A and/or B Rapid Antigen Test (RAT) performed with a 
commercially available test kit on an adequate anterior nasal specimen, in accordance 
with the manufacturer’s instructions.  A negative initial RAT should be repeated within 
one hour.  
3. Presence of fever at time of screening of ≥38.0 ºC (≥100.4 ºF) taken orally, or ≥38.5 ºC 
(≥101.2 ºF) taken rectally. A subject self-report of a history of fever or feverishness 
within the 24 hours prior to screening will also qualify for enrollment in the absence of 
documented fever at the time of screening.   
4. Presence of at least one respiratory symptom (cough, sore throat, or nasal symptoms) of 
at least moderate severity. 
5. Presence of at least one constitutional symptom (myalgia [aches and pains], headache, 
feverishness, or fatigue) of at least moderate severity. 
6. Onset of symptoms no more than 48 hours before presentation for screening. 
7. Written informed consent. 
8.1.2 
Exclusion Criteria 
Subjects to whom any of the following criteria apply will be excluded from the study: 
1. Women who are pregnant or breast-feeding. 
2. Presence of clinically significant signs of acute respiratory distress 
3. History of severe chronic obstructive pulmonary disease (COPD) or severe persistent 
asthma. (See Section  15.2). 
4. History of congestive heart failure requiring daily pharmacotherapy with symptoms 
consistent with New York Heart Association Class III or IV functional status within the 
past 12 months. (See Section  15.1). 
5. Screening ECG which suggests acute ischemia or presence of medically significant 
dysrhythmia. 
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6. History of chronic renal impairment requiring hemodialysis and/or known or suspected to 
have moderate or severe renal impairment (actual or estimated creatinine clearance <50 
mL/min). 
7. 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. 
8. Current clinical evidence, including clinical signs and/or symptoms consistent with otitis, 
bronchitis, sinusitis and/or pneumonia, or active bacterial infection at any body site that 
requires therapy with oral or systemic antibiotics. 
9. Presence of immunocompromised status due to chronic illness, previous organ transplant, 
or use of immunosuppressive medical therapy which would include oral or systemic 
treatment with > 10 mg prednisone or equivalent on a daily basis within 30 days of 
screening. 
10. Currently receiving treatment for viral hepatitis B or viral hepatitis C. 
11. Presence of known HIV infection with a CD4 count <350 cell/mm3. 
12. Current therapy with oral warfarin or other systemic anticoagulant. 
13. Receipt of any doses of rimantadine, amantadine, zanamivir, or oseltamivir in the 7 days 
prior to screening. 
14. Immunized against influenza with live attenuated virus vaccine (FluMist®) in the 
previous 21 days. 
15. Immunized against influenza with inactivated virus vaccine within the previous 14 days. 
16. Receipt of any intramuscular injection within the previous 14 days. 
17. History of alcohol abuse or drug addiction within 1 year prior to admission in the study. 
18. Participation in a previous study of intramuscular or intravenous peramivir or previous 
participation in this study. 
19. Participation in a study of any investigational drug or device within the last 30 days. 
8.1.3 
Removal of Subjects from Therapy or Assessment 
All subjects are permitted to withdraw from participation in this study at any time and for any 
reason, specified or unspecified, and without prejudice.  The Investigator or sponsor may 
terminate the subject’s participation in the study at any time for reasons including the following: 
1. Adverse event; 
2. Intercurrent illness; 
3. Non-compliance with study procedures; 
4. Subject’s decision; 
5. Administrative reasons; 
6. Lack of efficacy; 
7. Investigator’s opinion to protect the subject’s best interest. 
Any subject who withdraws because of an adverse event will be followed until the sign(s) or 
symptom(s) that constituted the adverse event has/have resolved or is determined to represent a 
stable medical condition. 
A subject should be withdrawn from the trial if, in the opinion of the Investigator, it is medically 
necessary, or if it is the desire of the subject. If a subject does not return for a scheduled visit, 
every effort should be made to contact the subject and determine the subject’s medical condition.  
In any circumstance, every effort should be made to document subject outcome, if possible. 
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If the subject withdraws consent, no further evaluations should be performed and no attempts 
should be made to collect additional data. 
 
9 
TREATMENTS 
9.1 
Treatments Administered 
Peramivir is an investigational drug.  Peramivir for intramuscular injection is a small-volume 
parenteral and will be supplied as a 75mg/mL solution in sodium citrate/ citric acid buffer.  The 
pH is approximately 3.0. 
A matched placebo solution of sodium citrate/ citric acid buffer with 1.2% sodium chloride at a 
pH of approximately 3.0 will be supplied. 
The gluteal site of injection and the syringe needle length are to be recorded in the subjects CRF. 
Procedures for intramuscular injection, with a recommended needle length appropriate to the 
physical characteristics of the subject, are provided in the study drug administration manual. 
9.2 
Identity of Investigational Product(s) 
Peramivir and placebo peramivir will be supplied in clear 2mL vials.  An individual study drug 
kit will contain 2 vials of blinded study drug (peramivir and/or placebo, depending upon the 
treatment group). Syringes and needles will be provided in which to draw up the solution for 
intramuscular injection. All study drug kits must be stored at 2-8oC.   
Each individual study drug kit will be labeled with some or all of the following information as 
required by local regulations: 
• 
Sponsor name and contact information, study protocol number, kit number, description of 
the contents of the container, instructions for the preparation of the syringe and 
administration of the study drug, conditions for storage, statement regarding the 
investigational (clinical trial) use of the study drug and date for retest or expiry date. 
Each vial of study drug will be labeled with some or all of the following information as required 
by local regulations: 
• 
Sponsor name, study protocol number, description of the contents of the vial, instructions 
for the preparation of the syringe, statement regarding the investigational (clinical trial) 
use of the study drug and lot number. 
9.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be centrally randomized in a ratio of 2:1 to a single dose peramivir 300mg or 
placebo, in accordance with a computer-generated randomization schedule prepared by a non-
study statistician. Each subject’s assignment to treatment will be stratified according to smoking 
status and RAT test for influenza A or B. 
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Once a subject is eligible for randomization, he/she will be assigned a study drug kit number that 
will be obtained by study staff from the study interactive voice response system (IVRS).  Once a 
study drug kit number has been assigned to a subject, it cannot be reassigned to any other subject.   
9.4 
Study Medication Accountability 
The Investigator/pharmacist must maintain accurate records of the disposition of all study drugs 
received from the sponsor, issued to the subject or directly administered to the subject (including 
date and time), and any drug accidentally destroyed.  The sponsor will supply a specific drug-
accountability form.  At the end of the study, information describing study drug supplies (e.g., lot 
numbers) and disposition of supplies for each subject must be provided, signed by the 
Investigator or designee, and collected by the study monitor.  If any errors or irregularities in any 
shipment of study medication to the site are discovered at any time, the Project Manager must be 
contacted immediately. 
At the end of the study, all medication not dispensed or administered and 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 at the participating institution. 
9.5 
Blinding/Unblinding of Treatments 
This is a double-blind study.  The treatment group assignment will not be known by the study 
subjects, the investigator, the clinical staff, the CRO, or Sponsor staff during the conduct of the 
study. 
Section  11.2.4 provides information regarding the process for unblinding the treatment 
assignment, if necessary, in the event of an SAE. 
9.6 
Prior and Concomitant Therapies 
All medications, by any route of administration, used during this study must be documented on 
the Case Report Form (CRF).  Prescription as well as non-prescription medications should be 
recorded. Medication used for the treatment of influenza-related symptoms will be captured by 
the subject in the diary card provided by BioCryst. 
9.7 
Overdose and Toxicity Management 
To date there is no experience with overdose of intramuscular or intravenous peramivir.  If 
overdose occurs, subjects should receive indicated supportive therapy and evaluation of 
hematologic and clinical chemistry laboratory tests should be conducted.  The effect of 
hemodialysis on elimination of peramivir is unknown. 
9.8 
Dose Interruption 
As this is a study of a single dose of peramivir or placebo, guidelines for treatment interruption 
for drug related SAEs or toxicities are not applicable. 
 
