Conditions: Virus Diseases
Keywords: Anti-inflammatory Danirixin Influenza Hospitalized patients
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
Danirixin (DNX) is a novel, selective, and reversible antagonist of the C-X-C chemokine receptor (CXCR) 2 and has been shown to decrease neutrophil transmigration and activation to areas of inflammation. An intravenous (IV) formulation of DNX hydrobromide (HBr) is being developed as an anti-inflammatory agent for treatment of adults hospitalized with influenza (IFV). While early therapy with antivirals decreases severity and duration of symptoms of influenza, there are no drugs that have demonstrated clinical efficacy in randomized clinical trials in this population. Current treatment guidelines for hospitalized IFV recommend neuraminidase inhibitors as standard of care therapy. IFV studies in animals have demonstrated that therapeutic treatment with the combination of a CXCR2 antagonist and a neuraminidase inhibitor reduced lung neutrophils and showed trends for improvements in clinical scores, lung function and pathology with no evidence of worsening outcomes, including viral load. This Phase 2, randomized, double-blind (for IV DNX), placebo-controlled (for IV DNX) 3-arm study will be the first study to determine the efficacy and safety of IV DNX when co-administered (in all groups) with standard of care antiviral treatment (open-label oral oseltamivir \[OSV\]) in subjects hospitalized with IFV. The primary objective of the study is to assess the efficacy of treatment with IV DNX twice daily given with oral OSV compared to oral OSV twice daily on time to clinical response (TTCR). In this study, subjects will be randomized in a 2:2:1 ratio to 15 milligram (mg) free base equivalent (FBE) IV DNX, 50 mg FBE IV DNX, or matching placebo twice daily. All subjects will also receive open-label 75 mg oral OSV, twice daily (given as standard of care). The study treatment duration will be for up to 5 days. The investigator may elect to continue treatment with OSV after 5 days of study treatment. Follow up will continue until Day 45 for all subjects. The study will begin with enhanced safety monitoring in sentinel cohorts, leading to stepwise enrollment of subjects. Subjects will be enrolled based on increasing levels of renal impairment, and less severe hospitalized subjects will be enrolled prior to enrollment of critically ill subjects, as this is the first study conducted in the hospitalized population with severe IFV. Approximately 300 subjects are targeted to be enrolled in the study.

Detailed description:

Arms:
arm 1: Subjects will receive double blind 15 mg FBE IV danirixin twice daily with open label 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued. arm 2: Subjects will receive double blind 50 mg FBE IV danirixin twice daily with 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued. arm 3: Subjects will receive double blind IV placebo of DNX twice daily with 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued.

Interventions: intervention 1: Danirixin 15 mg FBE intervention 2: Danirixin 50 mg FBE intervention 3: Placebo intervention 4: Oseltamivir 75 mg
Intervention descriptions: intervention 1: This intervention is available as a 50 mg FBE sterile lyophilized powder containing DNX (hydrobromide salt hemihydrate) equivalent to 50mg of free base along with Beta-cyclodextrin sulfobutylether, mannitol, citric acid and sodium hydroxide. The formulation is supplied as lyophilized powder/cake contained in a 30mL vial. Each vial is reconstituted with 9.5 mL water for injection and further diluted with saline for IV infusion to provide a dose of 15 mg FBE. intervention 2: This intervention is available as a 50 mg FBE sterile lyophilized powder containing DNX (hydrobromide salt hemihydrate) equivalent to 50mg of free base along with Beta-cyclodextrin sulfobutylether, mannitol, citric acid and sodium hydroxide. The formulation is supplied as lyophilized powder/cake contained in a 30mL vial. Each vial is reconstituted with 9.5 mL water for injection and further diluted with saline for IV infusion. intervention 3: No vials of placebo to match IV DNX will be provided. A normal saline solution of matched volume will be prepared by unblinded personnel at the site to act as a placebo to DNX. Clear solution of placebo will be administered as IV infusion. intervention 4: Oseltamivir (Tamiflu - manufactured by Roche) formulation is available as 75 mg Capsule and as powder for oral suspension. After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL). No oseltamivir capsules or powder for oral suspension will be provided. Sites will source the OSV locally and it will be provided open-label.

Protocol document:
Prot_000.pdf: 
2016N281688_00
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GlaxoSmithKline group of companies
201023
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase II, global, randomized study to evaluate the efficacy and 
safety of Danirixin (GSK1325756) co-administered with a 
standard-of-care antiviral (oseltamivir), in the treatment of adults 
hospitalized with influenza
Compound Number:
GSK1325756
Development Phase
IIB
Effective Date:
12-JUL-2016
Author(s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary 
Medical 
Monitor (EU)
 
Stockley Park 
west, 1-3 
Ironbridge Rd, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BS, UK
Primary
Medical 
Monitor
(USA, 
Mexico)
 
1250 South 
Collegeville Road,  
Collegeville, PA 
19426
SAE contact  
information 
Stockley Park 
west, 1-3 
Ironbridge Rd, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BS, UK
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): IND 121591; EudraCT 2016-002512-40
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about their obligations. Mechanisms are in place to ensure that 
site staff receives the appropriate information throughout the study.
Investigator Name:  ______________________________
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201023........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVES AND ENDPOINTS...........................................................................15
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.1.1.
Sentinel Cohorts with Enhanced Safety Monitoring......................18
4.1.2.
Safety Review Prior to Enrollment of Subjects with Severe 
Conditions at Baseline .................................................................20
4.1.3.
Study Design Change in the Event of Widespread OSV 
Resistance...................................................................................21
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................23
4.5.
Dose Justification........................................................................................24
4.6.
Benefit:Risk Assessment ............................................................................25
4.6.1.
Risk Assessment .........................................................................26
4.6.1.1.
Oseltamivir Risk Assessment .....................................29
4.6.2.
Benefit Assessment.....................................................................29
4.6.3.
Overall Benefit:Risk Conclusion...................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................33
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Premature Discontinuation of Investigational Product ..................36
5.4.2.
Liver Chemistry Stopping Criteria ................................................36
5.4.3.
Corrected QT Interval (QTc) Stopping Criteria.............................36
5.4.4.
Other Stopping Criteria ................................................................37
5.5.
Subject and Study Completion....................................................................37
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.1.1.
IV IP and OSV Administration......................................................39
6.1.1.1.
Preparation of IV IP for Infusion..................................39
6.1.1.2.
Preparation of OSV at the site....................................39
6.1.1.3.
Administration of IV IP................................................39
6.1.1.4.
Administration of OSV ................................................40
6.2.
Treatment Assignment................................................................................40
6.3.
Planned Dose Adjustments.........................................................................41
6.4.
Blinding.......................................................................................................41
6.5.
Packaging and Labeling..............................................................................42
6.6.
Preparation/Handling/Storage/Accountability..............................................42
6.7.
Compliance with Study Treatment Administration.......................................43


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6.8.
Treatment of Study IP Overdose.................................................................43
6.9.
Treatment after the End of the Study ..........................................................44
6.10.
Lifestyle and/or Dietary Restrictions............................................................44
6.10.1.
Dietary Restrictions......................................................................44
6.11.
Concomitant Medications and Non-Drug Therapies....................................44
6.11.1.
Permitted Medications and Non-Drug Therapies..........................44
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................46
7.2.
Critical Baseline Assessments....................................................................52
7.3.
Efficacy.......................................................................................................53
7.3.1.
Primary Endpoint .........................................................................53
7.3.2.
Secondary Efficacy Endpoints .....................................................54
7.3.3.
Clinical Measures ........................................................................55
7.3.4.
Virologic Measures and Biomarker Sampling...............................56
7.3.5.
Health and Value Outcomes ........................................................58
7.4.
Safety .........................................................................................................58
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........58
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................58
7.4.1.2.
Method of Detecting AEs and SAEs ...........................59
7.4.1.3.
Follow-up of AEs and SAEs........................................59
7.4.1.4.
Cardiovascular and Death Events ..............................59
7.4.1.5.
AEs of Special Interest ...............................................60
7.4.1.6.
Regulatory Reporting Requirements for SAEs............60
7.4.2.
Pregnancy ...................................................................................61
7.4.3.
Physical Exams ...........................................................................61
7.4.4.
Vital Signs....................................................................................61
7.4.5.
Electrocardiogram (ECG).............................................................61
7.4.6.
Clinical Safety Laboratory Assessments ......................................61
7.5.
Pharmacokinetics .......................................................................................63
7.5.1.
Blood Sample Collection..............................................................63
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................64
7.6.1.
Novel Biomarkers ........................................................................64
7.6.1.1.
RNA Transcriptome Research....................................65
7.6.1.2.
Proteome Research....................................................65
7.7.
Genetics .....................................................................................................65
7.8.
Viral Genotyping and Phenotyping..............................................................65
7.9.
Value Evidence and Outcomes...................................................................66
8.
DATA MANAGEMENT ...........................................................................................66
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................66
9.1.
Hypotheses.................................................................................................66
9.2.
Sample Size Considerations.......................................................................67
9.2.1.
Sample Size Assumptions ...........................................................67
9.2.2.
Sample Size Sensitivity................................................................68
9.2.3.
Sample Size Re-estimation or Adjustment...................................68
9.3.
Data Analysis Considerations .....................................................................69
9.3.1.
Analysis Populations....................................................................69
9.3.2.
Interim Analysis ...........................................................................69


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9.4.
Key Elements of Analysis Plan ...................................................................70
9.4.1.
Efficacy........................................................................................70
9.4.1.1.
Primary Analysis.........................................................70
9.4.1.2.
Secondary Analyses...................................................71
9.4.1.3.
Subgroup Analyses ....................................................71
9.4.2.
Safety Analysis ............................................................................71
9.4.3.
Virology Analyses ........................................................................72
9.4.4.
PK and PK/PD Analyses..............................................................72
9.4.5.
Other Analyses ............................................................................72
10. STUDY GOVERNANCE CONSIDERATIONS........................................................72
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............72
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................72
10.3.
Quality Control (Study Monitoring) ..............................................................74
10.4.
Quality Assurance.......................................................................................74
10.5.
Study and Site Closure ...............................................................................74
10.6.
Records Retention......................................................................................75
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................76
10.8.
Review Committees....................................................................................76
10.8.1.
Independent Data Monitoring Committee.....................................76
11. REFERENCES.......................................................................................................77
12. APPENDICES........................................................................................................80
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................80
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................83
12.3.
Appendix 3 - Genetic Research ..................................................................85
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................88
12.4.1.
Definition of Adverse Events........................................................88
12.4.2.
Definition of Serious Adverse Events...........................................89
12.4.3.
Definition of Cardiovascular Events .............................................90
12.4.4.
Recording of AEs and SAEs ........................................................91
12.4.5.
Evaluating AEs and SAEs............................................................91
12.4.6.
Reporting of SAEs to GSK...........................................................93
12.5.
Appendix 5:  Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Averse Events Version 1.0, December 2004; 
Clarification August 2009............................................................................94
12.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................111
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............111
12.6.2.
Collection of Pregnancy Information ..........................................112
12.7.
Appendix 7: Patient Reported Outcomes Questionnaires .........................114
12.7.1.
FluPro........................................................................................114
12.7.2.
Katz ADL Score .........................................................................116
12.8.
Appendix 8 - Country Specific Requirements............................................117
12.9.
Appendix 9  Statistical considerations.......................................................118
12.9.1.
Introduction................................................................................118


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12.9.2.
Statistical Modeling....................................................................118
12.9.2.1.
Hazard Model:..........................................................118
12.9.2.2.
The dose –response Model: .....................................119
12.9.3.
Allocation...................................................................................119
12.9.4.
Evaluation of Arm Dropping, Trial Success and Futility..............119
12.9.5.
Probability of success ................................................................119
12.9.6.
Arm Dropping ............................................................................119
12.9.7.
Early Futility...............................................................................119
12.9.8.
Early success ............................................................................120
12.9.9.
Trial completion .........................................................................120
12.9.10. Simulation Scenarios .................................................................120
12.9.11. Operating Characteristics ..........................................................120


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1.
PROTOCOL SYNOPSIS FOR STUDY 201023
Rationale
Seasonal influenza affects 5-10% of the world’s population annually, causing 3-5 million 
severe infections and 250,000 – 500,000 deaths.  While early therapy with antivirals 
decreases severity and duration of symptoms of influenza, there are no drugs that have 
demonstrated clinical efficacy in randomized clinical trials in this population. Current 
treatment guidelines for hospitalized influenza recommend neuraminidase inhibitors as 
standard of care therapy. Following infection by a respiratory virus, neutrophils are the 
most abundant cells that migrate to the lungs. Influenza studies in animals have 
demonstrated that therapeutic treatment with the combination of a C-X-C chemokine 
receptor 2 (CXCR2) antagonist and a neuraminidase inhibitor reduced lung neutrophils 
and showed trends for improvements in clinical scores, lung function and pathology with 
no evidence of worsening outcomes, including viral load.
This study is designed to investigate an anti-inflammatory agent, danirixin (DNX; 
GSK1325756) co-administered with an antiviral treatment oseltamivir (OSV) for 
treatment of patients hospitalized for influenza infection and will be the first study to 
evaluate the efficacy and safety of intravenous DNX in this population.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To assess the efficacy of treatment with 
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily on time to clinical response 
(TTCR)

Time to Clinical Response (composite) 

Hospital discharge
OR 

Normalization of:
-- Temperature; and
--Oxygen saturation; and
--Respiratory status/Heart 
Rate/Systolic BP (SBP)
(normalization of 2 out of these 3 
parameters)
Secondary

To assess the efficacy of treatment with  
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir  
twice daily on time to respiratory response 
(TTRR)

Time to Respiratory Response defined 
as meeting at least one criterion below 

Return to pre-morbid oxygen 
requirement (subjects with chronic 
oxygen use), OR 

Return to no requirement of 
supplemental oxygen, OR 


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Objectives
Endpoints

Respiratory rate ≤24/min (without 
supplemental oxygen)

To evaluate clinical measures of 
influenza illness following treatment with  
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily

Time to absence of fever

Time to improved oxygen saturation

Time to improved heart rate

Time to improved SBP

Proportion of subjects with clinical 
response over time

Proportion of subjects with improved 
respiratory status over time 

Time to improvement of ventilation 
status: modality, frequencies and durations
of invasive and non-invasive ventilator 
support, duration of oxygen 
supplementation.

Length of stay in the Intensive care unit
(ICU)

Frequency of ICU admission and 
readmission

Length of stay in the hospital

Rates of development of septic shock

Frequency of antibiotic use

Proportion of subjects with 
improvement in Ordinal scale of clinical 
efficacy over time : 

Death

Mechanical vent

In the ICU

Non-ICU hospitalization 

Hospital discharge

To characterize the safety and 
tolerability of IV DNX twice daily given 
with oral oseltamivir compared to oral 
oseltamivir twice daily

Frequency of adverse events (AEs) and 
serious adverse events (SAEs)

Frequency of adverse events of special 
interest (AESIs)

Change from baseline in clinical 
laboratory evaluations, and electro 


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Objectives
Endpoints
cardiogram (ECG) parameters

To characterize the pharmacokinetics of 
IV DNX in subjects hospitalized for 
influenza

Standard pharmacokinetic parameters 
for IV DNX (i.e. area under the curve
[AUC], maximum observed concentration 
[Cmax], average concentration [Cavg].
Overall Design
This study is a Phase 2, randomized, double-blind (for IV DNX), placebo-controlled (for 
IV DNX) 3-arm study in adults to determine the efficacy and safety of IV DNX when co-
administered (in all groups) with standard of care antiviral treatment (open-label oral 
75 mg OSV) for patients hospitalized with influenza.
An Independent Data Monitoring Committee (IDMC) will perform monitoring and 
reviews of available safety and efficacy data.  In the first influenza season, the IDMC will 
review unblinded safety data across all study cohorts, after every approximately 10-20 
subjects have completed the post-treatment (PT) Day 3 visit. Frequency of IDMC 
reviews in subsequent seasons will be determined based on safety results of the interim 
analysis.
Treatment Arms and Duration
Subjects will be randomized in a 2:2:1 ratio to receive:

15 mg FBE IV DNX +75 mg OSV; 

50 mg FBE IV DNX+75 mg OSV;  or 

IV DNX placebo+75 mg OSV
Treatment duration will be 5 days.  The investigator may elect to continue open-label 
oseltamivir treatment.  Follow up will continue until Day 45 for all subjects.
Type and Number of Subjects
The study will recruit adult patients with influenza infection requiring hospitalization. 
Influenza patients with conditions of respiratory failure requiring mechanical ventilation, 
chronic kidney disease, acute renal failure, sepsis, or hemodynamic instability are 
considered a more severe population.
A maximum of 300 subjects are planned to be enrolled in the study, depending on study 
dose changes implemented after each of two planned interim analyses.  Interim analyses 
are planned after each influenza season if there are more than 75 subjects enrolled.  
Completion of enrolment in this study is expected to take multiple influenza seasons.


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Analysis
The sample size of 300 was selected based on simulations to achieve at least 80% overall 
power under assumption of HR =1.5 for 50 mg of DNX FBE and HR =1.2 for 15 mg of 
DNX FBE and keep type I error less than 10% under no-effect assumption.
An adaptive design is employed that allows for dropping a dose at interim analyses. 
These interim analyses also allow for early stopping for futility or efficacy.  Probability 
of success for efficacy will be calculated, defined as a statistically significant treatment 
effect (p-value<0.025 for hazard ratio of TTCR >1) in a future two-arm comparative 
superiority study with 300 subjects per arm, given observed data. 
Exposure to study medication, measured by the number of days on study drug, will be 
summarized by treatment arm. The proportion of subjects reporting adverse events (AEs) 
will be tabulated for each treatment arm. 


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2.
INTRODUCTION
GSK1325756 (danirixin; DNX) is a novel, potent, selective, and reversible antagonist of 
the C-X-C chemokine receptor (CXCR) 2 and has been shown to decrease neutrophil 
transmigration and activation to areas of inflammation.  An intravenous (IV) solution for 
infusion is being developed as an anti-inflammatory agent for hospitalized influenza 
(IFV) patients. Clinical development of an oral formulation for the treatment of chronic 
obstructive pulmonary disease (COPD) has also commenced. 
Severe viral respiratory tract infections can cause direct injury through cytopathicity as 
well as tissue damage through an excessive immune response [Garcia, 2010; Perrone, 
2008].  Selective CXCR2 antagonists potentially maintain a balance between inhibiting 
excessive immune response while preserving antimicrobial function by only partially 
reducing neutrophils, selectively inhibiting CXCR2 over CXCR1 (CXCR1 is involved in 
neutrophil degranulation), and maintaining acquired humoral immunity and cell-mediated 
immunity [Jones, 1996; Hartl, 2007; Seiberling, 2013; GSK Document Number 
YM2010/00163/07].
2.1.
Study Rationale
This study is designed to investigate an anti-inflammatory agent (DNX) co-adminstered 
with an antiviral treatment (OSV) for treatment of patients hospitalized for influenza 
infection. 
Seasonal influenza affects 5-10% of the world’s population annually, causing 3-5 million 
severe infections and 250,000 – 500,000 deaths [Hayward, 2014].  While early therapy 
with antivirals decreases severity and duration of symptoms of influenza, there are no 
drugs that have demonstrated clinical efficacy in randomized clinical trials in this 
population. Current treatment guidelines for hospitalized influenza recommend 
neuraminidase inhibitors as standard of care therapy.
Following infection by a respiratory virus, neutrophils are the most abundant cells that 
migrate to the lungs, and excessive migration has been demonstrated to cause lung 
damage through release of tissue-destructive enzymes and reactive oxygen species and 
formation of neutrophil extracellular traps [Narasaraju, 2011].  Respiratory neutrophil 
levels and/or their associated chemokines involved in recruitment are correlated with 
clinical symptom severity of influenza infection in humans [Taubenberger, 2008; Short, 
2014; Hayden, 1998].
Influenza studies in animals have demonstrated that therapeutic treatment with the 
combination of a CXCR2 antagonist and a neuraminidase inhibitor reduced lung 
neutrophils and showed trends for improvements in clinical scores, lung function and 
pathology with no evidence of worsening outcomes, including viral load [GSK Document 
Number YM2010/00163/07]. In addition, nonclinical and clinical studies support the 
hypothesis that selective antagonism of CXCR2 has an acceptable safety profile [GSK 
Document Number YM2010/00163/07].
This will be the first study to evaluate efficacy and safety of intravenous DNX
(GSK1325756) given with a standard-of-care antiviral, oral oseltamivir (OSV), for 


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treatment of patients hospitalized with influenza infection. An IV formulation of DNX, 
danirixin hydrobromide (DNX HBr) has been developed and will be used for treatment in 
this study, since parenteral administration would be a preferred mode of delivery of 
medication in this hospitalized population, especially in critically ill patients. In this 
document, the IV DNX HBr dose will be presented as the free base equivalent (FBE). 
2.2.
Brief Background
Danirixin free base (DNX-FB) has undergone a comprehensive non-clinical assessment, 
including 39-week dog and 26-week rat toxicology studies, during which no signals were 
observed that might preclude further assessment in clinical trials.  DNX-HBr has 
undergone a 4-week rat bridging toxicity study, a 14 day mouse pre-oncogenicity study 
and a full non-clinical assessment of reproductive toxicology comprising rat and rabbit 
embryofetal development studies in addition to male and female rat fertility studies.
A summary of the nonclinical information for DNX-FB and DNX-HBr, including a list of 
nonclinical Pharmacodynamic, Pharmacokinetic & Product Metabolism and Toxicology 
studies completed to date is provided in Section 4 of the Investigator’s Brochure (IB) 
[GSK Document Number YM2010/00163/07]. 
Across the COPD and IFV programs, the number of subjects exposed to DNX is 
approximately 270.  Six phase 1 clinical studies in healthy volunteers (HV) have been 
completed using oral and IV DNX treatment and over 180 HV subjects have been treated 
with DNX (10-400 mg DNX).  The HV studies initially utilized the FB oral (up to 400 
mg) and IV formulations of DNX (up to 50 mg twice daily (BID) for 5 days or 100 mg 
single dose).  Most recently, Study 201037 in elderly HV has used the oral HBr 
formulation of DNX (50 mg single dose).  Study 201682/DAISI was a phase II placebo-
controlled study in uncomplicated outpatient influenza subjects (N=45).  Subjects were 
treated with 75 mg oral DNX or placebo (PBO) BID and 75 mg oral OSV or PBO BID
for 5 days.  Safety of DNX treatment in the IFV population is being studied in a staged 
manner.  DAISI was conducted in an outpatient IFV population prior to this study which 
investigates DNX treatment in less severe hospitalized subjects, followed by critically ill 
hospitalized subjects this study (Study 201023; DAHLIA).  In DAHLIA, the HBr 
formulation of DNX will be provided as an IV infusion.  Further information is located in 
the Investigator’s Brochure [GSK Document Number YM2010/00163/07].  


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the efficacy of treatment with 
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily on time to clinical response 
(TTCR)

Time to Clinical Response (composite) 

Hospital discharge
OR 

Normalization of:
-- Temperature; and
--Oxygen saturation; and
--Respiratory status/Heart Rate/SBP 
(normalization of 2 out of these 3
parameters)
Secondary

To assess the efficacy of treatment with  
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir  
twice daily on time to respiratory response 
(TTRR)

Time to Respiratory Response defined 
as meeting at least one criterion below 

Return to pre-morbid oxygen 
requirement (subjects with chronic 
oxygen use), OR 

Return to no requirement of 
supplemental oxygen, OR 

Respiratory rate ≤24/min (without 
supplemental oxygen)

To evaluate clinical measures of 
influenza illness following treatment with  
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily

Time to absence of fever

Time to improved oxygen saturation

Time to improved heart rate

Time to improved SBP

Proportion of subjects with clinical 
response over time

Proportion of subjects with improved 
respiratory status over time 

Time to improvement of ventilation 
status: modality, frequencies and durations
of invasive and non-invasive ventilator 
support, duration of oxygen 
supplementation.

Length of stay in the ICU

Frequency of ICU admission and 


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Objectives
Endpoints
readmission

Length of stay in the hospital

Rates of development of septic shock

Frequency of antibiotic use

Proportion of subjects with 
improvement in Ordinal scale of clinical 
efficacy over time : 

Death

Mechanical vent

In the ICU

Non-ICU hospitalization 

Hospital discharge

To characterize the safety and 
tolerability of IV DNX twice daily given 
with oral oseltamivir compared to oral 
oseltamivir twice daily

Frequency of adverse events (AEs) and 
serious adverse events (SAEs)

Frequency of adverse events of special 
interest (AESIs)

Change from baseline in clinical 
laboratory evaluations, and ECG 
parameters

To characterize the pharmacokinetics of 
IV DNX in subjects hospitalized for 
influenza

Standard pharmacokinetic parameters 
for IV DNX (i.e. AUC, Cmax, Cavg).
Exploratory 

To assess changes in influenza viral 
load from nasopharyngeal swabs following 
treatment with  IV DNX twice daily given 
with oral oseltamivir compared to oral 
OSV twice daily; perform resistance 
analysis and a multiplex PCR assay with 
respiratory virus panel to assess co-
infection.

Change in quantitative influenza viral 
load over time and change from baseline 
measured from nasopharyngeal swab 
samples and lower respiratory tract 
samples, as determined by qRT-PCR and 
quantitative virus culture (qVC)

Percentage of subjects with no 
detectable influenza viral RNA by qRT-
PCR and qVC.

Percentage of subjects with co-infected 
viruses by multiplex RT PCR.

Percentage by type of co-infected 
viruses by multiplex RT PCR.

Change in quantitative viral load of 
other virus co-infections over time and 


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Objectives
Endpoints
change from baseline measured from 
nasopharyngeal swab samples and lower 
respiratory tract samples, as determined by 
qRT-PCR.

Frequency of emergent resistance to 
OSV

To explore the effects of IV DNX twice 
daily given with oral oseltamivir compared 
to oral OSV twice daily with IV DNX
placebo on biomarkers of inflammation and
immune response from nasal samples or 
fluid, endotracheal samples, whole blood, 
bronchoalveolar lavage, and/or serum.

Quantitative and qualitative changes in 
exploratory biomarkers (may include but 
are not limited to: IL-8, procalcitonin, 
respiratory neutrophil cell counts, 
neutrophil elastase, and myeloperoxidase).

To characterize the PK response 
relationship of IV DNX.

PK exposure for DNX and 
pharmacodynamic parameters.

To determine health outcome impact of  
IV DNX twice daily given with oral OSV
compared to oral OSV twice daily

FLU PRO questionnaire

Activities of daily living (Katz ADL 
Score)

Activity level

Hospital readmission rates
4.
STUDY DESIGN
4.1.
Overall Design
This study is a Phase 2, randomized, double-blind (for IV DNX), placebo-controlled (for 
IV DNX) 3-arm study in adults to determine the efficacy and safety of IV DNX when co-
administered (in all groups) with standard of care antiviral treatment (open-label oral 
75 mg OSV) for patients hospitalized with influenza.
Subjects will be assessed for influenza with a rapid diagnostic test provided by 
GlaxoSmithKline (GSK) (such as next generation rapid antigen test, commercial reverse 
transcriptase-polymerase chain reaction [RT-PCR], molecular assay), or local influenza 
test.  A confirmatory RT-PCR test will be done by the central laboratory. Following 
confirmation of influenza with a rapid-diagnostic test, and meeting all other eligibility 
criteria, subjects will enter the study.  Subjects will receive one of two doses of DNX
given as an IV infusion, twice daily. Enrollment of subjects will be in a 2:2:1 ratio of 15 
mg FBE IV DNX, 50 mg FBE IV DNX, or matching placebo.  All subjects will also 
receive open-label oral OSV, twice daily (given as standard of care). Study treatment 
duration will be for up to 5 days.  The investigator may elect to continue treatment with
OSV after 5 days of study treatment.


