Clinical trial NCT02798978
Conditions: Cancer Neoplasms
Keywords: pharmacokinetics TLR4 agonist cancer tolerability GSK1795091 pharmacodynamics safety
Sponsor: GlaxoSmithKline
Start date: 2017-01-10; Completion date: 2017-10-13
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is an ascending dose first-time-in-human study to determine the safety, tolerability, pharmacodynamic (PD), and pharmacokinetics (PK) profile of GSK1795091 in healthy subjects. The results will support the design of future clinical trials of GSK1795091 administered to subjects with advanced malignancies in combination with immune system modulators.

Part 1 will be a randomized, double-blind (sponsor-unblinded), placebo-controlled, single center, single dose escalation, sequential group evaluation of intravenously administered GSK1795091 to evaluate the safety and tolerability in healthy subjects. Part 2 will be an open-label, parallel group evaluation of 2 doses of GSK1795091 administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2). In Part 2, on Day 1, subjects will receive intravenous GSK1795091 at a dose determined by results from Part 1. The total duration of this study is approximately 10 weeks from screening to the last study visit.

Detailed description:

Arms: arm 1: In Part 1, subjects in sequential cohorts will receive single ascending doses of intravenous (IV) injection of GSK1795091 or matching placebo, with a starting dose of 7 nanogram (ng), on Day 1 until the highest dose is evaluated. arm 2: In Part 2 Cohort 1, subjects will receive IV injection of GSK1795091 on Day 1, at dose determined in part 1, and second dose on Day 8 (one week apart) arm 3: In Part 2 Cohort 2, subjects will receive IV injection of GSK1795091 on Day 1, at dose determined in part 1, and a second dose on Day 15 (two weeks apart)
Interventions: intervention 1: GSK1795091 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK1795091 will be supplied as solution for injection vial. Each 5 mL vial contains 0.001 milligram/mL (mg/mL; 1000 ng/mL) or 0.0001 mg/mL (100 ng/mL)of GSK1795091 and will be administered as IV bolus over 2-5 minutes (min) followed by a IV bolus of 10 mL normal saline. intervention 2: Matching placebo will be supplied as a solution for injection vial and will be administered as IV bolus over 2-5 min followed by a IV bolus of 10 mL normal saline

Protocol documents:
Prot_000.pdf: 
2015N236402_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
204685
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 2-part randomized, double-blind (sponsor-unblinded), 
placebo-controlled, ascending dose and parallel group study of 
TLR4 agonist (GSK1795091) administered to healthy subjects
Compound Number:
GSK1795091
Development Phase:
1
Effective Date:
12-APR-2017
Protocol Amendment Number:  03
Author (s):
Clinical Pharmacology Science & Study Operations, 
Australia
Oncology Research and Development, USA
Clinical Biomarkers, IOC DPU, UP, USA
GSK  R&D PCPS, CPMS, USA
Clinical Statistics, USA
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N236402_00
2016-MAR-11
Original
2015N236402_01
2016-NOV-29
Amendment No. 1
This protocol amendment is to clarify several sections of protocol text regarding the dose 
selection process and associated in-vitro and in-vivo data to support the dose escalation 
regime. Additional text was clarified by outlining replacement subjects, review of data 
from Part 1, obtaining ethics approval before starting Part 2 and additional assessments 
added to the Time and Events table.
All changes are detailed in Appendix 7.
2015N236402_02
2016-DEC-02
Amendment No. 2
This protocol amendment is to correct administrative formatting in Section 5.2 to ensure 
the numbers were consecutive for the exclusion criteria.
2015N236402_03
2017-APR-12
Amendment No. 3
This protocol amendment is revising Part 1 dose escalations and subject numbers 
following a halt in dosing after one subject experienced a transient heart rate increase
from 68 bpm to 125 bpm, meeting protocol-defined stopping criteria as a grade 3 change.  
For Part 1, this protocol amendment is intended to generate additional clinical data while 
applying the available clinical data to maximize the safety of subjects enrolled in 
subsequent cohorts.  Repeating the 60 ng cohort will further characterize the frequency 
and magnitude of heart rate increases and temperature increases before taking any 
additional steps.  The stopping rules have been modified to, now, include an effect 
threshold as well as an increase from baseline is supported by the good tolerability profile 
of GSK1795091 in cohorts 1 – 3. In turn, because clinical signs and symptoms are now 
being observed, future dose increments are smaller and the potential top dose has been 
lowered.  
Minor typographical errors and other sections have been amended for clarification.  
All changes are detailed in Appendix 7, Section 12.7.3.


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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
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Dr 
1250 S. 
Collegeville 
Road, 
Collegeville, PA 
19426
Secondary 
Medical 
Monitor
Dr 
1250 S. 
Collegeville 
Road, 
Collegeville, PA 
19426
SAE contact 
information 
Medical Monitor 
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):  EudraCT 2016-000759-28 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204685.
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
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 Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204685........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................19
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................25
4.4.
Design Justification.....................................................................................25
4.5.
Dose Justification........................................................................................26
4.5.1.
Starting dose selection.................................................................26
4.5.1.1.
Calculation of Minimum Anticipated Biological 
Effect Level ................................................................27
4.5.1.2.
Rabbit pyrogenicity.....................................................27
4.5.1.3.
Comparison to Lipopolysaccharide (LPS)...................28
4.5.2.
Dose escalation ...........................................................................28
4.5.3.
Top dose selection.......................................................................29
4.5.4.
Summary .....................................................................................29
4.6.
Benefit:Risk Assessment ............................................................................30
4.6.1.
Risk Assessment .........................................................................31
4.6.2.
Benefit Assessment.....................................................................32
4.6.3.
Overall Benefit:Risk Conclusion...................................................32
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............32
5.1.
Inclusion Criteria.........................................................................................32
5.2.
Exclusion Criteria........................................................................................34
5.3.
Screening/Baseline/Run-in Failures............................................................36
5.4.
Withdrawal/Stopping Criteria.......................................................................36
5.4.1.
Subject withdrawal procedures ....................................................36
5.4.2.
Liver Chemistry Stopping Criteria ................................................37
5.4.3.
QTcF Stopping Criteria ................................................................37
5.5.
Subject and Study Completion....................................................................38
6.
STUDY TREATMENT ............................................................................................38
6.1.
Investigational Product and Other Study Treatment....................................38
6.2.
Treatment Assignment................................................................................39
6.3.
Blinding.......................................................................................................39
6.4.
Packaging and Labeling..............................................................................40
6.5.
Preparation/Handling/Storage/Accountability..............................................40
6.6.
Compliance with Study Treatment Administration.......................................40
6.7.
Management Guidelines for Adverse Events ..............................................40
6.8.
Treatment of Study Treatment Overdose....................................................41
6.9.
Treatment after the End of the Study ..........................................................41
6.10.
Lifestyle and/or Dietary Restrictions............................................................42


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6.10.1.
Meals and Dietary Restrictions ....................................................42
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................42
6.10.3.
Activity .........................................................................................42
6.11.
Concomitant Medications and Non-Drug Therapies....................................42
6.11.1.
Permitted Medications and Non-Drug Therapies..........................42
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................42
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
7.1.
Time and Events Table...............................................................................44
7.1.1.
Screening ....................................................................................44
7.1.2.
Part 1: In-House Assessments.....................................................45
7.1.3.
Part 1 Outpatient Assessments....................................................47
7.1.4.
Part 2: In-House Assessments.....................................................48
7.1.5.
Part 2 Assessments.....................................................................49
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Safety .........................................................................................................50
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.3.1.2.
Method of Detecting AEs and SAEs ...........................51
7.3.1.3.
Follow-up of AEs and SAEs........................................51
7.3.1.4.
Regulatory Reporting Requirements for SAEs............51
7.3.2.
Pregnancy ...................................................................................51
7.3.3.
Physical Exams ...........................................................................52
7.3.4.
Vital Signs....................................................................................52
7.3.5.
Electrocardiogram (ECG).............................................................52
7.3.6.
Clinical Safety Laboratory Assessments ......................................52
7.3.7.
Assessment windows...................................................................54
7.4.
Pharmacokinetics .......................................................................................54
7.4.1.
Blood Sample Collection..............................................................54
7.4.1.1.
Part 1 .........................................................................54
7.4.1.2.
Part 2 .........................................................................54
7.4.2.
Urine Sample Collection ..............................................................54
7.4.3.
Sample Analysis ..........................................................................55
7.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................55
8.
DATA MANAGEMENT ...........................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................56
9.2.1.
Sample Size Assumptions ...........................................................56
9.2.2.
Sample Size Sensitivity................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...................................57
9.3.
Data Analysis Considerations .....................................................................57
9.3.1.
Analysis Populations....................................................................57
9.3.2.
Interim Analysis ...........................................................................57
9.3.3.
Final Analysis ..............................................................................57
9.4.
Key Elements of Analysis Plan ...................................................................57
9.4.1.
Primary Analyses.........................................................................57
9.4.2.
Secondary Analyses ....................................................................58
9.4.2.1.
Pharmacokinetic Analyses (Part 1 and Part 2)............58


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9.4.2.2.
Pharmacokinetic Analysis for Part 2 Only...................59
9.4.3.
Other Analyses ............................................................................60
9.4.3.1.
Exploratory Biomarker(s) Analyses.............................60
9.4.3.2.
Pharmacokinetic/Pharmacodynamic Analyses ...........60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................61
10.5.
Study and Site Closure ...............................................................................61
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1: Abbreviations and Trademarks................................................66
12.2.
Appendix 2: FDA Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical 
Trials...........................................................................................................69
12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................75
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................77
12.4.1.
Definition of Adverse Events........................................................77
12.4.2.
Definition of Serious Adverse Events...........................................78
12.4.3.
Recording of AEs and SAEs ........................................................80
12.4.4.
Evaluating AEs and SAEs............................................................80
12.4.5.
Reporting of SAEs to GSK...........................................................82
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................83
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............83
12.5.2.
Collection of Pregnancy Information ............................................84
12.6.
Appendix 6: Country Specific Requirements...............................................85
12.7.
Appendix 7: Protocol Changes....................................................................86
12.7.1.
AMENDMENT 1...........................................................................86
12.7.2.
AMENDMENT 2...........................................................................98
12.7.3.
AMENDMENT 3...........................................................................98


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1.
PROTOCOL SYNOPSIS FOR STUDY 204685
Rationale
GSK1795091 is a synthetic Toll-like receptor (TLR4) agonist that is being developed as 
an immunological adjuvant to be administered in combination with immune system 
modulators for the treatment of cancers. GSK1795091 is being evaluated in this 
ascending dose first-time-in-human (FTIH) study to provide safety, pharmacokinetic 
(PK), and pharmacodynamic (PD) data in healthy subjects.  The results will support the 
design of future clinical trials of GSK1795091 administered to subjects with advanced 
malignancies in combination with other immune system modulators. 
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
GSK1795091 when administered to healthy 
subjects.

Safety data comprising adverse events, vital 
signs, laboratory tests, and 12-lead ECGs.
Secondary

To evaluate the systemic pharmacokinetics 
of GSK1795091 following administration of 
a single intravenous dose to healthy 
subjects.

Plasma pharmacokinetic parameters such 
as Cmax, tmax, AUC(0-t), AUC(0-last), 
AUC(0-), CL, Vd, and t1/2. 

To evaluate the pharmacodynamic effects 
of GSK1795091 following administration as 
a single intravenous dose to healthy 
subjects.

Vital signs, CRP measurements, WBC 
and differential. 

To evaluate the systemic pharmacokinetics 
of GSK1795091 following a second 
intravenous dose administered to healthy 
subjects 1 week or 2 weeks after the first 
dose.

Plasma pharmacokinetic parameters such 
as Cmax, tmax, AUC(0-t), AUC(0-last), and 
AUC(0-), CL, Vss, t1/2 and accumulation 
and time invariance (as possible).