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10 STUDY CONDUCT 
A study schedule of evaluations is presented in Figure 1.  A detailed list of the evaluations and 
visits is also provided in the following sections. 
10.1 Evaluations 
All subjects enrolled in this study will undergo the following evaluations: 
10.1.1 Informed Consent 
Prior to any  study-related procedure subjects will be administered informed consent. For further 
discussion of consent see section  10.2.1. 
10.1.2 Medical History 
Medical history, influenza vaccination status within the previous 12 months and demographic 
data (including smoking behavior) will be recorded at Screening/Baseline. 
10.1.3 Rapid Antigen Test for Influenza 
At Screening/Baseline, a commercially available, rapid antigen test (RAT) for influenza A and B 
will be performed on an adequate specimen collected by swabbing the anterior nose in 
accordance with the RAT manufacturer’ instructions.  A negative initial RAT should be repeated 
within one hour.  Refer to the Study Manual [or RAT test package insert(s)] for instructions 
regarding the use of the RAT kits provided for this study.  Sites may use the kits provided by the 
Sponsor or any other commercially approved RAT available at their site to document a confirmed 
influenza infection.  
10.1.4 Physical Examination and Influenza-related Complications Assessments 
The Investigator will perform a physical examination at Screening/Baseline.  Subject’s height and 
weight, and BMI will be recorded at Screening/Baseline in the subjects CRF. 
Study personnel will be provided with an influenza-related complications (IRC) checklist in the 
CRF to evaluate the subject for the presence of clinical signs and/or symptoms of the following 
influenza-related complications: sinusitis, otitis, bronchitis and pneumonia. Note that subjects 
with clinical signs and/or symptoms consistent with otitis, bronchitis, sinusitis, and/or pneumonia 
at screening are not eligible for enrollment in this study (See Section  8.1.2: exclusion criteria 
number 8). 
If an IRC is suspected then a targeted physical examination will be conducted to record the 
presence/absence of the IRC. If the investigator determines that the subject experiences (or is 
presumed to experience) an IRC as noted above, he/she will record that assessment on the IRC 
CRF page and any medication used to treat the condition will be recorded on the concomitant 
medication page.  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 adverse events. Any injection site reactions noted will be recorded in the CRFs as adverse 
events. 
10.1.5 Vital Signs 
Vital signs evaluations will include blood pressure, pulse rate, and respiration rate. The 
investigator will record oral or rectal body temperature at baseline. Thereafter the subject will 
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record oral temperature twice daily in the study diary card. 
Vital signs will be measured at Screening/Baseline, pre-dose, and at 15 minutes following the 
study drug injection on Day 1, then once daily on Days 3, 5, 9, and 14. 
10.1.6 Electrocardiogram Measurements 
A 12-lead electrocardiogram (ECG) will be obtained at Screening/Baseline. The principal 
investigator will be responsible for interpretation of the Screening ECG. This interpretation may 
be performed by the investigator or he/she may delegate this action to another physician and the 
investigator will acknowledge the interpretation.  If this baseline ECG is interpreted as meeting 
the exclusionary criteria listed in section 8.1.2 the subject will not be enrolled in this study.  If the 
ECG is interpreted as being abnormal but does not meet the exclusionary criteria, the subject may 
be enrolled unless other exclusion criteria apply.  The principal investigator is responsible to 
ensure that such an enrolled subject be informed of the nature of the abnormal ECG and that any 
medically indicated repeat ECG examinations and/or referral of the subject for further evaluation 
is made either during subject's participation in the study or immediately after the subject's 
discharge from the study.  
10.1.7 Clinical Laboratories 
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). 
Hematology will include complete blood count (CBC) with differential. 
Urinalysis will include tests for protein, glucose, ketones, blood, urobilinogen, nitrite, pH, and 
specific gravity and microscopic evaluation for RBCs and WBCs. For any subject with a Day 3 
positive test for urine protein of 2+ or higher, who had a Baseline/ Day 1 protein of <2+, a 24 
hour urine collection for assessment of protein will be completed. All urinalysis tests will be 
completed by the central laboratory. 
Clinical laboratory studies (clinical chemistries, hematology, and urinalysis) will be completed at 
Screening/Baseline, and on Days 3, 5 and 14.  
10.1.8 Urine Pregnancy Test 
Females of childbearing potential will be evaluated for pregnancy at Screening/Baseline and Day 
14 using a urine pregnancy test. 
10.1.9 Serology for Influenza  
Paired blood samples for determination of antibody to influenza A and B (serology) will be 
obtained with the clinical laboratory tests at Screening/Enrollment and at Day 14. These 
specimens will be stored at the central laboratory and will be analyzed if needed to confirm the 
diagnosis of influenza. 
10.1.10 Samples for Virologic Laboratory Assessments 
An adequate specimen will be collected by swabbing the anterior nose (bilateral) and posterior 
pharynx for virologic laboratory assessments including culture for the isolation of influenza virus 
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and/or quantitative PCR assay at Screening/Baseline, and at Days 3, 5, and 9.  Refer to the 
Laboratory Manual for instructions regarding the processing and shipment of these specimens. 
10.1.11  Subject Self Assessments 
Subject self assessments will be performed beginning pre-dose on Day 1 and recorded in the 
subject’s Study Diary including the following: 
• 
Oral temperature measurements with an electronic thermometer (provided by the Sponsor for 
the study) every 12 hours.  With the exception of the baseline measurement, all temperature 
measurements will be obtained at least 4 hours after, or immediately before, administration of 
oral acetaminophen (paracetamol, provided) or other anti-pyretic medications. The times of 
each temperature determination will be recorded in the Study Diary.  The baseline 
temperature will be recorded at the screening/Day 1 visit prior to dosing, regardless of 
whether the subject had recently taken an anti-pyretic. 
• 
Assessment of seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia 
[aches and pains], headache, feverishness, and fatigue) on a 4-point severity scale (0, absent; 
1, mild; 2, moderate; 3, severe) twice daily, beginning pre-dose on Day 1 and through Day 9, 
then once daily through Day 14. 
• 
Assessment of the subject’s time lost from work or usual activities and productivity compared 
to normal using a 0-10 visual analogue scale once daily through Day 14. 
The subject’s diary card will be reviewed by study staff at each visit for completion of the record 
of all required items, with particular emphasis on alleviation of symptoms as well as relapse of 
symptoms.  Relapse is defined as the recurrence of at least one respiratory symptom and one 
constitutional symptom (both greater than mild in severity) for 24 hours and the presence of fever 
(unless influenced by antipyretic use).  Relapse can only occur after the subject has met the 
endpoint criteria for alleviation of symptoms.  Study staff will not attempt to ask subjects to 
retrospectively complete missing diary card data for any scheduled assessments that have not 
been completed prior to the clinic visit.  Study staff should, however, remind the subject to 
complete the diary card at all scheduled times. 
10.1.12  Concomitant Medications 
All concomitant medications used during this study, with the exception of those medications 
taken for symptomatic relief of influenza symptoms, which will be recorded by the subject in 
their diary card, must be documented on the Case Report Form (CRF).  
10.1.13  Adverse Events 
AEs will be assessed from the time of administration of study medication through the final study 
visit. 
10.1.14  Pharmacokinetic Exposure Samples 
All subjects will have two pharmacokinetic (PK) samples drawn to assess peramivir drug levels. 
The first PK sample will be drawn on day 1 between 30 and 60 minutes following study drug 
administration in all subjects. The second PK sample will be drawn at the day 3 visit in all 
subjects. The sample will be drawn at the same time as the blood draw is completed for clinical 
laboratory investigations. The 30-60 minute sample (treatment day 1) and the day 3 PK sample 
will be analyzed for plasma concentrations of peramivir (ng/mL) and evaluated in a population 