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The study will begin with enhanced safety monitoring in sentinel cohorts, leading to step-
wise enrollment of subjects.  Subjects will be enrolled based on increasing levels of renal 
impairment (Section 4.1.1), and less severe hospitalized subjects will be enrolled prior to
enrollment of a critically ill subjects (Section 4.1.2 and Section 4.3), as this is the first 
study conducted in the hospitalized population with severe influenza. 
Approximately 100 subjects are targeted to be enrolled in the study in the first influenza 
season and up to 100 subjects are planned to be enrolled in each of two additional 
influenza seasons for a total of approximately 300 subjects in the study.
Pharmacokinetic analysis will be done in batches during the study to provide 
confirmation of exposure to DNX.  Similarly, to obtain evidence of target engagement, 
nasal and/or endotracheal samples may be evaluated in batches to determine respiratory 
biomarker (neutrophil) patterns following treatment with DNX.
Interim analyses of efficacy and safety data will be conducted to confirm dose regimens 
for subjects in the remainder of the influenza seasons. The first interim analyses will 
occur after the first flu season if there are more than 75 subjects enrolled. Additional 
interim analyses may be performed after approximately 50-66% of subjects have been 
enrolled. 
Four potential outcomes of the interim analysis include the following: (1) stop the study 
for safety reasons, (2) stop the study for futility or efficacy, (3) continue with one DNX 
dose arm, or (4) continue with the two original DNX arms. The Bayesian decision 
criteria with regards to TTCR together with other efficacy, pharmacokinetic (PK) and 
safety data will be provided to support decisions on dose selection and study stopping 
after each interim analysis.  
An Independent Data Monitoring Committee (IDMC) will perform monitoring and 
reviews of available safety and efficacy data.  In the first influenza season, the IDMC will 
review unblinded safety data across all study cohorts, after every approximately 10-20 
subjects have completed the post-treatment (PT) Day 3 visit. Study halting and dose arm 
halting criteria have been designed to guide IDMC review and decisions (summarized in 
Section 10.8.1 and detailed in the IDMC charter).  Frequency of IDMC reviews in 
subsequent seasons will be determined based on safety results of the interim analysis.
The final analysis will occur when both accrual and follow-up are complete for all 
subjects. Formal statistical decision rules of interim and final analysis for TTCR are 
defined in Section 9.
4.1.1.
Sentinel Cohorts with Enhanced Safety Monitoring
Sentinel cohorts with enhanced safety monitoring will be enrolled as part of a step-wise 
enrollment of subjects with different levels of renal impairment and disease severity (less 
severe and critically ill, Section 4.3).  Subjects in the sentinel cohorts will have more 
stringent eligibility criteria (baseline creatinine clearance criteria and exclusion of 
subjects with diabetes mellitus and chronic kidney disease). The IV DNX formulation 
developed for this study contains 750 mg -Cyclodextrin Sulfobutylether (SBE-β-CD, 
Captisol) per 50 mg of GSK1325756 (free base equivalent [FBE]), to achieve the desired 


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5mg/mL concentration (FBE) and ensure DNX remains in solution when added to the IV 
saline bag.  Captisol is renally cleared with the potential for accumulation in subjects 
with severe renal impairment.  As such, this study includes enhanced monitoring to 
evaluate for renal function.  Subjects in the sentinel cohorts will undergo serum 
creatinine, eGFR and urine output assessments twice a day for the treatment period.  
Additional enhanced monitoring will be based on disease severity, peripheral neutropenia 
and bacterial infections.
Approximately 30 subjects who are less severely ill and have baseline creatinine 
clearance within normal reference ranges (creatinine clearance 80 mL/min) will be 
enrolled in sentinel cohort 1 (Figure 1).  The IDMC will first review available safety data 
after completion of the PT Day 3 visit, from approximately 10 subjects who are less 
severely ill and have normal renal function enrolled in sentinel cohort 1.  Enrollment of 
subjects with normal renal function will continue during this review.
Following a review of all available data from the approximately 30 subjects in sentinel 
cohort 1, and an acceptable outcome from the IDMC, approximately 10 subjects with 
mild renal impairment, defined as baseline creatinine clearance of 50-79 mL/min will be 
enrolled in sentinel cohort 2, while continuing to enroll subjects with normal renal 
function in the study. At this stage, both less severely ill and the more critically ill 
subjects may be enrolled.
The IDMC will review the available safety data after completion of PT Day 3 from 
subjects in sentinel cohort 2 with mild renal impairment. Additional subjects with mild 
renal impairment will not be enrolled until the safety review is conducted by the IDMC, 
and the determination of an acceptable outcome.  
Following an acceptable outcome from the IDMC review of the subjects with mild renal 
impairment, further enrollment of subjects with mild renal impairment will resume and 
approximately 10 subjects with moderate renal impairment (defined as baseline creatinine 
clearance of 30-49 mL/min) will be enrolled in sentinel cohort 3.  The IDMC will review 
the available safety data after PT Day 3 from subjects in sentinel cohort 3 with moderate 
renal impairment. Following an acceptable outcome from the IDMC review, additional 
subjects with moderate renal impairment may be enrolled in the study.


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Figure 1
Enrollment and Evaluation in Sentinel Cohorts
NOTE: CrCL = creatinine clearance
4.1.2.
Safety Review Prior to Enrollment of Subjects with Severe 
Conditions at Baseline
The enrollment of critically ill hospitalized subjects will be delayed until IDMC review 
of the safety data from approximately 30 subjects considered to be less severe (Section 
4.3). 
The available safety data from subjects in this less severe population will be reviewed by 
the IDMC (unblinded) and GSK Safety Review Team (SRT) (blinded) after completion 
of study treatment.  Enrollment of critically ill subjects (with normal renal function, and 
those with mild or moderate renal impairment) will only begin after an acceptable 
outcome is reported from the IDMC review of approximately 30 less severe subjects with 
normal renal function. 


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4.1.3.
Study Design Change in the Event of Widespread OSV 
Resistance
A contingency study design is included in this protocol to facilitate rapid implementation 
of a global design change should widespread resistance to OSV occur during the course 
of the study.
If pre-defined criteria for widespread OSV resistance are met, OSV will be temporarily or 
permanently discontinued.  Antivirals that are recommended at the time of OSV 
resistance will be provided as open-label treatment, and enrollment in the study will 
continue. The criteria for implementation of this study design change are:

Evidence of substantial OSV resistance in circulating influenza viruses in 
participating countries in the relevant geographic areas reported by World Health 
Organization (WHO) or Centers for Disease Control (CDC), defined as 20% 
resistance in total of all circulating strains (e.g. 50% resistance in Pandemic 
Influenza A (H1N1) viruses which constitutes 20% of circulating strains), OR

WHO or CDC recommend against treatment with single agent OSV.
In the absence of recommendations from WHO or CDC, other national health agencies in 
participating countries may recommend against treatment with single agent OSV for 
influenza treatment based on resistance patterns within a specific geographical area or 
country, or medical consensus. In these situations, a decision on whether to put 
enrollment on temporary hold at impacted site(s) should be made by investigators in 
consultation with local institutional review boards or ethics committees (IRB/IECs) and 
regulatory authorities.
While rapid diagnostic tests are not widely available to determine influenza strain or 
resistance, some study sites will have access to local laboratories with these capabilities 
that could allow appropriate subjects to continue to be enrolled.
The OSV arm may be re-instated if the level of OSV resistance diminishes below the 
criteria defined in the protocol, and if it is appropriate to do so, based on predicted 
patterns of circulating influenza strains.
4.2.
Treatment Arms and Duration
Subjects will be randomized in a 2:2:1 ratio to receive:

15 mg FBE IV DNX BID +75 mg OSV BID; 

50 mg FBE IV DNX BID + 75 mg OSV BID;  or 

IV DNX placebo BID + 75 mg OSV BID
Treatment duration will be up to 5 days (Figure 2). The investigator may elect to 
continue open-label oseltamivir treatment.  If a subject is discharged from the hospital in 
less than 5 days, treatment with IV DNX will discontinue, irrespective of whether the 
investigator elects to continue oral OSV treatment at discharge. Follow up will continue 
until Day 45 for all subjects.


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Figure 2
Study Schematic
Day 1
Day 5
N=300
2:2:1 
Randomization
15 mg FBE IV DNX
+
75 mg oral OSV
IV DNX Placebo
+
75 mg oral OSV
50 mg FBE IV DNX
+
75 mg oral OSV
Randomized Treatment Period
Inpatient 
(daily visits up to 5 days)
PT 
Day 3
P-D visits/TCs  
For  Outpatients
PT- daily visits up to Day 45
For Inpatients
Day 8
Day 15
Day 22
Day 30
Day 45
PT : Post–Treatment  Assessments for inpatients
P-D: Post-Discharge Visits/Telephone Contacts for outpatients
Clinic Visits
Telephone Contacts
Inpatient Assessments
4.3.
Type and Number of Subjects
The study will recruit adult patients with influenza infection requiring hospitalization. 
Influenza patients with conditions of respiratory failure requiring mechanical ventilation, 
chronic kidney disease, acute renal failure, sepsis, or hemodynamic instability are 
considered a more severe population.
For the purposes of safety monitoring, the definitions below will be used.
Less severe hospitalized subjects are those who (but not limited to):

are hemodynamically stable;

may require oxygenation with facemask, facetent, nasal canula, etc;

may or may not have radiological signs of lower respiratory tract disease; or

may have exacerbation of underlying chronic disease, including asthma, chronic 
obstructive pulmonary disease (COPD), or other cardiovascular conditions not leading to 
hemodynamic compromise.


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Critically ill hospitalized subjects are those who (but not limited to):

require CPAP (i.e. new use for respiratory distress and not for chronic purposes such 
as sleep apnea), BIPAP,  mechanical ventilation;

have hemodynamic instability (with or without pressor support); or

have central nervous system involvement (eg encephalopathy, encephalitis).
A maximum of 300 subjects are planned to be enrolled in the study, depending on study 
dose changes implemented after each of two planned interim analyses.  The first interim 
analyses will occur after the first flu season if there are more than 75 subjects enrolled. 
Additional interim analyses may be performed after approximately 50-66% of subjects 
have been enrolled. Completion of enrolment in this study is expected to take multiple
influenza seasons in the case of no early stopping for futility or success, with a total 
enrollment of approximately 300 subjects.
4.4.
Design Justification
This will be the first study conducted with DNX in the hospitalized influenza population.  
As such the study design includes stepwise enrolment of sentinel cohorts with more 
stringent eligibility criteria as well as enhanced safety monitoring to assess the safety and 
tolerability of DNX.  Following acceptable outcomes from IDMC reviews, additional 
subjects will be enrolled in the study.
The IV formulation of the HBr salt of DNX has been developed as treatment in this 
study, because parenteral administration would be a preferred mode of delivery in this 
hospitalized population. 
All treatment groups in this study will receive open-label OSV, one of the recommended 
antiviral treatments for this population hospitalized for influenza [CDC, 2011; WHO, 
2010]. One treatment group will receive matching IV DNX placebo as a double-blind 
control, while receiving open label OSV. 
The primary composite endpoint of Time to Clinical Resolution (TTCR) was considered 
following guidelines developed by the Food and Drug Administration (FDA) for 
treatment of seriously ill hospitalized patients with influenza. While efficacy endpoints 
have not been definitively validated for all types of influenza trials, TTCR incorporates 
FDA guidance for inclusion of clinical signs and symptoms [FDA Guidance for Industry, 
2011].
A key efficacy endpoint for this study is Time to Respiratory Resolution (TTRR) and is 
being evaluated as a secondary endpoint. Because DNX’s mechanism of action is 
expected to be predominantly localized to the lung, TTRR will be analyzed to assess if it 
is a more relevant physiological measure. In this first study with DNX (co-administered 
with OSV) in hospitalized influenza, safety assessments are also a key secondary 
endpoint.
In alignment with the mechanism of action of DNX as an anti-inflammatory agent, which 
impacts the host response and not as a direct-acting antiviral, virologic endpoints are 


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being evaluated as exploratory endpoints. Additional exploratory endpoints include
biomarkers (important in influenza infection and to demonstrate target effect) and health 
outcomes. 
4.5.
Dose Justification
Two doses of DNX are proposed for evaluation in this study. The proposed doses are 15 
mg and 50 mg FBE, administered twice daily as a 1 hour IV infusion. 
The doses for investigation are within the clinical experience of IV DNX in healthy 
subjects. Clinical exposure limits will be based upon NOAEL/2 for testicular toxicity, 
aligned with written responses received from the United States (US) FDA’s Division of 
Pulmonary, Allergy, and Rheumatology Products in July 2013 for GSK’s development of 
DNX in COPD. The projected systemic exposures for both of the selected doses in 
DAHLIA fall below the NOAEL/2 exposure for testicular toxicity. In Study 201022 
(safety, tolerability and pharmacokinetics study in healthy subjects), DNX administered 
as the FB formulation was well tolerated and had an acceptable safety profile, as single 
doses of 10 mg (1h infusion), 25 mg (1h infusion) and 100 mg (2h infusion) and as twice 
daily repeat doses of 25 mg and 50 mg IV infusions (given over 1 hour) for 5 days 
(Section 5.3.1, DNX Investigator’s Brochure). When DNX was administered as the FB 
tablet in Study 201682 (acute uncomplicated influenza subjects), no safety concerns were 
identified.
In Figure 3 the projected DNX concentration-time profile at steady-state for the proposed 
IV doses is shown with overlay of IC50 and IC90 for the sigmoidal 
PK/pharmacodynamic (PD) relationship between blood concentrations of DNX and their 
effect on C-X-C chemokine ligand (CXCL)-1 induced CD11b activated neutrophil levels 
in ex vivo blood samples (direct surrogate for CXCR2 antagonism) observed for healthy 
subject data pooled from Studies CX3112483 and CX3114922 (Table 4; DNX 
Investigator’s Brochure Section 5.2.6). The data demonstrate that projected DNX levels 
for 15 mg and 50 mg exceed the IC90 (707 ng/mL) value for on average 1 and 4 hours 
respectively over the dosing interval. The projected DNX blood concentrations averaged 
over the 12 hour dosing interval will achieve concentrations in the region of IC70 and 
IC90, and at trough IC40 and IC70 for 15 mg and 50 mg respectively. A level of 50-70% 
CXCL1-induced CD11b expression has been associated with reduction of migration of 
neutrophils into the lungs in preclinical inflammation models and in human experimental 
medicine ozone challenge studies with a related CXCR2 antagonist, elubrixin (SB-
656933) [Lazaar, 2011]. 


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Figure 3
Projected Steady-state Concentration-Time Profile Over a Dosing 
Interval for IV DNX DNX-HBr FBE 15mg and 50mg with Overlay of 
IC50 and IC90 for CXCL-1-induced CD11b-activated Neutrophil 
Levels in Ex Vivo Blood Samples by DNX
NOTE: solid line=median population prediction; dashed lines=90% prediction interval;  Projected DNX levels derived 
from a PK model defined for the IV data from Study 201022 (healthy subject PK study), where steady-state is projected 
to be reached within 3 days of repeat BID dosing, with minimal accumulation.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DNX
can be found in the Investigator’s Brochure.  The following section outlines the risk 
assessment and mitigation strategy for this protocol:  


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK 1325756
Reduction in Peripheral Blood Neutrophils
Peripheral neutropenia has been reported in 
clinical trials of other irreversible CXCR2 
antagonists MK-7123 [Seiberling, 2013], 
SCH527123 [Nair, 2012] and AZD5069 [Kirsten, 
2015]. Reduction in peripheral blood neutrophils 
may occur after a single dose. Peripheral blood 
neutrophils return to baseline approximately 24 
to 48 hours after withdrawal of the CXCR2 
antagonist.
Refer to the Time and Events Table (Section 7.1) 
for neutrophil monitoring. Peripheral blood 
neutrophil count of <1.0 x Gi/L is an exclusion 
criterion. Also, any subject that has a peripheral 
blood neutrophil count of <0.5 × Gi/L at two 
successive measures, will be withdrawn from IP 
and monitored until the neutrophil count returns 
to pre-dose levels.
Infection Risk
Neutrophils are an important component of host 
defense and innate immunity. Inhibition of 
neutrophil migration and activation could impact 
host defense and innate immunity and increase 
the risk of bacterial super- infection or worsening 
influenza virus-mediated disease..
Nonclinical studies in mice and ferrets with two 
CXCR2 antagonists in the same chemical class 
as DNX have not shown an increase in influenza 
viral load [GSK Document Number 
YM2010/00163/07] Secondary bacterial 
infections after viral infection have not been 
directly evaluated in nonclinical studies.
The site will monitor adverse events, 
complications of influenza (such as pneumonias 
[bacterial, ventilator, hospitalized and 
community], pneumothorax, pleural effusion, 
ARDS, myositis, encephalitis, myocarditis, 
bacterial bronchitis, otitis media, sepsis, sinusitis, 
bacteremia) and frequency of new associated 
antibiotic use and clinical symptoms of subjects 
during treatment and post-treatment. Also chest 
x-ray will be obtained at baseline for clinical 
comparison throughout treatment.
Subjects will be discontinued from IP if develop 
significant worsening of symptoms or strong 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
suspicion or confirmation of progressive 
secondary bacterial infections or require 
antibiotics.  In addition, the study has halting 
criteria that are part of the IDMC review.
Testicular Effects and Male Fertility
Testicular effects were observed in preclinical 
studies in mice, rats and dogs. Findings in rats at 
≥150 mg/kg/day DNX or 500 mg/kg/day DNX 
HBr and dogs at 30 mg/kg/day DNX included 
spermatid degeneration, seminiferous tubular 
degeneration and secondary epididymal changes 
after 4 weeks of dosing with irreversible 
seminiferous tubule degeneration with oedema 
and atrophy following 26 weeks of dosing in rats. 
The male rat fertility study showed that the male 
rat fertility and gonadal function were affected 
without affecting libido or mating performance. 
No male-mediated fatal developmental toxicity 
was observed after 8 or 63 days of dosing.
No adverse events related to testicular effects 
have been reported in clinical studies dosed up 
to 6 months to date. Short duration of treatment 
(5 days) in this study is considered to have low 
risk of the testicular effects.
Systemic exposure margins for the NOAEL for 
reproductive effects in male rats are 15- and 50-
fold from the projected mean clinical systemic 
exposure (AUC) at a clinical BID dose of 15 mg 
DNX FBE and 50 mg DNX FBE, respectively,
every twelve hours. 
Systemic exposure margins for the NOAEL for 
potential male-mediated developmental toxicity 
in rats are 57- and 191-fold from the projected 
mean systemic clinical exposure (AUC) at a 
clinical dose of 15 mg DNX FBE and 50 mg DNX 
FBE, respectively, every twelve hours. 
Systemic exposure margins for the NOAEL/2 for 
testicular effects in the 26 week rat toxicity study 
are 4- and 12-fold from the projected mean 
clinical systemic exposure (AUC) at a clinical BID 
dose of 15 mg DNX FBE and 50 mg DNX FBE, 
respectively, every twelve hours.
For the short duration of treatment, this is 
considered sufficient to support the proposed 
clinical dosing regimen.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Renal Risk
The IV formulation of DNX contains Captisol that 
is renally cleared and has a potential for 
accumulation in renally impaired patients.
Healthy volunteers have been dosed in a phase 
1 study with an IV DNX formulation containing 
higher concentrations of Captisol with no safety 
concerns.
The study has intensive renal monitoring and 
stepwise inclusion of subjects with normal renal 
function followed by subjects with mild and then 
moderate renal impairment after review by an 
IDMC.  The IDMC will include an ad hoc 
nephrologist member if there are 10 subjects 
across all treatment arms withdrawn due to the 
renal stopping criteria or if renal expertise is 
needed.   
Subjects with CrCl <30 mL/min will be excluded 
from the study.
At the current doses, the Captisol concentrations 
in subjects with CrCl >30 mL/min are predicted to 
be below that obtained clinically with marketed 
Captisol containing IV voriconazole.


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4.6.1.1.
Oseltamivir Risk Assessment
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information is available in the local product label for oseltamivir.
Currently, there are no drugs that have demonstrated clinical efficacy in randomized 
clinical trials in the hospitalized influenza population.  Twice daily 75 mg OSV is 
approved for treatment of uncomplicated acute influenza and is recommended for
treatment in the hospitalized population, in the Infectious Diseases Society of America 
guidelines [Harper, 2009], guidelines from Centers for Disease Control and Prevention 
[CDC, 2011] and World Health Organization [WHO, 2010]. In the on-going Study 
201682, oral 75 mg DNX and 75 mg OSV were co-administered to subjects with 
uncomplicated influenza, with no safety concerns identified to date.
4.6.2.
Benefit Assessment
Currently, there is an unmet medical need for more effective treatments of viral lower 
respiratory tract infections (LRTI) requiring hospitalization. This study will provide an 
opportunity to determine if an anti-inflammatory drug with a novel mode of action may 
offer clinical benefit for the treatment of hospitalized influenza.  This study follows an 
ongoing study of DNX alone or in combination with OSV in subjects with acute, 
uncomplicated influenza where no concerns have been identified to date.
In Phase I clinical trials to date and also in a phase IIa study in subjects with mild 
influenza who had co-administered OSV, all AEs (e.g. the most commonly observed AEs 
are headache and diarrhea) were mild-to-moderate in intensity in healthy subjects. In this 
study, the efficacy and safety of DNX co-administered with OSV will be evaluated in 
subjects hospitalized for influenza infections. 
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to patients participating in this 
Phase II clinical trial, the potential risks identified in association with GSK1325756/DNX 
are justified by the anticipated benefits that may be afforded to patients with severe viral 
respiratory tract infections.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigator’s Brochure 
2016; and oseltamivir prescribing information.
Written informed consent must be obtained from each potentially eligible subject or by 
an LAR for subjects who are incapable of consenting themselves such as those who are 
unconscious or due to their medical condition (e.g. too weak or debilitated, severe 
shortness of breath), prior to the initiation of any study procedures as outlined in this 
protocol.  The consent form must have been approved by the Institutional Review 


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Board/Independent Ethics Committee (IRB/IEC).  After signing an informed consent, 
subjects will complete assessments to determine subject eligibility. Each subject being 
evaluated for study enrollment will be assigned a subject number.  This number will be 
given sequentially in chronological order of subject presentation according to a numeric 
roster provided by GSK.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Adults 18 years (as per local laws) of age and older at the time of signing the 
informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2.
Presence of fever (38.0C [100.4F] by any route) at Baseline (enrollment) or 
history of fever/feverishness during the 48 hours prior.
3.
O2 saturation <95% on room air by trans-cutaneous method OR need for any 
supplemental oxygenation (non-invasive ventilation, facemask, facetent, nasal 
canula, etc) or ventilator support (mechanical ventilation, bi-level positive airway 
pressure [BIPAP], continuous positive airway pressure [CPAP]) or increase in 
oxygen supplementation requirement of 2 liters for subjects with chronic oxygen 
dependency.  For those subjects with a history of chronic hypoxia (without 
supplemental oxygen), an oxygen saturation of at least 3% below the subject’s 
historical baseline oxygen saturation.
AND AT LEAST 2 out of the following 3:

Respiratory rate >24 breaths per minute. For those subjects who require 
ventilator support or oxygen supplementation, this requirement is waived.

Heart rate >100 bpm

Systolic bp <90 mm Hg.
4.
Severity of symptoms at enrollment: 

Less severe hospitalized subjects are those who (but not limited to):

are hemodynamically stable;

may require oxygenation with facemask, facetent, nasal canula, etc;

may or may not have radiological signs of lower respiratory tract disease; or

have exacerbation of underlying chronic disease, including asthma, chronic 


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obstructive pulmonary disease (COPD), or other cardiovascular conditions not 
leading to hemodynamic compromise.

Critically ill hospitalized subjects are those who (but not limited to):

require CPAP, BIPAP, mechanical ventilation;

have hemodynamic instability (with or without pressor support); or

have central nervous system involvement (eg encephalopathy, encephalitis).
5.
Presence of influenza that in the Investigator’s judgment requires hospitalization for 
treatment and supportive care
6.
Onset of influenza symptoms within 6 days prior to study enrolment. Symptoms may 
include cough, dyspnea, sore throat, feverishness, myalgias, headache, nasal 
symptoms (rhinorrhea, congestion), fatigue, diarrhea, nausea and vomiting.
7.
A positive result from a rapid influenza test (provided by GSK) or other available, 
local laboratory diagnostic test; 
8.
Baseline renal criteria as follows:
Sentinel Cohorts:

Normal renal function: Baseline creatinine clearance within normal reference 
ranges (80 mL/min) for the first approximately 30 subjects enrolled;

Mild renal impairment: Baseline creatinine clearance of 50-79 mL/min for the 
next approximately 10 subjects enrolled into the sentinel cohort;

Moderate renal impairment: Baseline creatinine clearance of 30-49 mL/min for 
the next approximately 10 subjects enrolled into the sentinel cohort.
Post-sentinel cohorts:

Normal renal function, mild or moderate renal impairment: creatinine clearance 
>30mL/min.
9.
Baseline Liver Function Tests as follows:
Liver parameter
ALT≤5xULN
ALT>5 and 8xULN
ALT>8xULN
Bilirubin ≤2x ULN
Include
Include only if bilirubin <1.5xULN
Exclude
Bilirubin >2x ULN
Exclude
Exclude
Exclude
SEX
10. Male or Female subjects could be eligible if :
Males:
Male subjects with female partners of child bearing potential must comply with the 


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following contraception requirements from the time of first dose of study medication 
until at least 36 hours (five half-lives) after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
b.
Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable 
cases a blood sample with simultaneous follicle stimulating hormone (FSH) and 
estradiol levels consistent with menopause (refer to laboratory reference ranges for 
confirmatory levels)].  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal 
status prior to study enrolment.
c.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 6 ) from the first dose of study 
medication until at least 36 hrs after the last dose of study medication and completion 


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of the PT Day 3 visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
11. Subjects willing and able to give written informed consent to participate in the study 
and to adhere to the procedures stated in the protocol OR Legally acceptable 
representative (LAR) willing and able to give written informed consent on behalf of 
the subject to participate in the study for unconscious adults, and those incapable of 
consenting themselves due to their medical condition (e.g. too weak or debilitated, 
severe shortness of breath), due to literacy issues or included as permitted by local 
regulatory authorities, IRB/IECs or local laws.
COUNTRY-SPECIFIC
12. French subjects: In France, a subject will be eligible for inclusion in this study only 
if either affiliated to or a beneficiary of a social security category.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Subjects who, in the opinion of the investigator, are not likely to survive the next 48 
hours beyond Baseline;
2. Immunosuppression, whether due to primary immunosuppressive conditions, such as
history of inherited immunodeficiency syndromes, HIV infection, or secondary 
conditions, such as immunosuppressive medication, stem cell or solid organ 
transplantation, or malignancy;
3. Documented current liver disease (including Hepatitis A, B, or C), or known hepatic 
or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones);
4. QTc Criteria: QTcB or QTcF >480 msec or >500 msec with bundle branch block;
5. For subjects enrolled in the sentinel cohorts: diabetes mellitus and chronic kidney 
disease;
6. Subjects who require dialysis, or are on renal replacement therapies;
7. Subjects who require extra corporeal membrane oxygenation (ECMO) at baseline 
(enrolled subjects who subsequently require ECMO may continue in the study)
8. Women who are pregnant as determined by a positive human chorionic 
gonadotrophin (hCG) ultrasensitive test prior to dosing or women who are 


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breastfeeding;
CONCOMITANT MEDICATIONS
9. Subjects who received other treatments for influenza including vitaglutam, 
umifenovir, and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) for 
more than 72 hours during current acute illness;
10. Subjects who received any immunoglobulins within 6 months of screening or planned 
administration of any of these products during the treatment period.
11. Subjects treated with cytotoxic or immunosuppressive drugs within six months of 
study enrolment.  Topical, intra-articularly injected, or inhaled glucocorticoids, 
topical calcineurin inhibitors or imiquimod are allowed.
RELEVANT HABITS
12. Known history of drug abuse within 6 months of study start.
CONTRAINDICATIONS 
13. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
14. Absolute neutrophil count <1.0 Gi/L
15. Subjects who have participated in a clinical trial using an investigational product 
within the following time period prior to the first dosing day in the current study: 30 
days, 5 half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer).


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5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
5.4.
Withdrawal/Stopping Criteria
A subject is considered to be withdrawn prematurely from the study if they do not 
complete the Day 45 Visit.
Criteria for premature study withdrawal include:

Adverse event

protocol deviation

non-compliance

subject lost to follow up

subject withdraws consent

investigator discretion

sponsor terminates the study
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and if necessary a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 


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5.4.1.
Premature Discontinuation of Investigational Product
A subject is considered to have prematurely discontinued investigational product (IP) if 
they have not completed 5 days of randomized treatment (not applicable for subjects 
discharged from the hospital due to symptom improvement). 
If a subject is prematurely discontinued from IP, the investigator must make every effort 
to perform all the remaining study visits as described in the Time and Events Table, 
including the final Day 45 Visit.
5.4.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
If any of the stopping criteria for parameters below are observed and confirmed, cessation 
of drug dosing and further evaluations will be instituted.
Liver Parameter
ALT ≤10xULN
ALT >10xULN
Bilirubin ≤2xULN
Continue
Discontinue IP
Bilirubin >2xULN
(>35% direct)
Discontinue IP if ALT 
>5xULN, report as an 
SAE
Discontinue IP, report as 
an SAE
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.3.
Corrected QT Interval (QTc) Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and withdrawal from the study.  This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for withdrawal of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety electrocardiograms (ECGs) and other non-
protocol specified ECGs are an exception.  