To evaluate the clinical and 
pharmacodynamic effects of GSK1795091 
following a second intravenous dose 
administered to healthy subjects 1 week or 
2 weeks after the first dose.

Vital signs, CRP measurements, WBC and 
differential, and laboratory tests.


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Objectives
Endpoints
Exploratory

To evaluate immune system effects 
following intravenous administration of 
GSK1795091.

To evaluate the pharmacodynamic effects 
of intravenous administration of 
GSK1795091 on gene signature analysis of 
Peripheral Blood Mononuclear Cells 
(PBMCs) from part 2 healthy subjects.

To explore the relationship between 
pharmacokinetics, pharmacodynamic 
markers, and adverse events.

To characterize the metabolic profile of 
GSK1795091 

Cytokine measurements in plasma and 
immune cell phenotyping of leukocytes.

Gene signature analysis

Correlation between pharmacokinetics and 
pharmacodynamic markers, such as  vital 
signs and CRP, and adverse events

Collection of samples to characterize the 
metabolites in plasma and urine.
Overall Design
The study will be conducted in two parts.
Part 1 will be a randomized, double-blind (sponsor-unblinded), placebo-controlled, 
single-center, single-dose escalation, sequential-group evaluation of intravenously 
administered GSK1795091 to evaluate the safety and tolerability in healthy subjects. 
Part 2 will be an open-label, parallel-cohort evaluation of 2 doses of GSK1795091 
administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2).  
In Part 2, on Day 1 subjects will receive intravenous GSK1795091 at a dose determined 
by results from Part 1.  
Treatment Arms and Duration
The duration of the study for each subject, including screening, is approximately 10 
weeks. 
Subjects will be evaluated in the clinical unit for a screening visit and, if eligible, will 
receive study product within 30 days.  Subjects will be admitted to the clinical unit two 
days prior to dosing (Day -2).  
Part 1
Part 1 is planned to enrol up to 7 sequential cohorts of 8 subjects per cohort (at protocol 
Amendment 03, the planned number of cohorts is reduced).  Subjects enrolled in Part 1 
will participate in the study for approximately 60 days from screening to the follow-up 
visit. 


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In Part 1, on Day 1 subjects will be randomised in a 3:1 ratio to receive intravenous 
GSK1795091 or matching placebo. Subjects will be observed as inpatients for 96 hours at 
which time they will be discharged after assessments have been performed by the 
investigator.  Subjects will have a follow up visit as an outpatient on Day 7 and a final 
follow up contact by phone or by visit on Day 30.  
Part 2
Part 2 is planned to enrol 2 parallel cohorts of 6 subjects per cohort.  Subjects enrolled in 
Part 2 will participate in the study for approximately 67 to 75 days from screening until 
the follow-up visit.
In Part 2, on Day 1 subjects will receive intravenous GSK1795091 at a dose determined 
by results from Part 1. Subjects will be observed as inpatients for at least 96 hours, after 
assessments have been performed by the investigator. Subjects in Cohort 1 will remain 
in-house until Day 12. Subjects in Cohort 2 will be discharged after completion of the 
Day 5 (96 hour) assessments and will return to the clinical unit for a second inpatient visit 
on Day 13 (Part 2, Cohort 2). If AEs attributed to the first dose of GSK1795091 have 
resolved, subjects will receive a second dose of GSK1795091 on Day 8 (Part 2, Cohort 1) 
or Day 15 (Part 2, Cohort 2; Otherwise, subjects will not receive the second dose and will 
be followed according to the schedule for Part 1).  Subjects will be followed according to 
the same schedule as after the first dose of GSK1795091.
Type and Number of Subjects
Approximately 68 subjects may be enrolled in the study.  Between 8 and 56 subjects will 
be enrolled in Part 1.  Twelve (12) subjects will be enrolled in Part 2.
Part 1 is planned to enrol up to 7 cohorts of 8 subjects per cohort. 
Part 2 is planned to enrol 2 cohorts of 6 subjects per cohort.    
Subjects may not participate in more than one cohort. 
Analysis
Primary Analyses
Clinical safety observations will include Adverse Events (AEs), vital sign measurements, 
12-lead ECG and clinical laboratory assessments.  Safety data will be tabulated and 
where appropriate, analysed by the use of descriptive statistics.  Safety data will be 
tabulated for safety population.
The probability of safety events (e.g. liver toxicity defined by an ALT greater than 
3xULN, QTcF > 500 msec, change from baseline QTcF > 60 msec) will be estimated and 
with associated 95% corresponding confidence intervals for each cohort using the 
binomial distribution. 


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Secondary Analyses
Drug concentration and pharmacokinetic parameters will be listed and summarized by 
dose cohorts in Part 1 and Part 2.  Concentration-time data will be presented in graphical 
form both individually and by cohort as mean and median values.  If data permit, dose 
proportionality, accumulation ratio, and time invariance will be determined.
Exploratory Analysis
Exploratory graphical PK/PD analyses may be performed to examine the relationship 
between GSK1795091 PK and response as measured by vital signs (e.g., body 
temperature, heart rate, etc.) or PD biomarkers (e.g., cytokines/chemokines) or other 
endpoints if warranted by the data (e.g., grade, onset and duration of AEs).  The 
relationship(s) between PD endpoints and PK parameters initially will be explored 
graphically.  Plots of PD endpoint versus PK parameters of GSK1795091 will be 
generated.  
Plasma for cytokine analysis, blood for immunophenotyping, and PBMCs for gene 
signature analysis will be collected for analysis. Immunophenotyping of blood will be 
done on an on-going basis, whereas cytokine analysis and gene signature analysis will be 
done after the study completion. Graphical representations will be created based on the 
exploratory biomarker data.


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2.
INTRODUCTION
Toll-like receptors (TLRs) are a family of cell surface proteins primarily expressed on 
immune and epithelial cells that function as activators of innate immunity in response to 
microbial-related molecules known as Pathogen-Associated Molecular Patterns 
(PAMPs).  PAMPs include molecules such as nucleic acids, flagellar proteins, and 
lipopolysaccharide (LPS) (the natural ligand for TLR4).  TLR engagement results in the 
production of various inflammatory cytokines/chemokines such as TNF, IL6, G-CSF, 
and type I interferons (IFN, IFN) and enhanced uptake, processing, and presentation of 
antigens. Accordingly, TLR agonists are being developed for a variety of therapies 
where immune modulation is desirable such as for vaccine adjuvants and for treatments 
for allergy and asthma, chronic viral infections, and cancer.  GSK1795091 is a synthetic 
TLR4 agonist that is being developed as an immunological adjuvant to be administered in 
combination with immune system modulators for the treatment of cancers. 
2.1.
Study Rationale
GSK1795091 is being evaluated in this ascending dose first-time-in-human (FTIH) study 
to provide safety, pharmacokinetic (PK), and pharmacodynamic (PD) data in healthy 
subjects.  The results will support the design of future clinical trials of GSK1795091 
administered to subjects with advanced malignancies in combination with immune 
system modulators. 
The study will be conducted in two parts.  
In Part 1, sequential cohorts of healthy subjects will receive single ascending doses of 
GSK1795091. The safety and tolerability will be characterized. PK and PD data will also 
be collected. Results will inform the design of a first-in-cancer-patient clinical trial.
In Part 2 of the study, two parallel cohorts of subjects will receive 2 doses of 
GSK1795091 at a dose determined by results from Part 1 (Section 4.2), either 1 week 
apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2). The second dose will provide 
clinical and laboratory results that can be compared to those following the first dose in 
order to understand if tolerance (i.e., a diminished pharmacologic response upon repeat 
administration of drug) to GSK1795091 is observed, as has been reported with repeat 
doses of other TLR agonists [Astiz, 1995; de Vos, 2009]. Thus, Part 2 of the study will 
provide data relevant to selection of an appropriate dosing interval to be evaluated in the 
first-time-in-cancer-patient study.
Conduct of the FTIH study in healthy subjects is preferable to a study in cancer patients.  
The preclinical safety profile of GSK1795091 and historical experience with the drug 
class readily accommodate development in healthy subjects.  Preclinical safety data for 
GSK1795091 do not suggest risks for adverse events that are irreversible or that cannot 
be monitored.  Clinical safety data for the drug class is characterized by a predictable 
tolerability profile of fever and flu-like symptoms (e.g. chills, nausea, malaise, etc.)  
[Bahador, 2007].  Meanwhile, GSK1795091 would not be expected to demonstrate anti-
tumor activity in a FTIH study in patients with cancer. TLR agonists have been studied 
extensively in cancer patients, as systemically-administered single agents, and robust 


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anti-tumor activity has not been observed [Guha, 2012]. Additionally, because 
GSK1795091 stimulates the immune system, dose escalation must start from a very low 
level (i.e. minimum anticipated biologic effect level; MABEL).  Given the need for a low 
starting dose and the anticipated lack of monotherapy, anti-tumor activity, a FTIH study 
in healthy subjects is the preferred development approach to avoid exposing subjects with 
advanced malignancies to an ineffective investigational product.  
The safety, PK, and PD results from the FTIH study will facilitate the design of a clinical 
trial in cancer patients where the benefits of GSK1795091 are more likely to be realized 
as an adjuvant in combination with a checkpoint modulator.  The results of this FTIH 
study will maximize the safety and potential for efficacy in a first-time-in-cancer-patient 
study.
2.2.
Brief Background
TLR biology
TLRs engage pathways responsible for innate immune system responses to pathogen-
associated molecular patterns (PAMPs) such as microbial nucleic acids, flagellar 
proteins, or lipopolysaccharide. TLRs are primarily expressed in myeloid cells, 
monocytes, macrophages and dendritic cells (DC), where they are involved in immune 
surveillance. Many vaccine adjuvants and stand-alone immunomodulators appear to 
interact with members of the TLR family. TLR engagement activates intracellular 
signalling pathways via interaction with intracellular adapter molecules such as MyD88, 
TRIF, TIRAP, and TRAM. These adapter molecules can regulate the expression of 
inflammatory cytokines/chemokines such as TNF, interferons and many others.  
GSK1795091 was developed in the course of structure-activity studies on LPS, the 
naturally occurring ligand of TLR4. GSK1795091 is a monosaccharide 
immunomodulator from the aminoalkyl glucosaminide 4-phosphates (AGPs) class of 
compounds intended for use as a vaccine adjuvant or an immune modulator.  Additional 
details are provided in the Investigator’s Brochure.
GSK1795091 is an agonist of TLR4 that induces immunologic responses in vitro and in 
vivo.  GSK1795091, as a single-agent, stimulates cytokine production (in vitro and in 
vivo), changes in immune cell populations (in vivo) and generates fever response (in 
vivo). When administered by intravenous bolus and combined with the immune 
checkpoint modulator, OX86, mouse surrogate OX40 agonist antibody, induced a potent 
immunologic response and significant tumor shrinkage in a syngeneic mouse model of 
cancer. Four (4) groups of 10 Balb/c mice (with intact immune systems) were implanted 
with syngeneic CT-26 tumors.  Mice received either placebo, GSK1795091, OX86, or the 
combination of GSK1795091 and OX86.  While the monotherapies had modest effects 
on tumor growth (Figure 1), the combination produced durable responses.