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exposure response analysis. 
At selected sites a separate sub-study will also be conducted to collect additional PK samples for 
the purpose of conducting an exposure-response analysis.  This sub-study will be conducted 
under a separate protocol, BCX1812-311PK.  Data from these two PK samples in all subjects will 
be combined with data from the PK sub-study (BCX1812-311PK) to perform a population based 
exposure-response analysis.  This analysis will be described as part of the sub-study analysis plan.  
All PK samples will be processed at a central bioanalytical laboratory. Refer to the instructions 
provided regarding the processing and shipment of these PK samples. 
10.2 Screening Period 
10.2.1 Informed Consent 
The nature and purpose of the study and the expectations of a participating subject will be 
described to potential study subjects, their questions will be answered, and the subjects will then 
be asked to sign an informed consent document.  Study subjects will then undergo the screening 
evaluation as noted in Section  10.2.2 
10.2.2 Screening/Baseline Evaluation and Enrollment 
Screening/baseline evaluation may be conducted in the investigator’s office or clinic, or in the 
subject’s home, in which case all evaluations must be conducted by appropriately trained and 
qualified staff. 
Clinical laboratory assessments performed at Screening are for the purpose of establishing a 
baseline.  Subjects may be enrolled and receive treatment with study drug prior to receiving 
results of the laboratory assessments (with the exception of urine pregnancy test result, which 
must be known). 
Eligible subjects will be enrolled and randomized to blinded study treatment.  The randomization 
will be stratified by smoking status and RAT test for influenza A or B.  The Investigator will 
prepare a request for blinded study drug assignment which includes the subject’s screening 
number.  The Investigator or designee at the clinical study center will contact the central 
randomization Interactive Voice System (IVRS call center).  The IVRS call center will advise the 
study center of the investigational study drug kit number that is assigned to that subject at 
enrollment. 
Subjects that are determined to be ineligible will be advised accordingly, and the reason for 
ineligibility will be discussed.  If desired by the subject the reason for ineligibility may be 
provided and/or discussed with their health-care provider by the Investigator or designee.  
Ineligible subjects who have been screened for the study will also be entered on the IVRS.  For 
such subjects, the screening number assigned, subject’s date of birth and a reason for ineligibility 
will be entered on to the IVRS.  All ineligible subjects must be entered onto the IVRS within 
24 hours of screening, to assist with surveillance analysis during the course of the study. 
10.3 Treatment Period—Study Day 1 
Day 1 represents the only day of study drug dosing.  Study drug administration should occur as 
soon as possible following informed consent, screening and randomization.  Therefore, it is 
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expected that the date of Screening/ Baseline and Day 1 will usually be the same date.  
10.3.1 Pre-dose Evaluations-Study Day 1 
Following an explanation of the Subject Self Assessment measures (Section 10.1.11), the subject 
shall complete the record of these assessments in their Study Diary prior to dosing.  The subject 
will be counseled regarding the expectations for recording these assessments through Day 14. 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) and a 
12 lead ECG will be obtained prior to dosing.  
A nasopharyngeal swab for influenza culture/ PCR assay will be obtained prior to dosing. 
10.3.2 Post-dose Evaluations-Study Day 1 
The blinded study drug will be administered (hour 0) as bilateral intramuscular injections within a 
period of ≤ 10 minutes. The calendar date and 24-hour clock time of the first and second 
injections will be recorded. The gluteal site of injection and the syringe needle length are also to 
be recorded in the subjects CRF.  Sites are instructed to follow procedures for intramuscular 
injection, with a recommended needle length appropriate to the physical characteristics of the 
subject, provided in the study drug administration manual.  
The following evaluations will be performed post-dose on Study Day 1: 
• 
Vital sign measurements (blood pressure, pulse rate, respiration rate, and oral temperature) 15 
minutes following the second intramuscular injection of blinded study drug; record the exact 
24-hour clock time of the vital sign measurements in the subjects CRF. 
• 
Draw a PK sample between 30 and 60 minutes following the second intramuscular injection 
of blinded study drug; record the exact 24-hour clock time of the blood draw. 
• 
Record any concomitant medications. 
• 
Record any AEs. 
10.4 Post-Treatment Assessment Period 
10.4.1 Days 2, 3, 5, 9 and 14 
Study evaluations will be performed on Days 2, 3, 5, 9 and 14 in accordance with the schedule of 
evaluations (Figure 1). Subjects with persistent moderate or severe influenza symptoms at day 14 
will also complete a Day 21 visit, and if required a Day 28 visit.  
Visits may be conducted in the investigator’s office or clinic, or in the subject’s home, in which 
case all evaluations must be conducted by appropriately trained and qualified staff. 
Study staff will attempt to contact the subjects on Day 2 by telephone to confirm their compliance 
with completion of the Subject Self Assessments, to note any concomitant medications and 
adverse events.  Any adverse events reported by the subject during this telephone contact will be 
recorded on the adverse event form and verified during the visit on day 3. 
For any subject with a Day 3 positive test for urine protein of 2+ or higher, who had a Baseline/ 
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Day 1 protein of <2+, a 24 hour urine collection for assessment of protein will be completed. 
At each visit it is important that the subject’s Study Diary record be reviewed for completion of 
daily Subject Self Assessments.  The subjects should be counseled as necessary regarding self 
assessments and Study Diary record requirements.  The subject’s diary card will be reviewed by 
study staff for alleviation of symptoms as well as relapse of symptoms.  Relapse is defined as the 
recurrence of at least one respiratory symptom and one constitutional symptom (both greater than 
mild in severity) for 24 hours and the presence of fever (unless influenced by antipyretic use).  
Relapse can only occur after the subject has met the endpoint criteria for alleviation of symptoms. 
Day 3: 
The second PK sample for all subjects will be obtained on Day 3 at the same time as the clinical 
laboratory blood specimen is obtained. The exact 24-hour clock time of the blood draw will be 
recorded in the subjects CRF.  
Day 14: 
If a subject has one or more persistent or recurrent symptoms of influenza (of the seven 
symptoms assessed) of either moderate or severe intensity at the Day 14 visit then the subject 
must be evaluated in further follow-up visits, at day 21 (± 3 days), and if required at day 28 (± 3 
days)  If a subject reports moderate or severe influenza symptoms then the investigator will 
record the intensity of each of the influenza symptoms on a visit specific CRF page at the day 21 
and day 28 visits. After day 14 the subject will not record symptoms in a diary. 
Day 21 (if applicable): 
The day 21 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 14. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at the Day 21 visit and such action(s) will be recorded 
on the Day 21 CRF page. The investigator will recall the subject for a further study visit at day 28 
(± 3 days) if moderate or severe symptom(s) of influenza persist at Day 21.  
Day 28 (if applicable): 
The day 28 visit is to be completed only if the subject reports symptoms of influenza of moderate 
or severe intensity at day 21. The investigator will make a clinical judgment as to the appropriate 
medical course of action for such subjects at this visit and such action(s) will be recorded on the 
Day 28 CRF page. No further follow-up visits beyond day 28 are to be formally scheduled unless 
in the clinical judgment of the investigator further follow-up is required. The investigator will use 
his/her clinical judgment to manage the subject, referring the subject, if appropriate, for further 
medical care. 
10.4.2 Adverse Events Reported at Post-treatment Visits 
In this study, symptoms of influenza will be considered separately from adverse events reported 
during the post-treatment period. Accordingly, adverse events that have onset in the post-
treatment period will be assessed and followed as specified in 11.2. Specifically, 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. 
 