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
The QTc stopping criteria should be based on averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.
A subject who meets either of the bulleted criteria below will be permanently 
discontinued from IP:

QTc >530 msec 

Increase in QTcF or QTcB by more than 60 msec compared to baseline on two 
separate ECG tracings.
5.4.4.
Other Stopping Criteria
Subjects should be permanently discontinued from IP if any of the following conditions 
are met:

Serum creatinine: 0.5 mg/dL increase from baseline, on 2 successive readings;

eGFR of <60 on two consecutive readings using the CKD-EPI calculation (eGFR of 
<30 for moderate renal impairment);

Peripheral neutropenia: absolute neutrophil counts <0.5 Gi/L on 2 successive 
assessments.
5.5.
Subject and Study Completion
A completed subject is one who has completed the Day 45 Assessment.
The end of the study is defined as the last scheduled procedure shown in the Schedule of 
Activities for the last participant in the trial globally. 
Completion of the trial globally is required in order to provide sufficient subjects as 
defined in Section 9.2, Sample Size Considerations.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.


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Table 1
Characteristics of Study Treatments
Study Treatment
Product name:
danirixin
GSK1325756
Placebo1
Oseltamivir2
Formulation 
description:
A  sterile 
lyophilized powder
containing 
GSK1325756H 
(hydrobromide 
salt hemihydrate) 
equivalent to 
50mg of free base 
along with Beta-
cyclodextrin 
sulfobutylether 
(Captisol ), 
mannitol, citric 
acid and sodium 
hydroxide
Capsule: Grey/light yellow 
containing pregelatinized 
starch, talc, povidone K30, 
croscarmellose sodium, 
and sodium stearyl 
fumarate
Oral suspension: sorbitol, 
monosodium citrate, 
xanthan gum, titanium 
dioxide, tutti-frutti flavoring, 
sodium benzoate, 
saccharin sodium and 
water.
Dosage form:
Infusion
Infusion1
Capsules2
Unit dose 
strength(s)/Dosage 
level(s):
15 mg FBE; 50 
mg FBE
N/A
75 mg
Route of Administration
For IV infusion
For IV infusion
Oral
Dosing instructions:
250 mL infusion
250 mL infusion
Dosing as per Prescribing 
Instructions
Physical description:
lyophilized 
powder/cake 
contained in a 
30mL vial. 
Clear solution
Capsules: grey/light yellow 
hard gelatin capsules. 
“ROCHE” is printed in blue 
ink on the grey body and 
“75 mg” is printed in blue 
ink on the light yellow cap.
For Oral Suspension: 
Supplied as a white 
powder blend in a glass 
bottle. 


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Study Treatment
Product name:
danirixin
GSK1325756
Placebo1
Oseltamivir2
Method for 
individualizing dosage:
Each vial is 
reconstituted with 
9.5 mL water for 
injection and 
further diluted with 
saline for IV 
infusion
Saline for IV 
infusion1
Capsules.  Available in 
blister packages of 10
Oral Suspension: After 
constitution, the powder 
blend produces a white 
tutti-frutti–flavored oral 
suspension. After 
constitution with 55 mL of 
water, each bottle delivers 
a usable volume of 60 mL 
of oral suspension 
equivalent to 360 mg 
oseltamivir base (6 
mg/mL). 
1
No vials of placebo to match IV DNX will be provided. A normal saline solution of matched 
volume will be prepared by unblinded personnel at the site to act as a placebo to DNX.
2
No oseltamivir capsules or powder for oral suspension will be provided. Sites will source 
the OSV locally and it will be provided open-label. OSV is manufactured by Roche 
Pharmaceuticals.
6.1.1.
IV IP and OSV Administration
6.1.1.1.
Preparation of IV IP for Infusion
Unblinded personnel should prepare the IV IP infusion (DNX or matching PBO.  
Complete details on preparation of IV DNX will be provided in the pharmacy manual.  
The unblinded personnel should prepare a normal saline (0.9% sodium chloride) infusion 
for placebo to match IV DNX.
6.1.1.2.
Preparation of OSV at the site
Details on preparation of oral suspension if needed for patients who are unable to 
swallow the capsules are available in the manufacturers prescribing information.
6.1.1.3.
Administration of IV IP
IP infusion should be administered at a constant rate over approximately 1 hour (e.g. at 
an infusion rate of 250 mL/hour for a 250 mL infusion volume). Infusions should be 
given approximately 12 hours apart. If the first infusion of the day is administered after 
12 noon, the next dose should be administered the following morning.


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6.1.1.4.
Administration of OSV
OSV dose is 75 mg to be administered twice daily for subjects who are able to swallow 
intact capsules.  Dose adjustments of OSV (ie renal dosing) may be made as indicated in 
the prescribing information.  For subjects unable to swallow intact capsules, qualified 
personnel may compound the appropriate dose of oseltamivir by opening capsules and 
pouring the contents of the capsules into a suitable small amount of sweetened food 
product such as sugar water, chocolate syrup, cherry syrup, dessert toppings to mask the 
bitter taste. The mixture should be stirred and the entire contents given to the subject.
The mixture must be swallowed immediately after its preparation [Tamiflu SPC, 2010].
Alternatively, the contents of the capsules can be made into suspension as per Tamiflu 
Prescribing Information or standard site procedures for administration via mouth, 
nasogastric, nasojejunal or gastrostomy tube. If the first dose of the day is administered 
after 12 noon, the next dose should be administered the following morning.
6.2.
Treatment Assignment
Study treatment in this protocol refers to the blinded investigational drug IV DNX, IV 
DNX placebo and the open label oral OSV. Subjects will be assigned to 15 mg FBE IV 
DNX, 50 mg FBE IV DNX or IV DNX Placebo, in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
A description of each regimen is provided in the table below:
Table 2
Treatment Regimens for Study 201023/DAHLIA
Treatment 
Arm
Sample Size per influenza 
season / study (3 infuenza 
seasons)
Treatment Label
Treatment Regimena
A
40/120
15 mg FBE DNX
15 mg FBE IV DNX given twice 
daily with 75 mg oral OSV given 
twice daily
B
40/120
50 mg FBE DNX
50 mg FBE IV DNX given twice 
daily with 75 mg oral OSV given 
twice daily
C
20/60
PBO
IV DNX placebo given twice 
daily with 75 mg oral OSV given 
twice daily
a.
OSV dose adjustments may be made as indicated in the prescribing information.
Subjects will be randomized using the RAMOS NG system. This system will be used by 
the investigator or designee to register the subject. 
Details of how to use the RAMOS NG system to register and randomize subjects is 
provided in the study reference manual (SRM).


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Subjects meeting all eligibility criteria will be randomized 2:2:1 to one of three treatment
groups in accordance with the central randomization schedule generated by Clinical 
Statistics prior to the start of the study, using validated internal software. Minimization 
criteria will be based on influenza medication prior to hospitalization (Relenza, Tamiflu, 
peramivir or other), number of days of symptoms prior to hospitalization (0-3, 4-6), 
subject origin prior to hospitalization (nursing home, rehabilitation unit, home).
All randomized subjects will take investigational drug or matching placebo twice daily 
for up to 5 days in the hospital. 
Once a randomization number has been assigned, it must not be re-assigned. 
6.3.
Planned Dose Adjustments
No pre-specified dose adjustments are planned in the first influenza season. Dose 
adjustments of OSV may be made as indicated in the prescribing information.  Samples 
taken for PK analysis are planned to be analyzed during the study. Following the 
availability of the PK results sites will be informed if any dosing changes are to be made.  
Dose adjustments may also be determined following the IDMC review of safety data. 
Further details will be provided in the IDMC charter.
6.4.
Blinding
This will be a double-blind study for the investigational product and both study staff and 
the subject will remain blinded to the investigational treatment.  However, there will be 
qualified personnel at each study site who will be unblinded to allow preparation of study
medication. Unblinding of GSK to the aggregated summary results by treatment group of 
the interim analyses is addressed in the IDMC charter.
The GSK team members will not have access to subject specific treatment assignment so 
as to not potentially introduce bias in discussions with the study center.
During the blinded randomized treatment period, subjects will receive an intravenous 
infusion (DNX or placebo) twice daily plus open label OSV oral therapy twice daily.

IV infusion: Unblinded personnel will prepare an IV infusion of active DNX (15 
mg FBE or 50 mg FBE) or normal saline infusion for each subject twice daily.

Oral therapy: Qualified personnel will prepare the open-label oral oseltamivir 
therapy for each subject twice daily.

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition when 
knowledge of the study treatment is essential for the appropriate clinical management or 
welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding the 
subject’s treatment assignment. 


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
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the safety of 
subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the case report 
form (CRF).
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to investigators in accordance 
with local regulations and/or GSK policy.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of 15 mg FBE IV 
DNX, 50 mg FBE IV DNX and IV DNX placebo will be detailed in a Study Specific 
Technical Agreement/Memo (TTS) or Pharmacy Manual which will be accompanied by 
a Quality Agreement.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be stored 
in a secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 


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unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK
study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.7.
Compliance with Study Treatment Administration
Subjects will receive study treatment directly from the investigator or designee, under 
medical supervision.  The date and time of each dose administered in the clinic will be 
recorded in the source documents.  The study subject identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering 
the study treatment.
15 mg FBE DNX, 50 mg FBE DNX and DNX placebo will be intravenously 
administered to subjects at the site.  
Open label 75 mg OSV will be provided for oral administration by the investigator or 
designee to all subjects.
Administration will be documented in the source documents and reported in the CRF.
6.8.
Treatment of Study IP Overdose
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator or treating physician should:

contact the Medical Monitor immediately

closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until IP can no longer be detected 
systemically (at least 3 days for IP)

obtain a blood sample for pharmacokinetic (PK) analysis within 48 hours from 
the date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).  PK sample may not be required for 
subjects known to be receiving placebo or non-GSK comparator treatments. 
Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw on the eCRF. If the date or 
time of the last dose is unclear, provide the subject’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. 
Instructions for sample handling and shipping are in the SRM.

document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.


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6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because currently the investigational medication is for acute treatment in the 
hospital and this is the first study evaluating efficacy and safety of IV DNX in subjects 
hospitalized for influenza.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Dietary Restrictions

Subjects who use tobacco products will be allowed to take part, as long as they refrain 
from smoking for the duration of the hospitalization, but use of nicotine containing 
products will be recorded;

Subjects should abstain from consuming alcohol for the duration of hospitalization.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
In general, concomitant medications (prescription and non-prescription) will be permitted 
during the study at the investigator’s discretion (except for prohibited medications 
described in Section 6.11.2) and should be administered only as medically necessary 
during the study. All concomitant medications taken during the study will be recorded in 
the eCRF. The minimum requirement is that the drug name, dates and times of 
administration are to be recorded.
6.11.2.
Prohibited Medications and Non-Drug Therapies
The only approved antiviral drug permitted during the study is 75 mg OSV. All other 
approved or investigational influenza antiviral drugs are not permitted during the study 
(i.e. zanamivir, peramivir, laninamivir, amantadine, rimantadine, ribavirin, vitaglutam, 
umifenovir).
Immunosuppressive medications are prohibited during the treatment period including but 
not limited to rituximab, alkylating agents such as cyclophosphamide, nitrosoureas, 
platinum compounds; purine analogs such as fluorouracil; cytotoxic antibiotics such as 
dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin. 
Immunoglobulins are prohibited during the treatment period.


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, biomarker or virological assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer 
to the time of peak plasma concentrations) to ensure appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study
for study assessments, including any extra study assessments that may be 
required.


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7.1.
Time and Events Table
Table 3
Time and Events Table: Assessments at Baseline and During Treatment
Eligibility 
Assessments
During Treatment - 5 daysa
Inpatient
Post-
treatment 
(PT)
Inpatient
Procedures
Baseline/
Study Day 1a
Study Day 2
Study Day 3
Study Day 4
Study Day 5 /day 
of last dosea
Study Day 6 if 
applicableb
Written informed consent
X
X
Subject demography
X
X
Physical examinationc
X
X
X
X
X
X
Daily
Influenza Test – locally performed 
(equipment provided by GSK)
X
X
Medical/Prior Medication/Drug/Smoking 
History
X
X
HIV and Liver Disease Historyd
X
X
Influenza symptomse
X
X
HIV, Hep B and Hep C Testf
X
X
Chronic underlying illness assessment
X
X
Inclusion/Exclusion Criteria
X
Safety/Efficacy Assessments
Chest X-rayg
X
ECGh
X
X
X
X
Adverse events
X
X
X
X
X
X
Daily
Concomitant medicationsi
X
X
X
X
X
X
Daily
Complications of influenza/associated 
antibiotic usej
X
X
X
X
X
X
Daily
Vital signs (temperature, HR, BP, 
respiratory rate, oxygen saturation, 
ventilation status)k
X
X
X
X
X
X
X
3 x Daily
Flu PRO
X
X
X
X
X
X
Daily
Katz Activities of Daily Livingl
X
X
X
X
X
X
Daily
Activity levelm
X
X
X
X
X
X
Daily
Laboratory Assessments


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Eligibility 
Assessments
During Treatment - 5 daysa
Inpatient
Post-
treatment 
(PT)
Inpatient
Procedures
Baseline/
Study Day 1a
Study Day 2
Study Day 3
Study Day 4
Study Day 5 /day 
of last dosea
Study Day 6 if 
applicableb
Chemistry including Liver Function 
Tests (Local+Central)n
X
X
X
X
X
Day 6,7,8
Serum creatinine (Local+Central) o
X
X
X
X
X
X
X
Day 6,7,8
Hematology (Local+Central) p
X
X
X
X
X
Day 6,7,8
Urine Output q
X
X
X
X
X
X
Pregnancy testr
X
X
PT Day 3
Nasopharyngeal swabs
X
X
X
X
Day 
8,12,16,20,24,
28,32
Nasal Swabt
X
X
BALu
X
X
X
X
Endotracheal aspiratev
X
X
X
X
Day 
8,16,24,32, 45
Nasal SAM strips (biomarkers)w
X
X
X
X
Day 
8,16,24,32, 
discharge or 
Day 45
Nasal washesx
X
X
X
X
Day 
8,16,24,32, 
discharge or 
Day 45
Exploratory Biomarkers (Blood Sample)
X
X
X
X
Day 
8,16,24,32, 
discharge or 
Day 45
PK sample (Dried Blood Spot)y
X
X
X
X
Genetics Sample (Blood Sample)z
X
Transcriptomics (Blood Sample)z
X
X
X
X
Day 8, 16, 24, 
32, discharge 
or Day 45


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Eligibility 
Assessments
During Treatment - 5 daysa
Inpatient
Post-
treatment 
(PT)
Inpatient
Procedures
Baseline/
Study Day 1a
Study Day 2
Study Day 3
Study Day 4
Study Day 5 /day 
of last dosea
Study Day 6 if 
applicableb
Study Treatments
Administration of investigational 
medication (IV) and oseltamivir (oral) 
twice daily
X
X
X
X
X
X
a.
A ‘Day’ is defined as a 24 hour period (Treatment Day), therefore depending on the start time of the first dose of IV DNX, a Treatment Day may span two calendar days.
b.
Day 6 assessments only applicable if last day of dose of randomized treatment is on Day 6 (i.e for subjects who received first dose after 12 noon on Baseline/Day 1.
c.
Physical exam to be performed twice daily for subjects in the sentine cohort.
d.
Enrollment into the study will be based on history of diagnosis of HIV and liver disease. Blood samples will be analyzed after enrollment to retrospectively determine if subject is 
HIV, Hep B or Hep C postivie; however, results will not be available until after completion of dosing.
e.
Influenza symptoms to be assessed only at baseline for inclusion.
f.
Enrollment into the study will be based on any history of diagnosis of HIV and liver disease. 
g.
Chest X-ray at Baseline and whenever clinically indicated. 
h.
ECG: For the ECG on Baseline/Day 1, one 12-lead ECG (can be done within approximately 24 hours prior to dosing). At Baseline and on Day 5 or last treatment day, a monitoring 
strip can be utilized if a 12-lead ECG cannot be performed.
i.
Concomitant medications for influenza treatment of the current episode to be recorded from Day -7 (i.e. one week prior to baseline), if available.
j.
Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, ARDS, myositis, encephalitis, myocarditis, and associated antibiotic use will be recorded 
on all assessment days.
k.
Vital signs and ventilation status to be assessed three times daily during the treatment period between approximately 8 AM and 8 PM. 
l.
Katz ADL score collected once daily while hospitalized.
m.
Activity level to be recorded as one of three responses (bed rest, limited ambulation or unrestricted) everyday while hospitalized
n.
Chemistry panel including Liver Function Tests to be required once every other day during treatment (local testing (L) of LFTs for subject management as well as central 
laboratory testing (C)).
o.
Serum creatinine level required at Baseline and twice daily during treatment for subjects in the sentinel cohort. For all other subjects, serum creatinine level required at Baseline 
and once daily during treatment (local testing (L) for subject management as well as central testing(C)).  
p.
Hematology panel including CBC with differential required every other day during treatment (local testing (L) for subject management as well as central testing(C))
q.
Urine output to be measured twice daily for subjects in the sentinel cohort.
r.
Ultrasensitive urine or blood pregnancy test required in women of childbearing potential prior to dosing and 3 days post last dose of study treatment.
s.
Nasopharyngeal swab will be used for influenza Subtype RT-PCR, qRT-PCR, quantitative culture and may also be used for rapid influenza diagnosis; Will also be used for viral 
genotyping and phenotyping if needed and multiplex PCR assay.
t.
Nasal swab collected for influenza diagnostic test or other local test for influenza diagnosis


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u.
BAL samples (for biomarkers) are requested only if the procedure/sampling is being carried out for routine management of the patient and at any timepoint throughout the study
v.
Endotracheal aspirates (biomarkers/neutrophil counts) are required for subjects who are intubated.
w.
Nasal samples for biomarkers will be collected at the days indicated from all subjects using nasal SAM strips.
x.
An optional procedure, nasal wash, will be used to collect nasal samples from as many non-intubated subjects as feasible.
y.
PK samples will be drawn on Day 1 (pre-dose), Days 3 and 5 to coincide with PD measurements (nasal washes if done, endotracheal samples and a blood draw for exploratory 
biomarkers).  In sentinel cohort 1 (less severe subjeccts with normal renal function), PK samples will be additionally drawn on Day 3 at pre-dose, and 0.5, 1 (end of infusion), 
1.5, 2, 3, 4, 8 and 12 hours post-dose. Note: PK draws must be collected from the opposite arm from the infusion arm.
z.
Informed consent for optional substudies (e.g., genetic research and transcriptomics), must be obtained before collecting samples.  In subjects who consent, a blood sample for 
genetic research is collected at the baseline visit, or at the earliest point possible during the treatment period for genetic research testing; blood samples for transcriptomics 
are taken on each of the indicated days and used to evaluate changes in transcriptome profiles. 


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Table 4
Time and Events Table: Post-Treatment and Post-Discharge Assessments
Post-Discharge Visits/TCs and Assessments
Outpatient a
Procedures
PT Day 3 (Visit)
Study Day 8 
(TC)
Study Day 
15 (TC)
Study Day 22 (TC)
Study Day 30 
(TC)
Study Day 45 (Visit)
Safety/Efficacy Assessments
Adverse events
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Brief Physical Exam
X
X
Complications of influenza / associated 
antibiotic useb
X
X
X
X
X
X
Temperature 
X
X
X
X
X
X
Other Vital signs (HR, BP, respiratory rate, 
oxygen saturation, ventilation status)c
X
X
Flu PROd
Daily through Day 14
Daily through 
Day 14
X
X
X
X
Katz Activities of Daily Livinge
X
X
X
X
X
X
Activity levelf
Daily through Day 14
Daily through 
Day 14
X
X
X
X
Laboratory Assessments
Clinical chemistryincluding LFTsg 
(Local+Central)
X
X
Serum Creatinineh
(Local+Central)
X
X
Hematologyi
(Local+Central)
X
X
Pregnancy testj
X
Nasopharyngeal swabs
X
Exploratory Biomarkers (Blood Sample)k
X
X
Transcriptomics (blood sample)l
X
X
Nasal SAM strips (biomarkers)m
X
X
Nasal washesm
X
X
Hospital Readmission Status
X
X
X
X
X
X
a.
Following discharge from hospital, outpatient clinic visit/TC schedule of assessments will be followed for those patients who are discharged before Day 45.  For 5 days treatment, 
PT Day 3 will be the same as Day 8 and will be a clinic visit.


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b.
Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, ARDS, myositis, encephalitis, myocarditis, and associated antibiotic use will be recorded 
on all assessment days.
c.
Vital signs and ventilation status will be assessed at clinic visits (PT Day 3 and Day 45).
d.
FLU PRO to be measured once daily through Study Day 14.
e.
Activities of Daily Living (Katz Scale) to be done at clinic visits and at TCs. 
f.
Activity level assessed by reporting on a 3 point scale of bed rest (1), limited ambulation (2) or unrestricted (3) to be done daily through Study Day 14. 
g.
Clinical chemistry including LFTs to be required once every other day until PT Day 3 (for LFTs, local testing for subject management until PT Day 3; central testing for all 
assessments, including at Day 45).
h.
Serum creatinine required once every day until PT Day 3 (local testing for subject management until PT Day 3; central testing for all assessments, including at Day 45).
i.
Hematology panel including CBC with differential required once every other day until PT Day 3 (local testing for subject management until PT Day 3; central testing for all 
assessments, including at Day 45).
j.
Ultrasensitive urine pregnancy test required in women of childbearing potential on PT Day 3.
k.
Blood samples will be collected for exploratory biomarkers at PT Day 3, and at Study Day 45.
l.
Blood samples for transcriptomics will be collected on PT Day 3 and Study Day 45 and are optional. Samples will be collected only from those subjects who provide informed 
consent for genetic research.
m.
Nasal samples for biomarkers will be collected at PT Day 3 and Study Day 45 from all subjects using nasal SAM strips.  In addition, an optional procedure, nasal wash, will be 
used to collect nasal samples from as many non-intubated subjects as feasible.


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7.2.
Critical Baseline Assessments

Demographic parameters to be collected include: year of birth, sex, race and 
ethnicity. Date and primary reason of hospitalization (influenza or not influenza related) 
will be recorded and if applicable, the date of intubation.

Nasal swabs or nasopharyngeal sample will be taken for confirming an influenza 
infection. A rapid diagnostic influenza test will be provided by GSK or other local, 
validated laboratory test for influenza can be used. 

Vital signs to include temperature, heart rate, systolic and diastolic blood pressure, 
respiration rate, oxygen saturation. Oxygen delivery and ventilation status to be recorded 
approximately within approximately 1 hour prior to administration of the first dose of 
study medication;

Influenza symptoms will be assessed at baseline prior to administration of study 
treatments. The presence of the following symptoms will be recorded: nasal symptoms 
(rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, dyspnea, 
headache, sore throat, nausea and vomiting. The date of first onset of influenza like 
symptom(s) will also be recorded. The investigator or designee will assess and record 
influenza symptoms based on interview with the subject. In situations when subjects may 
not be able to communicate their symptoms, for example in subjects ventilated and/or 
sedated, the investigator or designee will record those signs/symptoms as ‘unable to 
assess’;

Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed 
at baseline.

Medical/medication/family history will be assessed as related to the
inclusion/exclusion criteria listed in Section 5.

Chronic underlying illness (including but not limited to asthma, COPD, diabetes, 
hypertension, Congestive Heart Failure) will be recorded.

Pre-morbid functional status (defined as the best functional status in the 4 weeks prior 
to enrolment) and status at Baseline as measured by the Katz ADL scale and activity 
level (bed rest, limited ambulation or unrestricted) will be recorded in the eCRF. For 
subjects unable to communicate their pre-morbid functional status, this information 
should be requested from another close member of the household, close family member, 
or the subject’s regular physician (if the subject has been under the care of a single 
physician for 3 months or longer).

Laboratory evaluations:

Samples for clinical chemistry and hematology will be collected for analysis at a
central laboratory (Table 7).

Samples for serum creatinine concentration, CBC with differential and liver 
function tests (LFTs) will also be obtained locally. The calculated creatinine
clearance value will be recorded in addition to the serum creatinine 
concentration. Absolute neutrophil counts (ANC) and LFTs will be recorded.


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
Nasopharyngeal swab to be collected prior to dosing for influenza subtype RT-
PCR, qRT-PCR, quantitative culture and viral phenotype and genotype analysis
and multiplex PCR. 

An endotracheal aspirate is requested only if the subject is intubated and a BAL 
sample is requested only if the procedure/sampling is being carried out for the 
routine management of the patient.  

Nasal Synthetic Absorption Matrix (SAM) strips will be used to collect samples 
from all subjects.  

An optional nasal wash procedure will be used for collecting samples and is 
requested from subjects who are not intubated; 

An ultrasensitive urine pregnancy test will be performed on women of 
childbearing potential;

ECG: One baseline 12-lead ECG is required within approximately 24 hours prior to
dosing. Any ECG that has been performed for clinical care can be utilized. A
monitoring strip can also be utilized if a 12-lead ECG cannot be performed.

Chest X-ray: Chest X-ray results (abnormal findings and normal findings) should be 
taken within 48 hours before the first dose of study medication and are to be recorded in 
the eCRF. 
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Baseline purposes provided the 
procedure meets the protocol-defined criteria and has been performed within the 
timeframe defined in the Time and Events Schedule.
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified.
Limited data will be collected on subjects who withdraw after providing informed 
consent but before initiation of treatment in the eCRF.
7.3.
Efficacy
Clinical, virological and health outcomes assessments will be conducted as described in 
the Time and Events Tables Table 3, Table 4, to evaluate endpoint detailed in Section
7.3.3, Section 7.3.4, Section 7.3.5.
7.3.1.
Primary Endpoint
The primary endpoint is time to clinical response (TTCR) (Table 5).
Clinical response is defined as resolution of at least 4 of the 5 signs described below 
within the respective resolution criteria, maintained for at least 24 hours, or hospital 
discharge, whichever comes first.


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Table 5
Criteria for Time to Clinical Response
Sign of clinical response
Response criteria
Hospital discharge
Subjects who are discharged from hospital will be considered to 
have met the clinical response endpoint at the time of hospital 
discharge and are not required to have documented resolution 
of at least 4 response criteria (i.e. achieved success at the time 
of discharge if not observed prior to it).
OR
Temperature1
≤36.6°C (≤97.9°F) – axilla, or
≤37.2°C (≤99°F) – oral, or
≤37.7°C (≤99.9°F) – rectal/core5, tympanic
AND
Oxygen saturation 2,3
≥95% (without supplemental oxygen)
AND 2 out of the following 3 criteria:
Respiratory status

Return to pre-morbid oxygen requirement (subjects 
with chronic oxygen use), OR

Need for supplemental oxygen (administered by any 
modality – ventilator, non-invasive ventilation, facemask, 
facetent, nasal canula, etc) to no need for supplemental 
oxygen, OR

Respiratory rate ≤24/min (without supplemental 
oxygen)
Heart rate
≤100/min
Systolic blood pressure4
≥90 mmHg
1.
Without the use of antipyretics within 8 hours
2.
A subject with a history of chronic hypoxia (without supplemental oxygen) will satisfy normalization criteria for 
oxygen saturation if the value (without supplemental oxygen) is ≤2% from subject’s historical oxygen saturation 
baseline as recorded within 12 months prior to enrolment as documented in the subject’s medical records.
3.
This requirement will be waived for subjects with a history of chronic supplemental oxygen requirement who have 
a baseline oxygen saturation <95% with supplemental oxygen, within 12 months prior to enrolment as 
documented in the subject’s medical records.
4.
Without inotropic support administered within 2 hours.
5.
Core temperatures include measurements via a temporal artery thermometer, indwelling catheters and Swan 
Ganz catheters.
7.3.2.
Secondary Efficacy Endpoints

Time to Respiratory Response (TTRR): TTRR is defined as meeting at least one 
criterion below:

Return to pre-morbid oxygen requirement (subjects with chronic oxygen use or 
ventilator support), OR 

Return to no requirement of supplemental oxygen, OR 

Respiratory rate ≤24/min (without supplemental oxygen)


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
Clinical measures of influenza illness will be evaluated as follows: 

Time to absence of fever

Time to improved oxygen saturation

Time to improved heart rate

Time to improved SBP

Proportion of subjects with clinical response over time

Proportion of subjects with improved respiratory status over time 

Time to improvement of ventilation status: modality and duration of invasive 
and non-invasive ventilator support, duration of oxygen supplementation.

Length of stay in the ICU

Frequency of ICU admission and readmission

Length of stay in the hospital

Rates of development of septic shock

Frequency of associated antibiotic use

Proportion of subjects with improvement in Ordinal scale of clinical efficacy 
over time: 
o
Death
o
Mechanical vent
o
In the ICU
o
Non-ICU hospitalization 
o
Hospital discharge
7.3.3.
Clinical Measures

Vital Signs and Respiratory Status:

Temperature, heart rate, systolic and diastolic blood pressure and respiration rate 
will be assessed three times daily during hospitalization between approximately 
8 AM to 8 PM. Three times daily assessments should be made at approximately 
the same time each day, morning, afternoon and evening, and at least 5 hours 
apart. Measurements will be made once at clinic visits post-discharge.