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Figure 1
CT26 Tumor Volume
The reduction in tumor volume translated to significant improvement in the survival of 
animals (Figure 2).  Approximately, 70% of animals that received the combination of 
GSK1795091 and OX86 survived more than 100 days.  By contrast, only 10-20% of the 
animals that received either monotherapy survived 100 days. 
Figure 2
Survival of mice
This model provides support for the evaluation of this combination in patients with 
cancer.  Additional details are available in the Investigator’s Brochure.
Healthy subject experience with TLR4 agonists
TLR4 agonists have been evaluated extensively in healthy subjects.  Following 
administration, subjects experience mild to moderate flu-like symptoms and increases in 
body temperature and heart rate.  Clinical changes are attributable to increases in 
cytokines and typically peak within several hours and subside quickly.  Overall, the drug 


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class is well-characterized and not associated with toxicities that are irreversible or that 
cannot be monitored.  
The prototypical TLR4 agonist, LPS, has been administered for decades to healthy 
subjects and to patients for experimental and therapeutic objectives.  The typical dose of 
LPS administered in clinical trials is 2 to 4 ng/kg at which adverse effects such as fever, 
tachycardia, headache, nausea, and vomiting may be observed.  A review of studies 
comprising 1000’s of healthy subjects that have been administered LPS notes that long-
term toxicities have not been described, [Bahador, 2007].
LPS has been evaluated in an ascending dose study designed to investigate biomarker and 
clinical findings at doses below the commonly investigated 2 to 4 ng/kg range [Dillingh, 
2014].  Healthy subjects were administered LPS at doses ranging from 0.5 to 2.0 ng/kg.  
All adverse events were reported to be mild, and the most commonly reported adverse 
event was headache.  Dose dependent changes in vital signs were observed, with peak 
changes approximately 3 to 4 hours after LPS administration.  At the highest dose, mean 
temperature increased by 1.5oC and mean heart rate by 28 beats per minute. Dose 
dependent increases from baseline were observed for TNF, IL6, and IL8.  IL1levels 
trended higher with increasing dose, however, many measurements were below the limit 
of quantitation and no statistical analysis was performed.  C-reactive protein, synthesized 
by the liver in response to IL6 and IL1, also increased with dose and remained elevated 
24 hours after LPS administration, by virtue of a longer half-life relative to cytokine 
markers [Clyne, 1999].  Total white blood cell count and neutrophil count transiently 
increased and peaked 4 hours after LPS administration.  Multiple other hematologic 
parameters, including haemoglobin, lymphocyte count, and platelet count, transiently 
decreased.  Clinical and laboratory parameters, except as noted, returned to baseline in 12 
to 24 hours.  Thus, when administered to healthy subjects, at doses up to 2.0 ng/kg, LPS 
produced mild adverse events and transient, dose-dependent changes in vital signs and 
laboratory parameters.  
Synthetic TLR4 agonists, such as monophosphoryl lipid A (MPL), have similarly been 
studied in ascending dose studies [Astiz, 1995]. MPL is used as a vaccine adjuvant in 
Fendrix, a hepatitis B vaccine, and Cervarix, a human papillomavirus vaccine [Kanzler, 
2007]. Early in development of MPL, healthy subjects received escalating intravenous 
doses from 1 to 20 µg/kg.  The 20 ug/kg dose was considered safe and biologically 
active.  Systemic adverse events and cytokine increases were observed after doses of 10 
µg/kg.  At the highest doses tested, 6 of 6 subjects experienced adverse events including 
fevers, chills, headache, myalgia, and pain at the injection site.  Adverse events were mild 
to moderate in severity.  Changes in vital signs, as compared to control, included 
increases in mean temperature of 2oC and increases in mean heart rate of 30 beats/min.  
Changes in respiratory rate and blood pressure were not observed.  Vital sign changes 
peaked within 3 to 4 hours and returned to normal within 12 hours.  Total white blood 
cell count transiently increased and total lymphocyte count transiently decreased.  
Laboratory biomarkers, TNF, IL6 and IL8 peaked within 2 to 4 hours. Clinical and 
laboratory parameters returned to baseline in 6 to 24 hours.  A second cohort of subjects 
received 20 µg/kg MPL followed by a dose of endotoxin 24 hours later.  Subjects that 
received endotoxin 24 hours after MPL experienced diminished cytokine release and 
improved tolerability consistent with drug tolerance which has been described following 


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repeat dosing of TLR agonists [de Vos, 2009]. This study provides an example of a 
synthetic TLR4 agonist that was safely administered intravenous (IV) in ascending doses 
to healthy subjects and produced transient changes in clinical and laboratory 
measurements. 
Rare serious adverse events have been reported in clinical trials of LPS administered to 
healthy subjects.  One group, with experience administering LPS to approximately 2200 
healthy subjects, observed 2 cases of severe hypotension and sinus arrest and identified 2 
similar cases in the literature [van Eijk, 2004].  Although all subjects recovered quickly, 
the report highlights that these subjects had a prior history of syncope in 3 of 4 cases and 
lacked pre-hydration. The authors conclude that administration of LPS is “a safe means 
of studying inflammation in humans” but recommend hydration and exclusion of subjects 
with a history of vagal reactions from participation in clinical trials. 
At extreme doses (1 mg; >3500-fold above the standard dose administered to healthy 
subjects) LPS has caused symptoms similar to septic shock [Taveira da Silva, 1993].  In a 
case report, an individual presented with fever (40oC), hypotension (42mm/20mm), and 
tachycardia (114 bpm) 2.5 hours after self-administering 1 mg of endotoxin.  The subject 
received intravenous fluids and pressors.  All cytokines that were measured peaked 
within 24 hours (e.g. TNFa 3.6 hours, IL6 and IL8 6.8 hours, and GCSF 22.5 hours).  
Remarkably, the subject was reported to be “alert, oriented, and afebrile” within 44 hours 
and discontinued pressors after 50 hours.  At that time, the subject required diuretics for 
pulmonary edema. Within approximately 4 days, clinical parameters including vital signs 
and haematological analytes had returned to normal.  Thus, although massive doses of 
LPS produced excessive cytokine elevations and severe hypotension, the case report 
indicates that over-activation of TLR4 produces toxicities that are qualitatively similar to 
those observed at lower doses.   
TLR4 agonist development plan
The development plan for GSK1795091 includes a healthy subject clinical trial to 
optimize collection of safety, PK and PD data and to inform the design of future 
combination therapy trials in cancer patients.  The combination of TLR4 agonists with 
novel immunotherapies holds promise in treating patients with cancer.  Systemically 
administered TLR agonists, including TLR4 agonists, have not demonstrated robust anti-
tumor activity as monotherapies [de Bono, 2000; Isambert, 2013; Guha, 2012]. However, 
one model of a “cancer-immune cycle” describes a series of steps that positively feed-
forward to enhance anti-tumor activity [Chen, 2013].  These steps include:
-
Release of cancer cell antigens
-
Cancer antigen presentation
-
Priming and activation
-
Trafficking of T cells to tumors
-
Infiltration of T cells into tumors
-
Recognition of cancer cells by T cells
-
Killing of cancer cells
It is possible that immunotherapies acting at different steps in the cycle could have 
improved therapeutic indices over currently available monotherapies.  Thus, a TLR4 


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agonist may enhance anti-tumor effects of checkpoint modulators by its actions on 
dendritic cells and antigen presenting cells. This hypothesis is supported by nonclinical 
data (Figure 1 and Figure 2).
Relevance of a healthy subject study to future development in cancer patients
Part 1 of this study in healthy subjects will provide relevant monotherapy safety, 
pharmacokinetic and pharmacodynamic information for GSK1795091 to support a 
subsequent trial in patients with cancer.  To ensure the safety of subjects in a FTIH study 
of an immune system agonist, whether the trial is performed in healthy subjects or in 
cancer patients, the starting dose is conservative and anticipated to have minimal 
biological activity.  As dose escalation progresses, pharmacologically relevant doses can 
be identified safely in healthy subjects based on monitorable and reversible, mild to 
moderate clinical effects (e.g. changes in body temperature, heart rate, and flu-like 
symptoms, etc.). Subsequently, a pharmacologically active dose could reasonably be 
explored as a starting dose in a study in cancer patients.  Thus, by beginning development 
of GSK1795091 in healthy subjects, it will be possible to conduct the FTIH study safely 
while avoiding the exposure of cohorts of cancer patients to pharmacologically inactive 
doses of the study drug. 
The pharmacodynamic markers to be measured in this FTIH study are directly relevant to 
a subsequent study to be conducted in cancer patients.  For example, we will measure IL-
1, TNFα, IL-6 cytokines as markers of TLR4 signaling and immune activation; these 
markers will also be measured in patient studies to confirm TLR4 signaling and to 
explore the relationship between the markers and clinical activity.  In study 204685, we 
will also measure immune cell activation and immune cell expression of target proteins 
of interest (e.g., OX40, ICOS, and others) in peripheral blood.  This cellular phenotype 
information will inform our understanding of the pharmacologic effects of GSK1795091 
on circulating immune cells and may suggest additional immunotherapy combinations of 
interest. By conducting study 204685 in healthy subjects, it will enable detailed PK and 
PD assessments (e.g., multiple time points to characterize time-course) that would be 
more difficult to obtain from a study in cancer patients due to blood-draw volume 
considerations and the inconvenience.
A primary goal of Part 2 of study 204685 is to optimize the dosing interval for 
GSK1795091 in future studies.  Administration of TLR agonists can be associated with 
tachyphylaxis when the dosing interval is short.  Therefore, two parallel cohorts of
subjects will receive 2 doses of GSK1795091, either 1 week apart (Part 2, Cohort 1) or 2 
weeks apart (Part 2, Cohort 2). The pharmacodynamic effects of the second dose will be 
compared to those of the first dose using biomarker endpoints.  This part of the study will 
provide a more robust assessment of the dosing interval for GSK1795091 than would be 
possible in a cancer patient study.
This study in healthy subjects will provide the relevant monotherapy safety, 
pharmacokinetic and pharmacodynamic information to support a combination 
immunotherapy trial in patients with cancer.


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
GSK1795091 when administered to healthy 
subjects.

Safety data comprising adverse events, vital 
signs, laboratory tests, and 12-lead ECGs.
Secondary

To evaluate the systemic pharmacokinetics 
of GSK1795091 following administration of 
a single intravenous dose to healthy 
subjects.

Plasma pharmacokinetic parameters such 
as Cmax, tmax, AUC(0-t), AUC(0-last), 
AUC(0-), CL, Vd, and t1/2.

To evaluate the pharmacodynamic effects 
of GSK1795091 following administration as 
a single intravenous dose to healthy 
subjects.

Vital signs, cytokine measurements, 
WBC and differential, immune cell 
phenotype. 

To evaluate the systemic pharmacokinetics 
of GSK1795091 following a second 
intravenous dose administered to healthy 
subjects 1 week or 2 weeks after the first 
dose..

Plasma pharmacokinetic parameters such 
as Cmax, tmax, AUC(0-t) , AUC(0-last), 
and AUC(0-), CL, Vss, t1/2 and 
accumulation and time invariance (as 
possible).

To evaluate the clinical and 
pharmacodynamic effects of GSK1795091 
following a second intravenous dose 
administered to healthy subjects 1 week or 
2 weeks after the first dose.

Vital signs, cytokine measurements, WBC 
and differential, immune cell phenotype, 
and laboratory tests.
Exploratory

To evaluate immune system effects 
following intravenous administration of 
GSK1795091.

To evaluate the pharmacodynamic effects 
of intravenous administration of 
GSK1795091 on gene signature analysis of 
PBMCs from part 2 healthy subjects.

To explore the relationship between 
pharmacokinetics, pharmacodynamic 
markers, and adverse events

To characterize the metabolic profile of 
GSK1795091 

Cytokine measurements in plasma and 
immune cell phenotyping of leukocytes.

Gene signature analysis

Correlation between pharmacokinetics and 
pharmacodynamic markers, such as  vital 
signs and CRP, and adverse events

Collection of samples to characterize the 
metabolites in plasma and urine


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4.
STUDY DESIGN
4.1.
Overall Design
The study will be conducted in two parts.
Part 1 will be a randomized, double-blind (sponsor-unblinded), placebo-controlled, single 
center, single dose escalation, sequential group evaluation of intravenously administered 
GSK1795091 to evaluate the safety and tolerability in healthy subjects. 
Part 2 will be an open-label, parallel group evaluation of 2 doses of GSK1795091 
administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2).  
GSK1795091 will be administered at a dose determined by results from Part 1 (Section 
4.2).
Figure 3
Part 1 study schematic
Treatment Period 
GSK1795091A 
or PBO
Day-2 Day-1 Day 1 Day 2 Day 3 Day 4 Day 5
Admission
Discharge
Day 7 
Outpatient visit
Day 30 (+/- 2)
Outpatient visit
Screening
Within 30 days
Figure 4
Part 2 study schematic

Subjects will attend the clinical unit for a screening visit and, if eligible, will 
attend to participate in the study within 30 days.