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Figure 1 
Study Measurements and Visit Schedule 
 
Treatment 
Period 
Assessment Day 
End of Study 
Early Withdrawal 
Assessments 
Screening 1
(Baseline) 
Day 11 
Day 22 
Day 3 
Day 5 
(±1 day) 
Day 9 
(±3 day) 
Day 14 
(±3 day) 8 
Informed Consent 
X 
 
 
 
 
 
 
Rapid Antigen test for 
Influenza A and B 
X 
 
 
 
 
 
 
Medical History/Physical Exam 
X 
 
 
 
 
 
 
Influenza-related complications (IRC) 
checklist3 
X 
 
 
X 
X 
X 
X 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
Clinical Chemistries4 
X 
 
 
X 
X 
 
X 
Hematology4 
X 
 
 
X 
X 
 
X 
Exposure Pharmacokinetic Sample9 
 
X 
 
X4 
 
 
 
Serology (serum) Sample 
X 
 
 
 
 
 
X 
Urinalysis10 
X 
 
 
X 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
ECG6 
X 
 
 
 
 
 
 
Sample (nasopharyngeal swab) for 
Influenza Virus Culture/ PCR assay 
and for resistance studies 
 
X 
 
X 
X 
X 
 
Study Drug Administration 
 
X 
 
 
 
 
 
Subject Diary Review7 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Study Measurements and Visit Schedule Figure Legend on Next Page 
 
BioCryst Pharmaceuticals, Inc. 
 
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Study Measurements and Visit Schedule Figure Legend 
 