The following evaluations will be recorded for respiratory status: Oxygen 
saturation (by transcutaneous oximetry), modality and quantity of oxygen 
administration; duration of oxygen supplementation and method of support, with 
dates and times will be recorded for invasive methods such as BiPAP, CPAP
(i.e. new use in the hospital for respiratory distress and not for chronic use such 
as for sleep apnea), and mechanical ventilation; and for non-invasive methods 
such as nasal canula, facetent facemask etc. Respiratory status will be assessed 


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three times daily during hospitalization between approximately 8 AM to 8 PM, 
and once daily at clinic visits post-discharge. Three times daily assessments 
should be made at approximately the same time each day, morning, afternoon 
and evening, and at least 5 hours apart. 

Influenza symptoms: The presence and severity of influenza symptoms (nasal 
symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, 
diarrhea, dyspnea, headache, sore throat, nausea and vomiting) will be recorded 
once daily during hospitalization. The investigator or designee will assess and 
record influenza symptoms based on interview with the subject at approximately 
the same time each day. In situations when subjects may not be able to 
communicate their symptoms, for example in subjects ventilated and/or sedated, 
the investigator or designee will record those signs/symptoms as ‘unable to 
assess’.

Development of septic shock will be assessed by occurrence of hypotension 
requiring vasopressive therapy and serum lactate level >2 mM after adequate 
fluid resuscitation [Shankar-Hari, 2016; Seymour, 2016; Singer, 2016].  
Additional information will be provided in the SRM.

The number of days in the hospital, date and time of ICU admission and 
discharge, if applicable, and date and time of hospital discharge will also be 
recorded.
7.3.4.
Virologic Measures and Biomarker Sampling
Samples for virologic measures and biomarker sampling will be collected locally as in 
the Time and Events Tables (Section 7.1). These samples will include nasal swabs, 
nasopharygeal swabs, nasal samples (SAM strips and optional nasal washes), 
endotracheal aspirates (from intubated subjects), whole blood samples (ribonucleic acid 
[RNA] transcriptome analysis, deoxyribonucleic acid [DNA]), serum, and BAL samples 
from subjects where it is part of routine management.  When multiple respiratory samples 
are to be taken at any visit, samples will be collected in the following order (Table 6).


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Table 6
Sampling Order of Respiratory Samples for Virologic and Biomarker 
Assessments
Sequence 
of 
Collection
Sample Type
Study Day
(inpatients)
Outpatient 
Assessments
Number 
and 
location of 
samples
Purpose
1
Nasal swab or 
nasopharyngeal 
swab
Day 1 
N/A
Nare 1
Influenza 
diagnostic test
2
Nasal SAM
strips
Day 1, 3, 5, 
8, 16, 24, 32; 
also at 
discharge or 
Day 45
PT Day 3, Day 
45
Both nares
Biomarker 
analysis
3
Nasopharyngea
l swabs
Day 1, 3, 5, 
8, 12, 16, 20, 
24, 28, 32;
PT Day 3
Nare 2
Virology analysis
4
Nasal washa
Day 1, 3, 5, 
8, 16, 24, 32;
also at 
discharge or 
Day 45
PT Day 3, Day 
45
Both nares
Neutrophil 
counts/biomarker 
analyses
Endotracheal 
samplesb
Day 1, 3, 5, 
8, 16, 24, 32, 
45
N/A
ET aspirate
Neutrophil 
counts/biomarker 
analyses
a.
Requested from subjects who are not intubated (optional procedure).
b.
Required from subjects who are intubated.

Nasal swabs will be collected at baseline to confirm influenza infection with a rapid 
influenza diagnostic test provided by GSK or other local test.

Nasopharyngeal swabs will be collected for influenza Subtype RT-PCR, qRT-PCR, 
quantitative culture and may also be used for rapid influenza diagnosis. 
Nasopharyngeal samples will also be used for viral genotyping and phenotyping if 
needed and for multiplex PCR assay.

Endotracheal (ET) aspirates will be collected from subjects who are intubated. The 
endotracheal samples will be used for biomarker evaluation and neutrophil counts 
(Section 7.6).  

Nasal SAM strips will be used to collect nasal samples and will be used for biomarker 
evaluation.  


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7.3.5.
Health and Value Outcomes
Patient reported outcomes on intensity of influenza symptoms with the FluPRO [Powers
2016], impact of influenza on activities of daily living with the Katz ADL score [Katz
1970; Katz, 1983] and activity level (3 point scale –bed-rest, ambulatory, unrestricted), 
will be assessed with questionnaires during hospitalization and following discharge from 
the hospital. Readmission rates will be determined for discharged subjects who are 
readmitted to the hospital by Study Day 45.
The FluPRO, the Katz ADL Score and the Activity Level will be evaluated once a day 
during treatment. Flu PRO will also be measured once daily while in the hospital and 
once daily after discharge until Day 14. Other assessments times are specified in the 
Time and Events Tables (Section 7.1).
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
The IDMC will perform reviews of unblinded safety data on a regular basis (Section 
10.8.1).  The GSK SRT will routinely review blinded safety data during the study.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4 (Section 12.4)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. Severity of AEs is to be 
reported as defined according to the Division of AIDS (DAIDS) table (Appendix 5, 
Section 12.5).
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will 
be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up contact
(see Section 7.4.1.3), at the timepoints specified in the Time and Events Table (Section 
7.1).

Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical Conditions 
section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.


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
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator must promptly notify 
GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 7.4.1.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 4.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the eCRF within one week of receipt of 
a CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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7.4.1.5.
AEs of Special Interest
The following disease related events are common in subjects hospitalized for influenza 
and can be serious/life threatening.  These events will be considered as AEs of special 
interest (AESI):

Pneumonias (bacterial, ventilator, hospitalized and community; guidelines for 
diagnosis [Mandell, 2007], [Niederman, 2005])

Pneumothorax

Pleural effusion

ARDS

Myositis

Encephalitis

Myocarditis

Bacterial bronchitis

Otitis media

Sepsis

Sinusitis

Bacteremia
These events will be recorded on the AESI page in the subject’s CRF.  These AESIs will 
be monitored by the IDMC and the GSK SRT on a routine basis. Relevant medical tests 
and treatment, including antibiotics use, and clinical symptoms of subjects during 
treatment and post-treatment, will be recorded in all assessments for these events.  
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.


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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and in female partners of male subjects
will be collected after the start of dosing and until 3 days post last dose.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems ie assessment of 
the head, eyes, ears, nose, sinuses, skin, thyroid, neurological, lungs, cardiovascular, 
abdomen (liver and spleen), lymph nodes and extremities. Height and weight will also be 
measured and recorded.

A brief physical examination will include, at a minimum assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses
7.4.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate. 
7.4.5.
Electrocardiogram (ECG)
Single (baseline) and triplicate (post-enrollment) 12-lead ECGs will be obtained at each 
timepoint during the study using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.3 for QTc 
stopping criteria and additional QTc readings that may be necessary.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments (Table 7) must be conducted in accordance 
with the Laboratory Manual, and Protocol Time and Events Schedule. Laboratory 
requisition forms must be completed and samples must be clearly labelled with the 
subject number, protocol number, site/centre number, and visit date. Details for the 
preparation and shipment of samples will be provided by the central laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional protocol-specified or non-protocol specified laboratory assessments 
performed at the institution’s local laboratory result in a change in subject management 


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or are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
For safety laboratory assessments, approximately 20 mLs of blood sample will be 
obtained at each visit. For laboratory parameters that will be assessed at the local 
laboratory for subject management as per the Time and Events Tables (Section 7.1), an 
additional approximately 20 mLs of blood sample will be obtained.
All study-required laboratory assessments will be performed by a central laboratory. In 
addition, CBC with differential (for evaluating neutropenia), LFTs and serum creatinine 
will also be measured by the local laboratory and used for subject management. Local 
laboratory values for neutrophils, serum creatinine and LFTs (aspartate transaminase, 
AST; alanine transaminase, ALT) will be recorded in the eCRF. These values will be 
utilized by the Investigator for subject management and by the IDMC prior to data from 
central laboratory being available.

The results of each laboratory test that is considered clinical significant should be 
reported as an AE or SAE as applicable and must be entered into the eCRF.
NOTE: Additional local laboratory results are only required in the event that the central 
laboratory results are not available in time for either a treatment and/or response 
evaluation to be performed. If a local sample is required it is important that the sample 
for central analysis is obtained at the same time. Additionally if the local laboratory 
results are used to make either a treatment or response evaluation, the results must be 
entered into the eCRF.
Hematology, clinical chemistry and additional parameters to be tested are listed in Table 
7.
Table 7
Protocol Required Safety Laboratory Assessments
Central Laboratory 
Assessments/Approximate 
Volume per Assessment
Parameters
Haematology/2 mL
Platelet Count
RBC 
Indices:
WBC count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry a/4.5 mL
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein


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Central Laboratory 
Assessments/Approximate 
Volume per Assessment
Parameters
Glucose 
Calcium
Alkaline 
phosphatise
Albumin
Other Screening 
Tests/17 mL

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

Ultrasensitive urine hCG Pregnancy test (for women 
of child bearing potential) at Baseline and Day 3 Post-
treatment b
a.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Appendix 2, Section 12.2.
b.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committee.
All laboratory tests with values that are considered clinically significantly abnormal 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
A blood sample (1-2 mL) for the provision of dried blood spot (DBS) collection and 
subsequent analysis of DNX concentration, will be collected at the time points indicated 
in Section 7.1, Time and Events Tables. The actual date and time of each blood sample 
collection will be recorded. The timing of PK samples may be altered and/or PK samples 
may be obtained at additional time points to ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the Study Reference Manual 
(SRM).
Blood (DBS) analysis will be performed under the control of Platform Technology and 
Science – InVivo/ InVitro Translation PTS- IVIVT/ Third Party Resources TPR, 
GlaxoSmithKline, the details of which will be included in the SRM.  Concentrations of 
DNX will be determined in blood (DBS) samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the blood has been analyzed for DNX any remaining blood may be analyzed for 
other compound-related metabolites and the results reported under a separate PTS-
IVIVT, GlaxoSmithKline protocol.


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7.6.
Biomarker(s)/Pharmacodynamic Markers
Blood samples and serum separated for analysis (approximately 10 mL whole blood) will 
be collected at each time point indicated in Section 7.1, Time and Events Table for 
exploratory biomarker testing to identify biomarkers for neutrophil activation and 
accumulation, immune responses, inflammation, factors that may be associated with or 
influence influenza infection as well as biological and clinical responses to DNX 
treatment in combination with OSV. Exploratory markers may include but are not 
limited to interleukin-8 (IL-8), procalcitonin, respiratory neutrophil cell counts, 
neutrophil elastase, myeloperoxidase.
7.6.1.
Novel Biomarkers
Nasal wash sample(s) may be collected from non-intubated subjects and endotracheal 
aspirates will be collected from intubated subjects during this study.  Nasal samples will 
be collected from all subjects using SAM strips.  Collected samples may be used for the 
purposes of measuring novel biomarkers to identify factors that may influence or be 
associated with influenza infection as well as the biological and clinical responses to 
DNX.  
Samples will be collected at the timepoints indicated in Section 7.1. The timing of the 
collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic (PD) data from this study or other new information in order to ensure 
optimal evaluation of the PD endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with influenza or medically related conditions and/or the action of 
DNX may be identified by application of:

RNA transcriptome analysis of whole blood samples;

Protein biomarker analysis of the serum, endotracheal, BAL and/or nasal samples; 
and

Cellular composition evaluation from the nasal, endotracheal and/or BAL samples.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
Analysis and reporting of these biomarkers may occur after issue of the full Clinical 
Study Report.


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7.6.1.1.
RNA Transcriptome Research
Transcriptome studies may be conducted using microarray, and/or alternative equivalent 
technologies, which facilitates the simultaneous measurement of the relative abundances 
of thousands of RNA species resulting in a transcriptome profile for each blood sample.  
This will enable the evaluation of changes in transcriptome profiles that may correlate 
with biological and clinical response relating to influenza or the action of DNX.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.6.1.2.
Proteome Research
Serum, endotracheal, BAL and/or nasal sample proteome studies may be performed by 
immunoassay, or an alternative equivalent procedure.  Proprietary algorithms and 
standard statistical techniques, such as ANOVA and ANCOVA, may be used to identify 
individual proteins exhibiting statistically acceptable changes in their levels between 
samples, and between groups of samples. The levels of the proteins will be measured by 
immunoassay or equivalent technology.  This will enable the evaluation of changes in 
proteome profiles that may correlate with biological response relating to influenza and 
medically related conditions, or the action of DNX.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.7.
Genetics
Information regarding genetic research is included in Appendix 3 .
7.8.
Viral Genotyping and Phenotyping
Samples for viral genotyping and phenotyping will be collected at time points indicated 
in the Time and Events Table (Section 7.1).
Resistance analyses will be carried out to investigate the occurrence of OSV resistance in 
circulating influenza viruses in participating countries. Phenotyping and genotyping 
(Neuraminidase and hemagglutinin sequencing) will be performed on nasopharyngeal 
swabs collected on Baseline/Day 1 and the last visit with detectable virus. Further visits 
may be analyzed if phenotype, genotype and viral load results indicate that resistance 
may be present.
Genotypic and phenotypic analyses will be carried out at a central laboratory.
Detailed information on sample handling, labeling, storage and shipment are provided in
the SRM.


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7.9.
Value Evidence and Outcomes
Assessments for Patient Reported Outcomes will be done at time points indicated in the 
Time and Events Table (Section 7.1).
Exploratory endpoints of patient reported outcomes on intensity of influenza symptoms 
with the FluPRO [Powers, 2016], impact of influenza on activities of daily living with the 
Katz ADL score [Katz, 1970; Katz, 1983] and activity level (3 point scale –bed-rest, 
ambulatory, unrestricted), will be assessed with questionnaires during hospitalization and 
following discharge from the hospital. Readmission rates will be determined for subjects 
who are discharged from the hospital within 30 days post treatment. 
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.  

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The goal of the study is to assess the efficacy of twice daily 15 mg and 50 mg FBE IV 
DNX given with standard of care 75 mg oseltamivir twice daily, in hospitalized patients 
with influenza. The primary endpoint is the TTCR in subjects with confirmed influenza. 
TTCR and Clinical response is defined in Section 9.4.1.  
A probability inference approach will be used for decision-making. A Bayesian 
predictive probability of success will be provided to support assessment of early stopping 
for futility and/or efficacy and for final efficacy. Observed data at interim analyses or 
final analysis of this study will be used to calculated predictive probability of success of a 
future study with larger sample size. Success is defined as a statistically significant 
treatment effect (p-value<0.025 for hazard ratio of TTCR >1) in a future two-arm 
comparative superiority study with 300 subjects per arm.    


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The TTCR endpoint was used in GSK Study NAI14373 (IV zanamivir), conducted in a 
similar population of hospitalized influenza subjects. The TTCR endpoint from 
NAI114373 was calculated as defined in the protocol.  Median TTCR from Kaplan-Meier 
estimates in the oseltamivir treatment group from the confirmed influenza population are 
summarized (Table 8), and applied to the less severe subjects and for critically ill subjects 
at baseline separately. Hazard ratio estimates from the proportional hazard model of IV 
zanamivir vs oseltamivir range from 1.6 – 1.7 in the Mechanical ventilation at baseline 
sub-group in study NAI114373.  Hazard ratio and clinical improvement in days over 
oseltamivir are provided in the table for reference.
Table 8
Hazard Ratio and Clinical Improvement over oseltamivir
Population 
Median 
Recovery time 
(days) 
Hazard 
Ratio 
Clinical effect 
Improvement in 
Days
Less severe sub-population 
5.8
1.2
1
1.5
2
Critically ill sub-population
20.1
1.2
3.4
1.5
6.7
TTCR is assumed to follow exponential distribution with constant hazard rate .  To 
incorporate prior information on the oseltamivir arm, a weak informative prior of Gamma 
(4, 4/0.83) distribution with mean parameter of 0.83 and weight parameter of 4, will be 
used for in the oseltamivir arm.  The mean and median hazard rates for the Gamma 
distribution are 0.83 and 0.76, respectively, with 2.5th percentile of 0.226 and 97.5th 
percentile of 1.819.  A constant hazard rate of 0.83 for exponential distribution centers 
the recovery time at 5.8 days.  A weight parameter of 4 provides relative small weight on 
the prior and will allow data to dominate the posterior, the 95% recovery time could 
range from 2.6 to 21.4 days to allow wide range possible outcomes.  A non-informative 
prior will be used for DNX arms. 
The sample size of 300 was selected based on simulations to achieve at least 80% overall 
power under assumption of HR =1.5 for 50 mg of DNX FBE and HR =1.2 for 15 mg of 
DNX FBE and keep type I error less than 10% under no-effect assumption.
The study will enrol approximately 300 subjects with ratio 2:2:1 to 15mg IV DNX FBE+ 
OSV, 50mg IV DNX FBE + OSV and IV DNX placebo +OSV arms. An informative 
prior on the oseltamivir arm for the Bayesian analysis provides additional data from prior 
study for the control arms, combining prior data and data from this study allows us to 
have fewer subjects on the control arm with a 2:2:1 randomization ratio.  
It is assumed that there is no difference in treatment effect between the less severe and 
severe population.  Assuming a treatment effect of HR =1.5 for 50 mg of DNX FBE and 


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a clinically meaningful treatment effect of HR =1.2 for 15 mg of DNX FBE, there is an 
82% chance that at least one dose will meet the success criteria described below:
At interim:  
Probability (success) >90%
Final: 
Probability (success)>50%
Assuming a HR of 1 for both doses, the overall type I error is 9%, i.e. there is a 9% 
chance of one or more doses being declared success incorrectly.
Table 9
Type I error by Interim and Overall
Hazard 
ratio
Type I error for Interim 1
n=100
Type I error for Interim 2
n=200
Overall Type I Error
Criteria
Probability (success) >90%
Probability (success) 
>90%
Probability (success) >50%
L: HR=1 
H: HR=1
1%
0%
9%
9.2.2.
Sample Size Sensitivity
In order to characterize and understand the performance of the design, the study was 
simulated under several different scenarios.
The powers for different scenario range from 45-90% and detail result are shown in 
Appendix 9.
Scenarios considered for the true hazard ratios for low dose and high dose DNX are 
shown in Table 10.
Table 10
Dose-Response profile for Hazard Ratio
DNX FBE 15 mg  + 
OSV
DNX FBE 50mg + OSV
1. No effect
1
1
2. Small effect
1.2
1.2
3. Large effect
1.5
1.5
4. Mixed effect
1.2
1.5
5. High dose large effect
1
1.5
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned. 
An adaptive design is employed that allows for dropping a dose at interim analyses. 
These interim analyses also allow for early stopping for futility or efficacy.  The target 


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sample size is 300 subjects; if early futility or efficacy criteria are met, as few as 75-100 
subjects may be enrolled.  The first interim analyses will occur after the first flu season if 
there are more than 75 subjects enrolled. Additional interim analyses may be performed 
after approximately 50-66% of subjects have been enrolled. 
Assuming an effective drug (HR = 1.2 and 1.5 for low and high dose respectively), there 
is 26% probability, the sample size is 100 subjects at the end of the study, and 67% 
probability the sample is less than 220. Assuming an ineffective drug (HR =1 for both 
doses),  there is 47% probability, the sample size is 100 subjects at the end of the study, 
and 86% probability the sample is less than 220. Average sample size for each Dose-
response profile is provided in Appendix 9.  
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent to Treat Exposed Population (ITT-E) will consist of all randomized 
subjects who receive at least one dose of investigational product.  Subjects will be 
assessed according to their randomized treatment, regardless of the treatment they 
receive.  The ITT-E population will be used for summaries of study population and 
disposition.
The Influenza positive population (IPP) will consist of all subjects in the ITT-E 
population with influenza infection (positive influenza PCR or culture at any timepoint)
confirmed by central lab testing.  Unless stated otherwise, the IPP will be used as the 
primary population for the primary efficacy analysis and all other efficacy analyses.
The safety population will consist of all randomized subjects who receive at least one 
dose of investigational product.  Subjects will be assessed according to their actual 
treatment received, regardless of the randomization assigned.  This will be the primary 
population for safety analysis.
The Pharmacokinetic population: This population includes all subjects who underwent 
blood PK sampling during the study and from whom one or more blood concentration is 
determined. This population will be used for listing of plasma concentration-time data, 
non-compartmental PK and population PK analysis, as data permit.
Per Protocol Population (PP): The PP population will exclude subjects from the IPP 
who have no post-baseline data or who have protocol deviations that lead to exclusion 
from PP population. To decide which subjects should be removed from PP population, 
the study team will review protocol deviation prior to unblinding of the data.  If 
warranted, the Per Protocol population will be used for sensitivity analysis in the primary 
efficacy comparisons
9.3.2.
Interim Analysis
An Independent Data Monitoring Committee (IDMC) will review key safety data from 
the sentinel cohorts. Enrollment in the study will continue during IDMC review.  In the 
first influenza season, the IDMC will continue to review unblinded safety data, after 


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every approximately 10-20 subjects have completed treatment in the study. Frequency of 
IDMC reviews in subsequent seasons will be determined based on safety results of the 
interim analysis. 
Pharmacokinetic analysis will be done in batches during the study with special emphasis 
to process and analyze after each sentinel group has completed treatment, to provide an 
early confirmation of exposure to DNX.  Similarly, to obtain early evidence of target 
engagement, nasal wash and/or endotracheal samples may be evaluated in batches during 
the study to determine neutrophil patterns following treatment with DNX.
Interim analyses of efficacy and safety data will be conducted to confirm dose regimens 
for subjects in the remainder of the influenza seasons. The first interim analyses will 
occur after the first flu season if there are more than 75 subjects enrolled. Additional 
interim analyses may be performed after approximately 50-66% of subjects have been 
enrolled. 
Detail of data to be reviewed and decision criteria will be included in the IDMC charter.
9.4.
Key Elements of Analysis Plan
9.4.1.
Efficacy
9.4.1.1.
Primary Analysis
Probability of success, denoted Prob(Success), will be calculated. Success is defined as a 
statistically significant treatment effect (p-value<0.025 for hazard ratio of TTCR >1) in a 
future two-arm comparative superiority study with 300 subjects per arm, given observed 
data. 
Let T0 be the time to clinical response for the control arm with exponential distribution
Where is the hazard rate constant of subjects in the control arm, the parameter is 
modeled as:
Where n is prior weight parameter and µ is prior mean parameter, we set n=4 and µ=0.83 
based on the hazard rate observed in study NAI114373. 
Let Td be the time to clinical response for the dose level d:
where 
, and θd is log-hazard ratio and modeled with independent dose-dose 
response model.


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Kaplan-Meier estimates for the median of TTCR for each treatment group and the 
median difference and 95% confidence interval (CI) between DNX arms and OSV will 
be provided.
9.4.1.2.
Secondary Analyses
Median, median difference and 95% for the median differences between DNX arms and 
OSV for Time to respiratory response and each component of TTCR will be provided. 
Proportion of subjects with clinical response, improved respiratory status and resolution 
of each component of TTCR over time will be summarized.
Proportion of subjects with improvement in Ordinal scale of clinical efficacy over time 
will be provided.
9.4.1.3.
Subgroup Analyses
To evaluate the benefit of DNX in a sub-population, one key subgroup has been pre-
specified for evaluation of efficacy. 

Disease severity at baseline:  Patients requiring CPAP (i.e. new use for 
respiratory distress and not for chronic purposes such as sleep apnea), BIPAP, 
mechanical ventilation, those who have hemodynamic instability (with or without 
pressor support), or have central nervous system involvement (eg encephalopathy, 
encephalitis) are considered a more severe population.  
Additional subgroups will be pre-specified in the reporting analysis plan.
The KM estimates for the primary analysis and key secondary analyses will be repeated 
by the subgroups. 
9.4.2.
Safety Analysis
All safety analyses will be based on the Safety Population defined in Section 9.3.1.
Exposure to study medication, measured by the number of days on study drug, will be 
summarized by treatment arm. The proportion of subjects reporting adverse events (AEs) 
will be tabulated for each treatment arm. The following summaries of AEs will be 
provided:
Incidence and severity of All AEs;
Incidence and severity of treatment related AEs;
Incidence and severity of AEs leading to withdrawal from study;
Incidence of serious AEs (SAEs).


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Laboratory data, vital signs and ECG data (absolute values and change from Baseline) 
will be summarized by visit and treatment group. In addition, the maximum post-baseline 
toxicity grade will be tabulated by treatment.
9.4.3.
Virology Analyses
Change from baseline in influenza viral load by qRT-PCR and by quantitative virus 
culture from nasopharyngeal swabs will be summarized and plotted by treatment and 
visit.  Summary of proportion of subjects with no detectable influenza viral RNA by 
qRT-PCR and by quantitative virus culture from nasopharyngeal swabs.
9.4.4.
PK and PK/PD Analyses
Blood concentration data will be listed and summarized by day, and planned sampling 
time in both tabular and graphical forms. Blood PK parameters will be listed and 
summarized by treatment. 
A population-based PK model may be constructed based on the DNX PK data. 
Population PK analyses will be done under separate Population-PK Reporting and 
Analysis Plans.
Relationships between various blood DNX PK parameters and pharmacodynamic 
measures (e.g., TTCR, TTRR, clinical response, biomarkers, or safety measures) may be 
explored using simple correlation analyses or population-based PK/PD approach.
9.4.5.
Other Analyses
The results of the biomarker investigations may be reported separately from the main 
clinical study report. All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data. 
Additional exploratory analyses may be performed to further characterize the biomarker 
results.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.


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The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study. 
It is anticipated that many subjects who will be eligible for this study will not be able to 
give consent themselves due to their medical condition. In such cases, and if allowed by 
applicable local laws, consent may be obtained from a legally acceptable representative 
(LAR). The investigator and/or the sites IEC/IRB have responsibility for applying local 
laws in the matter of who has the capacity to consent and who qualifies as a LAR of a 
potential subject, or according to IRB/IECs and local laws in special situations where the 
subject may be included without consent beforehand by a LAR.
When appropriate, in addition to the consent provided by the LAR, subjects who are 
determined not to have the capacity to provide informed consent should be given 
information according to his/her capacity to understand and asked for their written assent 
to participate in the study.
Subjects enrolled in the study on the basis of consent by a LAR will be given the 
opportunity to provide written confirmatory consent when and if they become able to do 
so. If the subject declines to confirm consent they will be withdrawn from the study at 
the point where they decline consent.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data entered in the eCRFs that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending 
on the study; also current medical records must be available.

Definition of what constitutes source data can be found in the SRM
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.


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
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where applicable). 
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
for a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, and/or 
institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of the 
records in the event the investigator is no longer associated with the site.


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Independent Data Monitoring Committee
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety issues in order to protect the ethical and safety interests of 
subjects and to protect the scientific validity of the study.  The IDMC will meet at a 
minimum of approximately every 10-20 subjects during the first influenza season. 
Frequency of meetings for the subsequent seasons will be determined based on results of 
the interim analysis.
The IDMC will be provided guidelines on study halting criteria. While recommendations 
for stopping have been provided as a guide, the IDMC will base its recommendation to 
halt, or modify the study based on all available evidence.  The guidance is not a substitute 
for the medical, scientific or statistical expertise of the IDMC body.  Based on the data 
review, the IDMC will also determine whether a DNX dose needs to be dropped. While 
the IDMC will receive all available safety data, it is purported that, based on the 
mechanism of action of DNX, decisions will include comparison between treatment 
groups for parameters such as neutropenia, AESIs, SAEs, incidence of bacterial 
infections and disease progress. The details of the schedule of planned interim analyses 
and the analysis plan for IDMC review is described in the charter which is available upon 
request.


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11.
REFERENCES
Centers for Disease Control and Prevention CDC 2011. Antiviral Agents for the 
Treatment and Chemoprophylaxis of Influenza. MMWR 60(1): January 21.
Danirixin Investigators Brochure, Version 09, YM2010/00163/07, April 2016.
Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). 
Guidance for Industry Influenza: Developing Drugs for Treatment and/or Prophylaxis. 
April 2011.
Garcia CC, Russo RC, Guabiraba R, Fagundes CT, Polidoro RB, Tavares LP, et al. 
Platelet-activating factor receptor plays a role in lung injury and death caused by 
Influenza A in mice. PLoS Pathog. 2010 Nov;6(11):e1001171. 
Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, et al. Seasonal Influenza in 
Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional 
Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of 
America CID. 2009;48:1004.
Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, et al. Cleavage of 
CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 
2007;13(12):1423-30
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, et al., editors. Contraceptive 
Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011a:28.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, et al., editors. Contraceptive 
Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011: 50.  Table 3 2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, and Straus SE. Local and 
Systemic Cytokine Responses during Experimental Human Influenza A Virus Infection. J 
of Clin Invest. 1998;101(3): 643-649.
Hayward AC, Fragaszy EB, Bermingham A, Wang L, Copas A, et al. Comparative 
community burden and severity of seasonal and pandemic influenza: results of the Flu
watch cohort study. Lancet Resp Med 2014;2: 445-54.
ICH Guideline M3(R2) on non- clinical safety studies for the conduct of human clinical 
trials and marketing authorisation for pharmaceuticals. 2009 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002720.pdf (accessed 11 November 2014).