For both Part 1 and Part 2, subjects will be admitted to the clinical unit 2 days 
prior to dosing (Day -2). On Day -1, adverse events and vital signs will be 
recorded according to the schedule on Day 1.


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
In Part 1, each subject will be randomised to receive an intravenous dose of 
GSK1795091 or matching placebo in a 3:1 ratio. Subjects will then be observed 
as inpatients until discharge on Day 5, after assessments have been performed. 

For Part 1, subjects will return on Day 7 for clinic visit and have a follow up 
contact on Day 30. 

In Part 2, on Day 1 subjects will receive intravenous GSK1795091 administered 
at a dose determined by results from Part 1 (see Section 4.2). 

Subjects in Part 2 Cohort 1 will be observed as inpatients and remain inhouse 
until discharge on Day 12.

Subjects in Part 2 Cohort 2 will be observed as inpatients until discharge on Day 
5, after assessments have been performed. They will return to the clinical unit for 
a second inpatient visit on Day 13. 

Each subject will receive a second dose of GSK1795091 on Day 8 (Part 2, Cohort 
1) or Day 15 (Part 2, Cohort 2) (unless AEs attributable to the first dose of 
GSK1795091 have not resolved, in which case the subject will not receive the 
second dose). 

For Part 2, subjects will return to the clinical unit for a clinic visit 7 days after the 
second dose of GSK1795091 and have a follow up contact 30 days after their 
second dose of GSK1795091.
Details of the assessments and procedures subjects will undergo are listed in Section 7. 
The timings and time windows for the visits are provided in the Time and Events table, 
(Section 7.1).
4.2.
Treatment Arms and Duration
Overview
The duration of the study, including screening, is approximately 10 weeks. 
Part 1 is planned to enrol up to 7 sequential cohorts of 8 subjects per cohort (at protocol 
Amendment 03, the planned number of cohorts is reduced, and the dose of GSK1795091 
for cohorts 5, 6 and 7 lowered. Cohort 4 is a repeat of the 60 ng dose; refer to Section 
4.5.2).  Subjects enrolled in Part 1 will participate in the study for approximately 60 days 
from screening to the follow-up visit.
Part 2 is planned to enrol 2 parallel cohorts of 6 subjects per cohort.  Subjects enrolled in 
Part 2 will participate in the study for approximately 67 to 75 days from screening until 
the follow-up visit.
Subjects will be evaluated in the clinical unit for a screening visit and, if eligible, will 
receive study product within 30 days.  Subjects will be admitted to the clinical unit 2 days 
prior to dosing (Day -2).  


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Part 1
In Part 1, on Day 1, 8 subjects will be randomised in a 3:1 ratio to receive intravenous 
GSK1795091 or matching placebo. Subjects will be observed as inpatients for 96 hours at 
which time they will be discharged after assessments have been performed by the 
investigator.  Subjects will have a follow up visit as an outpatient on Day 7 and a final 
follow up contact by phone or by visit on Day 30.  
In Part 1, dosing of study product for each cohort will be staggered, with approximately 1 
day of observation between at least 4 subgroups. No more than 2 subjects will be dosed 
per day, and administration of study product will be separated by at least 1 hour when 
subjects are dosed on the same day.  A sentinel group of 2 subjects will receive study 
product in a ratio of 1 GSK1795091: 1 placebo.  The remaining 6 subjects will receive 
study product in a ratio of 5 GSK1795091: 1 placebo.  
In Part 1, the Principal Investigator should pause dosing of new subjects, within a cohort, 
for review with the GSK Medical Monitor in the following cases:

If 1 or more subjects experience a Grade 3 or greater adverse event that can 
reasonably be attributed to GSK1795091 or a serious adverse event or QTcF 
>500 msec or an increase in QTcF by 60 msec or more compared to baseline, 
dosing of additional subjects within the cohort should stop.

If 1 or more subjects experience a Grade 2 or greater adverse event that lasts 
more than 24 hours and can reasonably be attributed to GSK1795091, dosing of 
additional subjects within a cohort should be held until the adverse event has 
resolved to Grade 1 or less.  
In Part 1, cohorts will be opened sequentially after evaluation of adverse events, vital 
signs, laboratory tests, and 12-lead ECGs by the Principal Investigator (blinded), GSK 
Medical Monitor (unblinded), GSK statistician (unblinded).  All available safety and 
tolerability data (adverse events, vital signs, 12-lead ECG and safety laboratory 
assessments) will be reviewed from ongoing and preceding cohorts.  Safety data from 96 
hours after administration of study product must be available for a decision to dose-
escalate to be taken.  Additionally, safety data from at least 5 of the 6 subjects who were 
randomized to receive GSK1795091 must be available in order for a decision to dose-
escalate to be taken. If subjects prematurely discontinue from the study, additional 
replacement subjects may be enrolled and assigned to the same treatment at the discretion 
of the Sponsor in consultation with the Investigator. Up to 8 subjects may be replaced 
during the study.
Progression to the next higher dose level will be stopped if any of the following occur:

1 or more subjects experience a serious adverse event that can reasonably be 
attributed to GSK1795091.

1 or more subjects experience a Grade 3 or greater adverse event that can 
reasonably be attributed to GSK1795091.

1 or more subjects experience a transaminase increase 3xULN (see Section 
5.4.2).


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
1 or more subjects experience QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.

3 or more subjects in a cohort experience Grade 2 adverse events that can 
reasonably be attributed to GSK1795091.

Any other event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor. 
The grading of adverse events will be guided by the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(Appendix 2) with the exception of fluctuations in white blood cell counts (which are 
anticipated and may be considered adverse events only after >24 hours) and fever and 
tachycardia which also require a change from time-matched baseline (per table below).  
Grade 1
Grade 2
Grade 3
Grade 4
Temperature 
>0.5oC change
AND
>38.0oC
>1.5oC
change
AND
>38.5oC
>3 oC change 
(<24 hours)
AND
>39.0oC
>3oC change 
(24 hours)
AND
>40oC
Heart rate 
>15 bpm
change
AND
>101 bpm
>30 bpm
change
AND
>116 bpm
>45 bpm
change
AND
>130 bpm
Emergency 
intervention 
required
Following blinded review of safety data and attribution assessments by the study 
investigator, the medical monitor may determine that the investigator can be unblinded to 
study treatment in cases where adverse events in a placebo-treated subject might stop 
dose escalation.
If dose escalation stops, all safety data will be reviewed to determine whether (1) 
additional subjects should be enrolled at the current dose level or at a lower level to 
confirm safety findings or (2) Part 1 of the study should be considered complete.  PD data 
may be reviewed.  
Following completion of Part 1, the safety data and proposed dose level for Part 2 will be 
submitted to the Ethics Committee for review. Once the Ethics Committee vote is 
received, Part 2 will begin. 
Part 2
In Part 2, on Day 1 subjects will receive intravenous study product GSK1795091 at a 
dose determined by results from Part 1.  


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If dose escalation in Part 1 was stopped for one of the following reasons, GSK1795091 
will be administered in Part 2 at a dose one level below the highest dose evaluated in Part 
1:

1 or more subjects experienced a serious adverse event that can reasonably be 
attributed to GSK1795091.

1 or more subjects experienced a Grade 3 or greater adverse event that could 
reasonably be attributed to GSK1795091.

1 or more subjects experienced a transaminase increase 3xULN.

1 or more subjects experience QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.

Another event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor. 
If dose escalation in Part 1 was stopped for the following reason, GSK1795091 will be 
administered in Part 2 at the highest dose evaluated in Part 1:
3 or more subjects in a cohort experienced Grade 2 adverse events that could 
reasonably be attributed to GSK1795091.
In Part 2, dosing of study product will be staggered, with approximately 1 day of 
observation between at least 3 subgroups and no more than 2 subjects within each cohort 
dosed per day. Administration of study product will be separated by at least 1 hour when 
subjects are dosed on the same day.  
Subjects will be observed as inpatients for at least 96 hours, after assessments have been 
performed by the investigator. Subjects in Cohort 1 will remain inpatients until Day 12. 
Subjects in Cohort 2 will be discharged after completion of the Day 5 (96 hour) 
assessments and will return to the clinical unit for a second inpatient visit on Day 13 (Part 
2, Cohort 2). If AEs attributed to the first dose of GSK1795091 have resolved, subjects 
will receive a second dose of GSK1795091 on Day 8 (Part 1, Cohort 1) or Day 15 (Part 2, 
Cohort 2).  Subjects will be followed according to the same schedule as after the first 
dose of GSK1795091. In addition, the Principal Investigator should review all available 
safety data following the second dose of GSK1795091 and interrupt subsequent dosing 
(within or between cohorts) if any of the following occur 

1 or more subjects experiences a serious adverse event that can reasonably be 
attributed to GSK1795091.

1 or more subjects experience a Grade 3 or greater adverse event that can 
reasonably be attributed to GSK1795091.

1 or more subjects experience a transaminase increase 3xULN (see Section 
5.4.2).

1 or more subjects experience QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.


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
Any other event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor.
In the event that dosing is interrupted, administration of GSK1795091 in Part 2 will only 
resume after approval by the Ethics Committee and Higher Health Authority following a 
substantial amendment.
Table 1
Part 2 dosing regimen (parallel cohorts)
Cohort
Dose Interval
Subjects
1
1 week
6
2
2 weeks
6
Details of the assessments and procedures, including acceptable windows, are described 
in Section 7 and the Time and Events Table (Section 7.1).
4.3.
Type and Number of Subjects
Approximately 68 subjects will be enrolled in the study. Between 8 and 56 subjects will 
be enrolled in Part 1.  Twelve (12) subjects will be enrolled in Part 2.
Part 1 is planned to enrol up to 7 cohorts of 8 subjects per cohort. 
Part 2 is planned to enrol 2 cohorts of 6 subjects per cohort.    
If subjects prematurely discontinue from the study, additional replacement subjects may 
be enrolled and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the Investigator. Up to 8 subjects may be replaced during the study.
4.4.
Design Justification
GSK1795091 is being evaluated in this single ascending dose FTIH study to provide 
safety, PK, PD, and exploratory biomarker data in healthy subjects.  
A healthy subject population is an appropriate population for the FTIH study.  A healthy 
subject study will allow for robust PK and PD data to be collected in a population free of 
confounding co-morbidities, concomitant medications, and other intrinsic and extrinsic 
factors that increase variability of these data. Meanwhile, the preclinical safety profile of 
GSK1795091 and historical experience with the drug class support development in 
healthy subjects.  Preclinical safety data do not suggest that subjects are at risk for 
adverse events that are irreversible or that cannot be monitored.  Likewise, experience 
with the drug class has shown that TLR agonists have a predictable tolerability profile 
characterized by fever and flu-like symptoms.  Finally, a FTIH study in healthy subjects 
avoids exposing subjects with advanced malignancies to an investigational product 
unlikely to have anti-tumor activity when administered systemically as a monotherapy.  
Adverse event grading is based upon Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix 2), 