1 It is expected that the date of Screening and Day 1 (date of administration of study drug) will be the same. Visits at Screening and on 
subsequent study days may occur in subject’s home by the investigator (all visits) or appropriately trained study center staff (Day 3, 5, 9 
visits). 
2  Day 2 will be a telephone contact with the subject to ensure compliance with diary card completion, concomitant medication and adverse 
event review. 
3  If an IRC is suspected then a targeted physical examination will be conducted to record the presence/absence of the IRC. 
4  Clinical laboratory assessments performed at Screening are for the purpose of establishing a baseline.  Subject may be enrolled and begin 
treatment with study drug prior to receiving results. A PK sample will be drawn 30-60 minutes following the second treatment 
administration injection. On Day 3 an extra tube will be included with the safety blood sample to collect the second PK sample for 
evaluation of peramivir concentrations. 
5  Vital sign measures will include blood pressure, pulse rate and respiration rate.  Vital signs will be recorded at Screening, pre-dose and at 
15 min following the study drug administration on Day 1, then once on remaining days as stipulated. The investigator will record oral 
temperature at baseline.  Thereafter the subject will report oral temperature measurements twice daily in the Study Diary 
6  If the baseline ECG is interpreted by the conducting physician as meeting the exclusionary criteria listed in section 8.1.2 the subject will 
not be enrolled in this study.  If the ECG is interpreted as being abnormal and does not meet the exclusionary criteria (e.g. acute ischemia, 
medically significant dysrhythmia) then this subject may be enrolled If the conditions highlighted in section 10.1.5 are met for the subject.
7  Subjects record symptom assessment in Study Diary, twice daily, beginning pre-dose on Day 1 through Day 9, then once daily through 
Day 14.  Subjects record time lost from work or usual activities and rating of productivity compared to normal once daily through Day 14.  
Subjects record oral temperature twice daily throughout as well as all influenza related medications. 
8   For any subject with unresolved moderate or severe intensity influenza symptoms a follow up assessment will be scheduled at Day 21 (± 
3 days) and Day 28 (± 3 days) if required  (See Section 10.4.1).  
9   A PK sample will be drawn 30-60 minutes following the second treatment injection on Day 1, and on Day 3. 
10For any subject with a Day 3 positive test for urine protein of 2+ or higher, who had a Baseline/ Day 1 protein of <2+, a 24 hour urine 
collection for assessment of protein will be completed. 
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11 ADVERSE EVENT MANAGEMENT 
11.1 Definitions 
11.1.1 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. 
AEs may be designated as “nonserious” or “serious” (see Section 11.1.2). 
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 seven influenza symptoms (cough, sore throat, nasal obstruction, myalgia [aches 
and pains], headache, feverishness, and fatigue) will be documented in a subject’s study diary and 
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as 
AEs unless the symptom(s) worsen to the extent that the outcome fulfils the definition of an SAE, 
which then must be recorded as such (see Section  11.1.2).  Likewise, a RAT for influenza is 
required at screening in order to determine eligibility for the study, and therefore a positive RAT 
is not considered an AE.    
11.1.2 Serious Adverse Event 
A SAE is an adverse event that results in any of the following outcomes: 
• 
Death 
• 
Is life-threatening (subject is at immediate risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe) 
• 
Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., there is a substantial disruption 
of a person’s ability to carry out normal life functions) 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event 
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 
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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. 
In addition Suspected Unexpected Serious Adverse Reactions (SUSAR) may also be reported to 
competent authorities where this type of reporting is required (e.g. European Union Directives). 
See section 11.2.3. 
11.2 Method, Frequency, and Time Period for Detecting Adverse Events and Reporting 
Serious Adverse Events 
Reports of AEs are to be collected from the time of study drug administration through the 
follow-up period ending on Day 14.  The Investigator or designee must completely and promptly 
record each AE on the appropriate CRF.  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. 
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. 
11.2.1 Definition of Severity 
All AEs will be assessed (graded) for severity and classified into one of four clearly defined 
categories as follows: 
• 
Mild: 
(Grade 1): Transient or mild symptoms; no limitation in activity; no 
intervention required.  The AE does not interfere with the participant’s 
normal functioning level.  It may be an annoyance. 
• 
Moderate: 
(Grade 2): Symptom results in mild to moderate limitation in activity; 
no or minimal intervention required.  The AE produces some 
impairment of functioning, but it is not hazardous to health.  It is 
uncomfortable or an embarrassment. 
• 
Severe: 
(Grade 3): Symptom results in significant limitation in activity; 
medical intervention may be required.  The AE produces significant 
impairment of functioning or incapacitation. 
• 
Life-threatening: 
(Grade 4): Extreme limitation in activity, significant assistance 
required; significant medical intervention or therapy required; 
hospitalization. 
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11.2.2 Definition of Relationship to Study Drug 
The blinded Principal Investigator 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). 
11.2.3 Reporting Serious Adverse Events 
Any SAE / SUSAR (Suspected Unexpected Serious Adverse Reaction) must be reported to 
BioCryst or its designee within 24 hours of the Investigator’s recognition of the SAE by first 
notifying the Medical Monitor at the number listed below: 
Telephone: 
Europe: +44 1628 548000;  
North America: 1-888-724-4908 
Facsimile: 
Europe: +44 1628 540028;  
North America: 1-888-887-8097  
 
 
 
 
 
 
 
          or 1-609-734-9208 
In addition to the telephone numbers listed above, local country-specific toll free numbers may be 
provided within the study reference manual. 
The site is required to fax a completed SAE / SUSAR Report Form (provided as a separate report 
form) within 24 hours.  All additional follow-up evaluations of the SAE / SUSAR must be 
reported and sent by facsimile to BioCryst or its designee as soon as they are available. 
The Principal Investigator or designee at each site is responsible for submitting the IND safety 
report (initial and follow-up) or other safety information (e.g., revised Investigator’s Brochure) to 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and for retaining a copy 
in their files. 
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If the Investigator becomes aware of any SAE / SUSAR occurring within 30 days after a subject 
has completed or withdrawn from the study, he or she should notify BioCryst or its designee.   
Any SAEs / SUSARs considered possibly related to treatment will be reported to the FDA and 
other Regulatory Competent Authorities as applicable via the MedWatch / CIOMS reporting 
system in accordance with FDA and other applicable regulations. However, the Investigator is not 
obligated to actively seek reports of AEs in former study participants. 
While pregnancy is not considered an AE, all cases of fetal drug exposure via parent as study 
participant (see Section 4.4) are to be reported immediately to BioCryst or its designee.  
Information related to the pregnancy must be given on a “Pregnancy Confirmation and Outcome” 
form that will be provided by the Sponsor or its designee. 
11.2.4 Emergency Procedures 
In the event of an SAE / SUSAR, the Principal Investigator may request the unblinding of the 
treatment assignment for the subject affected.  If time allows (i.e., if appropriate treatment for the 
SAE is not impeded), the Principal Investigator will first consult with the Medical Monitor 
regarding the need to unblind the treatment assignment for the subject.  At all times, the clinical 
well-being of any subject outweighs the need to consult with the Medical Monitor. 
The Principal Investigator may contact the IVRS central randomization center and request the 
unblinding of the treatment assignment that corresponds to the affected subject.  The IVRS center 
will record the name of the Investigator making the request, the date and time of the request, the 
subject number and date of birth.  The Sponsor will be informed within 24 hours if unblinding 
occurred. 
12 STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary and other selected efficacy endpoints.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation (SD), minimum, and maximum for continuous data and frequencies and 
percentages for categorical data.  The term “treatment group” refers to randomized treatment 
assignment: peramivir 300 mg or placebo.  All data collected during the study will be included in 
data listings.  Unless otherwise noted, the data will be sorted first by treatment assignment, 
subject number, and then by date within each subject number.   
Unless specified otherwise, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
12.1 Data Collection Methods 
The data will be recorded on the CRF approved by BioCryst. All documentation supporting the 
CRF data, such as laboratory or hospital records, must be readily available to verify entries in the 
CRF. 
Documents (including laboratory reports, hospital records subsequent to SAEs, etc.) transmitted 
to BioCryst should not carry the subject’s name.  This will help to ensure subject confidentiality. 
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12.2 Statistical Analysis Plan 
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. 
12.3 Study Hypothesis 
The primary hypothesis for evaluating the primary objective may be stated as follows: 
The null hypothesis (H0) is that the time to alleviation of influenza symptoms is the same for 
subjects treated with placebo and for subjects treated with peramivir 300mg. 
 