2016N281688_00
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.
Jones SA, Wolf M, Qin S, Mackey CR, Baggiolini M Different functions for the 
interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and 
phosphlipase D are activated through IL-8R1 but not IL-8R2. Proc Natl Acad Sci USA. 
1996;93:6682-6686
Katz, S. (1983). Assessing self-maintenance: Activities of daily living, mobility and 
instrumental activities of daily living. JAGS, 31(12), 721- 726.
Katz, S., Down, T.D., Cash, H.R., & Grotz, R.C. (1970) Progress in the development of 
the index of ADL. The Gerontologist, 10(1), 20-30.
Kirsten AM, Foerster K, Radeczky E, Linnhoff A, Balint B, Watz H, et al. The safety and 
tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-
to-severe COPD. Pulmonary Pharmacology & Therapeutics 2015;31:36-41.
Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C, Tal-Singer R. SB-656933,
a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone
induced airway inflammation in humans. Br. J. Clin. Pharmacol. 2011;72:282-293.
Mandell LA, Wunderink RG, Anzueto A, BartlettJG, Campbell GD, et al. Infectious 
Diseases Society of America/American Thoracic Society Consensus Guidelines on the 
Management of Community-Acquired Pneumonia in Adults. Clinical Infectious Diseases 
2007;44:S27–72.
Nair P, Gaga M, Zervas E, Alagha K, Hargreave FE, O'Byrne PM, et al. Safety and 
efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a 
randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012 Jul;42(7):1097-103.
Narasaraju U, Yang E, Samy RP, Ng HH, Poh WP, et al. Excessive Neutrophils and 
Neutrophil Extracellular Traps Contribute to Acute Lung iNjury of Influenza 
Pneumonitis Am J Pathol 2011;179:199-210.
Niederman MS, Craven DE, Bonten MJ, Chastre J, Craig WA, et al. Guidelines for the 
Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-
associated Pneumonia. Am J Respir Crit Care Med 2005;171:388–416.
Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM. PLoS Pathog. H5N1 
and 1918 pandemic influenza virus infection results in early and excessive infiltration of 
macrophages and neutrophils in the lungs of mice. 2008 1;4(8):e1000115
Powers JH, Lourdes-Guerrero M, Leidy NK, Fairchok MP, Rosenberg A, et al. 
Development of the Flu-PRO: a patient reported outcome (PRO) instrument to evaluate 
symptoms of influenza BMC Infectious Diseases. 2016;16:1-11.


2016N281688_00
CONFIDENTIAL
201023
79
Seiberling M, Kamtchoua T, Stryszak P, Ma X, Langdon RB, Khalilieh S. Humoral 
immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with 
MK-7123, a selective CXCR2 antagonist. Int Immunopharmacol. 2013;17:178-183.
Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, et al. Assessment of 
Clinical Criteria for Sepsis For the Third International Consensus Definitions for Sepsis 
and Septic Shock (Sepsis-3). JAMA 2016;315(8):762-774.
Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, et al. Developing a 
NewDefinition and Assessing NewClinical Criteria for Septic Shock For the Third 
International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA
2016;315(8):775-787.
Short KR, Veldhuis-Kroeze EJB, Fouchier RAM, Kuiken T. Pathogenesis of influenza-
induced acute respiratory distress syndrome. Lancet Infect Dis 2014;14:57-69.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, et al. The Third 
International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 
2016;315(8):801-810.
Tamiflu Summary of Product Characteristics, 2010.
Taubenberger JK and Morens DM. The Pathology of Influenza Virus Infections. Annu. 
Rev. Pathol. Mech. Dis. 2008;3:499-522.
WHO (World Health Organization) 2010. Guidelines for Pharmacological Management 
of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses.  Available at :  
http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical
_mngt.pdf


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALT
Alanine Aminotransferase
AMD
Age-Related Macular Degeneration
ANC
Absolute Neutrophil Count
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AV
Atrioventricular
BCRP
Breast Cancer Resistance Protein
BID
Twice Daily
BIPAA
Bilevel positive airway pressure
BMD
Bone mineral density
CDC
Centers for Disease Control
CI
Confidence Interval
Cmax
Maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstruction Pulmonary Disease
CPK
Creatine Phosphokinase
CPAP
Continuous Positive Airway Pressure
CRF
Case report form
CXCL1
Chemokine (C-X-C motif) ligand 1
CXCR1
C-X-C Chemokine Receptor 1
CXCR2
C-X-C Chemokine Receptor 2
CV
Cardiovascular
CVA
Cerebral vascular accident
CYP
Cytochrome P450
DAIDS
Division of AIDS
DBS
Dried Blood Spot
DNA
Deoxyribonucleic Acid
DNX
Danirixin
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigiliance
GSK
GlaxoSmithKline
H1N1
Pandemic Influenza A Virus
HBsAg
Hepatitis B S antigen
hCG
Human Chorionic Gonadotrophin


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Hep-B
Hepatitis B Virus
Hep-C
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HR
Hazard ratio
HPLC
High performance liquid chromatography
IB
Investigator Brochure
IMB
Inter-menstrual bleeding
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDMC
Independent Data Monitoring Committee
IEC
Institutional Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
ITT-E
Intent to Treat Exposed Population
IL-8
Interleukin 8
INR
International Normalized Ratio
IP
Investigational Product
IPP
Influenza Positive Population
IRB
Institutional Review Board
IV
Intravenous
LAR
Legally acceptable representative
LDH
Lactate Dehydrogenase
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MSDS
Material Safety Data Sheet
NOAEL
No Observed Adverse Effect Level
OSV
Oseltamivir
PBO
Placebo matching Danirixin
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PK
Pharmacokinetics
PP
Per Protocol Population
PR
PR interval; duration in milliseconds from the beginning of 
P wave to onset of ventricular depolarization (R)
PTS-DMPK
Platform Technology and Science - Drug Metabolism and 
Pharmacokinetics
QRS
QRS interval; duration in milliseconds of the QRS complex, 
the deflections in an electrocardiographic tracing, 
representing ventricular activity of the heart
qRT-PCR
Quantitative Reverse Transcription – Polymerase Chain 
Reaction
QT
QT interval; duration in milliseconds between the Start of Q 
Wave and end of T Wave
QTc
Corrected QT interval


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QTcB 
Corrected QT Interval using Bazette’s formula 
QTcF 
Corrected QT Interval using Fridericia forumula 
RAP 
Reporting and Analysis Plan 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAM 
Synthetic Absorption Matrix 
SRM 
Study Reference Manual 
TPN 
Total parenteral nutrition 
TTCR 
Twice daily on time to clinical response 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
  
Trademarks not owned by the 
GlaxoSmithKline group of companies 
RELENZA 
  
Capt
iso
l 
 
  
F
luPRO 
 
  
Katz ADL 
 
  
Tam
if
lu 
 


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II Liver Chemistry Stopping Criteria
Liver Parameter
ALT ≤10xULN
ALT >10xULN
Bilirubin ≤2xULN
Continue
Discontinue IP
Bilirubin >2xULN
(>35% direct)
Discontinue IP if ALT >5xULN, 
report as an SAE
Discontinue IP, report as an SAE
Required Actions and Follow-up Assessments to Liver Stopping Criteria
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment. Permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 3 days after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 


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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week) [James, 2009]. 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT>5x upper limit of normal (ULN) . 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT > 5xULN and bilirubin 2xULN (>35% direct bilirubin), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold 
value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  


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12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

Influenza susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for deoxyribonucleic acid (DNA) extraction. The 
blood sample is collected at the baseline visit, after the subject has been randomized and 
provided informed consent for genetic research. Instructions for collection and shipping 
of the genetic sample are described in the laboratory manual. The DNA from the blood 
sample may undergo quality control analyses to confirm the integrity of the sample. If 
there are concerns regarding the quality of the sample, then the sample may be destroyed.
The blood sample is taken on a single occasion unless a duplicate sample is required due 
to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


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destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue to 
be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012;33: 467-486.


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming 
intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease (influenza symptoms), 
unless judged by the investigator to be more severe than expected for the subject’s 
condition.

Influenza symptoms: nasal symptoms (rhinorrhea, congestion), feverishness, 
cough, myalgia, fatigue, diarrhea, dyspnea, headache, sore throat, nausea and 


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vomiting.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity


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NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 5xULN and total bilirubin* 2xULN (>35% direct), or

ALT > 10xULN.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy


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
Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative 
to the event.

The investigator will then record all relevant information regarding an AE/SAE in the 
CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to submission 
of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by the 
scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and grade each AE and SAE according to the DAIDS toxicity scales 
(Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse 


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Events, Appendix 5).

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

[If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.]

New or updated information will be recorded in the originally completed CRF.


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
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the 
SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, the site can report this information on a paper SAE form or to the SAE coordinator 
by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject is 
the preferred method to transmit SAE information to the protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the protocol contact. The site will enter the SAE data into PIMS 
as soon as the system becomes available.


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12.5.
Appendix 5:  Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Averse Events Version 1.0, 
December 2004; Clarification August 2009
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE Grading 
Table 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Symptoms 
causing inability 
to perform basic 
self-care 
functions OR 
Medical or 
operative 
intervention 
indicated to 
prevent 
permanent 
impairment, 
persistent 
disability, or 
death 
SYSTEMIC
Acute systemic 
allergic reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated
Localized urticaria 
with medical 
intervention 
indicated OR Mild 
angioedema with 
no medical 
intervention 
indicated
Generalized 
urticaria OR 
Angioedema with 
medical 
intervention 
indicated OR 
Symptomatic mild 
bronchospasm
Acute 
anaphylaxis OR 
Life-threatening 
bronchospasm 
OR laryngeal 
edema
Chills
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Incapacitating 
fatigue/ malaise 
symptoms 
causing inability 
to perform basic 
self-care 
functions
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Pain (indicate body 
site)
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain)
See also Headache, 
Arthralgia, and 
Myalgia
Pain causing no 
or minimal 
interference with 
usual social & 
functional 
activities
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Pain causing 
inability to perform 
usual social & 
functional activities
Disabling pain 
causing inability 
to perform basic 
self-care 
functions OR 
Hospitalization 
(other than 
emergency room 
visit) indicated
Unintentional weight 
loss
NA
5 – 9% loss in 
body weight from 
baseline
10 – 19% loss in 
body weight from 
baseline
20% loss in 
body weight from 
baseline OR  
Aggressive 
intervention 
indicated [e.g., 
tube feeding or 
total parenteral 
nutrition (TPN)]
INFECTION
Infection (any other 
than HIV infection)
Localized, no 
systemic 
antimicrobial 
treatment 
indicated AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Systemic 
antimicrobial 
treatment indicated 
OR Symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Systemic 
antimicrobial 
treatment indicated 
AND Symptoms 
causing inability to 
perform usual 
social & functional 
activities OR 
Operative 
intervention (other 
than simple 
incision and 
drainage) indicated
Life-threatening 
consequences 
(e.g., septic 
shock)
INJECTION SITE REACTIONS
Injection site pain 
(pain without 
touching)
Or
Tenderness (pain 
when area is 
touched) 
Pain/tenderness 
causing no or 
minimal limitation 
of use of limb
Pain/tenderness 
limiting use of limb 
OR 
Pain/tenderness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Pain/tenderness 
causing inability to 
perform usual 
social & functional 
activities
Pain/tenderness 
causing inability 
to perform basic 
self-care function 
OR 
Hospitalization 
(other than 
emergency room 
visit) indicated for 
management of 
pain/tenderness


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Injection site reaction (localized)
Adult > 15 years
Erythema OR 
Induration
of 5x5 cm – 9x9 
cm (or 25 cm2 –
81cm2)
Erythema OR 
Induration OR
Edema 
> 9 cm any 
diameter
(or > 81 cm2)
Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis 
(involving dermis 
and deeper 
tissue)
Pediatric 15 
years
Erythema OR 
Induration OR 
Edema present 
but 2.5 cm 
diameter
Erythema OR 
Induration OR 
Edema > 2.5 cm 
diameter but < 
50% surface area 
of the extremity 
segment (e.g., 
upper arm/thigh)
Erythema OR 
Induration OR 
Edema involving 
50% surface 
area of the 
extremity segment 
(e.g., upper 
arm/thigh) OR 
Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis 
(involving dermis 
and deeper 
tissue)
Pruritis associated 
with injection 
See also Skin: Pruritis 
(itching - no skin 
lesions)
Itching localized to 
injection site AND 
Relieved 
spontaneously or 
with < 48 hours 
treatment 
Itching beyond the 
injection site but 
not generalized 
OR Itching 
localized to 
injection site 
requiring 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual 
social & functional 
activities
NA
SKIN – DERMATOLOGICAL
Alopecia
Thinning 
detectable by 
study participant 
(or by caregiver 
for young children 
and disabled 
adults)
Thinning or patchy 
hair loss 
detectable by 
health care 
provider
Complete hair loss
NA


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Cutaneous reaction –
rash
Localized macular 
rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash 
OR Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash 
with vesicles or 
limited number of 
bullae OR 
Superficial 
ulcerations of 
mucous membrane 
limited to one site
Extensive or 
generalized 
bullous lesions 
OR Stevens-
Johnson 
syndrome OR 
Ulceration of 
mucous 
membrane 
involving two or 
more distinct 
mucosal sites OR 
Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or 
generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or 
generalized
NA
NA
Pruritis (itching – no 
skin lesions) 
(See also Injection 
Site Reactions: 
Pruritis associated 
with injection)
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Itching causing 
inability to perform 
usual social & 
functional activities 
NA
CARDIOVASCULAR
Cardiac arrhythmia 
(general)
(By ECG or physical 
exam)
Asymptomatic 
AND No 
intervention 
indicated
Asymptomatic 
AND Non-urgent 
medical 
intervention 
indicated
Symptomatic, non-
life-threatening 
AND Non-urgent 
medical 
intervention 
indicated 
Life-threatening 
arrhythmia OR 
Urgent 
intervention 
indicated
Cardiac-
ischemia/infarction
NA
NA
Symptomatic 
ischemia (stable 
angina) OR 
Testing consistent 
with ischemia 
Unstable angina 
OR Acute 
myocardial 
infarction
Hemorrhage 
(significant acute 
blood loss)
NA
Symptomatic AND 
No transfusion 
indicated
Symptomatic AND 
Transfusion of 2 
units packed RBCs 
(for children 10 
cc/kg) indicated 
Life-threatening 
hypotension OR 
Transfusion of > 
2 units packed 
RBCs (for 
children > 10 
cc/kg) indicated


2016N281688_00
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201023
98
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Hypertension
Adult > 17 
years
(with repeat 
testing at 
same visit)
140 – 159 mmHg 
systolic
OR
90 – 99 mmHg 
diastolic
160 – 179 mmHg 
systolic
OR
100 – 109 mmHg 
diastolic
≥180 mmHg 
systolic
OR
≥110 mmHg 
diastolic
Life-threatening 
consequences 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated (other 
than emergency 
room visit)
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to 100 -109 from > 100-109 
(diastolic) and 
in Grade 3 to 180 from > 180 (systolic) and to 110 from > 110 (diastolic).
Pediatric 17 
years
(with repeat 
testing at 
same visit)
NA
91st –  94th
percentile adjusted 
for age, height, 
and gender 
(systolic and/or 
diastolic)
≥ 95th percentile 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic)
Life-threatening 
consequences 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated (other 
than emergency 
room visit)
Hypotension
NA
Symptomatic, 
corrected with oral 
fluid replacement
Symptomatic, IV 
fluids indicated
Shock requiring 
use of 
vasopressors or 
mechanical 
assistance to 
maintain blood 
pressure
Pericardial effusion
Asymptomatic, 
small effusion 
requiring no 
intervention
Asymptomatic, 
moderate or larger 
effusion requiring 
no intervention
Effusion with non-
life threatening 
physiologic 
consequences OR 
Effusion with non-
urgent intervention 
indicated
Life-threatening 
consequences 
(e.g., tamponade) 
OR Urgent 
intervention 
indicated


2016N281688_00
CONFIDENTIAL
201023
99
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Prolonged PR interval
Adult > 16 
years
PR interval 
0.21 – 0.25 sec
PR interval
> 0.25 sec
Type II 2nd degree 
AV block OR 
Ventricular pause 
> 3.0 sec
Complete AV 
block 
Pediatric ≤ 16 
years
1st degree AV 
block
(PR > normal for 
age and rate)
1.
Type I 2nd
degree 
AV block 
2.
Type II 
2nd
degree 
AV block 
Complete AV 
block
Prolonged QTc
Adult > 16 
years
Asymptomatic, 
QTc interval 0.45 
– 0.47 sec OR 
Increase interval < 
0.03 sec above 
baseline
Asymptomatic, 
QTc interval 0.48 –
0.49 sec OR 
Increase in interval 
0.03 – 0.05 sec 
above baseline
Asymptomatic, 
QTc interval 
0.50 sec OR 
Increase in interval 
0.06 sec above 
baseline
Life-threatening 
consequences, 
e.g. Torsade de 
pointes or other 
associated 
serious 
ventricular 
dysrhythmia
Pediatric ≤ 16 
years
Asymptomatic, 
QTc interval 0.450 
–
0.464 sec 
Asymptomatic, 
QTc interval 0.465 
–
0.479 sec 
Asymptomatic, 
QTc interval 
0.480 sec 
Life-threatening 
consequences, 
e.g.  Torsade de 
pointes  or other 
associated 
serious 
ventricular 
dysrhythmia
Thrombosis/embolism
NA
Deep vein 
thrombosis AND 
No intervention 
indicated (e.g., 
anticoagulation, 
lysis filter, invasive 
procedure) 
Deep vein 
thrombosis AND 
Intervention 
indicated (e.g., 
anticoagulation, 
lysis filter, invasive 
procedure) 
Embolic event 
(e.g., pulmonary 
embolism, life-
threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any 
kind)
Present without 
loss of 
consciousness 
Present with 
transient loss of 
consciousness
NA 
NA


2016N281688_00
CONFIDENTIAL
201023
100
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Ventricular 
dysfunction 
(congestive heart
failure)
NA
Asymptomatic 
diagnostic finding 
AND intervention 
indicated
New onset with 
symptoms OR 
Worsening 
symptomatic 
congestive heart 
failure
Life-threatening 
congestive heart 
failure
GASTROINTESTINAL
Anorexia
Loss of appetite 
without decreased 
oral intake
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss
Loss of appetite 
associated with 
significant weight 
loss
Life-threatening 
consequences 
OR Aggressive 
intervention 
indicated [e.g., 
tube feeding or 
total parenteral 
nutrition (TPN)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used 
as a guideline when grading anorexia, this is not a requirement and should not be used as a substitute for 
clinical judgment. 
Ascites
Asymptomatic
Symptomatic AND 
Intervention 
indicated (e.g., 
diuretics or 
therapeutic 
paracentesis)
Symptomatic 
despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND 
Medical 
intervention 
indicated
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-threatening 
consequences 
(e.g., sepsis or 
perforation) 
Constipation 
NA
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated
Life-threatening 
consequences 
(e.g., obstruction)


2016N281688_00
CONFIDENTIAL
201023
101
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Diarrhea
Adult and 
Pediatric 1 
year
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period
Persistent 
episodes of 
unformed to watery 
stools OR Increase 
of 4 – 6 stools over 
baseline per 24-
hour period
Bloody diarrhea 
OR Increase of ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Pediatric < 1 
year
Liquid stools 
(more unformed 
than usual) but 
usual number of 
stools
Liquid stools with 
increased number 
of stools OR Mild 
dehydration
Liquid stools with 
moderate 
dehydration
Liquid stools 
resulting in 
severe 
dehydration with 
aggressive 
rehydration 
indicated OR 
Hypotensive 
shock
Dysphagia-
Odynophagia 
Symptomatic but 
able to eat usual 
diet
Symptoms causing 
altered dietary 
intake without 
medical 
intervention 
indicated
Symptoms causing 
severely altered 
dietary intake with 
medical 
intervention 
indicated
Life-threatening 
reduction in oral 
intake
Mucositis/stomatitis 
(clinical exam)
Indicate site (e.g., 
larynx, oral)
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-
Odynophagia and 
Proctitis
Erythema of the 
mucosa
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma
Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 
OR Life-
threatening 
consequences 
(e.g., aspiration, 
choking)
Nausea 
Transient (< 24 
hours) or 
intermittent 
nausea with no or 
minimal 
interference with 
oral intake
Persistent nausea 
resulting in 
decreased oral 
intake for 24 – 48 
hours
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids)
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not 
indicated (other 
than emergency 
room visit)
Symptomatic AND 
Hospitalization 
indicated (other 
than emergency 
room visit)
Life-threatening 
consequences 
(e.g., circulatory 
failure, 
hemorrhage, 
sepsis)


2016N281688_00
CONFIDENTIAL
201023
102
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Proctitis (functional-
symptomatic)
Also see 
Mucositis/stomatitis 
for clinical exam
Rectal discomfort 
AND No 
intervention 
indicated
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated 
Life-threatening 
consequences 
(e.g., perforation)
Vomiting
Transient or 
intermittent 
vomiting with no 
or minimal 
interference with 
oral intake
Frequent episodes 
of vomiting with no 
or mild dehydration
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids)
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
NEUROLOGIC
Alteration in 
personality-behavior 
or in mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Alteration causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Alteration causing 
inability to perform 
usual social and
functional activities 
Behavior 
potentially 
harmful to self or 
others (e.g., 
suicidal and 
homicidal 
ideation or 
attempt, acute 
psychosis) OR 
Causing inability 
to perform basic 
self-care 
functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder)
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Confusion, 
memory 
impairment, 
lethargy, or 
somnolence 
causing inability to 
perform usual 
social & functional 
activities
Delirium OR 
obtundation, OR 
coma


2016N281688_00
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201023
103
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Ataxia 
Asymptomatic 
ataxia detectable 
on exam OR 
Minimal ataxia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Symptomatic 
ataxia causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Symptomatic 
ataxia causing 
inability to perform 
usual social & 
functional activities 
Disabling ataxia 
causing inability 
to perform basic 
self-care 
functions
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not
indicated
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis 
indicated
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis 
indicated
Disability causing 
inability to 
perform basic 
self-care 
functions OR 
Institutionalization 
indicated
CNS ischemia
(acute)
NA
NA
Transient ischemic 
attack
Cerebral vascular 
accident (CVA, 
stroke) with 
neurological 
deficit 
Developmental delay 
– Pediatric 16 
years
Mild 
developmental 
delay, either 
motor or cognitive, 
as determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay,  either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or 
cognitive, as 
determined by 
comparison with 
a developmental 
screening tool 
appropriate for 
the setting


2016N281688_00
CONFIDENTIAL
201023
104
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Symptoms 
causing inability 
to perform basic 
self-care 
functions OR 
Hospitalization 
indicated (other 
than emergency 
room visit) OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic 
function 
Insomnia
NA
Difficulty sleeping 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Difficulty sleeping 
causing inability to 
perform usual 
social & functional 
activities
Disabling 
insomnia causing 
inability to 
perform basic 
self-care 
functions
Neuromuscular 
weakness 
(including myopathy 
& neuropathy) 
Asymptomatic 
with decreased 
strength on exam 
OR Minimal 
muscle weakness 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Muscle weakness 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
weakness 
causing inability 
to perform basic 
self-care 
functions OR 
Respiratory 
muscle weakness 
impairing 
ventilation
Neurosensory 
alteration (including 
paresthesia and 
painful neuropathy)
Asymptomatic 
with sensory 
alteration on exam 
or minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration 
or paresthesia 
causing inability to 
perform usual 
social & functional 
activities
Disabling sensory 
alteration or 
paresthesia 
causing inability 
to perform basic 
self-care 
functions


2016N281688_00
CONFIDENTIAL
201023
105
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Seizure: (new onset) 
– Adult ≥ 18 years
See also Seizure: 
(known pre-existing 
seizure disorder)
NA
1 seizure 
2 – 4 seizures 
Seizures of any 
kind which are 
prolonged, 
repetitive (e.g., 
status 
epilepticus), or 
difficult to control 
(e.g., refractory 
epilepsy)
Seizure: (known pre-
existing seizure 
disorder) 
– Adult ≥ 18 years
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of 
these levels.
NA
Increased 
frequency of pre-
existing seizures 
(non-repetitive) 
without change in 
seizure character 
OR Infrequent 
break-through 
seizures while on 
stable medication 
in a previously 
controlled seizure 
disorder
Change in seizure 
character from 
baseline either in 
duration or quality 
(e.g., severity or  
focality) 
Seizures of any 
kind which are 
prolonged, 
repetitive (e.g., 
status 
epilepticus), or 
difficult to control 
(e.g., refractory 
epilepsy)
Seizure 
– Pediatric < 18 
years
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
lasting < 5 
minutes with < 24 
hours post ictal 
state
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
lasting 5 – 20 
minutes with 
< 24 hours post 
ictal state
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
lasting 
> 20 minutes 
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
requiring 
intubation and 
sedation
Syncope (not 
associated with a 
procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing 
no or minimal 
interference with 
usual social & 
functional 
activities
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities
Disabling vertigo 
causing inability 
to perform basic 
self-care 
functions
RESPIRATORY
Bronchospasm 
(acute)
FEV1 or peak flow 
reduced to 
70 – 80%
FEV1 or peak flow 
50 – 69%
FEV1 or peak flow 
25 – 49% 
Cyanosis OR 
FEV1 or peak 
flow < 25% OR 
Intubation


2016N281688_00
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201023
106
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Dyspnea or respiratory distress
Adult ≥ 14 years
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Dyspnea at rest 
causing inability to 
perform usual 
social & functional 
activities 
Respiratory 
failure with 
ventilatory 
support indicated
Pediatric < 14 
years
Wheezing OR 
minimal increase 
in respiratory rate 
for age
Nasal flaring OR 
Intercostal 
retractions OR 
Pulse oximetry 90 
– 95%
Dyspnea at rest 
causing inability to 
perform usual 
social & functional 
activities OR Pulse 
oximetry < 90%
Respiratory 
failure with 
ventilatory 
support indicated
MUSCULOSKELETAL
Arthralgia
See also Arthritis
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Joint pain causing 
inability to perform 
usual social & 
functional activities
Disabling joint 
pain causing 
inability to 
perform basic 
self-care 
functions
Arthritis
See also Arthralgia
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities
Disabling joint 
stiffness or 
swelling causing 
inability to 
perform basic 
self-care 
functions 
Bone Mineral Loss
Adult ≥ 21 years
Bone mineral 
density BMD t-
score 
-2.5 to -1.0 
BMD t-score < -2.5
Pathological 
fracture (including 
loss of vertebral 
height)
Pathologic 
fracture causing 
life-threatening 
consequences 
Pediatric < 21 
years
BMD z-score 
-2.5 to -1.0
BMD z-score < -
2.5
Pathological 
fracture (including 
loss of vertebral 
height)
Pathologic 
fracture causing 
life-threatening 
consequences 
Myalgia
(non-injection site)
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Muscle pain 
causing inability to 
perform usual 
social & functional 
activities
Disabling muscle 
pain causing 
inability to 
perform basic 
self-care 
functions


2016N281688_00
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201023
107
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Osteonecrosis
NA
Asymptomatic with 
radiographic 
findings AND No 
operative 
intervention 
indicated
Symptomatic bone 
pain with 
radiographic 
findings OR 
Operative 
intervention 
indicated
Disabling bone 
pain with 
radiographic 
findings causing 
inability to 
perform basic 
self-care 
functions
GENITOURINARY
Cervicitis 
(symptoms)
(For use in studies 
evaluating topical  
study agents) 
For other cervicitis 
see Infection: 
Infection (any other 
than HIV infection) 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform basic 
self-care 
functions 
Cervicitis 
(clinical exam)
(For use in studies 
evaluating topical  
study agents) 
For other cervicitis 
see Infection: 
Infection (any other 
than HIV infection) 
Minimal cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or 
friability) OR 
Epithelial 
disruption 
< 25% of total 
surface
Moderate cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or 
friability) OR 
Epithelial 
disruption of 25 –
49% total surface
Severe cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or 
friability) OR 
Epithelial 
disruption 
50 – 75% total 
surface
Epithelial 
disruption 
> 75% total 
surface
Inter-menstrual 
bleeding (IMB)
Spotting observed 
by participant OR 
Minimal blood 
observed during 
clinical or 
colposcopic 
examination
Inter-menstrual 
bleeding not 
greater in duration 
or amount than 
usual menstrual 
cycle
Inter-menstrual 
bleeding greater in 
duration or amount 
than usual 
menstrual cycle
Hemorrhage with 
life-threatening 
hypotension OR 
Operative 
intervention 
indicated
Urinary tract 
obstruction (e.g., 
stone)
NA
Signs or symptoms 
of urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction
Signs or symptoms 
of urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction
Obstruction 
causing life-
threatening 
consequences