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consistent with the use of TLR agonists as immune adjuvants and the anticipated adverse 
event profile.  Fever and tachycardia are graded according to changes from baseline 
values, with Grade 2 event thresholds approximating the mean increases for tolerated 
doses reported for other TLR4 agonists.  Thus, the anticipated adverse events in this trial 
should not exceed the severity of the toxicities reported in other trials of TLR agonists 
administered to healthy subjects.  
In Part 1, a standard dose escalation design is planned.  The starting dose selection and 
dose escalation increments are based upon preclinical safety, PK and PD data and in vitro
comparisons to LPS as described in Section 5.2.  The starting dose was selected 
conservatively, as described below (Section 4.5.1).  The dose increments between cohorts 
progressively decline from 3-times to 1.5-times the previous dose and progressively 
increase overlap of GSK1795091 exposures.
A placebo control and double-blind (sponsor-unblinded) design are intended to reduce 
bias in the reporting and collection of subjective data. 
The staggered dosing in Part 1 is planned as a conservative measure because 
GSK1795091 has not been previously administered to humans.  The 1 day interval 
between subgroups is supported by the transient preclinical pharmacodynamic effects of 
GSK1795091 and rapid (<24 hour) resolution of clinical and laboratory effects of other 
TLR4 agonists (Astiz, 1995; Dillingh, 2014).  The inpatient observation period of 96 
hours provides an opportunity to ensure that adverse events have resolved or are 
resolving prior to discharge of subjects from the inpatient unit.  Additionally, the 
extended inpatient period provides a controlled environment that reduces the likelihood 
of subjects engaging in routine daily activities associated with adverse events similar to 
those caused by TLR agonists (e.g. headache, myalgia, etc.)  The review of safety data 
and the stopping rules and adverse event grading are consistent with standard FTIH 
designs. 
In Part 2, a second dose will be administered based upon the definition of a tolerated dose 
level in Part 1.  A second dose will only be administered if subjects have recovered from 
adverse events considered at least possibly related to study product.  The cohorts in Part 2 
will be conducted in parallel given that the safety of the second dose is expected to be 
similar to or better than the first dose (due to the known tolerance that develops with 
repeat doses of TLR agonists) (Astiz, 1995; de Vos, 2009). However, dosing will be 
staggered so that a second dose will only be administered to 2 subjects on a single day.  
4.5.
Dose Justification
4.5.1.
Starting dose selection
The proposed starting dose for the study was determined after due consideration of all 
available in vitro and in vivo preclinical data, in accordance with EMEA and FDA 
regulatory guidance for first-time-in-human studies.  


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4.5.1.1.
Calculation of Minimum Anticipated Biological Effect Level
The dose is calculated using the in vivo Minimum Anticipated Biological Effect Level 
(MABEL) in the 6-week cynomolgus monkey study, and secondarily, supported by rabbit 
pyrogenicity studies and in vitro potency comparisons to LPS.  The cynomolgus monkey 
was chosen as the in vivo toxicology model based upon greatest sensitivity and highest 
similarity to humans as determined by cytokine production following exposure of whole 
blood from several species to GSK1795091 ex vivo. Five (5) cytokines were measured in 
vivo; these cytokines were selected for evaluation based upon high ex vivo sensitivity of 
whole blood to GSK1795091 (IL10 and IP10) or based upon increases following 
administration of TLR4 agonists to healthy subjects in published clinical trials (TNFa, 
IL6, and IL8) [Astiz, 1995]. Vehicle or GSK1795091, at doses of 0.05, 2, and 200 µg/kg, 
was administered to cynomolgus monkeys.  IP10 and IL10 were the most sensitive 
pharmacodynamic markers and were detectable in all evaluable monkeys at 0.05 µg/kg.  
There were minor decreases in lymphocytes, monocytes, eosinophils, and NK cells at 
doses of 0.05 µg/kg, and transient increases in heart rate and body temperature at doses 
of 2 µg/kg, all of which were considered non-adverse.  As such, the no observed 
adverse effect level (NOAEL) is 200 µg/kg/week, the highest dose tested. Additional 
details are available in the Investigator’s Brochure.
Ten percent effect concentration (EC10) values were calculated for each cytokine based 
upon peak plasma concentrations. IL10 and IP10 had the lowest EC10 values (0.0281 
ng/ml and 0.0405 ng/ml, respectively), and the other cytokines had values greater than 
0.3 ng/ml. IL10 was the most sensitive pharmacodynamic marker and the EC10 value of 
0.0281 ng/ml provided a basis for calculation of the MABEL.  The dose of GSK1795091 
that was estimated to have a Cmax of 0.0281 ng/ml when administered to cynomolgus 
monkeys is 3 ng/kg.  
The human equivalent dose (HED) of the cynomolgus monkey 3 ng/kg dose was 
calculated using two methods.  The first predicted human concentration-time data by 
constructing a Dedrick plot based on dose-normalized cynomolgus monkey 
concentration-time data.  The elementary Dedrick plot was generated using fixed-
exponent scaling, assuming single animal (monkey) power allometric exponents (1 for 
volumes and 0.67 for clearance resulting in an exponent of 0.33 for physiological time).  
Using the predicted human clearance and volume values from this analysis, the human 
dose needed to obtain a Cmax of 0.0281 ng/ml is approximately 200 ng.  The second 
calculation used the FDA Guidance for Industry for Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.  
Based upon the scaling factor of 3.1, the 3 ng/kg dose in the cynomolgus monkey 
corresponds to a HED of 1 ng/kg, or 70 ng for a 70 kg subject.  The latter approach was 
adopted for the starting dose calculation since it provides a more conservative value. 
Thus, the HED of the 3 ng/kg dose in the cynomolgus monkey is 70 ng.  The addition of 
a 10-fold margin for safety provides a starting dose of 7 ng. 
4.5.1.2.
Rabbit pyrogenicity
Rabbits are commonly used as models for assessing endotoxin contamination of 
parenteral formulations due to their high sensitivity. Therefore, GSK1795091 was given 


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to New Zealand white rabbits at single intravenous doses of 0.1, 0.5, 1, 2.5 and 5 ng/kg in 
5% dextrose. Rabbits given single doses of 5 ng/kg had increases in body temperature of 
0.5oC 60 minutes post dose and generally returned to baseline temperature by 180 
minutes post dose, consistent with the expected pharmacologic actions of GSK1795091. 
Lower doses were not considered to be pyrogenic. Based on a scaling factor of 3.1, the 
2.5 ng/kg dose in the rabbit corresponds to a HED of 0.8 ng/kg, or 56 ng for a 70 kg 
subject.  Thus, the HED of the non-pyrogenic dose in rabbits is 8-fold higher than the 
proposed starting dose of 7 ng.
4.5.1.3.
Comparison to Lipopolysaccharide (LPS)
The typical dose of LPS administered to healthy subjects in clinical trials is 2 to 4 ng/kg 
(approximately 140 ng to 280 ng).  Following administration, subjects experience mild to 
moderate flu-like symptoms and increases in body temperature and heart rate.  To 
confirm the safety of the proposed 7 ng starting dose of GSK1795091, the potencies of 
GSK1795091 and E.coli-derived LPS (commonly used for clinical trials of healthy 
subjects) were compared.  Human whole blood was incubated in vitro with either 
GSK1795091 or LPS, and cytokines were measured to assess the relative potencies of the 
two TLR4 agonists.  At concentrations of 0.2 ng/ml (approximating the plasma 
concentration following a 8.6 ng/kg dose of LPS for a 70 kg subject with a 3000 ml 
plasma volume), LPS was as potent or more potent than GSK1795091 by a factor of 1 to 
4 for a panel of 5 measureable cytokines.  If GSK1795091 is estimated to be of 
comparable potency to LPS, the doses of LPS routinely administered to healthy subjects 
are 20-fold to 40-fold greater than the 7 ng starting dose of GSK1795091. Thus, the 
planned starting dose is appropriately conservative.
4.5.2.
Dose escalation
Dose escalation will proceed as follows:  
Cohort Number
Dose (ng)
1
71
2
211
3
601
4
602
5
100
6
150
7
210
1.
Cohorts completed under Protocol Amendment 2.
2.
Study restart dose following stopping criteria met in one subject 
under Protocol Amendment 2
The dose increments between cohorts progressively decline from 3-times to 1.4-times the 
previous dose.


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4.5.3.
Top dose selection
The original maximum proposed dose level proposed on preclinical data was 630 ng but 
was revised to 210 ng based on emerging clinical data cohorts 1-3 in Part 1. 
Dose escalation may stop at a lower dose level based on criteria in Section 4.2. In the 
repeat dose intravenous toxicity studies in rats and monkeys, GSK1795091 was 
associated with expected pharmacologic, pro-inflammatory actions of a TLR4 agonist. 
Therefore, adverse events that stop dose escalation are likely to include mild to moderate 
flu-like symptoms and increases in body temperature and heart rate.   
The original top dose of 630 ng was selected to accommodate a possible range of 
potencies of GSK1795091, based on in vitro evaluations.  In vitro data suggest that the 
relative potency of LPS is 1- to 4-times that of GSK1795091. If GSK1795091 is 
equipotent with LPS, dose escalation is predicted to stop in accordance with Section 4.2
at 2-4 ng/kg (i.e. 140 to 280 ng). If GSK1795091 is less potent than LPS by a factor of 4, 
higher dose levels will be required to elicit pharmacologic effects similar to LPS; this 
possibility is accommodated by the maximum proposed dose level of 630 ng (i.e. 
approximately 4.5-fold greater than the LPS dose of 2 ng/kg). 
Based on the maximum predicted human exposure of approximately Cmax 0.09 ng/mL 
and AUC 2.6 ng.h/mL at a dose of 630 ng, the margin to the NOAEL dose in rat (15 
µg/kg/dose) is approximately 777X (Cmax) and 121X (AUC) and in monkey (200 
µg/kg/dose) is approximately 19,100X (Cmax) and 8461X (AUC). Thus, at a dose level
of 630 ng, severe or irreversible toxicities are not expected.
Based on emerging clinical data from Part 1, the GSK1795091 is likely to produce effects 
similar to LPS at a dose between 140 to 280 ng.  Therefore, the top dose in the study was 
revised to 210 ng.
4.5.4.
Summary
The starting dose of 7 ng is expected to be safe and appropriately conservative for a 
healthy subject study.  Sensitive assays in a cynomolgus monkey model were used to 
calculate the MABEL.  At the dose defining the MABEL, animals experienced neither 
adverse events nor histopathological changes.  Furthermore, the dose is 8-fold higher than 
the HED of the non-pyrogenic dose in rabbits. Additionally, clinical experience with 
TLR4 agonists administered to healthy subjects provides a reference value against which 
the starting dose of GSK1795091 can be compared.  Since GSK1795091 has in vitro
potency similar to (or lower than) LPS, a starting dose of 7 ng is conservative in 
comparison to the 20 to 40-fold higher doses of LPS routinely administered to healthy 
subjects.  These estimates provide a high level of confidence that the starting dose of 7 ng 
can safely be administered to healthy subjects. Dose escalation is expected to stop, at or 
below 210 ng, based on mild to moderate toxicities that are reversible and readily 
monitored.  The top dose in the study, 210 ng, does not approach the Cmax or AUC at the 
NOAEL in rats or in monkeys. Thus, dose escalation proceeds from a conservative 
starting dose to a top dose unlikely to be associated with severe or irreversible effects.


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4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1795091 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 1795091] 
Cytokine-associated symptoms (flu-like 
symptoms, fever, tachycardia, etc.) or cytokine 
release syndrome.
TLR agonists (including TLR4 agonists) are 
known to increase serum cytokine levels based 
upon extensive evaluations in laboratory 
animals, healthy subjects and patients.

Starting dose defined based upon MABEL.

Stopping rules designed to not exceed 
tolerability precedents from prior TLR4 
agonist studies in healthy subjects.

Staggered dosing of subjects.

Study conduct in medical center-based 
phase I unit with experience administering 
immune system agonists.

Enrolment of subjects with no prior 
significant medical conditions. Frequent 
vital sign measurements and telemetry for 
24 hours.

Adverse event management with 
supportive care and paracetamol. 

Reference to management algorithms for 
managing severe cytokine release 
syndrome (CRS).
Hypotension
Rare cases of severe hypotension have been 
described in healthy subjects receiving LPS.  
Risks for these events may include prior history 
of syncope and inadequate hydration.