The alternative hypothesis (H1) is that subjects treated with peramivir 300mg have an 
improvement in time to alleviation of influenza symptoms over those treated with placebo. 
12.4 Sample Size Estimates 
From preliminary results of a phase 2 study evaluating peramivir treatment of uncomplicated 
influenza, it is expected that the median time to alleviation of symptoms will be 137.0 hours (95% 
CI: 115.9, 165.8) for subjects receiving placebo treatment. Additionally, it is expected that the 
median time to alleviation for the 300 mg dose peramivir arm will be reduced by 30% compared 
to placebo yielding a hazard ratio of 0.70.  Data from the phase 2 study suggested that the activity 
of peramivir against influenza B was limited. Therefore, this study will be sized to ensure that a 
minimum number of influenza A subjects is enrolled to achieve study power. 
Using these assumptions, a sample size of 450 evaluable subjects with influenza A (300 in the 
300 mg treatment group and 150 evaluable subjects in the placebo group) is sufficient to provide 
at least 90% power to detect a hazard ratio of 0.70 using a log-rank statistic and α = 0.05 (SAS 
version 9.1.3; total accrual time 7 months; total enrollment time 6 months). 
12.5 Analysis Populations 
The populations for analysis will include the intent-to-treat (ITT), intent-to-treat infected (ITTI 
and ITTI-A), per-protocol infected (PPI), and safety populations. 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.  
Subjects will be analyzed in the treatment group to which they were 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 
randomized, received study drug, and have confirmed influenza by culture or PCR.  Subjects will 
be analyzed according to the treatment randomized.  If a discrepancy is noted in the final database 
for any subject, such that the drug differs from the randomized treatment assignment, efficacy 
analyses may be repeated with the subjects analyzed according to the treatment received.  The 
ITTI population will be used for primary analyses of efficacy. 
Intent-To-Treat Infected Population-A: The ITTI-A population will include all subjects who 
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are randomized, received study drug, and have confirmed influenza A by culture or PCR.  
Subjects will be analyzed according to the treatment randomized.  If a discrepancy is noted in the 
final database for any subject, such that the drug differs from the randomized treatment 
assignment, efficacy analyses may be repeated with the subjects analyzed according to the 
treatment received.  The ITTI-A population will be used for supportive analyses of efficacy. 
Per-Protocol Infected: The PPI population includes all subjects in the ITTI population who 
receive an adequate intramuscular injection. The definition of an adequate intramuscular injection 
will be further described in the SAP. The PPI population will be used for supportive analyses of 
efficacy.  
Safety Population: The safety population will include all subjects who received study drug.  
Subjects will be analyzed according to the treatment received.  This population will be used for 
all safety analyses. 
12.6 Interim and End of Study Analyses 
Interim Analysis 
An independent DMC will review safety data on an ongoing basis.  Safety analyses will be 
presented in a manner consistent with the presentations intended for the final analysis. 
End of Study Analysis 
A final analysis is planned after the last subject completes or discontinues the study, and the 
resulting clinical database has been cleaned, quality checked, and locked. 
12.7 Efficacy Analyses 
12.7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to alleviation of symptoms of influenza in subjects 
diagnosed with influenza, defined as the time from injection of study drug to the start of the time 
period when a subject has Alleviation of Symptoms.  A subject has Alleviation of Symptoms if 
all of the seven symptoms of influenza (nasal congestion, sore throat, cough, aches and pains, 
fatigue (tiredness), headache, feeling feverish) assessed on his/her subject diary are either absent 
or are present at no more than mild severity level and at this status for at least 21.5 hours (24 
hours - 10%). 
Descriptive statistics for the primary efficacy variable will be tabulated by treatment group.  
Alleviation of symptoms will be determined by assessment of symptoms as reported on each 
subject’s diary card.  Time to alleviation of symptoms will be summarized for each treatment 
group (300 mg peramivir and placebo).  Treatment comparisons between the 300 mg peramivir 
group and placebo will be assessed using a Wilcoxon-Gehan19 statistic stratified by smoking 
status and positive PCR or viral culture for influenza A or B at screening for the ITTI and PPI 
populations.  Subjects who do not experience alleviation of symptoms will be censored at the date 
of their last non-missing post-baseline assessment.  
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12.7.2 Secondary Efficacy Endpoints 
All secondary endpoints will be summarized using descriptive statistics by treatment group, and 
study day/time, if appropriate.  Statistical comparisons for each endpoint will be constructed 
without adjustment for multiple endpoints. 
The reduction in viral shedding will be assessed as the change in viral titers defined as the time-
weighted change from baseline in log10 tissue culture infective dose50 (TCID50/mL) and will be 
summarized for each treatment group.  The time-weighted average change from baseline will be 
calculated on a by-subject basis through Day 9 using the trapezoidal rule with all available data 
(data after initiation of study treatment) minus the baseline value.  Specifically, the time-weighted 
area under the curve for time a (ta) to time b (tb) is given by the formula  
)
(
)
(
b
a
b
a
t
t
t
t
AUC
TWAUC
−
−
=
, 
where 
∑
−
=
−
+
−
+
=
−
1
1
1
2
)
)(
(
)
(
b
a
i
i
i
i
i
b
a
t
t
y
y
t
t
AUC
 and ti represents the date of the ith viral titer 
assessment and yi represents the log10 value of the ith viral titer assessment. If there is a baseline 
value and only one follow-up value, yi then the time-weighted change from baseline is defined as 
the difference between yi and baseline.  If there is a baseline value and no follow-up value, the 
subject is excluded from analysis.  The differences between the 300 mg peramivir treatment 
group and placebo will be evaluated using a van Elteren Test adjusting for smoking status and 
positive PCR or viral culture for influenza A or B at screening. 
Subject’s oral temperature will be summarized by study visit and treatment group.  Differences 
between the 300 mg peramivir treatment group and placebo will be assessed using the van Elteren 
test controlling for smoking status and positive PCR or viral culture for influenza A or B at 
screening. A subject has Resolution of Fever if he/she has a temperature < 37.2°C (99.0°F) and 
no antipyretic medications have been taken for at least 12 hours.  The time to resolution of fever 
will be estimated using the method of Kaplan-Meier using temperature and symptom relief 
medication information obtained from the subject diary data.  Differences between the treatment 
groups will be assessed using the Wilcoxon-Gehan statistic controlling for smoking status and 
positive PCR or viral culture for influenza A or B at screening.  Subjects who do not have 
resolution of fever will be censored at the time of their last non-missing post-baseline temperature 
assessment. 
The number and percentage of subjects experiencing influenza related complications will be 
summarized by complication preferred term and treatment group.  The difference between the 
treatment groups (300 mg peramivir and placebo) will be assessed using a Cochran-Mantel-
Haenszel (CMH) test statistic controlling for smoking status, and positive PCR or viral culture for 
influenza A or B at screening, if applicable. 
12.7.3 Exploratory Endpoints 
The MRU, MRU-related direct costs, and indirect costs attributable to days missed of work and 
work productivity and/or performance losses will be summarized by treatment group, smoking 
status, and positive PCR or viral culture for influenza A or B at screening, if applicable.  Methods 
for describing differences between treatment groups will be presented in the SAP. 
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Genotypic (including Hemagglutinin and Neuraminidase), phenotypic, viral culture and PCR data 
will be listed for each subject.  These listings will be constructed in a manner consistent with the 
FDA June 2006 Guidance Document: “Guidance for Submitting Influenza Resistance Data”.18  
Additionally, the number and percentage of genotypic changes from wild-type amino acid will be 
summarized separately for treatment group, protein type, and study visit. 
12.8 Safety Analyses 
AEs will be mapped to a MedDRA-preferred term and system organ classification.  The 
occurrence of TEAEs will be summarized by treatment group using MedDRA-preferred terms, 
system organ classifications, and severity.  If a subject experiences multiple events that map to a 
single preferred term, the greatest severity and strongest Investigator assessment of relation to 
study drug will be assigned to the preferred term for the appropriate summaries.  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 study 
visit.  Laboratory abnormalities will be graded according to the DAIDS Table for Grading 
Adverse Events for Adults and Pediatrics (Publish Date: December 2004).  The number and 
percentage of subjects experiencing treatment-emergent graded toxicities will be summarized by 
treatment group. Laboratory toxicity shifts from baseline to Day 3, Day 5, and Day 14 will be 
summarized by treatment group. 
Abnormal physical examination findings will be presented by treatment group.  The number and 
percent of subjects experiencing each abnormal physical examination finding will be included. 
Concomitant medications will be coded using the WHO dictionary.  These data will be 
summarized by treatment group. 
Subject disposition will be presented for all subjects.  The number of subjects who completed the 
study and discontinued from the study will be provided.  The reasons for early discontinuation 
also will be presented. 
12.9 Sub-Study and Pharmacokinetic Analysis 
A sub-study to collect pharmacokinetic samples in up to 60 peramivir treated subjects to examine 
exposure response will be conducted at selected sites. The data from the sub-study will be 
combined with the two PK samples (collected on all subjects at 30-60 minutes following 
administration of study drug and on study day 3) to perform a population exposure-response 
analysis. All analyses related to exposure-response will be completed as part of the sub-study. All 
statistical methods will be outlined as part of the sub-study protocol and exposure-response 
analysis plan. All sub-study analyses, and exposure-response analyses from PK samples obtained 
in this study and a companion study BCX1812-312, will be reported in a separate sub-study 
report. 
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12.10 
General Issues for Statistical Analysis 
12.10.1 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons are currently planned. 
12.10.2 
Covariates 
Primary and secondary efficacy analyses will be adjusted for smoking status and positive PCR or 
viral culture for influenza A or B at screening, where appropriate.  
12.10.3 
Planned Sub-Groups 
The primary efficacy endpoint will be summarized separately by smoking status and positive 
PCR or viral culture for influenza A or B at screening using descriptive statistics by treatment 
group and study day, where appropriate.  No formal statistical testing will be utilized. 
Additional analyses may be performed by country, if necessary, for submission to local 
regulatory authorities. 
12.10.4 
Missing Data 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized.  No attempt will be made retrospectively to obtain missing subject 
reported data (including influenza symptom severity assessments, temperature, ability to perform 
usual activities, missed days of work and impact of influenza on subject’s work performance 
and/or productivity) 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.   
In assessing the primary efficacy endpoint, for subjects who withdraw or who do not experience 
alleviation of symptoms, missing data will be censored using the date of subject’s last non-
missing assessment of influenza symptoms.  Missing assessments of influenza symptoms 
conservatively will be imputed as having severity above absent or mild (as failures).  For the 
subject diary data, the following data conventions will be utilized.  Missing diary completion will 
be imputed as 11:59 for diary entries designated as morning and 23:59 for evening and daily 
reported values.  Select exploratory sensitivity analyses may be conducted to ascertain the effect, 
if any, of these methods.  These sensitivity analyses are further described in the SAP.  Secondary 
efficacy endpoints with time to event data will be censored using the date of subject’s last non-
missing assessment of the given endpoint. 
 