2016N281688_00
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201023
108
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Vulvovaginitis 
(symptoms)
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection)
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform basic 
self-care 
functions 
Vulvovaginitis 
(clinical exam)
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection)
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial 
disruption 
< 25% of total 
surface
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial 
disruption of 25 -
49% total surface
Severe vaginal 
abnormalities on 
examination OR 
Epithelial 
disruption 
50 - 75% total 
surface
Vaginal 
perforation OR 
Epithelial 
disruption
> 75% total 
surface
OCULAR/VISUAL
Uveitis
Asymptomatic but 
detectable on 
exam
Symptomatic 
anterior uveitis OR 
Medical 
intervention 
indicated
Posterior or pan-
uveitis OR 
Operative 
intervention 
indicated
Disabling visual 
loss in affected 
eye(s) 
Visual changes (from 
baseline)
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities
Visual changes 
causing inability to 
perform usual 
social & functional 
activities
Disabling visual 
loss in affected 
eye(s)
ENDOCRINE/METABOLIC
Abnormal fat 
accumulation
(e.g., back of neck, 
breasts, abdomen)
Detectable by 
study participant 
(or by caregiver 
for young children 
and disabled 
adults)
Detectable on 
physical exam by 
health care 
provider
Disfiguring OR 
Obvious changes 
on casual visual 
inspection
NA
Diabetes mellitus
NA
New onset without 
need to initiate 
medication OR 
Modification of 
current 
medications to 
regain glucose 
control
New onset with 
initiation of 
medication 
indicated OR 
Diabetes 
uncontrolled 
despite treatment 
modification
Life-threatening 
consequences 
(e.g., 
ketoacidosis, 
hyperosmolar 
non-ketotic coma) 


2016N281688_00
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201023
109
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Gynecomastia
Detectable by 
study participant 
or caregiver (for 
young children 
and disabled 
adults)
Detectable on 
physical exam by 
health care 
provider
Disfiguring OR 
Obvious on casual 
visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences 
(e.g., thyroid 
storm)
Hypothyroidism
Asymptomatic
Symptomatic 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences 
(e.g., myxedema 
coma)
Lipoatrophy
(e.g., fat loss from the 
face, extremities, 
buttocks)
Detectable by 
study participant 
(or by caregiver 
for young children 
and disabled 
adults)
Detectable on 
physical exam by 
health care 
provider
Disfiguring OR 
Obvious on casual 
visual inspection
NA


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
HEMATOLOGY
Standard International Units are listed in italics
Absolute CD4+ count 
– Adult and 
Pediatric 
> 13 years
(HIV NEGATIVE
ONLY)
300 – 400/mm3
300 – 400/µL
200 –  299/mm3
200 – 299/µL
100 – 199/mm3
100 – 199/µL
< 100/mm3
< 100/µL
Absolute lymphocyte 
count 
– Adult and 
Pediatric
> 13 years
(HIV NEGATIVE
ONLY)
600 – 650/mm3
0.600 x 109 –
0.650 x 109/L
500 – 599/mm3
0.500 x 109 –
0.599 x 109/L
350 – 499/mm3
0.350 x 109 –  
0.499 x 109/L
< 350/mm3
< 0.350 x 109/L
Comment:  Values in children ≤ 13 years are not given for the two parameters above because the absolute 
counts are variable.
Absolute neutrophil count (ANC) 
Adult and 
Pediatric, 
> 7 days
1,000 – 1,300/mm3
1.000 x 109 –
1.300 x 109/L
750 – 999/mm3
0.750  x 109 –
0.999 x 109/L
500 – 749/mm3
0.500  x 109 –
0.749 x 109/L  
< 500/mm3
< 0.500 x 109/L
Infant†, 2 – 7 
days
1,250 – 1,500/mm3
1.250  x 109 –
1.500 x 109/L
1,000 –
1,249/mm3
1.000 x 109 –
1.249 x 109/L
750 – 999/mm3
0.750  x 109 –
0.999  x 109/L
< 750/mm3
< 0.750 x 109/L
Infant†, ≤1 day
4,000 – 5,000/mm3
4.000 x 109 –
5.000 x 109/L
3,000 –
3,999/mm3
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm3
1.500 x 109 –
2.999 x 109/L
< 1,500/mm3
< 1.500 x 109/L
Comment: Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day”
Fibrinogen, 
decreased
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
0.75 – 0.99 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
0.50 – 0.74 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
0.25 – 0.49 x LLN
< 50 mg/dL 
< 0.50 g/L
OR
< 0.25 x LLN
OR 
Associated with 
gross bleeding 


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12.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.6.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant


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
Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011a] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.6.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Appendix 4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study]

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This applies 
only to subjects who are randomized to receive study medication. 


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
After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  Information 
on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.


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12.7.
Appendix 7: Patient Reported Outcomes Questionnaires
12.7.1.
FluPro
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


2016N281688_00
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Monday, August 27, 2012, FLU-PRO Version 1.0
Research Tool in Development: Do NOT copy or distribute
12.7.2.
Katz ADL Score
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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12.8.
Appendix 8 - Country Specific Requirements
French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.


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12.9.
Appendix 9
Statistical considerations
12.9.1.
Introduction
This document describes the adaptive design for study 201023 for danirixin (DNX; 
GSK1325756) in hospitalized influenza subjects.  The purpose of this document is to 
provide an overview of the trial design and simulation results. Simulations were 
performed using Dose finding module in FACTS version 4.0.
The trial design is based on the primary efficacy endpoint of time to clinical response. 
The goal of the trial is to assess the efficacy of DNX and to identify whether there is a 
dose with acceptable efficacy based on TTCR.  An adaptive design is proposed that 
allows for dropping an in-effective dose, stopping the study for futility and/or stopping 
the study for early success. 
The trial will enroll up to a maximum of approximately 300 subjects over the course of 3 
flu seasons.  Interim analyses will be conducted after each season with approximately 75
to 100 subjects.  At each interim analysis, the predictive probability of success based on 
TTCR will be calculated and used to support go/no-go decisions. 
12.9.2.
Statistical Modeling
At each interim analysis and at the final analysis, the TTCR data will be analyzed with 
independent dose-response models. The adaptation will be based on the predictive 
probability of success. 
12.9.2.1.
Hazard Model:
Let T0 be the time to clinical response for the control arm with exponential distribution
Where is the hazard rate constant of subjects in the control arm, the parameter is 
modeled as:
Where n is prior weight parameter and µ is prior mean parameter, we set n=4 and µ=0.83 
based on the hazard rate observed in study NAI114373. 
And Td be the time to clinical response for the dose level d:
where 
, and θd is log-hazard ratio. 


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12.9.2.2.
The dose –response Model:
Independent dose-response model estimate the response for each arm separately with 
normal distribution.  
Where θd is log-hazard ratio compared to control arm on the treatment arm d. The two 
dose levels considered are d=1 (15 mg BID), and d=2 (50 mg BID).  µd is the mean of 
dose d and 
is the variance of dose d. The same non-informative prior N(0,1) is used 
for all doses of the dose-response model. 
12.9.3.
Allocation
The allocation ratio is 1:2:2 for the control arm, DNX 15 mg (dose level 1) and DNX 50 
mg (dose level 2), respectively.  If an arm is dropped after interim analysis, allocation 
will be kept the same for the remaining arms and the study size will be decreased.
12.9.4.
Evaluation of Arm Dropping, Trial Success and Futility
There will be one interim analysis after each season, with expectation that approximately 
75-100 subjects will enroll in each season.  Overall safety, biomarker and other efficacy 
data will be used for the decision of stopping the trial for futility and success. Early 
futility and success rules described below rely on the efficacy result based on TTCR.
12.9.5.
Probability of success
Probability of success, denoted Prob(Success), will be used to evaluate futility, arm 
dropping and early success. Success is defined as a statistically significant treatment 
effect (p-value<0.025 for hazard ratio of TTCR >1) in a two-arm comparative superiority 
study with 300 subjects per arm, given observed data at interim and final analyses. 
12.9.6.
Arm Dropping
An ineffective DNX arm will be dropped if:
1. At least 75 subjects must have been enrolled.
2. Probability of success of the arm is less than 30%. 
Probd(success) <0.3
12.9.7.
Early Futility
To stop early for futility two conditions are required:
1. At least 75 subjects must have been enrolled.
2. Probability of success of the best dose, denoted as Probmax(success),  is less than
30%. 
Probmax(success) <0.3


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12.9.8.
Early success
To stop early for success two conditions are required:
1. At least 75 subjects must have been enrolled.
2. Probability of success of the best dose, denoted as Probmax(success),  is greater 
than 90%. 
Probmax(success) >0.9
12.9.9.
Trial completion
The final analysis will occur when both accrual and follow-up are complete for all 
subjects. If at the completion of the trial, Probmax(success) is at least 50% , there is 
evidence of efficacy with regard to TTCR.
Probmax(success) >0.5
12.9.10.
Simulation Scenarios
In order to characterize and understand the performance of the design, we simulated the 
trial under several different scenarios.
Scenarios considered for the true hazard ratios for low dose and high dose DNX are 
shown in Table 11.
Table 11
Dose- Response profile for Hazard Ratio
DNX 15mg  + OSV
DNX 50mg + OSV
1. No effect
1
1
2. Small effect
1.2
1.2
3. Large effect
1.5
1.5
4. Mixed effect
1.2
1.5
5. High dose large effect
1
1.5
12.9.11.
Operating Characteristics
Table 12 shows the operating characteristics for different scenarios by interim analysis 
and final analysis.  Figure 1 and Figure 2 show the possible sample size, corresponding 
probability of the sample size and cumulative probability of sample size under two 
selected scenarios. 


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Table 12
Operating Characteristics by Interim of Selected Scenarios
Scenario
Hazard 
ratio
Interim 1
n=100
Interim 2
n=200
Final 
P(drop 
low 
dose)
P(drop 
high dose)
P(stop study 
for futility)
(Observed 
HR 0.85 –
1.2)
P(stop 
study for 
efficacy)
(Observed 
HR 1.5 –
3.2)
P(drop 
low 
dose)
P(drop high 
dose)
P(stop study 
for futility) 
(Observed 
HR 1 – 1.15)
P(stop study 
for efficacy) 
(Observed 
HR 1.55 –
2.7)
Overall 
Power
(Obs’d HR 
final  
success 
1.27- 2)
Average 
Sample size
1. No effect
L: HR=1 
H: HR=1
15%
19%
46%
1%
2%
3%
25%
0%
9%
160
2. Small effect
L: HR=1.2 
H: HR=1.2 
16%
15%
22%
5%
4%
5%
10%
3%
45%
208
3. Large effect
L: HR=1.5 
H: HR=1.5
7%
8%
4%
26%
1%
1%
2%
19%
90%
208
4. Mixed effect
L: HR=1.2
H: HR=1.5
31%
2%
8%
18%
8%
0%
3%
13%
82%
207
5. High dose 
large effect
L: HR=1
H: HR=1.5
54%
1%
10%
18%
12%
0%
3%
12%
81%
191
Futility rule at Interim:  Drop dose: Prob(success) for the dose < 30%, Stop study for futility: Prob(success) for best dose< 30%, Stop study for efficacy: Prob(success) for best dose> 
90%;  Final success criteria: Prob(success) for best dose>50%  
Success is defined one side p<=0.025 in a two arm superiority study with n=300 per arm. 


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Figure 4
Sample Size Distribution for an effective drug and an ineffective 
drug
Location of brown line on x-axis shows possible study sample size, height of brown line 
shows probability of the sample size, and blue line shows the cumulative probability of 
study sample size. Top panel shows an example of an ineffective drug with HR =1 for 
both doses; the bottom panel shows an example of an effective drug with HR =1.2 for 
low dose and HR=1.5 for high dose. 
Ineffective drug HR=1 
47%  Sample size =100
66%  Sample size <=160
86%  Sample size <=220
Effective drug HR=1.2 1.5
26%  Sample size =100
42%  Sample size <=200
67%  Sample size <=220

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201023
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan (RAP) for 201023: A Phase II, 
global, randomized study to evaluate the efficacy and safety 
of Danirixin (GSK1325756) co-administered with a standard-
of-care antiviral (oseltamivir), in the treatment of adults 
hospitalized with influenza
Compound Number 
:
GSK1325756
Effective Date 
:
05-SEP-2017
Description :
1.
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Synoptic Report for study 201023. This document contains the RAP 
Amendment 01.
2.
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
Director  (Statistics, PAREXEL)
Director (Clinical Statistics, GSK)
Electronically Approved by: 
05-SEP-2017
Director (Clinical Statistics, GSK)
Manager (Programming, GSK)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
201023
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses...................................................................................9
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
7.
PRIMARY STATISTICAL ANALYSES....................................................................14
7.1.
Efficacy Analyses........................................................................................14
7.1.1.
Overview of Planned Efficacy Analyses .......................................14
7.1.2.
Planned Efficacy Statistical Analyses...........................................14
8.
SECONDARY STATISTICAL ANALYSES .............................................................16
8.1.
Efficacy Analyses........................................................................................16
8.1.1.
Overview of Planned Efficacy Analyses .......................................16
8.2.
Safety Analyses..........................................................................................17
8.2.1.
Overview of Planned Adverse Events Analyses...........................17
8.2.2.
Overview of Planned Clinical Laboratory Analyses ......................18
8.2.3.
Overview of Planned Other Safety Analyses................................19
8.3.
Pharmacokinetic Analyses..........................................................................20
8.3.1.
Overview of Planned Pharmacokinetic Analyses .........................20
8.3.2.
Drug Concentration Measures .....................................................20
8.3.3.
Pharmacokinetic Parameters.......................................................20
8.3.3.1.
Deriving Pharmacokinetic Parameters........................20
8.3.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................21
8.3.4.
Population Pharmacokinetic (PopPK) Analyses...........................21
8.4.
Biomarker Analyses....................................................................................21
8.4.1.
Overview of Planned Biomarker Analyses ...................................21
8.5.
Pharmacodynamic / Biomarker Statistical Analyses....................................22
8.5.1.
Overview of Planned Pharmacodynamic / Biomarker 
Analyses......................................................................................22
8.6.
Pharmacokinetic / Pharmacodynamic Analyses..........................................22
8.7.
Health Outcome Analyses ..........................................................................23
8.7.1.
Overview of Planned Health Outcome Analyses..........................23


CONFIDENTIAL
201023
3
9.
VIROLOGY ANALYSES.........................................................................................23
9.1.
Overview of Planned Virology Analyses......................................................23
9.2.
Planned Virology Statistical Analyses .........................................................24
10. REFERENCES.......................................................................................................26
11. APPENDICES........................................................................................................27
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................28
11.2.
Appendix 2: Time & Events.........................................................................28
11.2.1.
Protocol Defined Time & Events ..................................................28
11.3.
Appendix 3: Assessment Windows .............................................................32
11.4.
Appendix 4: Treatment States and Phases.................................................32
11.4.1.
Treatment Phases .......................................................................32
11.4.2.
Treatment States .........................................................................32
11.4.2.1.
Treatment States for Concomitant Medications 
Data ...........................................................................33
11.4.2.2.
Treatment States for AE Data.....................................33
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
11.5.1.
Study Treatment & Sub-group Display Descriptors......................33
11.5.2.
Baseline Definition & Derivations .................................................34
11.5.2.1.
Baseline Definitions....................................................34
11.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................34
11.5.3.
Reporting Process & Standards...................................................34
11.6.
Appendix 6: Derived and Transformed Data ...............................................36
11.6.1.
General........................................................................................36
11.6.2.
Study Population..........................................................................36
11.6.3.
Safety ..........................................................................................37
11.6.4.
Efficacy........................................................................................38
11.6.5.
Biomarker ....................................................................................39
11.6.5.1.
Biomarkers and Source..............................................39
11.6.6.
Health Outcomes.........................................................................40
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............42
11.7.1.
Premature Withdrawals................................................................42
11.7.2.
Handling of Missing Data.............................................................42
11.7.2.1.
Handling of Missing Dates..........................................42
11.7.2.2.
Handling of Partial Dates............................................43
11.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................43
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................43
11.8.1.
Laboratory Values........................................................................43
11.8.2.
ECG.............................................................................................43
11.8.3.
Vital Signs....................................................................................43
11.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............44
11.9.1.
Examination of Covariates, Subgroups & Other Strata.................44
11.10. Appendix 10: Multiple Comparisons & Multiplicity .......................................44
11.10.1. Handling of Multiple Comparisons & Multiplicity...........................44
11.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................44
11.11.1. Statistical Analysis Assumptions..................................................44
11.12. Appendix 12 – Abbreviations & Trade Marks ..............................................44


CONFIDENTIAL
201023
4
11.12.1. Abbreviations...............................................................................44
11.12.2. Trademarks .................................................................................44
11.13. Appendix 13: List of Data Displays..............................................................45
11.13.1. Data Display Numbering..............................................................45
11.13.2. Mock Example Shell Referencing ................................................45
11.13.3. Deliverable [Priority].....................................................................46
11.13.4. Study Population Tables..............................................................47
11.13.5. Efficacy Tables ............................................................................49
11.13.6. Efficacy Figures ...........................................................................49
11.13.7. Safety Tables...............................................................................51
11.13.8. Safety Figures .............................................................................53
11.13.9. Pharmacokinetic Tables...............................................................54
11.13.10.Pharmacokinetic Figures .............................................................55
11.13.11.Biomarker Figures .......................................................................55
11.13.12.Pharmacodynamic / Biomarker Figures .......................................57
11.13.13.Pharmacokinetic / Pharmacodynamic Tables ..............................59
11.13.14.Pharmacokinetic / Pharmacodynamic Figures .............................59
11.13.15.Health Outcome Tables ...............................................................59
11.13.16.Virology Tables............................................................................60
11.13.17.Virology Figures...........................................................................60
11.13.18.ICH Listings .................................................................................61
11.13.19.Non-ICH Listings..........................................................................64
11.14. Appendix 14: Example Mock Shells for Data Displays ................................67


CONFIDENTIAL
201023
5
1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose

This RAP describes all the planned analyses and outputs required for the end of 
study Synoptic Report for study 201023. 
Protocol

This RAP is based on the original protocol [(Dated: 12/Jul/2016) of study 
201023(GSK Document No: 2016N281688_00] and eCRF Version 1
Primary 
Objective

To assess the efficacy of treatment with IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir twice daily on time to clinical response
(TTCR)
Primary 
Endpoint
Time to Clinical Response (composite)

Hospital discharge
OR

Normalization of:  
-
Temperature; and 
-
Oxygen status; and 
-
Respiratory status/Heart Rate/SBP(normalization of 2 out of these 3
parameters)
Study 
Design

Phase 2, randomized, double-blind (for IV DNX), placebo-controlled (for IV DNX) 
3-arm study in adults to determine the efficacy and safety of IV DNX when 
coadministered (in all groups) with standard of care antiviral treatment (open-
label oral 75 mg OSV) for patients hospitalized with influenza.

Enrolled Subjects will be randomized 2:2:1 to 15 mg FBE IV DNX, 50 mg FBE IV 
DNX, or matching placebo. All subjects will also receive open-label oral OSV, 
twice daily (given as standard of care).

Study treatment duration will be for up to 5 days. The investigator may elect to 
continue treatment with standard of care (OSV) after 5 days of study treatment.

The sample size of 300 was selected based on simulations to achieve at least 
80% overall power under assumption of HR =1.5 for 50 mg of DNX FBE and HR 
=1.2 for 15 mg of DNX FBE and keep type I error less than 10% under no-effect 
assumption. The study was terminated early after 10 subjects were enrolled. 

An Independent Data Monitoring Committee (IDMC) will perform monitoring and 
reviews of available safety and efficacy data. 

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to unblinding of the study data.
Planned 
Analyses

The final analysis will occur when both accrual and follow-up are 
complete for all subjects. 
Primary 
Analysis 
Populations

‘Influenza Positive Population’ (IPP) comprises of all subjects in the 
ITT-E population with influenza infection (positive influenza PCR or 
culture at any timepoint) confirmed by central lab testing.


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Overview
Key Elements of the RAP
Hypothesis

No formal hypotheses will be tested and only descriptive summaries will be 
created for the final analysis.
Primary 
Analyses

Kaplan-Meier estimates for the median of TTCR for each treatment 
group and 95% confidence interval (CI) will be provided.
Secondary 
Analyses

Median, and 95% CI for time to respiratory response will be provided.

Proportion of subjects with clinical response, and improved respiratory 
status will be summarized.

Frequency of antibiotic use

Frequency of adverse events (AEs) and serious adverse events (SAEs)

Frequency of adverse events of special interest (AESIs)

Change from baseline in clinical laboratory evaluations

Summarize standard pharmacokinetic parameters for IV DNX (i.e. AUC, 
Cmax, Cavg).
Exploratory 
Analyses

Change in quantitative influenza viral load over time and change from 
baseline measured from nasopharyngeal swab samples as determined by 
qRT-PCR and quantitative virus culture (qVC)

Percentage of subjects with no detectable influenza viral RNA by qRT-
PCR and qVC.

Percentage of subjects with co-infected viruses by multiplex RT 
PCR.

Percentage by type of co-infected viruses by multiplex RT PCR.

Quantitative and qualitative changes in exploratory biomarkers 
(may include but are not limited to: IL-8, procalcitonin, respiratory 
neutrophil cell counts, neutrophil elastase, and myeloperoxidase).

PK exposure for DNX and pharmacodynamic parameters.

FLU PRO questionnaire 

Activities of daily living (Katz ADL Score)
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Given that the study has been terminated early and only 10 subjects have been enrolled, 
no formal hypothesis testing will be performed for the study. All analyses will be 
descriptive and not intended for making definitive conclusions. Only a selected set of 
originally planned analyses will be performed and all data will be listed. 


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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary

To assess the efficacy of treatment with 
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily on time to clinical response  
(TTCR)
Time to Clinical Response (composite)
Hospital discharge
OR
Normalization of:  
-
Temperature; and 
-
Oxygen status; and 
-
Respiratory status/Heart 
Rate/SBP(normalization of 2 
out of these 3 parameters)
Secondary

To assess the efficacy of treatment with 
IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily on time to respiratory 
response (TTRR)
Time to Respiratory Response defined as 
meeting at least one criterion below
Return to pre-morbid oxygen 
requirement (subjects with chronic
oxygen use), OR
Return to no requirement of
supplemental oxygen, OR
Respiratory rate ≤24/min (without
supplemental oxygen)

To evaluate clinical measures of influenza 
illness following treatment with IV DNX 
twice daily given with oral oseltamivir 
compared to oral oseltamivir twice daily
Time to absence of fever
Time to improved oxygen status
Time to improved heart rate
Time to improved SBP
Proportion of subjects with clinical response 
over time
Proportion of subjects with improved 
respiratory status over time
Time to improvement of ventilation status: 
modality, frequencies and durations of 
invasive and non-invasive ventilator support, 
duration of oxygen supplementation.
Length of stay in the ICU
Frequency of ICU admission and readmission
Length of stay in the hospital
Rates of development of septic shock
Frequency of antibiotic use


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Objectives
Endpoints
Proportion of subjects with improvement in 
Ordinal scale of clinical efficacy over time :
Death
Mechanical vent
In the ICU/ non MV
Non-ICU hospitalization
Hospital discharge

To characterize the safety and tolerability 
of IV DNX twice daily given with oral 
oseltamivir compared to oral oseltamivir 
twice daily
Frequency of adverse events (AEs) and 
serious adverse events (SAEs)
Frequency of adverse events of special 
interest (AESIs)
Change from baseline in clinical laboratory 
evaluations, and ECG parameters

To characterize the pharmacokinetics of 
IV DNX in subjects hospitalized for 
influenza
Standard pharmacokinetic parameters for IV 
DNX (i.e. AUC, Cmax, Cavg).
Exploratory

To assess changes in influenza viral load 
from nasopharyngeal swabs following 
treatment with IV DNX twice daily given 
with oral oseltamivir compared to oral 
OSV twice daily; perform resistance 
analysis and a multiplex PCR assay with 
respiratory virus panel to assess 
coinfection.
Change in quantitative influenza viral load 
over time and change from baseline 
measured from nasopharyngeal swab 
samples as determined by qRT-PCR and 
quantitative virus culture (qVC)
Percentage of subjects with no detectable 
influenza viral RNA by qRT-PCR and qVC.
Percentage of subjects with co-infected 
viruses by multiplex RT PCR.
Percentage by type of co-infected viruses by 
multiplex RT PCR.
Change in quantitative viral load of other virus 
co-infections over time and change from 
baseline measured from nasopharyngeal 
swab samples, as determined by qRT-PCR.
Frequency of emergent resistance to OSV

To explore the effects of IV DNX twice 
daily given with oral oseltamivir compared 
to oral OSV twice daily with IV DNX 
placebo on biomarkers of inflammation 
and immune response from nasal 
samples or fluid, endotracheal samples, 
whole blood, bronchoalveolar lavage, 
and/or serum.
Quantitative and qualitative changes in 
exploratory biomarkers (may include but are 
not limited to: IL-8, procalcitonin, respiratory 
neutrophil cell counts, neutrophil elastase, 
and myeloperoxidase).

To characterize the PK response 
PK exposure for DNX and pharmacodynamic 


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Objectives
Endpoints
relationship of IV DNX.
parameters.

To determine health outcome impact of IV 
DNX twice daily given with oral OSV 
compared to oral OSV twice daily
FLU PRO questionnaire
Activities of daily living (Katz ADL Score)
Activity level
Hospital readmission rates
2.3.
Study Design
Subjects meeting all eligibility criteria will be randomized 2:2:1 to one of three treatment groups in 
accordance with the central randomization schedule generated by Clinical Statistics prior to the 
start of the study, using validated internal software. All randomized subjects will take investigational 
drug or matching placebo twice daily for up to 5 days in the hospital.
2.4.
Statistical Hypotheses
No statistical hypotheses will be formally tested.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An Independent Data Monitoring Committee (IDMC) will perform monitoring and reviews of 
available safety and efficacy data. Details are specified in the IDMC charter. No formal interim 
analysis will be performed.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects enrol in the study at the time of study termination have completed the 
study, which is defined as completing the Day 45 assessment.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to Ramos NG procedures.


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4.
ANALYSIS POPULATIONS
Table 1
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Intent to Treat 
Exposed 
Population (ITT-
E)

Comprised of all randomized subjects who 
receive at least one dose of investigational 
product. Subjects will be assessed according 
to their randomized treatment, regardless of 
the treatment they receive.

Study Population 
and disposition
Safety

Comprised of all randomized subjects who 
receive at least one dose of IP.

This population will be based on the treatment 
the subject actually received.

Safety
Influenza Positive 
Population (IPP)

Comprised of all subjects in the ITT-E 
population with influenza infection (positive 
influenza PCR or culture at any timepoint) 
confirmed by central lab testing.

Efficacy, Health 
Outcomes, Virology, 
Biomarker
PK

Comprised of all subjects who underwent 
blood PK sampling during the study and from 
whom one or more blood concentration is 
determined.

PK
All Subjects 
Screened

Comprised of all subjects screened for 
inclusion in the study

Study Population
NOTES : 
Please refer to Appendix 13: List of Data Displays which details the population to be used for each display being
generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Treatment States and Phases
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
11.10
Appendix 10: Multiple Comparisons & Multiplicity
11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
11.12
Appendix 12: Abbreviations and Trade Marks
Error! 
Referen
ce 
source 
not 
found.
Appendix 13: List of Data Displays
11.14
Appendix 14: example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT-E population, unless otherwise 
specified.
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 3
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition
Y[1]
Reasons for Screen Failure
Y
Reasons for Study Withdrawal
Y[2]
Y
Reasons for Discontinuation of Study Treatment
Y
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y [3]
Populations Analysed
Study Populations
Y
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y[1]
Y
Race and Racial Combinations
Y
Y[4]
Prior and Concomitant Medications
Concomitant Medications
Y
Prior Exposure to Oseltamivir
Y
Exposure 
Exposure to Study Treatment
Y
Y
Other
Flu Details (includes influenza subtypes)
Y[1]
Y
Past and Current Medical Conditions
Y
Y
Chronic underlying illness at baseline for Subjects with 
Renal Impairment
Y[5]
Ventilation and Oxygenation Status at Baseline and Any 
Time
Y
Y
Chest X-ray at Baseline
Y


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Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
NOTES :

Y = Yes display generated.
[1] For ITT-E and IPP
[2] Included in the Summary of Subject Disposition
[3] Listing also includes analysis population exclusions.
[4] Listing of race
[5] Renal impairment is based on Creatinine Clearance Criteria .