Exclusion of subjects with history of 
syncope.

Hydration of subjects prior to study product 
administration. 

Frequent vital sign measurements and 
telemetry for 24 hours.

Adverse event management with fluids, 
and if necessary, vasopressor support.
Study Procedures
Frequent phlebotomy 
Overall volume of blood drawn will not exceed 
500 ml.


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4.6.2.
Benefit Assessment
Healthy subjects enrolled in this study will not receive clinical benefit from volunteering.
4.6.3.
Overall Benefit:Risk Conclusion
The study is designed to minimize risks to subjects through the use of eligibility criteria, 
a conservative approach to dosing, guidance for stopping criteria, and rigorous safety 
monitoring by qualified personnel at a center equipped to conduct FTIH studies. The 
preclinical data, drug class, and safety precautions summarized in the protocol provide a 
benefit:risk consistent with standard clinical trials performed in healthy subjects.
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.
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. Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, laboratory tests, 
vital signs and 12-lead ECG. (A subject with a clinically insignificant abnormality or 
laboratory parameter(s) may be included only if the Investigator documents that the 
finding is unlikely to represent a safety risk and will not interfere with the study 
procedures.)  
WEIGHT
3. Body weight 55 - 95 kg and body mass index (BMI) within the range 19 – 30 kg/m2 
(inclusive).


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SEX
4. Male or 
Female of non-childbearing potential:
Males: 
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 the follow-up visit. .
Acceptable forms of contraception include:
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 female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum or urine human chorionic gonadotrophin (hCG) test), not lactating, and at 
least one of the following conditions applies:
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


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Postmenopausal defined as 24 months of spontaneous amenorrhea and follicle 
stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  
INFORMED CONSENT
5. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
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 QTcF INTERVAL) 
1.
History of any significant medical condition (e.g. cardiac, pulmonary, metabolic, 
renal, gastrointestinal, rheumatological, etc.)
2.
History of frequent (>1 per week) headache or myalgia.
3.
History of asthma.
4.
History of syncope.
5.
History of liver disease, or known hepatic or biliary abnormalities. 
6.
AST, ALT, gamma-GT and bilirubin >1.0xULN 
7.
Creatinine >1.0 x ULN. 
8.
Vital signs
SBP <90 and > 140 mmHG
DBP<50 and >90 mmHG
Heart Rate <50 and >90 bpm
Temperature >37.5C
9.
Clinically significant ECG abnormality and/or 
Heart Rate < 50 and > 90 bpm
PR Interval  > 220 msec
QRS Duration > 120
QTcF > 450 msec
Note that if ECG abnormalities are identified, the ECG should be repeated two more 
times (with 5 minutes between ECG readings) and the average of the 3 values used 
to determine eligibility.


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CONCOMITANT MEDICATIONS
10. Anticipated requirement for any prescription medication during the study.
RELEVANT HABITS
11. History of regular alcohol consumption within 6 months of the study averaging a 
weekly intake of >14 drinks for males or >7 drinks for females or inability to abstain 
from alcohol from 1 day prior to the inpatient period of the study until discharge.  
(One drink is equivalent to 8 g of alcohol: 200ml of beer, 100ml of wine or 1 
measure (25 ml) of spirits)  
12. Urinary cotinine levels indicative of smoking or history or regular use of tobacco or 
nicotine-containing products within 2 months prior to screening or inability to 
abstain from smoking during the study.
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. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
(anti-HBc Ab) result at screening or within 3 months prior to first dose of study 
treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA PCR test is 
obtained.
15. A positive pre-study drug/alcohol screen.
16. A positive test for HIV antibody.
17. Donation of blood or blood products in excess of 500 mL within a 56 day period.
18. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first visit (Day -2) in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
19. Exposure to more than four new chemical entities within 12 months prior to the first 
visit (Day -2).
20. Exposure to GSK1795091 in a previous cohort of this study.
21. Subject is unable to refrain from taking non-prescription drugs (including vitamins 
and dietary or herbal supplements), within 7 days prior to the first dose of study 
medication until completion of the follow-up visit, unless in the opinion of the 
investigator and sponsor the medication will not interfere with the study.
22. Subject is unable to understand and communicate in German/or native language of 
the site
23. Subject, or close relative of the subject, is the investigator or a subinvestigator, 
research assistant, pharmacist, study coordinator, or other staff directly involved with 
the conduct of the study at that site.
24. Vulnerable subjects (eg subjects kept in detention)


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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 7.3.1.4).
5.4.
Withdrawal/Stopping Criteria
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, behavioural or 
administrative reasons. Furthermore, any female subject who becomes pregnant while 
participating will be withdrawn from the study [see Section 12.5.2]. 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. 
5.4.1.
Subject withdrawal procedures
Where possible, if a subject decides to withdraw or is withdrawn during a study day, all 
scheduled assessments will be taken as planned. The investigator must also make every 
effort to perform the following evaluations if not already scheduled for that day:

Brief Physical exam

12-lead ECG

Supine vital signs

Clinical laboratory tests (clinical chemistry, haematology and urinalysis)

Adverse events and concomitant medications assessment

Pregnancy test (females only)


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If a subject prematurely withdraws or is withdrawn on a non-study visit day, then the 
investigator must make every attempt to conduct the above evaluations. 
Subjects who withdraw may be replaced following discussions between the investigator 
and GSK study team. Replacement subjects will be assigned to the same treatment as that 
of the subject they are replacing.
5.4.2.
Liver Chemistry Stopping Criteria
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
5.4.3.
QTcF Stopping Criteria

The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
A subject that meets either bulleted criterion below will be  monitored until parameters 
return to baseline values and will not be eligible to receive additional doses of 
GSK1795091 (if enrolled in Part 2 of the study).  

QTcF > 500 msec,

Change from baseline: QTcF >60 msec


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5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit or contact.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
On Day -1, subjects will be hydrated with approximately 1200 mL glucose/saline (2.5% 
glucose/0.45% sodium chloride) (e.g. intravenous drip 150 mL/hr). Intravenous hydration 
(sourced locally) should continue on Day 1, beginning approximately 2 hours prior to and 
continuing for 6 hours after administration of study product (intravenous drip 150 
mL/hr).
Subjects will receive GSK1795091 administered as an intravenous bolus slowly over 2-5 
minutes.
Study Treatment
Product name:
GSK1795091 Injection, 
0.001mg/mL, 5mL vial with 
5.2mL fill volume
Placebo
Sodium Chloride Injection
Formulation description:
A clear solution in a 5ml vial 
with a 20mm stopper and 
overcap.
Commercial saline solution
A clear colourless solution 
containing 0.9% sodium 
chloride
Dosage form:
Solution for Injection
Solution for Injection
Unit dose 
strength(s)/Dosage level(s):
0.001mg/mL (1000 nanogram 
per mL)
N/A
Route of Administration
Intravenous Injection 
Intravenous Injection
Dosing instructions:
Administered as an 
intravenous bolus slowly over 
2-5 minutes, followed by an 
intravenous bolus of 10mL of 
normal saline
To be administered in an 
identical manner to 
GSK1795091
Physical description:
A clear, colourless to slightly 
coloured solution, free from 
visible particles in a clear glass 
vial with grey stopper and 
aluminium grey brown 
overseal.
A clear colourless solution


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6.2.
Treatment Assignment
Subjects will be assigned to a specific treatment group for Part 1 in accordance with the 
randomization schedule generated by Clinical Statistics or designee using validated 
software. Subjects will be randomized prior to the first dose of the study treatment 
(GSK1795091 or placebo), after all screening assessments have been completed and after 
the Investigator has verified that they are eligible per the study inclusion/exclusion 
criteria.  No subject may receive the study treatment prior to randomization and 
assignment of a unique subject identification number. 
Each subject scheduled to receive the study treatment will receive a treatment allocation 
number when randomized.  The treatment number will indicate if the subject is to receive 
the scheduled dose of GSK1795091 or placebo. 
6.3.
Blinding
This study will be conducted in 2 parts. 
Part 1
Part 1 will be double-blind, with both the investigator and subject blinded to study 
treatment.  All site personnel with the exception of the pharmacy team will remain 
blinded to study treatment except as discussed below.  The sponsor’s team will be 
unblinded.
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.The unblinded site pharmacist will receive the 
randomization code and ensure that it is stored in a secure area, accessible by the PI, 
treating physician or designee, in emergency situations. 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. If 
GSK personnel are not contacted before the unblinding, the investigator must notify GSK 
as soon as possible after unblinding. The date and reason for the unblinding must be fully 
documented in the CRF/eSource.   
The GSK medical monitor, statistician, and pharmacokineticist will be unblinded to 
subject level data for each cohort. Following review of safety data and attribution 
assessments by the study investigator, the GSK medical monitor may determine that the 
investigator and GSK study team can be unblinded to study treatment in cases where 
adverse events in a placebo-treated subject might stop dose escalation. GSK’s Global 
Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment 
assignment for any subject with a SAE. Additionally, if a SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, GSK’s Global Clinical 
Safety and Pharmacovigilance (GCSP) staff may send a copy of the report, identifying 
the subject’s treatment assignment, to investigators in accordance with local regulations 
and/or GSK policy.


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Part 2
Part 2 will be open-label where the sponsor, investigator and subject will be open to study 
treatment.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK1795091 will 
be detailed in a Study Specific Technical Agreement/Memo (TTS) or Pharmacy Manual 
which will be accompanied by a Quality Agreement.

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. 

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.
6.6.
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 dose of study treatment and 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.  
GSK1795091 will be intravenously administered to subjects at the site.  Administration 
will be documented in the source documents and reported in the CRF/eSource.
6.7.
Management Guidelines for Adverse Events
GSK1795091 has not previously been administered to humans although drugs in this 
class have generally caused mild to moderate toxicities associated with systemic cytokine 


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production. In a case report of a subject that received a very high dose (1 mg) of LPS, 
supportive care was provided in an Intensive Care Unit (ICU).  Reported treatment 
included fluids and vasopressors to maintain hemodynamic stability and diuresis for 
pulmonary edema (Taveira da Silva, 1993).  Recent experiences with adoptive cell 
therapies in cancer patients have lead to the publication of guidelines for managing 
cytokine release syndrome (CRS) (Lee, 2014).  Patients with mild or moderate adverse 
events have been managed with supportive care, including fluids, vasopressors, and/or 
oxygen.  Patients with high grade CRS (described by Lee, 2014. as requiring multiple 
doses of vasopressors, hypoxia requiring >40% oxygen, or organ toxicity) have been 
managed in an intensive care unit and received immunosuppressive treatment. 
Anecdotally, tocilizumab (anti-IL6 receptor antibody) has produced rapid and complete 
correction of CRS associated with cellular therapies although it is not approved for this 
indication (Maude, 2014).  Lee, 2014 recommend administration of tocilizumab 4 mg/kg 
in adult patients as the first-line treatment of severe CRS with a repeat dose if clinical 
signs and symptoms do not improve within 24-48 hours. 
Based upon these experiences with LPS and with cytokine release syndrome, 
recommendations for managing adverse events are as follows.  Grade 1 and 2 adverse 
events should be managed with supportive care.  Paracetamol may be administered for 
Grade 1 and 2 adverse events.  Grade 3 and higher adverse events should be managed 
with supportive care, as determined by the investigator.  Fluids and vasopressors should 
be used to support blood pressure.  Tocilizumab may be considered if conventional 
supportive measures are unsuccessful or if transfer to an ICU is imminent.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK1795091 greater than the intended dose will be 
considered an overdose.
In the event of an overdose the investigator should:
1. contact the Medical Monitor immediately
2. closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities. 
3. obtain serial plasma samples for PK and PD analyses over the first 24 hours
4. document the quantity of the excess dose in the CRF/eSource.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation. Subjects may 
only participate in one cohort of this study.