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13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 Regulatory Authority Approvals 
This study will be conducted in compliance with the protocol; GCPs, including International 
Conference on Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements and in accordance 
with the ethical principles of the Declaration of Helsinki.  In addition, all applicable local laws 
and regulatory requirements relevant to the use of new therapeutic agents in the countries 
involved will be adhered to. 
The Investigator should submit written reports of clinical study status to their Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) annually or more frequently if 
requested by the IRB/ IEC.  A final study notification will also be forwarded to the IRB/IEC after 
the study is completed or in the event of premature termination of the study in accordance with 
the applicable regulations.  Copies of all contact with the IRB/ IEC should be maintained in the 
study documents file.  Copies of clinical study status reports (including termination) should be 
provided to BioCryst. 
13.1.2 Ethics Committee Approvals 
Before initiation of the study at each investigational site, the protocol, the informed consent form, 
the subject information sheet, and any other relevant study documentation will be submitted to 
the appropriate IRB/IEC.  Written approval of the study must be obtained before the study center 
can be initiated or the investigational medicinal product is released to the Investigator.  Any 
necessary extensions or renewals of IRB/IEC approval must be obtained, in particular, for 
changes to the study such as modification of the protocol, the informed consent form, the written 
information provided to subjects and/or other procedures. 
The Investigator will report promptly to the IRB/IEC 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/IEC with a report of the outcome of the study. 
13.1.3 Subject Informed Consent 
Signed informed consent must be obtained from each subject prior to performing any study-
related procedures.  Each subject should be given both verbal and written information describing 
the nature and duration of the clinical study.  The informed consent process should take place 
under conditions where the subject has adequate time to consider the risks and benefits associated 
with his/her participation in the study.  Subjects will not be screened or treated until the subject 
has signed an approved ICF written in a language in which the subject is fluent. 
The ICF that is used must be approved both by BioCryst and by the reviewing IRB/ IEC.  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 or their legal representatives the aims, 
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methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it 
may entail.  Subjects will be informed that they are free not to participate in the trial and that they 
may withdraw consent to participate at any time.  They will be told that refusal to participate in 
the study will not prejudice future treatment.  They will also be told that their records may be 
examined by competent authorities and authorized persons but that personal information will be 
treated as strictly confidential and will not be publicly available.  Subjects must be given the 
opportunity to ask questions.  After this explanation and before entry into the trial, consent should 
be appropriately recorded by means of the subject’s dated signature.  The subject should receive a 
signed and dated copy of the ICF.  The original signed informed consent should be retained in the 
study files.  The Investigator shall maintain a log of all subjects who sign the ICF and indicate if 
the subject was enrolled into the study or reason for non-enrollment. 
13.1.4 Payment to Subjects 
Reasonable compensation to study subjects may be provided if approved by the IRB/IEC 
responsible for the study at the Investigator’s site. 
13.1.5 Investigator Reporting Requirements 
The Investigator will provide timely reports regarding safety to his/her IRB/IEC as required. 
13.2 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 institution will allow 
BioCryst monitors or its designees and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
13.3 Quality Assurance 
The trial site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by BioCryst, 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. 
13.4 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. 
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13.5 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. 
13.6 Study Organization 
13.6.1 Data Monitoring Committee 
BioCryst will assemble an independent Data Monitoring Committee (DMC) to assess safety 
parameters of the trial on a periodic, ongoing basis while the trial is in progress. The committee 
will include a statistician and three physicians, two of whom will be Infectious Disease / Clinical 
Virology specialists. Full details of the composition of the DMC and how the DMC is to operate 
will be described in a separate DMC charter. 
13.7 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 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/IEC) or it may be a separate 
document, (approved by the IRB/IEC) or provided by the Investigator or Sponsor (without 
IRB/IEC approval).  It is the responsibility of the investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are 
required for U.S. sites only. 
13.8 Study Publication 
All data generated from this study are the property of BioCryst and shall be held in strict 
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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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14 REFERENCES 
 
1. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277–1282. 
2. Thompson WW, Shay KD, Weintraub E, Branner L, Cox N, et al. Mortality associated with 
influenza and respiratory syncytial virus in the United States. JAMA 2003;289(2):179–186. 
3. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, et al. Impact of oseltamivir treatment on 
influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 
2003;163(14):1667–1672. 
4. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, et al. Use of the oral neuraminidase 
inhibitor oseltamivir in experimental human influenza: randomized controlled trials for 
prevention and treatment. JAMA 1999;282(13):1240–1246. 
5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, et al. Resistant influenza 
A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759–
765. 
6. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, et al. Comparison of the anti-influenza 
virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents 
Chemother 2001;45(4):1162–1167. 
7. Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to 
different neuraminidase inhibitors. Antiviral Res 2002;54(3):143–147. 
8. Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, 
oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase 
inhibitor-resistant variants. Antimicrob Agents Chemother 2001;45(12):3403–3408. 
9. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine 
combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. 
Antimicrob Agents Chemother 2004;48(12):4855–4863. 
10. BioCryst Pharmaceuticals. Unpublished data. 
11. Arnold CS, Zacks MA, Dziuba N, Yun N, Linde N, Smith J, Babu YS, Paessler S. Injectable 
peramivir promotes survival in mice and ferrets infected with highly pathogenic avian 
influenza A/Vietnam/1203/04 (H5N1). V-2041B, ICAAC 2006, San Francisco 
12. Boltz, DA, Ilyushina NA, Arnold CS, Babu, YS, Webster RG and Govorkova EA. 
Intramuscular administration of neuraminidase inhibitor peramivir promotes survival against 
lethal H5N1 influenza infection in mice. Antiviral Research,2007; 74 (3): A32 
13. BioCryst Pharmaceuticals unpublished clinical study report BC-01-03. 
14. Tamiflu® Package Insert.  Roche Pharmaceuticals. Rev. December 2005. 
15. Quidel QuickVue Influenza A+B and Binax NOW Influenza A&B Test Kit product 
information sheets 
16. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R et al. Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283(8): 1016-
1024. 
17. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S et al. Efficacy and safety of oseltamivir in 
treatment of influenza: a randomised controlled trial. Lancet 2000; 355(9218): 1845-1850. 
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18. US Department of Health and Human Services, Food and Drug Administration Center for 
Drug Evaluation and Reserach (CDER). Attachment to Guidance on Antiviral Product 
Development- Conducting and Submitting Virology Studies to the Agency: Guidance for 
Submitting Influenza Resistance Data.  http://www.fda.gov/cder/guidance/7070fnlFLU.htm  
19. Gehan EA (1965): A generalized Wilcoxon test 
for co mparing arbitrarily  singl y censored 
samples. Biometrika 52:203-223 
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15 APPENDICES 
15.1 NYHA Functional Classification Criteria: Heart Failure and Angina 
 
NYHA Functional Classification of Heart Failure 
 
Class I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs 
does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly; 
walking uphill; walking or stair climbing after meals, in cold weather, in wind, 
or when under emotional stress causes undue fatigue or dyspnea. 
Class III 
Symptoms w ith less than ordinary phy
sical activity.  Walking one to two 
blocks on t he level and clim bing m ore th an one flight of stai rs in norm al 
conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or 
dyspnea. 
 
NYHA Functional Classification of Angina 
 
Class I 
Angina only with unusually strenuous activity. 
Class II 
Angina with slightl y more prolonged o r slightly more vigorous activit y than 
usual. 
Class III 
Angina with usual daily activity. 
Class IV 
Angina at rest. 
 
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15.2 Criteria for Severe COPD and Severe Asthma 
The following guidelines are provided to assist in the evaluation of subjects who have a medical 
history for Chronic Obstructive Pulmonary Disease (COPD) and/or Asthma. Subjects with severe 
COPD or severe persistent Asthma are to be excluded from this study. (See section  8.1.2, 
exclusion criteria number 3). 
Classification of Asthma from National Asthma and Education and Prevention Program 
 
 
 
For Adults and Children (> 5 yrs) who 
can use a spirometer or peak flow meter 
Classification 
Days with 
Symptoms 
Nights with 
Symptoms 
FEV1 or PEF 
% Predicted Normal 
PEF Variability 
(%) 
Severe persistent 
Continual 
Frequent 
≤ 60 
> 30 
Moderate Persistent 
Daily 
> 1/ week 
> 60 - < 80 
> 30 
Mild Persistent 
> 2 / week 
but < 1 
times / day 
> 2/ month 
≥ 80 
20 – 30 
Mild Intermittent 
≤ 2 / week 
< 2 / month 
≥ 80 
< 20 
FEV1: percentage predicted value for forced expiratory volume in 1 second. 
PEF: percentage of personal best for peak expiratory flow. 
Extracted from: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, 
Lung, and Blood Institute, National Asthma Education and Prevention Program. HHS/NIH 2007 
 
Spirometric Classification of COPD Severity based upon Post-Bronchodilator FEV1 
(GOLD Criteria) 
Stage 
Characteristics 
Mild COPD 
FEV1/FVC < 70% 
FEV1 ≥ 80% predicted 
Moderate COPD 
FEV1/FVC < 70% 
50 % ≤ FEV1 < 80% predicted 
Severe COPD 
FEV1/FVC < 70% 
30 % ≤ FEV1 < 50% predicted 
Very Severe COPD 
FEV1/FVC < 70% 
FEV1 < 30% predicted or FEV1 < 50% 
predicted plus chronic respiratory failure 
FEV1: percentage predicted value for forced expiratory volume in one second. 
FVC: forced vital capacity 
Extracted from: Rabe KF, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (GOLD Executive Summary). Am. J. Respir. Crit. Care Med. 2007:176;532-555. 
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