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
The primary efficacy analyses will be based on the IPP population, unless otherwise 
specified.  Table 5 provides an overview of the planned efficacy analyses, with full 
details of data displays being presented in Appendix 13: List of Data Displays.
7.1.1.
Overview of Planned Efficacy Analyses
Table 4
Overview of Planned Primary Efficacy Analyses
Endpoint
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Absolute
Time to Clinical Response (TTCR)
Y[1]
Y
Proportion of Subjects Achieving Improved Clinical 
Response by End of Study
Y[1]
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
[1]. Proportion of clinical response and Kaplan Meier estimates for the median of TTCR for each treatment group 
and 95% CI will be provided
7.1.2.
Planned Efficacy Statistical Analyses
The clinical response is defined as hospital discharge due to clinical improvement or 
meeting following vital signs/ventilation criteria.


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Sign of clinical response
Response criteria
Temperature1
≤36.6°C (≤97.9°F) – axilla/temporal, or
≤37.2°C (≤99°F) – oral, or
≤37.7°C (≤99.9°F) – rectal/core5, tympanic
AND
Oxygen saturation 2,3
≥95% (without supplemental oxygen)
AND 2 out of the following 3 criteria:
Respiratory status

For subjects with chronic hypoxia and 
supplemental oxygen use: return to pre-morbid 
oxygen requirement, OR

For subject with supplemental oxygen use at 
study entry: need for supplemental oxygen 
(administered by any modality – ventilator, non-
invasive ventilation, facemask, face-tent, nasal 
canula, etc) to no need for supplemental oxygen, 
OR

For subject without supplemental oxygen use 
and respiratory rate > 24/min at study entry: 
respiratory rate ≤24/min 
Heart rate
≤100/min
Systolic blood pressure4
≥90 mmHg
1.
Without the use of antipyretics within 8 hours
2.
A subject with a history of chronic hypoxia (without supplemental oxygen) will satisfy normalization criteria for 
oxygen saturation if the value (without supplemental oxygen) is ≤2% from subject’s historical oxygen saturation 
baseline as recorded within 12 months prior to enrolment as documented in the subject’s medical records.
3.
This requirement will be waived for subjects with a history of chronic supplemental oxygen requirement who have 
a baseline oxygen saturation <95% with supplemental oxygen, within 12 months prior to enrolment as 
documented in the subject’s medical records.
4.
Without inotropic support administered within 2 hours.
5.
Core temperatures include rectal, indwelling catheters and Swan Ganz catheters.


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Statistical Analyses
Endpoint(s)

Time to Clinical Response (TTCR), days.  
Derivation of TTCR
The clinical response based on vital signs/ventilation status requires 24-hour 
confirmation. Considering 2-hour assessment window, the response confirmation period 
is 22 hours, i.e. all assessments within 22 hours of the initial response and at least one at 
or beyond 22 hours need to meet the criteria in order for the response to be confirmed. 
Any missing scheduled assessment will be imputed with response value of 0 (1 means 
response). Only hospital discharge due to clinical response or a confirmed response based 
on vital signs/ventilation criteria is considered as event for the TTCR analysis. Hospital 
discharge due to clinical improvement can serve as 24-hour confirmation for the clinical 
response and the event date should be the onset of the vital signs response. Subjects who 
died prior to achieving a clinical response will be assigned a worst value of TTCR (99 
days). All other subjects who did not achieve a confirmed response will be censored at 
the last assessment date of vital signs.
For further details of the calculation of TTCR see Section 11.6.4.
Model Specification
Not applicable
Model Checking & Diagnostics

Not applicable
Model Results Presentation

Not applicable
Sensitivity and Supportive Statistical Analyses

No sensitivity analyses or subgroup analyses will be performed given the small number of 
subjects.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the IPP population, unless otherwise 
specified.  Table 5 provides an overview of the planned efficacy analyses, with full 
details of data displays being presented in Appendix 13: List of Data Displays. Given the 
small number of subjects, only time to respiratory response will be summarized. Data 
relevant to other secondary endpoints will be listed including vital signs, ventilation 
status, hospital discharge, hospital re-admission, and ICU stay.


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Table 5
Overview of Planned Secondary Efficacy Analyses
Endpoint
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Absolute
Time to Respiratory Response (TTRR)
Y[1]
[1] Proportion of clinical response and Kaplan Meier estimates for the median of TTCR for each treatment group and the 
median difference and 95% CI between two comparisons: each DNX arm and OSV will be provided
8.2.
Safety Analyses
8.2.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.  
The summaries include on-treatment and post-treatment assessments unless otherwise 
noted.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 6
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and Maximum Grade
Y
Y
All AEs by Overall Frequency
Y
Grade 2-4 AEs by Overall Frequency
Y
All Drug-Related AEs  by Overall Frequency
Y
All Non-Serious AEs by Overall Frequency
Y
Drug-Related Grade 2-4 AEs by Overall Frequency
Y
Relationship Between AE SOCs, PT & Verbatim Text
Y
Listing of Adverse Events for Subjects with Neutropenia by Grade (>=Grade 1)
Y[1]
Serious and Other Significant AEs
Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
Y
Serious AEs by SOC
Y
Reasons for Considering as a Serious AE
Y
Drug-Related Non-Fatal Serious AEs
Y
Drug-Related Serious AEs by SOC
Y
Adverse Events Leading to Withdrawal from Study  by Overall Frequency
Y
Adverse Events Leading to Permanent Discontinuation of Study Treatment by 
Overall Frequency
Y
Summary of Serious Adverse Events by System Organ Class and Preferred 
Y


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Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Term  (Number of Subjects and Occurrences)
Summary of Non-serious Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1].Toxicity Grading is based on the Division of AIDS Grading (Section 12.5 of the protocol)
8.2.2.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
The summaries include on-treatment and post-treatment assessments unless otherwise 
noted.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 7
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Summary of Data Supporting Safety Halting Criteria
Y[1]
Chemistry Changes from Baseline 
Y
Creatinine by Visit
Y
Y
Y
Hematology Changes from Baseline
Y
Individual Plot of Absolute Neutrophils Count by Visit by 
Subject
Y
All Laboratory
Summary of Maximum Treatment Emergent Toxicities of 
All Lab Parameters
Y
Laboratory Data Abnormalities of Potential Clinical 
Importance (Grade 3-4)
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
[1] Summary includes the proportion of subjects with creatinine increase of 0.5 mg/dl on 2 consecutive visits


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8.2.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 8
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
All ECG Values for Subjects with a Value of PCI[1]
Y
Abnormal ECG Findings[2]
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] When QTc data is evaluated for PCI, all of the QTcB, QTcF and QTc collected in the eCFR are considered. Any 
one of the three meeting the PCI range is identified as an ECG event of PCI..
[2] When QTc data is evaluated for ECG abnormality, all of the QTcB, QTcF and QTc collected in the eCFR are 
considered. Any one of the three meeting the abnormality criteria is identified as an abnormal ECG Finding.


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8.3.
Pharmacokinetic Analyses
8.3.1.
Overview of Planned Pharmacokinetic Analyses
PK samples will be drawn on Day 1 (pre-dose, prior to 2nd dose), Days 3 and 5 to 
coincide with PD measurements (biomarkers) and additionally drawn on Day 3 (5th or 6th
dose) at 0.5, 1 (end of infusion), 1.5, 2, 3, 4, 8 and 12 hours post-dose.
Table 9 provides an overview of the planned analyses with full details being presented in 
Appendix 13: List of Data Displays.
Table 9
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
DNX Concentrations
Y
Y
Y
Y
Y
DNX PK Parameters 
Y
Y
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.  
8.3.2.
Drug Concentration Measures
Concentrations of Danirixin (GSK1325756) in blood will be listed and summarised by 
treatment group, day and nominal time. 
Individual blood concentration-time profiles and median/mean profiles by treatment 
group will be plotted. Each of the figures will contain one plot on the untransformed scale 
(i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot).
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3
Reporting Process & Standards).
8.3.3.
Pharmacokinetic Parameters
8.3.3.1.
Deriving Pharmacokinetic Parameters
Pharmacokinetic parameters described in Table 10 will be determined from the 
concentration-time data, as data permits.
Table 10
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-12)
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t)) will be calculated using the linear 


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Parameter
Parameter Description
trapezoidal rule for each incremental trapezoid and the log trapezoidal 
rule for each decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the 
concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time 
data.
Cavg
Average concentration.
8.3.3.2.
Statistical Analysis of Pharmacokinetic Parameters
No formal statistical analysis of derived pharmacokinetics parameter will be performed.
8.3.4.
Population Pharmacokinetic (PopPK) Analyses
Given the small number of subjects enrolled population PK analysis for this study will 
not be performed.
8.4.
Biomarker Analyses
8.4.1.
Overview of Planned Biomarker Analyses
The Biomarker analyses will be based on the Influenza Positive Population, unless 
otherwise specified.
Table 11 provides an overview of the planned Biomarker analyses, with full details of 
data displays being presented in Appendix 13: List of Data Displays.
Table 11
Overview of Planned Biomarker Analyses
[Endpoint / 
Parameter/ Display  
Type]
Untransformed
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Serum Biomarkers
Y
Y
Nasal wash 
biomarkers[1]
Y
Y
Nasal SAM strips
biomarkers
Y
Y
BAL Biomarker
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
[1] includes neutrophil count


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8.5.
Pharmacodynamic / Biomarker Statistical Analyses
8.5.1.
Overview of Planned Pharmacodynamic / Biomarker Analyses
The Pharmacodynamic / Biomarker analyses will be based on the Influenza Positive 
Population, unless otherwise specified.
Table 12 provides an overview of the planned Biomarker / Pharmacodynamic analyses, 
with full details of data displays being presented in Appendix 13: List of Data Displays.
Table 12
Overview of Planned Pharmacodynamic / Biomarker Analyses
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Biomarkers vs. Biomarkers
Y[1]
Area under the curve for Serum Biomarkers 
TTCR
Y[2]
Area under the curve for Nasal wash 
biomarkers – TTCR
Y[2]
Area under the curve for Nasal  SAM Strips 
biomarkers – TTCR
Y[2]
Area under the curve for BAL biomarkers –
TTCR
Y[2]
Area under the curve for Serum Biomarkers 
– TTRR
Y[2]
Area under the curve for Nasal wash 
biomarkers – TTRR
Y[2]
Area under the curve for Nasal  SAM 
biomarkers – TTRR
Y[2]
Area under the curve for BAL biomarkers –
TTRR
Y[2]
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
[1] Matrix comparative plot of individual scatter plot of biomarkers vs. biomarkers for Each Biomarker. The x 
and the y-axis will include Serum, Nasal Wash, Nasal SAM Strips and BAL. Include  the Pearson’s 
correlation coefficient and p-value.
[2] Individual scatter plot of area under the curve biomarkers vs Time to Clinical Response, Time to 
Respiratory Response.
8.6.
Pharmacokinetic / Pharmacodynamic Analyses
Relationships between Danirixin systemic exposure and the following pharmacodynamic 
measures will be explored graphically:


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
Target engagement biomarker:  IL-8, respiratory neutrophil cell counts, neutrophil 
elastase, and myeloperoxidase.
Pharmacokinetic/pharmacodynamic modelling may be attempted to describe any 
relationship including appropriate models for longitudinal variables versus systemic 
exposure. Results of PK/PD modelling analysis will be done under a separate Reporting 
and Analysis Plan and will be reported separately from the main CSR.
8.7.
Health Outcome Analyses
8.7.1.
Overview of Planned Health Outcome Analyses
The health outcome analyses will be based on the IPP population, unless otherwise 
specified.
Table 13
Overview of Planned Health Outcome Analyses
Endpoints
Absolute
Change from BL
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
KATZ ADL
Y
Y
Flu PRO
Y
Y
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.  
  
9.
VIROLOGY ANALYSES
9.1.
Overview of Planned Virology Analyses
The virology analyses will be based on the IPP population, unless otherwise specified.
Table 14 provides an overview of the planned analyses, with full details being presented 
in Appendix 13: List of Data Displays.
Table 14
Overview of Planned Virology Analyses
Endpoints
Absolute
Change from BL
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Influenza Viral Load by qRT-
PCR
Y
Y[2,3]
Y[1,2,3]
Influenza Viral Load by qVC
Y
Y[2,4]
Y[1,2,4]


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Endpoints
Absolute
Change from BL
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Resistance Associated 
Mutations Detected in the NA  
Gene by Subtype -   -  
Nasopharyngeal
Y
Y
Resistance Associated 
Mutations Detected in the HA  
Gene by Subtype -   -  
Nasopharyngeal
Y
Y
Proportion of Subjects - Positive 
Other Viruses by Multiplex
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.  
[1] Change from baseline plot for nasopharyngeal
[2] For nasopharyngeal
[3]  Overall virus and by subtype
[4] For subjects culture positive at baseline, if warranted. 
9.2.
Planned Virology Statistical Analyses
qVC data will be summarized for subjects who are culture positive at baseline.  For the 
RT-PCR summaries for Flu A and Flu B combined, coinfected subjects values will be 
averaged.
The following is a list of viruses detected in the multiplex assay:

Adenovirus

Coronavirus 229E 

Coronavirus HKU1 

Coronavirus OC43 

Coronavirus NL63 

Human Metapneumovirus 

Human Rhinovirus/Enterovirus 

Influenza A

Influenza A/H1 

Influenza A/H1-2009

Influenza A/H3 

Influenza B 

Parainfluenza 1 


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
Parainfluenza 2 

Parainfluenza 3 

Parainfluenza 4

RSV A+B
For the viruses with multiple subtypes, the data will be summarized by same virus family 
(e.g. corona virus, parainfluenza, and RSV, influenza A)
The list of mutations which includes but is not limited to H275Y will be provided only if 
the data is available.  


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10.
REFERENCES
FDA. Guidance for Industry. Center for Drug Evaluation and Research, United States 
Food and Drug Administration; 1999. Population Pharmackinetics. 


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11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Treatment States & Phases
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.8
Appendix 8: Values of Potential Clinical Importance
Section 11.9
Appendix 9: Examination of Covariates and Subgroups
Section 11.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.12
Appendix 12: Abbreviations & Trade Marks
Section 11.13
Appendix 13: List of Data Displays
Section 11.14
Appendix 14: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
No Per Protocol Population will be used in the analysis.
11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Table 15
Time and Events Table: Assessments at Baseline and During 
Treatment
Eligibilit
y 
Assess
ments
During Treatment - 5 daysa
Inpatient
Post-
treatme
nt (PT)
Inpatien
t
Procedures
Baselin
e/
Study 
Day 1a
Study 
Day 2
Study 
Day 3
Study Day 4 Study Day 
5 /day of 
last dosea
Study 
Day 6 if 
applicab
leb
Written informed consent
X
X
Subject demography
X
X
Physical examinationc
X
X
X
X
X
X
Daily
Influenza Test – locally 
performed (equipment 
provided by GSK)
X
X
Medical/Prior 
Medication/Drug/Smoking 
History
X
X
HIV and Liver Disease 
Historyd
X
X
Influenza symptomse
X
X
HIV, Hep B and Hep C 
Testf
X
X
Chronic underlying illness 
assessment
X
X
Inclusion/Exclusion Criteria
X
Safety/Efficacy 
Assessments
Chest X-rayg
X
ECGh
X
X
X
X
Adverse events
X
X
X
X
X
X
Daily
Concomitant 
medicationsi
X
X
X
X
X
X
Daily
Complications of 
influenza/associated 
antibiotic usej
X
X
X
X
X
X
Daily
Vital signs 
(temperature, HR, BP, 
respiratory rate, 
oxygen saturation, 
ventilation status)k
X
X
X
X
X
X
X
3 x Daily


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Eligibilit
y 
Assess
ments
During Treatment - 5 daysa
Inpatient
Post-
treatme
nt (PT)
Inpatien
t
Procedures
Baselin
e/
Study 
Day 1a
Study 
Day 2
Study 
Day 3
Study Day 4 Study Day 
5 /day of 
last dosea
Study 
Day 6 if 
applicab
leb
Flu PRO
X
X
X
X
X
X
Daily
Katz Activities of Daily 
Livingl
X
X
X
X
X
X
Daily
Activity levelm
X
X
X
X
X
X
Daily
Laboratory Assessments
Chemistry including 
Liver Function Tests 
(Local+Central)n
X
X
X
X
X
Day 
6,7,8
Serum creatinine 
(Local+Central) o
X
X
X
X
X
X
X
Day 
6,7,8
Hematology 
(Local+Central) p
X
X
X
X
X
Day 
6,7,8
Urine Output q
X
X
X
X
X
X
Pregnancy testr
X
X
PT Day 
3
Nasopharyngeal swabs
X
X
X
X
Day 
8,12,16,
20,24,28
,32
Nasal Swabt
X
X
BALu
X
X
X
X
Endotracheal aspiratev
X
X
X
X
Day 
8,16,24,
32, 45
Nasal SAM strips 
(biomarkers)w
X
X
X
X
Day 
8,16,24,
32, 
dischar
ge or 
Day 45
Nasal washesx
X
X
X
X
Day 
8,16,24,
32, 
dischar
ge or 
Day 45
Exploratory Biomarkers 
(Blood Sample)
X
X
X
X
Day 
8,16,24,
32, 
dischar
ge or 
Day 45
PK sample (Dried Blood 
Spot)y
X
X
X
X
Genetics Sample (Blood 
Sample)z
X
Transcriptomics (Blood 
Sample)z
X
X
X
X
Day 8, 
16, 24, 


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Eligibilit
y 
Assess
ments
During Treatment - 5 daysa
Inpatient
Post-
treatme
nt (PT)
Inpatien
t
Procedures
Baselin
e/
Study 
Day 1a
Study 
Day 2
Study 
Day 3
Study Day 4 Study Day 
5 /day of 
last dosea
Study 
Day 6 if 
applicab
leb
32, 
dischar
ge or 
Day 45
Study Treatments
Administration of 
investigational 
medication (IV) and 
oseltamivir (oral) twice 
daily
X
X
X
X
X
X
a.
A ‘Day’ is defined as a 24 hour period (Treatment Day), therefore depending on the start time of the first dose of 
IV DNX, a Treatment Day may span two calendar days.
b.
Day 6 assessments only applicable if last day of dose of randomized treatment is on Day 6 (i.e for subjects who 
received first dose after 12 noon on Baseline/Day 1.
c.
Physical exam to be performed twice daily for subjects in the sentine cohort.
d.
Enrollment into the study will be based on history of diagnosis of HIV and liver disease. Blood samples will be 
analyzed after enrollment to retrospectively determine if subject is HIV, Hep B or Hep C postivie; however, 
results will not be available until after completion of dosing.
e.
Influenza symptoms to be assessed only at baseline for inclusion.
f.
Enrollment into the study will be based on any history of diagnosis of HIV and liver disease. 
g.
Chest X-ray at Baseline and whenever clinically indicated. 
h.
ECG: For the ECG on Baseline/Day 1, one 12-lead ECG (can be done within approximately 24 hours prior to 
dosing). At Baseline and on Day 5 or last treatment day, a monitoring strip can be utilized if a 12-lead ECG 
cannot be performed.
i.
Concomitant medications for influenza treatment of the current episode to be recorded from Day -7 (i.e. one week 
prior to baseline), if available.
j.
Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, ARDS, myositis, 
encephalitis, myocarditis, and associated antibiotic use will be recorded on all assessment days.
k.
Vital signs and ventilation status to be assessed three times daily during the treatment period between 
approximately 8 AM and 8 PM. 
l.
Katz ADL score collected once daily while hospitalized.
m.
Activity level to be recorded as one of three responses (bed rest, limited ambulation or unrestricted) everyday 
while hospitalized
n.
Chemistry panel including Liver Function Tests to be required once every other day during treatment (local testing 
(L) of LFTs for subject management as well as central laboratory testing (C)).
o.
Serum creatinine level required at Baseline and twice daily during treatment for subjects in the sentinel cohort. For 
all other subjects, serum creatinine level required at Baseline and once daily during treatment (local testing 
(L) for subject management as well as central testing(C)).  
p.
Hematology panel including CBC with differential required every other day during treatment (local testing (L) for 
subject management as well as central testing(C))
q.
Urine output to be measured twice daily for subjects in the sentinel cohort.
r.
Ultrasensitive urine or blood pregnancy test required in women of childbearing potential prior to dosing and 3 days 
post last dose of study treatment.
s.
Nasopharyngeal swab will be used for influenza Subtype RT-PCR, qRT-PCR, quantitative culture and may also 
be used for rapid influenza diagnosis; Will also be used for viral genotyping and phenotyping if needed and 
multiplex PCR assay.
t.
Nasal swab collected for influenza diagnostic test or other local test for influenza diagnosis


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u.
BAL samples (for biomarkers) are requested only if the procedure/sampling is being carried out for routine 
management of the patient and at any timepoint throughout the study
v.
Endotracheal aspirates (biomarkers/neutrophil counts) are required for subjects who are intubated.
w.
Nasal samples for biomarkers will be collected at the days indicated from all subjects using nasal SAM strips.
x.
An optional procedure, nasal wash, will be used to collect nasal samples from as many non-intubated subjects as 
feasible.
y.
PK samples will be drawn on Day 1 (pre-dose), Days 3 and 5 to coincide with PD measurements (nasal washes if 
done, endotracheal samples and a blood draw for exploratory biomarkers).  In sentinel cohort 1 (less severe 
subjeccts with normal renal function), PK samples will be additionally drawn on Day 3 at pre-dose, and 0.5, 1 
(end of infusion), 1.5, 2, 3, 4, 8 and 12 hours post-dose. Note: PK draws must be collected from the 
opposite arm from the infusion arm.
z.
Informed consent for optional substudies (e.g., genetic research and transcriptomics), must be obtained before 
collecting samples.  In subjects who consent, a blood sample for genetic research is collected at the baseline 
visit, or at the earliest point possible during the treatment period for genetic research testing; blood samples 
for transcriptomics are taken on each of the indicated days and used to evaluate changes in transcriptome 
profiles. 
Table 16
Time and Events Table: Post-Treatment and Post-Discharge 
Assessments
Post-Discharge Visits/TCs and Assessments
Outpatient a
Procedures
PT Day 3 
(Visit)
Study 
Day 8 
(TC)
Study 
Day 
15 
(TC)
Study Day 22 
(TC)
Study Day 
30 (TC)
Study Day 45 
(Visit)
Safety/Efficacy 
Assessments
Adverse events
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Brief Physical Exam
X
X
Complications of influenza / 
associated antibiotic useb
X
X
X
X
X
X
Temperature 
X
X
X
X
X
X
Other Vital signs (HR, BP, 
respiratory rate, oxygen 
saturation, ventilation status)c
X
X
Flu PROd
Daily 
through Day 
14
Daily 
through 
Day 14
X
X
X
X
Katz Activities of Daily Livinge
X
X
X
X
X
X
Activity levelf
Daily 
through Day 
14
Daily 
through 
Day 14
X
X
X
X
Laboratory Assessments
Clinical chemistryincluding 
LFTsg (Local+Central)
X
X
Serum Creatinineh
(Local+Central)
X
X
Hematologyi
(Local+Central)
X
X
Pregnancy testj
X
Nasopharyngeal swabs
X
Exploratory Biomarkers (Blood 
Sample)k
X
X
Transcriptomics (blood 
X
X


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sample)l
Nasal SAM strips 
(biomarkers)m
X
X
Nasal washesm
X
X
Hospital Readmission Status
X
X
X
X
X
X
a.
Following discharge from hospital, outpatient clinic visit/TC schedule of assessments will be followed for those 
patients who are discharged before Day 45.  For 5 days treatment, PT Day 3 will be the same as Day 8 and will 
be a clinic visit.
b.
Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, ARDS, myositis, 
encephalitis, myocarditis, and associated antibiotic use will be recorded on all assessment days.
c.
Vital signs and ventilation status will be assessed at clinic visits (PT Day 3 and Day 45).
d.
FLU PRO to be measured once daily through Study Day 14.
e.
Activities of Daily Living (Katz Scale) to be done at clinic visits and at TCs. 
f.
Activity level assessed by reporting on a 3 point scale of bed rest (1), limited ambulation (2) or unrestricted (3) to 
be done daily through Study Day 14. 
g.
Clinical chemistry including LFTs to be required once every other day until PT Day 3 (for LFTs, local testing for 
subject management until PT Day 3; central testing for all assessments, including at Day 45).
h.
Serum creatinine required once every day until PT Day 3 (local testing for subject management until PT Day 3; 
central testing for all assessments, including at Day 45).
i.
Hematology panel including CBC with differential required once every other day until PT Day 3 (local testing for 
subject management until PT Day 3; central testing for all assessments, including at Day 45).
j.
Ultrasensitive urine pregnancy test required in women of childbearing potential on PT Day 3.
k.
Blood samples will be collected for exploratory biomarkers at PT Day 3, and at Study Day 45.
l.
Blood samples for transcriptomics will be collected on PT Day 3 and Study Day 45 and are optional. Samples will 
be collected only from those subjects who provide informed consent for genetic research.
m.
Nasal samples for biomarkers will be collected at PT Day 3 and Study Day 45 from all subjects using nasal SAM 
strips.  In addition, an optional procedure, nasal wash, will be used to collect nasal samples from as many non-
intubated subjects as feasible.
11.3.
Appendix 3: Assessment Windows
This study will not use assessment windows.
11.4.
Appendix 4: Treatment States and Phases
11.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment, unless otherwise specified.
Treatment Phase
Definition
Pre-Treatment 
Date< Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
11.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.


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11.4.2.1.
Treatment States for Concomitant Medications Data
Treatment State
Definition
Pre- Treatment
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date
Post Treatment
Date > Study Treatment Stop Date
NOTES: 

If the study treatment stop date is missing then the assessment will be considered to be On-Treatment.  “On-
Study” is considered assessment on-treatment and post-treatment.
11.4.2.2.
Treatment States for AE Data
Unless otherwise noted, AE summaries will include both On-Treatment and Post-
Treatment AEs.
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date [+ Lag 
Time]
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Drug-related
If relationship is marked ‘YES’ on InForm OR value is missing
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.
11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A 
15 mg FBE IV DNX BID +75 mg OSV 
BID
15 mg DNX +OSV
2
B 
50 mg FBE IV DNX BID + 75 mg OSV 
BID
50 mg DNX +OSV
3
C 
IV DNX placebo BID + 75 mg OSV 
BID
PBO + OSV
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.


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11.5.2.
Baseline Definition & Derivations
11.5.2.1.
Baseline Definitions
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in Data 
Display
Screening
Day 1
Vital Signs (temperature, HR, BP,
respiratory rate, oxygen status,
ventilation status)
X
X
Day 1
12 Lead ECG
X
X
Day 1
Laboratory parameters
X
X
Day 1
Nasopharyngeal Swab
X
Day 1
Nasal Swab
X
X
Day 1
Nasal SAM strips (biomarkers)
X
Day 1
Nasal wash biomarker
X
Day 1
BAL biomarkers
X
Day 1
Serum Biomarkers 
X
Day 1
Katz ADL
X
Day 1
Flu PRO
X
Day 1
For all endpoints (unless stated otherwise) the baseline value will be the latest pre-dose 
assessment. This is generally expected to be from the Day 1 visit, although such values 
may be missing or unscheduled assessments may be performed before treatment start.
11.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
11.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and TSCG software will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Area
: \ARPROD\GSK1325756\MID201023\Final_xx
QC Spreadsheet
: \ARWORK\GSK1325756\MID201023\Final_xx\documents  
Analysis Datasets 


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Reporting Process

Final analysis and IDMC datasets will be created based on Integrated Data Standards 
Library (IDSL).

RTF files will be generated for final analysis.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables or figures, unless otherwise stated.

Unscheduled visits will be included in the maximum toxicity or maximum change from 
baseline for toxicity tables.   

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 


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Reporting Standards
Summary Statistics 
(Log Transformed)
of logged data and between geometric coefficient of variation (CVb (%)) will 
be reported.
o
CVb (%) = √ (exp(SD2) - 1) * 100
             (SD = SD of log transformed data)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a visit the value closest to the planned/target day for that visit will 
be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Treatment Start Date
Treatment start date is defined as follows:

Treatment start date is the date entered onto the IP exposure CRF for when study treatment 
started.
Study Day

Calculated as the number of days from initial study treatment start date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Treatment Start Date   → Study Day = Ref Date –Treatment Start Date    

Ref Data ≥ Treatment Start Date   → Study Day = Ref Date – (Treatment Start Date) + 1  
Note that Treatment Start Date is considered to be on Study Day 1 and the day before this is Study 
Day -1; i.e., there is no Study Day 0.
Post-baseline 

Post-baseline refers to the combined time periods of On-treatment and Post-treatment. 
11.6.2.
Study Population
Demographics
Age

Age, in whole years, will be calculated with respect to the subject’s Screening visit.  

GSK standard IDSL algorithms will be used for calculating age where birth date.

Birth date will be presented in listings as ‘YYYY’.