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6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions

Patients are required to consume fluids liberally from the time of admission to the 
inpatient unit until administration of study product.
6.10.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) from 24 
hours prior to admission to the inpatient unit until discharge

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
admission until after day 7 and 24h prior to the follow up

Regular use (i.e. more than 3 times per week) of tobacco products is not allowed 
from 2 months prior to screening until after the final follow-up visit.
6.10.3.
Activity
Subjects will abstain from strenuous exercise during the inpatient period of the study.  
Subjects may participate in light recreational activities (e.g., watch television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Occasional paracetamol or NSAIDs, at prescribed doses, are permitted. Other 
concomitant medication may be considered on a case by case basis by the investigator in 
consultation with the GSK Medical Monitor.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Except as noted above, subjects are not allowed to receive non-study medications.  
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


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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, pharmacodynamic/biomarker and exploratory biomarkers 
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 per subject will be collected over the duration of 
the study, including any extra assessments that may be required.


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7.1.
Time and Events Table
7.1.1.
Screening
Procedure
Screening (up to 30 days prior to
Day -1)
Informed consent
X
Outpatient visit
X
Inclusion and exclusion criteria
X
Demographics
X
Full physical exam including height and weight
X
Medical history1
X
Drug/Alcohol screen
X
Serum/urine pregnancy test ( WNCBP)
X
HIV, Hep B and Hep C screen
X
Haem/Clin Chem/PT & PTT/Urinalysis
X
12-lead ECG2
X
Vital signs (BP and heart rate)
X
Concomitant medication review
X
1.
To include substance usage, family history of premature cardiovascular disease, medication, drug/alcohol history
2.
Triplicate ECGs collected 5mins apart


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7.1.2.
Part 1: In-House Assessments
Procedure
Day 
-2
Day 
-1
Treatment Period Day 1
Day 2 (24h)
Day 3 (48h)
Day 4 (72h)
Day 5 (96h)
Pre dose
0h
5min
0.25h
0.5h
1h
2h
3h
4h
6h
8h
10h
12h
16h
Admission to the 
unit
X
Overnight stay
X
X
==========================================================================================================
Serum/urine 
pregnancy test 
(WNCBP)
X
Full physical exam 
including height and 
weight
X
Inclusion and 
exclusion criteria
X
X
Haem/Clin 
Chem/Urinalysis
/Coagulation
X
X
X
X
WBC with 
differential1
X
X
X
X
X
X
X
X
X
X
Drug/Alcohol test
X
12 lead ECG
X
X
X
X
X
X
Vital signs 
(Temperature, BP 
and Heart rate)
X2
X
X
X
X
X
X
X
X
X
X
X
X
Telemetry 
=======================================================================================
Dosing
X
Intravenous 
hydration
X
======================================================
PK blood sampling3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Day 
-2
Day 
-1
Treatment Period Day 1
Day 2 (24h)
Day 3 (48h)
Day 4 (72h)
Day 5 (96h)
Pre dose
0h
5min
0.25h
0.5h
1h
2h
3h
4h
6h
8h
10h
12h
16h
Cytokine 
measurements3
X
X
X
X
X
X
X
X
X
Leukocyte 
phenotyping3
X
X
X
AE/SAE review4
X
X
========================================================================================================
Concomitant 
medication review
X
X
==========================================================================================================
Discharge
X
1.
Where WBC+Differential and Haematology are scheduled for the same time, WBC+Differential may  be collected as part of the Haematology assessment
2.
Baseline Vital Signs to match Day 1  timepoints
3.
PK and Biomarker Sampling: The pre-dose blood samples should be collected within 1 hr before administration of GSK1795091. Every attempt should be made to collect 
samples within 5 min on samples up to 2 hrs, 20 min on samples up to 12 hrs, and 40 min on samples after 12 hrs. Actual date/time of sample collection and dosing must 
be recorded. Explanations are required for any deviations of >5 min from the planned time during the first 2 hrs and for deviations of more than 20 min from the planned time 
for samples collected at 3 hrs up to 10 hrs.
4.
Blood samples may be collected to explore biomarkers at the discretion of the Investigator


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7.1.3.
Part 1 Outpatient Assessments
Procedure
Day 7 
Follow-up
(23 days 2 days post-last visit) or early withdrawal
Outpatient Visit or Contact1
X
X
Serum/urine pregnancy test (WNCBP)
X
Full physical exam including height and weight
X
Haem/Clin Chem/Urinalysis/Coagulation
X
12 lead ECG
X
Vital signs (Temperature, BP and Heart rate)
X
PK blood sampling2
X
Cytokine measurements
X
Leukocyte phenotyping
X
AE/SAE review
X
X
Concomitant medication review
X
X
1.
Outpatient visit at Day 7; Outpatient visit or Contact at FU. All subjects with (1) new AE or (2) unresolved AEs or abnormal labs at the Day 7 visit should return for a follow-up visit. 
Female subjects should return for pregnancy testing. For all other subjects a FU contact is acceptable
2.
PK Sampling: Blood samples for analysis of GSK1795091 concentrations will be collected following dosing 144 hours (Day 7) after administration


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7.1.4.
Part 2: In-House Assessments
Procedure
Day 
-2
Day 
-1
Treatment Period Day 11
Day 2 (24h)
Day 3 (48h)
Day 4 (72h)
Day 5 (96h)
Pre dose
0h
0.083h 
(5min)
0.25h
0.5h
1h
2h
3h
4h
6h
8h
10h
12h
16h
Admission to the unit
X
Overnight stay
X
X
==============================================================================================
Serum/urine pregnancy test 
(WNCBP)
X
Full physical exam including 
height and weight
X
Inclusion and exclusion 
criteria
X
X
Haem/Clin Chem/Urinalysis/
Coagulation
X
X
X
X
WBC with differential2
X
X
X
X
X
X
X
X
X
Drug/Alcohol test
X
12 lead ECG3
X
X
Vital signs (Temperature, BP 
and Heart rate)
X4
X
X
X
X
X
X
X
X
X
X
X
X
Dosing
X
Intravenous hydration
X
====================================================
PK blood sampling5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolite urine sampling
X
============================================================================
Cytokine measurements5
X
X
X
X
X
X
X
X
X
Leukocyte phenotyping5
X
X
X
Gene signature analysis from 
PBMCs5
X
X
X
AE/SAE review6
==============================================================================================
X
Concomitant medication 
review
X
X
==============================================================================================
X
Discharge
X7


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1.
Day 1 and Day 8 C1/ Day 15 C2
2.
Where WBC+Differential and Haematology are scheduled for the same time, WBC+Differential may  be collected as part of the Haematology assessment
3.
Single ECGs all timepoints
4.
Baseline Vital Signs to match Day 1  timepoints
5.
PK and Biomarker Sampling: The pre-dose blood samples should be collected within 1 hr before administration of GSK1795091. Every attempt should be made to collect 
samples within 5 min on samples up to 2 hrs, 20 min on samples up to 12 hrs, and 40 min on samples after 12 hrs. Actual date/time of sample collection and dosing must 
be recorded. Explanations are required for any deviations of >5 min from the planned time during the first 2 hrs and for deviations of more than 20 min from the planned time 
for samples collected at 3 hrs up to 10 hrs.
6.
Blood samples may be collected to explore biomarkers at the discretion of the Investigator
7.
Cohort 2 only. Cohort 1 will remain inhouse until discharge on Day 13
7.1.5.
Part 2 Assessments
Procedure
7 Days Post Dose1
Follow-up2
(23 days 2 days post-last visit) or early withdrawal
Outpatient Visit 
X
X
Urine pregnancy test (WNCBP)
X
Full physical exam including height and weight
Haem/Clin Chem/ Urinalysis/Coagulation
12 lead ECG
Vital signs (Temperature, BP and Heart rate)
PK blood sampling
X
AE/SAE review
X
X
Concomitant medication review
X
X
1.
7 days post first dose assessments (Cohort 1 D7; Cohort 2 D14) will be conducted in house; 7 days post second dose (Cohort 1 D15; Cohort 2 D22) assessments will be 
conducted as an outpatient visit 
2.
Outpatient visit or Contact at FU. All subjects with (1) new AE or (2) unresolved AEs or abnormal labs at the Day 7 visit should return for a follow-up visit. Female subjects should 
return for pregnancy testing. For all other subjects a FU contact is acceptable


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7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed at screening and day -1 as related to 
the inclusion/exclusion criteria listed in Section 5.  
7.3.
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.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
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 7.3.1.3), 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/eSource.

All SAEs will be recorded and reported to GSK (or designee) within 24 hours, as 
indicated in Appendix 4.

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.


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7.3.1.2.
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?” 
7.3.1.3.
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 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 5.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK (or designee) 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.
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.
7.3.2.
Pregnancy

Details of all pregnancies in female partners of male subjects will be collected 
after the start of dosing and until final study follow-up contact.

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 5.


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7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include oral temperature, systolic and diastolic blood pressure and heart rate and 
respiratory rate.

Triplicate readings, separated by 1 minute or more, will be obtained at screening 
and at predose. Single readings will be obtained at all other timepoints.

The grading of heart rate adverse events should be performed according to time-
matched baseline measurements from Day -1. 
7.3.5.
Electrocardiogram (ECG)
ECG’s will be measured in the semi-supine position following a 10 minute rest. 

Triplicate 12-lead ECGs, separated by 5 minutes or more, will be obtained at 
screening, Day 1 and Day 4 in Part 1. Single 12 lead ECGs will be obtained at all 
other timepoints for both Part 1 and Part 2. An ECG machine will be used that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals.  Refer to Section 5.4.3 for QTcF withdrawal criteria and additional 
QTcF readings that may be necessary.

Continuous cardiac telemetry will be performed for the first 24 hours for subjects 
in Part 1.  Full disclosures will be reviewed in detail and the review maintained as 
part of the subject’s source documents.  As indicated, the investigator may 
perform unscheduled vital sign and/or ECG collections, based upon telemetry 
data, for the purpose of reporting adverse events.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 2, 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 laboratory and are 
detailed in the SRM OR the laboratory manual. Reference ranges for all safety 
parameters will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF/eSource.


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Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws. Haematology, clinical chemistry, urinalysis and 
additional parameters to be tested are listed in Table 2. 
Table 2
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Urea
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
CRP
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Coagulation 
Tests

prothrombin time (or international normalized ratio)

partial thromboplastin time
Other 
Screening 
Tests

HIV

Hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc 
Ab)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum or urine hCG Pregnancy test. 

Lipids, Total cholesterol, HDL, LDL

Gamma-GT
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.2 and 
Appendix 3
2.
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or ethics committee.


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7.3.7.
Assessment windows
Procedure
Time
Allowed deviation
ECG and Vitals
Pre-dose
- 60 minutes
5 min – 30 min
3 minutes
45 min – 4 hours
15 minutes
>4 hours
30 minutes
Labs
Pre-dose
- 60 minutes
24 hours
60 minutes
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples (4ml per timepoint) for pharmacokinetic (PK) analysis of GSK1795091 
will be collected at the time points indicated in Section 7.1, Time and Events Table.  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. 
Sample collection, processing and storage details will be provided in the Study Reference 
Manual. 
7.4.1.1.
Part 1
Blood samples for the determination of GSK1795091 will be obtained on Day 1 through 
7 following a single dose at the time points indicated in the Time and Events Table 
(Section 7.1).
7.4.1.2.
Part 2
For Cohort 1 (1 week repeat dose), blood samples for the determination of GSK1795091 
will be obtained on Day 1 through 7 following the first dose and on Day 8 through 15 
following the second dose at the time points indicated in the Time and Events Table 
(Section 7.1). For Cohort 2 (2 week repeat dose), blood samples for the determination of 
GSK1795091 will be obtained on Day 1 through 14 following the first dose and Day 15 
through 22 following the second dose at the time points indicated in the Time and Events 
Table (Section 7.1).
7.4.2.
Urine Sample Collection
Urine will be collected following the first dose in Part 2 for GSK1795091 and metabolite 
identification.  Urine will be collected pre-dose and 24 hours following the administration 
of GSK1975091. A 30 mL aliquot will be obtained from the pre-dose and 24-hour 
collections. 