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Demographics

Completely missing dates of birth will remain as missing, with no imputation applied. 
Consequently, the age of the subject will not be calculated and will remain missing.
Body Mass Index (BMI)

If not already provided, BMI will be calculated as Weight (kg) / [Height (m)]2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
11.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

Machine-read values of RR, QTcB or QTcF should not be replaced with re-derived 
values

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
Laboratory Parameters

Influenza Virus load data from Viroclinics will be imputed as following: 

LLOQ and LLOD per subtype are dependent on the data, assume the values are x.xx, 
y.yy, z.zz, and w.ww for LLOQ, LLOD for qPCR A and q PCR B, respectively


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ECG Parameters

qPCR A:   LLOQ=: x.xx log vp/ml,  LLOD: y.yy  log vp/ml
o
When CT neg (i.e. qPCRA<LLOD), impute y.yy - 0.01
o
When qPCRA between LLOD and LLOQ, impute x.xx – 0.01
o
When qualitative results are derived from qPCR: when CT is positive value then 
“Virus detected” and when CT is neg then “Virus not detected”.

qPCR B: LLOQ: z.zz log vp/ml, LLOD:w.ww log vp/ml
o
When CT neg (i.e. qPCRB <LLOD), impute w.ww – 0.01.
o
When qPCRB between LLOD and LLOQ, impute z.zz – 0.01
o
When qualitative results are derived from qPCR: when CT is positive value then 
“Virus detected” and when CT is neg then “Virus not detected”.

TCID50: LLOQ = 0.75
o
When <0.75 impute 0.75 – 0.01 = 0.74. 
o
When qualitative results are derived from TCID50: when TCID50 <0.75 impute 
“No Virus Isolated”, when >0.75 impute “Virus Isolated”.

For other laboratory values, if laboratory value which is expected to have a numeric value for 
summary purposes, has a non-detectable level reported in the database, where the numeric 
value is missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field) is present, the number of significant digits in the 
observed values will be used to determine how much to add or subtract in order to impute the 
corresponding numeric value. If a character value starting with “<=x”, then the numeric value 
will be x.
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ or ‘>=x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
11.6.4.
Efficacy
Time to Clinical Response (TTCR)
TTCR will be derived as detailed in Section 7.1.2 The following is further considerations 
for the derivation of TTCR

If an assessment time is missing the following times 
will be used in the calculation of TTCR:  8:00, 14:00, 20:00  respectively for 
morning, afternoon and evening assessments. The imputation will not be done for 
the study day 1.

If the subject was discharged but is missing the date of discharge then the latest 
day from individual components will be used. If subject was discharged but the 
time of discharge is missing, 12:00 time will be used.

If the subject withdraws consent on the same day as hospital discharge, TTCR will 
not be considered a failure. 


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
Deaths which occur after clinical response will not be considered a failure

When a subject met vital sign criteria and was discharged from hospital during the 
24 hour period of stability confirmation, the time of achieving TTCR was defined 
as the initial time at which vital signs were resolved and not the time of hospital 
discharge.

If the clinical response has not been achieved by study completion, TTCR will be 
censored at the last assessment date of vital signs.

If the subject did not achieve a clinical response the reason for censoring will be 
summarized (i.e. did not achieve vital sign resolution or reason for prematurely 
discontinuing the study).
Time to Respiratory Response (TTRR)

Time to Respiratory Response defined as the first time meeting below, for at least 24 hours:
o
Return to pre-morbid oxygen requirement (subjects with chronic oxygen use), OR
o
Need for supplemental oxygen (administered by any modality – ventilator, non-
invasive ventilation, facemask, facetent, nasal canula, etc) to no need for 
supplemental oxygen, OR
o
Respiratory rate >24/min and no supplement oxygen at baseline, and post baseline 
respiratory rate ≤24/min (without supplemental oxygen)

Subjects who meet the above criteria at baseline (i.e., normal respiratory response) will not 
be included in the Kaplan Meier analysis and these subject not be considered as 
“improved” in the response rate 

If the symptoms have not resolved at Day 45, it will be censored at Day 45.
11.6.5.
Biomarker
11.6.5.1.
Biomarkers and Source
SAM 
Serum 
Nasal Wash 
BAL 
IL-6, IL-10, IP-
10, IL-8, MPO, 
NE, IL-1b 
Procalcitonin 
IL-6, IL-10, IP-10, 
IL-8, MPO, NE, IL-
1b 
IL-6, IL-10, IP-
10, IL-8, 
MPO, NE, IL-
1b 
C1M, C3M,     EL-NE 
Neutrophil Cell 
Counts 
SP-D, sRAGE,
SP-D, sRAGE 
SP-D, sRAGE 
SP-D, sRAGE 


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Biomarker

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
AUC of Biomarker

The area under the curve (AUC) to Day 5, Day 45, and  PT Day 3 of biomarker as measured by 
the level of biomarker from biomarkers source;

The AUC will be calculated as
             AUC (0-Day x) = 0-l{½(Ci+Ci+1)(ti+1-ti)} 
Where, 
Ci = level of biomarker at actual time point i in Day
ti = actual time of assessment for time point i in Day
i = actual time of assessment in Day (e.g. Day 1, 3, 5, 8, 16, 24, 32,day 45)
l = last i (Day 5, Day 45, or PT Day 3 )

Actual study day will be used for the AUC calculation.

When baseline value of a biomarker is missing, AUC for the biomarker will be missing. 

When a subject has only baseline value, AUC will be missing.

When value of a biomarker is missing between visits, there will be no imputation for the 
missing value, e.g. subject has day 1, 3, 5, 8, 16, 32, 45 values, and day 24 value is 
missing, day 24’s value will not be imputed, AUC will be calculated using day 1,3,5, 8,16, 
32, and 45 values.

When value of a biomarker is missing at the end, last observation carried forward (LOCF) 
will be used to impute missing value, e.g, subject has day 1, 3, 5, 8, 16, 24, 32 values and 
day 45 is missing, day 45 value will be imputed using day 32 value (day 45 value will be 
assumed the same as day 32 value).

The value of the AUC(0-45) biomarker is missing if there is no assessment beyond week 
24.

The length of time from Baseline to PT Day 3 visit will vary for subjects who prematurely 
discontinue the study and so the biomarker will also vary.
11.6.6.
Health Outcomes
The FLU-PRO Total score is computed as a mean score across all 32 items comprising the 
instrument. Total scores can range from 0 (symptom free) to 4 (very severe symptoms).


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Six domain scores are also computed, representing symptom severity in each of the 
following body areas: Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal, and 
Body/Systemic. Each domain score is calculated as the mean of all items comprising the 
domain. Each FLU-PRO domain score also ranges from 0 to 4. Algorithms and 
instructions for computing scores for the FLU-PRO Total and domain scores (including 
rules for handling missing data) are provided below:
Domain
Items
Scoring 
Minimum Data 
Requirement
Nose
Runny or dripping nose
Congested or stuffy nose
Sneezing
Sinus pressure
Arithmetic mean of 4 
items within Nose
domain
3 of 4 items must 
be present to 
calculate domain 
score
Throat
Scratchy or itchy throat
Sore or painful throat
Difficulty swallowing
Arithmetic mean of 3 
items within Throat
domain
2 of 3 items must 
be present to 
calculate domain 
score
Eyes
Teary or watery eyes
Sore or painful eyes
Eyes sensitive to light
Arithmetic mean of 3 
items within Eyes
domain
2 of 3 items must 
be present to 
calculate domain 
score
Chest/Respiratory
Trouble breathing
Chest congestion
Chest tightness
Dry or hacking cough
Wet or loose cough
Coughing
Coughed up mucus or 
phlegm
Arithmetic mean of 7 
items within 
Chest/Respiratory 
domain
5 of 7 items must 
be present to 
calculate domain 
score
Gastrointestinal
Felt nauseous
Stomach ache
How many times did you 
vomit?
How many times did you 
have diarrhea?
Arithmetic mean of 4 
items within 
Gastrointestinal
domain
3 of 4 items must 
be present to 
calculate domain 
score
Body/Systemic
Headache
Head congestion
Felt dizzy
Lack of appetite
Sleeping more than usual
Body aches or pains
Weak or tired
Chills or shivering
Felt cold
Felt hot
Sweating
Arithmetic mean of 11 
items within 
Body/Systemic 
domain
8 of 11 items 
must be present 
to calculate 
domain score


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Total
All above 32 items
Arithmetic mean of all 
32 items within FLU-
PRO
In the presence 
of missing data, 
the above 
conditions for the 
calculation of all 
domain scores 
must be met in 
order to calculate 
the FLU-PRO 
total score.
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as a 
subject who completed the Day 45 assessment.

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.


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11.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will not be 
imputed.

The recorded partial date will be displayed in listings.
Adverse 
Events, 
Exposure

No missing data is expected for AE and EX.

Data Management will query any missing date of AE or EX.
11.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Time to 
Clinical 
Resolution 

For the primary analysis, a Discontinuation=Failure approach will be used (see 
Section 7.1.2).  This approach handles two types of missing data:
o
due to subjects who prematurely discontinued the study
o
sporadic missing vital sign assessments
11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Laboratory parameter will be graded according to the Division of AIDS (DAIDS) toxicity
scales (protocol Section 12.5 ).
11.8.2.
ECG
The following subdivision will be used to summarize the absolute and increase from 
baseline QTc interval data, and absolute PR interval by category
.
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>450 to ≤480
msec
Absolute QTc Interval
>480 to ≤500
msec
Absolute QTc Interval
>500
msec
Increase from Baseline QTc
>30 to ≤60
msec
Increase from Baseline QTc
>60
msec
Absolute PR interval
210-250
msec
Absolute PR interval
>250
msec
11.8.3.
Vital Signs
Due to patient population, vital signs will not be flagged as potential clinical importance.


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11.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
11.9.1.
Examination of Covariates, Subgroups & Other Strata
Given the small number of subjects, no subgroups will be assessed.
11.10.
Appendix 10: Multiple Comparisons & Multiplicity
11.10.1.
Handling of Multiple Comparisons & Multiplicity
There will be no adjustments for multiplicity.
11.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
11.11.1.
Statistical Analysis Assumptions
Not applicable
11.12.
Appendix 12 – Abbreviations & Trade Marks
11.12.1.
Abbreviations
11.12.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
RELENZA
Captisol
FluPRO 
KATZ ADL
SAS
Tamiflu


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11.13.
Appendix 13: List of Data Displays
11.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Biomarker
5.1 to 5.n
5.1 to 5.n
Pharmacodynamic / Biomarker
6.1 to 6.n
6.1 to 6.n
Pharmacokinetic / Pharmacodynamic
7.1 to 7.n
7.1 to 7.n
Health Outcome
8.1 to 8.n
8.1 to 8.n
Virology
9.1 to 9.n
9.1 to 9.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
11.13.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 14: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Biomarker
BM_Fn
BM_Tn
BM_Ln
Pharmacodynamic / Biomarker
BMPD_Fn
BMPD_Tn
BMPD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
Health Outcomes
HO_Fn
HO_Tn
HO_Ln
Virology
VR_Fn
VR_Tn
VR_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’


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11.13.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
DL
Data Look (blinded dry run)
IA 
Interim Analysis Statistical Analysis Complete
HL
Headline
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


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11.13.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Subject Disposition
1.1.
ITT-E
ES1
Summary of Subject Disposition
1.2.
ITT-E
SD4
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
Protocol Deviation
1.3.
ITT-E 
DV1
Summary of Important Protocol Deviations
Population Analysed
1.4.
All Subjects 
Screened
SP1
Summary of Study Populations
Demographic and Baseline Characteristics
1.5.
ITT-E
DM1
Summary of Demographic Characteristics
Add age groups <35, 35-<50, >=50 and < 65, >=65.  
Add BMI and BMI categories <=20, 20-<=25, 25-
<=30, 30-<=35, 40-<=45,>45 .  Add tobacco use.
1.6.
ITT-E
DM5
Summary of Race and Racial Combinations
Prior and Concomitant Medications
1.7.
ITT-E
POP T2
Summary of Prior Exposure to Oseltamivir
Add a footnote “Only influenza therapies taken within 
7 days of baseline visit were collected”
CMPRIOR=’Y” or if medication started prior to IP 
start.No imputation for missing values


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
1.8.
ITT-E
CM1
Summary of Prior Anti-influenzaTherapy
Includes pre-treatment CMs used for Anti-influenza 
therapy. Study team to review & provide list of CM 
terms prior to DBR
Add a footnote “Only influenza therapies taken within 
7 days of baseline visit were collected”
1.9.
ITT-E
CM1
Summary of Post-Treatment Anti-influenzaTherapy
Consider post-treatment as those records where the 
conmed start or end date are after the IP end date.  
Apply same logic for Table 1.11
1.10.
ITT-E
CM1
Summary of Pre-Treatment Steroids Use by Duration of Time
Add a column for “Pre-Treatment Steriod Use’
Add a footnote “Only influenza therapies taken within 
7 days of baseline visit were collected”
the steroid use will be grouped as 3 categories, <1 
week, 1 week – <6 months and 6 months and more, the 
table will summarize the number and percent of 
subject in each group
1.11.
ITT-E
CM1
Summary of Post-Treatment Steroid Use
Other
1.12.
ITT-E
POP T3
Summary of Flu Type and Symptoms
Includes influenza subtypes
1.13.
ITT-E
MH4
Summary of Past and Current Medical Conditions
By  ‘Past’, ‘Current’, ‘No’
1.14.
ITT-E
POP T4
Summary of Ventilation Status at Baseline 
1.15.
ITT-E
POP T6
Summary of Exposure to Study Treatment
1.16.
IPP
POP T4
Summary of Ventilation Status at Baseline 


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11.13.5.
Efficacy Tables
Efficacy Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Efficacy
2.1.
IPP
EFF T2
Summary of Improved Clinical Response 
2.2.
IPP
EFF T6
Summary of Improved Respiratory Response
2.3.
IPP
Summary of Post Baseline Ventilation Status
Mock per IVZ
2.4.
IPP
CM1
Summary of Frequency of Associated Antibiotic Use for 
Treatment of Complications of Influenza
List will be identified by study team prior to unblinding
11.13.6.
Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.1.
IPP
EFF F1
Individual Plot of Time to Clinical Response 
10 lines for 10 subjects with different 
symbols representing event or 
censoring and different color 
representing different treatment.


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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
2.2.
IPP
EFF F1
Individual of Time to Respiratory Response (Improved 
Respiratory Status)
10 lines for 10 subjects with different 
symbols representing event or 
censoring and different color 
representing different treatment, 
including any subject who resolved 
prior to baseline (negative response 
time, with a footnote).


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11.13.7.
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.1.
Safety
SAFE T1
Summary of All Adverse Events by System Organ Class and 
Maximum Grade
Please add a footnote to indicate “Mild 
or Grade 1”, “Moderate or Grade 2”, 
“Severe or Grade 3”, “Grade 4”.
3.2.
Safety
AE3
Summary of All Adverse Events by Overall Frequency
3.3.
Safety
AE3
Summary of Grade 2-4 Adverse Events by Overall Frequency
3.4.
Safety
AE3
Summary All Drug-Related Adverse Events by Overall 
Frequency
3.5.
Safety
AE1
All Non-Serious Adverse Events by SOC and PT
Eudra
3.6.
Safety
AE16
SAE with number of subjects and number of occurrences by 
SOC and PT
Eudra
3.7.
Safety
AE3
Summary of Drug-Related Grade 2-4 Adverse Events by Overall 
Frequency
3.8.
Safety
AE3
Summary of Adverse Events of Special Interest by Overall 
Frequency
AE terms for AESI will be provided prior 
to unblinding.
3.9.
Safety
AE8
Listing of Adverse Events for Subjects with Neutropenia (>= 
Grade 1)
3.10.
Safety
AE3
Summary of Non-Fatal Serious Adverse Events


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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.11.
Safety
AE1
Summary of Serious Adverse Events by System Organ Class
3.12.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class
3.13.
Safety
AE3
Summary of Drug-Related Non-Fatal Serious Adverse Events
3.14.
Safety
AE15
Summary of Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) 
3.15.
Safety
Summary of Maximum Treatment Emergent Toxicities of All Lab 
Parameters
IDMC output
3.16.
Safety
SAFE T2
Summary of Data Supporting Safety Halting Criteria
3.17.
Safety
LB1
Summary of Creatinine by Visit
3.18.
Safety
LB1
Summary of Change from Baseline for Serum WBCs, % 
Neutrophils, and Absolute Neutrophils Counts, Creatinine, Liver 
Function Test
IDMC output
3.19.
Safety
LB1
Summary of Absolute Neutrophils Count by Visit 


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11.13.8.
Safety Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
3.1.
Safety
Individual Plot of Creatinine by Visit by Subject
3.2.
Safety
Individual Plot of Absolute Neutrophils Count by Visit by Subject
Page per each subject with a vertical 
line on day of treatment discontinued, 
include treatment, sex, age, in addition 
to subject ID


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11.13.9.
Pharmacokinetic Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
4.3
PK
PK06
Summary of Derived Whole Blood Danirixin PK 
Parameters (non-transformed and log-transformed)  by 
Treatment 
4.4
PK
PK01
Summary of Whole Blood Danirixin Pharmacokinetic 
Concentration-Time Data (insert units) by Treatment and 
Day 
Replace (insert units) with unit of 
measure.
Include all subjects


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11.13.10. Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
4.1
PK
PK20
Median (IR)  Plot of Whole Blood Danirixin Concentration-
Time Plot (Linear and Semi-Log)  by Treatment 
1. Include line for LLQ along
with footnote defining LLQ
value
2. Overlay Day 1, 3 and 5.
4.2
PK
PK20
Mean (SE)  Plot of Whole Blood Danirixin Concentration-
Time Plot (Linear and Semi-Log)  by Treatment 
1. Include line for LLQ along
with footnote defining LLQ
value
2. Overlay Day 1, 3 and 5.
4.5
PK
PK16a
Individual Whole Blood Danirixin Concentration-Time
Plots by Subject (Linear and Semi-log) 
1. X-axis displays actual
relative time
2. Include line for LLQ along
with footnote defining LLQ
value
3. Include values below LLQ
4. Overlay Day 1, 3 and 5
11.13.11. Biomarker Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
5.1.
IPP
BM_F2
Individual Plot of Serum Biomarkers by Visit by Subject -
Influenza Positive Population  
spaghetti plot, one plot per biomarker 
per matrix. Subject ID and treatment 
group should be identifiable by 
color/symbol
5.2.
IPP
BM_F2
Individual Plot of Nasal Wash Biomarkers by Visit by Subject -
Influenza Positive Population  
spaghetti plot, one plot per biomarker. 
Subject ID and treatment group should 
be identifiable by color/symbol


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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
5.3.
IPP
BM_F2
Individual Plot of Nasal SAM Strips Biomarkers by Visit by 
Subject - Influenza Positive Population  
spaghetti plot, one plot per biomarker. 
Subject ID and treatment group should 
be identifiable by color/symbol
5.4.
IPP
BM_F2
Individual Plot of BAL Biomarkers by Visit by Subject - Influenza 
Positive Population  
spaghetti plot, one plot per biomarker. 
Subject ID and treatment group should 
be identifiable by color/symbol


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11.13.12. Pharmacodynamic / Biomarker Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
6.1.
IPP
BMPD_F3
Matrix Comparative Plot of Individual Scatter Plot of 
Biomarkers vs Biomarkers for Each Biomarker Source 
by  Select Visits
One page per biomarker. The x on y axis will 
contain the 5 biomarkers: Serum, Nasal wash, 
Nasal SAM Strips, BAL
Include the pearson’s correlation coefficient and 
p-value on the graph.   Use one color
One page for Day 1, Day 5, Day 45, PT Day 3
6.2.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Serum 
Biomarkers vs. Time to Clinical Response - Influenza 
Positive Population  
One page per biomarker.  TTCR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTCR, AUC(0-45) vs TTCR, AUC(0-
PT Day 3) vs TTCR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.3.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Serum 
Biomarkers vs.  Time to Respiratory Response -
Influenza Positive Population  
One page per biomarker.  TTRR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTRR, AUC(0-45) vs TTRR, AUC(0-
PT Day 3) vs TTRR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.4.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Nasal 
Wash Biomarkers vs. Time to Clinical Response -
Influenza Positive Population  
One page per biomarker.  TTCR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTCR, AUC(0-45) vs TTCR, AUC(0-
PT Day 3) vs TTCR , Different color for 
treatment.  Include a regression line for each 
treatment group


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No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
6.5.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Nasal 
Wash Biomarkers vs.  Time to Respiratory Response -
Influenza Positive Population  
One page per biomarker.  TTRR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTRR, AUC(0-45) vs TTRR, AUC(0-
PT Day 3) vs TTRR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.6.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Nasal 
SAM Strips Biomarkers vs. Time to Clinical Response -
Influenza Positive Population  
One page per biomarker.  TTCR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTCR, AUC(0-45) vs TTCR, AUC(0-
PT Day 3) vs TTCR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.7.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve Nasal 
SAM Strips Biomarkers vs.  Time to Respiratory 
Response - Influenza Positive Population  
One page per biomarker.  TTRR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTRR, AUC(0-45) vs TTRR, AUC(0-
PT Day 3) vs TTRR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.8.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve BAL 
Biomarkers vs. Time to Clinical Response - Influenza 
Positive Population  
One page per biomarker.  TTCR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTCR, AUC(0-45) vs TTCR, AUC(0-
PT Day 3) vs TTCR , Different color for 
treatment.  Include a regression line for each 
treatment group
6.9.
IPP
BMPD_F1
Individual Scatter Plot of Area Under the Curve BAL 
Biomarkers vs.  Time to Respiratory Response -
Influenza Positive Population  
One page per biomarker.  TTRR on y axis, AUC 
biomarker on x axis.
AUC(0-5) vs TTRR, AUC(0-45) vs TTRR, AUC(0-
PT Day 3) vs TTRR , Different color for 
treatment.  Include a regression line for each 
treatment group


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11.13.13. Pharmacokinetic / Pharmacodynamic Tables
Not Applicable
11.13.14. Pharmacokinetic / Pharmacodynamic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
7.12
IPP
Target Engagement Biomarker versus DNX PK Parameters 
Target engagement biomarkers include 
IL-8, MPO, neutrophil elastase and 
neutrophil counts (the one from nasal 
wash, not the one from blood)
11.13.15. Health Outcome Tables
No.
Populatio
n
IDSL / TST ID / 
Example Shell
Title
Programming Notes
8.1.
IPP
HO T2
Summary of Change from Baseline in KATZ ADL Score and 
each ADL Activity
Includes baseline value
8.2.
IPP
HO T5
Summary of FLU-PRO Total and Domain Scores
Use “Baseline” for label instead of 
“Baseline for CFB”
8.3.
     IPP
HO T5
Summary of Change from Baseline FLU-PRO Total and Domain 
Scores
Includes baseline value


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11.13.16. Virology Tables
No.
Populatio
n
IDSL / TST ID / 
Example Shell
Title
Programming Notes
9.1.
IPP
VR T1
Summary of Change from Baseline in Influenza Viral Load by 
qRT-PCR (log 10  VP/mL) Overall 
Includes baseline value
Summarize by A and B combined 
9.2.
IPP
VR T2
Summary of Change from Baseline in Influenza Viral Load by 
qVC (log10 TCID50/mL) for Subjects Culture Positive at 
Baseline –Nasopharyngeal 
Includes baseline value
9.3.
ITTE
VR T7
Proportion of Subjects with Other Co-infected Viruses by 
Multiplex RT PCR.
9.4.
IPP
VR T4
Summary of Resistance Associated Mutations Detected in the 
NA Gene by Subtype - Nasopharyngeal
9.5.
IPP
VR T4
Summary of Resistance Associated Mutations Detected in the 
HA Gene by Subtype - Nasopharyngeal
11.13.17. Virology Figures
No.
Populatio
n
IDSL / TST ID / 
Example Shell
Title
Programming Notes
9.1.
IPP
VR F1
Individual Plot of Change from Baseline in Influenza Viral Load 
by qRT-PCR (log10 VP/mL) by Subject for Influenza A and B -
Nasopharyngeal 
Include zero at baseline
9.2.
IPP
VR F1
Individual Plot of Change from Baseline in Influenza Viral Load 
by qVC (log10 TCID50/mL) for Subjects Culture Positive at 
Baseline -Nasopharyngeal
Include zero at baseline


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11.13.18. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Subject Disposition
1.
All Subjects 
Screened
ES7
Listing of Screen Reasons for Screen Failure
2.
ITT-E
ES2 
Listing of Reasons for Study Withdrawal
3.
ITT-E
SD2
Listing of Reasons for Study Treatment Discontinuation
4.
ITT-E
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
5.
ITT-E
TA1
Listing of Planned and Actual Treatments
Protocol Deviations
6.
ITT-E
DV2
Listing of Important Protocol Deviations 
7.
ITT-E
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Populations Analysed
8.
All Subjects 
Screened
SA3a
Listing of Subjects Excluded from Any Population
Demographic and Baseline Characteristics
9.
ITT-E
DM2
Listing of Demographic Characteristics
10.
ITT-E
DM9
Listing of Race


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
11.
ITT-E
CM2
Listing of Concomitant Medications
Add column to indicate ‘complications of influenza’
12.
ITT-E
MH2
Listing of Past and Current Medical Conditions
13.
ITT-E
MH2
Listing of Subjects with Renal Impairment
Renal impairment is based on Creatinine Clearance Criteria 
Any time during study including baseline and post baseline
14.
IIT-E
CM2
Listing of Subjects with Prior Oseltamivir Exposure
Exposure and Treatment Compliance
15.
Safety
EX3
Listing of Exposure Data
Adverse Events
16.
Safety
AE8
Listing of All Adverse Events
Add asterisk for subjects with baseline renal impairment
17.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
18.
Safety
AE8
Listing of Adverse Events of Special Interest
Serious and Other Significant Adverse Events
19.
Safety
AE8
Listing of Fatal Adverse Events
20.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
21.
Safety
SAFE L1
Listing of Reasons for Considering as a Serious Adverse Event
Use study 201682 as a reference


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
22.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study
23.
Safety
AE8
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment`
24.
Safety
MH2
Listing of Subjects with Liver Stopping Events
All Laboratory
25.
Safety
LB5 
Listing of Laboratory Data for Subjects with Abnormalities of 
Potential Clinical Concern (Grade 3-4)
26.
Safety
LB5
Listing of All Laboratory Data
ECG
27.
Safety
CP_EG3 
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance
28.
Safety
CP_EG5 
Listing of Abnormal ECG Findings


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11.13.19. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Need for early 
terminated 
study
Population
29.
ITT-E
POP L1
Listing of Flu Type and Symptoms
30.
ITT-E
POP L2
Listing of Chest X-Ray Results
Indicate if subject is included in IPP
Efficacy
31.
IPP
EFF L1
Listing of Time to Clinical Response 
32.
IPP
EFF L2
Listing of Time to Respiratory Response
33.
IPP
Listing of Vital Signs
34.
IPP
Listing of Ventilation Status – Mechanical Ventilation
Use NAI114373 as a reference
Add start and stop times
35.
IPP
Listing of Ventilation Status – Supplemental Oxygen
Use NAI114373 as a reference
Oxygen saturation history should be included in this listing
36.
IPP
Listing of Hospital Discharge
Include date, duration and reason
37.
IPP
Listing of Subjects Who Were Admitted to Intensive Care Unit 
Safety
38.
Safety
LB5
Listing of Absolute Neutrophils for Subjects with Grade 3-4 
Absolute Neutrophils or AE of Neutropenia
39.
Safety
LB5
Listing of Creatinine for Subjects with Creatinine Increase > 0.5
mg/dl in Two Consecutive Visits


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Need for early 
terminated 
study
PK
40.
PK
PK L1
Listing of Whole Blood Danirixin Pharmacokinetic Concentration 
Data
Include NQ values
41.
PK
LPK2
Listing of Whole Blood Danirixin Derived Pharmacokinetic 
Parameters
Biomarker
42.
ITT-E
Listing of Serum Biomarkers
43.
ITT-E
Listing of Nasal Wash Biomarkers
44.
ITT-E
Listing of Nasal SAM Strips Biomarkers
45.
ITT-E
Listing of BAL Biomarker
Virology
46.
ITT-E
VR L1
Listing of Influenza Viral RNA (qRT-PCR and TCID50) in 
Nasopharyngeal 
Use study 201682 as a reference
47.
IPP
VR L2
Listing of Co-infected Subjects
48.
ITT-E
Listing of Other Viruses by Multiplex RT PCR.
49.
ITT-E
Listing of Phenotypic IC50 Results
Use NAI114373 as a reference
50.
IPP
Listing of Resistant Mutations in NA and HA Genes
Use NAI114373 as a reference
Health Outcome
51.
IPP
HO L1
Listing of Hospital Readmission
52.
IPP
HO L2
Listing of ADL KATZ Score and each ADL Activity
53.
IPP
HO L3
Listing of 3-Point Scale (Bed Rest, Limit Ambulation, 
Unrestricted)


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Need for early 
terminated 
study
54.
IPP
HO L4
Listing of FLU-PRO Total and Domain Scores


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11.14.
Appendix 14: Example Mock Shells for Data Displays
The mock shells for data displays are contained in a separate document.