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7.4.3.
Sample Analysis
Plasma analysis will be performed under the control of PTS-BIB GlaxoSmithKline, the 
details of which will be included in the Study Reference Manual (SRM). Concentrations 
of GSK1795091 will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).  
Once the plasma has been analyzed for GSK1795091 any remaining plasma may be 
analyzed qualitatively for other compound-related metabolites and the results reported 
under a separate GlaxoSmithKline protocol.
Plasma and urine may be analyzed qualitatively for GSK1795091 and other compound-
related metabolites and results reported under a separate GlaxoSmithKline protocol.
7.5.
Biomarker(s)/Pharmacodynamic Markers
For exploratory Biomarkers, Blood samples will be collected at time points indicated in 
Section 7.1 to determine the pharmacodynamic effect of GSK1795091 on plasma 
cytokines which are, but not limited to, TNF-alpha, IL-10, IL-1beta, IL-1Ra, IFN-
gamma, IL-12p70, IL-2, IL-4, IL-5, IL-6, IL-8, GCSF, IP-10, MCP-1, RANTES by 
multiplex immunoassay, leukocyte populations and their activation status or phenotype 
by flow cytometry and PBMCs Pan cancer immune gene expression profiles, but not 
limited to, by nanostring. Details for sample collection, processing, storage, and shipment 
will be provided in the Study Reference Manual (SRM)
8.
DATA MANAGEMENT

All participant data relating to the study will be recorded on printed CRF/eSources 
or collected electronically (e.g. eCRF, an eSource system, Laboratory Information 
Management System/LIMS etc). The investigator is responsible for verifying that 
site data is accurate and complete by physically or electronically signing the CRF 
or eSource in the absence of a CRF.

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.  

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification 
to the Sponsor. 


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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to primarily investigate the safety, and tolerability of 
GSK1795091 following IV doses in healthy subjects, and to inform the design of the 
first-in-cancer patient clinical trial.  
Part 2 of the study is designed to inform the dosing interval to be evaluated in the first-in-
cancer patient trial. Bayesian decision criteria will be used to inform the recommendation 
regarding two proposed dosing intervals (i.e., Q1W or Q2W). The posterior probability 
that C-reactive protein (CRP) change from baseline of the second dose is less than that of 
the first dose will be evaluated at the end of study based on a minimally informative prior 
distribution describing CRP changes in concert with the observed data of CRP changes in 
both Part 1 and Part 2 of the study. Tolerance to GSK1795091 will be defined as a 33% 
decrease in change from baseline in CRP following the second dose of GSK1795091 
relative to that of the first dose with a posterior probability greater than 90%.
The pharmacokinetics of GSK1795091 will be investigated as secondary objectives.
No formal statistical hypotheses will be tested. An estimation approach providing point 
estimates and corresponding confidence intervals will be used, where appropriate. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
As this is the first in human study, sample size for part 1 is largely based on feasibility, 
i.e., no formal power calculations were performed. 
For part 2 of the study, the sample size was estimated based on the assumption that the 
dose of GSK1795091 administered would produce changes in CRP comparable to a 2 
ng/kg dose of LPS, 18 6 mg/L (Dillingh, 2014). The prior distribution of CRP changes 
from baseline for the first dose and second dose will follow a bivariate normal 
distribution with a minimal informative prior mean and covariance matrix.   This 
simulation assumes a correlation of 0.5 in the CRP change from baseline between day 1 
and day 7.  With a sample size of six subjects (n=6) and based on 1000 simulations, the 
chance of declaring an unacceptable dose interval is 11% when there is no difference in 
CRP change from baseline between the first dose and second dose.  The chance of 
declaring an unacceptable dosing interval will be 82% when there is a 33% decrease in 
the CRP following the second dose relative to that of the first dose. 
9.2.2.
Sample Size Sensitivity
No statistical sample size sensitivity calculations were performed


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9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
Analysis datasets will be created according to GSK standards within CDISC standards 
(SDTM IG Version 3.1.3 & AdaM IG Version 1.0].
9.3.1.
Analysis Populations
All Subjects Population: All subjects enrolled into the study who have received a dose 
of study medication (GSK1795091 or placebo) will be included in the safety population.  
This population will be used in the evaluation of safety/tolerability, subject disposition, 
and in the demographic summary.
PK Concentration Population: This population will include all subjects in the “All 
Subjects Population” for whom a pharmacokinetic blood sample was obtained and 
assayed. This population will be used for listing, summarizing and plotting of plasma 
concentration-time data.
PK Parameter Population: This population will include all subjects in the “PK 
Concentration Population” for whom valid and evaluable pharmacokinetic parameters 
were derived. This population will be used in the assessment and characterization of PK 
parameters.
PD Population: This population will include all subjects in the “All Subjects Population” 
for whom valid and evaluable pharmacodynamic parameters were derived.  This 
population will be used in the assessments and characterization of PD parameters.  
9.3.2.
Interim Analysis
No formal interim analyses are planned for this study except, as described above, for 
making dose escalation decisions (Section 4). 
9.3.3.
Final Analysis
Final analysis will be performed after all subjects enrolled have completed the study and 
after Data Base Freeze (DBF) and unblinding
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
No formal statistical hypothesis testing of safety data will be carried out. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.


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All subjects enrolled into the study who have received a dose of study medication 
(GSK1795091 or placebo) will be included in the safety population.  This population will 
be used in the evaluation of safety/tolerability, subject disposition, and in the 
demographic summary.
The probability of safety events (e.g. liver toxicity defined by an ALT greater than 
3xULN, QTcF > 500 msec, change from baseline QTc > 60 msec) will be estimated and 
with associated 95% corresponding confidence intervals for each cohort using the 
binomial distribution. 
If a certain safety adverse event is not observed at a dose level, it does not mean that the 
risk associated with this event is very low.  The upper limit of 95% confidence interval of 
the probability of such undesirable events that have not yet occurred in a finite number of 
subjects is estimated below using exact calculations (i.e. 1 – alpha (1/n)). 
Sample Size (n)
3
4
6
8
12
18
20
Upper limit of risk    0.63     0.52      0.39    0.31      0.22     0.15     0.14
So for example with 6 subjects, if no adverse event is seen at a dose level there is 
reasonably certainty that the rate of events in the population of subjects, at the dose level, 
will be less than 39%.
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetic Analyses (Part 1 and Part 2)
Non-Compartmental PK Analyses
Pharmacokinetic analysis of GSK1795091 concentration-time data will be conducted by 
non-compartmental methods.  The following PK parameters will be determined if data 
permit:

Maximum concentration (Cmax)

Time to maximum concentration (tmax)

Area under the concentration-time curve from time zero (pre-dose) to last time of 
quantifiable concentration [AUC(0-last)]

Partial area under the concentration-time curve to time =  [AUC(0-t)] (where t 
may be 24, 168 h or other as appropriate), and/or

Area under the concentration-time curve from time zero (pre-dose) extrapolated to 
infinite time [AUC(0-∞)]

Terminal half life (t1/2)

clearance (CL)

Volume of distribution (Vd) 

Volume of distribution (Vss) (where V = CL/MRTiv)


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Statistical Analyses of Pharmacokinetic Data
GSK1795091 concentration-time data will be listed for each subject and summarized by 
planned time point and dose cohort in Parts 1 and 2.
Except for tmax, pharmacokinetic parameters will be listed and summarized descriptively 
(mean, standard deviation [SD], median, minimum, maximum, geometric mean, and the 
SD, CV% and 95% confidence interval [CI] of loge-transformed parameters) by dose 
cohort in Parts 1 and 2. Tmax will be listed and summarized descriptively (mean, 
standard deviation [SD], median, minimum, maximum).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  
Dose Proportionality
If more than two dose cohorts are completed, dose proportionality of GSK1795091 
AUC(0-∞) (or AUC(0-t)) and Cmax following single dose administration and AUC(0- t) 
and Cmax following repeat dose administration will be evaluated graphically and using 
the power model as described below:
loge (PK parameter) = a + b * loge (dose)
where a is the intercept and b is the slope
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed.  Both the intercept and slope will be fitted as fixed effects.  If there is 
sufficient data, the model may also be fit with the intercept and/or slope as random 
effects depending on the ability of the model to converge and on estimation of variance-
covariance matrix.  The mean slope and corresponding 90% CI will be estimated from 
the power model.
9.4.2.2.
Pharmacokinetic Analysis for Part 2 Only
Accumulation Ratio
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) will be determined as AUC(0-τ) following the second dose to AUC(0-τ) after 
single dose, where τ is the dosing interval (1 or 2 weeks).  The ratio of AUC (0-τ) at 
steady-state to AUC (0-∞) for a single dose will be calculated to assess time invariance.
Time Invariance
For the repeat dose phase, an analysis of variance (ANOVA) with terms for subject as 
random-effect and day as fixed-effect will be presented by dose on the log-transformed 
AUC values.  The time invariance of GSK1795091 will be assessed by comparing 
AUC(0-) following a single dose on Day 1 and AUC(0-τ) following a second dose on 
either Day 7 (Cohort 1) or 14 (Cohort 2) for each dose and a listing of individual ratios 
will be presented.


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9.4.3.
Other Analyses
9.4.3.1.
Exploratory Biomarker(s) Analyses
The results of these 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 these Biomarkers.
9.4.3.2.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory graphical PK/PD analyses may be performed to examine the relationship 
between GSK1795091 PK and response as measured by vital signs (e.g., body 
temperature, heart rate, etc.) or PD biomarkers (e.g., cytokines/chemokines) or other 
endpoints if warranted by the data (e.g., grade, onset and duration of AEs).  The 
relationship(s) between PD endpoints and PK parameters initially will be explored 
graphically.  Plots of PD endpoint versus PK parameters of GSK1795091 will be 
generated.  
Further analysis may be conducted if the initial plots suggest a correlation between the 
PD and PK endpoints.  Models to describe the relationship(s) may include linear models 
and/or a maximum effect models.  Other more complex models may be explored if 
warranted by the data.  Results may be included in the final study report for this study or 
reported separately.
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 favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
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


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
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
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
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 CRF/ 
eSource will serve as the source document.
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.  


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
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.
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.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


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11.
REFERENCES
Astiz ME, Rackow EC, Still JG, Scott T, Cato A, Von Eschen K, Ulrich JT, Rudbach JA, 
McMahon G, Vargas R, Stern W. Pretreatment of normal humans with monophosphoryl 
lipid A induces tolerance to endotoxin: A prospective, double-blind, randomized, 
controlled trial. Critical Care Medicine. 1995;23:9-17. 
Bahador M, Cross AS. From therapy to experimental model:  a hundred years of 
endotoxin administration to human subjects. Journal of Endotoxin Research. 
2007;13:251-279. 
Chen DS, Mellman I. Oncology meets immunology: The cancer- immunity cycle. 
Immunity. 2013;39:July 25. 
Clyne B, Olshaker JS. The C-reactive protein. The Journal of Emergency Medicine. 
1999;17:1019-1025. 
de Bono JS, Dalgleish AG, Carmichael J, Diffley, J, Lofts FJ, Fyffe D, Ellard S, Gordon 
RJ, Brindley CJ, Evans, TRJ. Phase I study of ONO-4007, a synthetic analogue of the 
lipid A moiety of bacterial lipopolysaccharide. Clinical Cancer Research. 2000;6:397-
405. 
de Vos AF, Pater JM, van den Pangaart PS, de Kruif MD, van't VeerC, van der Poll T. In 
vivo lipopolysaccharide exposure of human blood leukocytes induces cross-tolerance to 
multiple TLR ligands. Journal of Immunology. 2009;183:533-542. 
Dillingh MR, van Poelgeest EP, Malone KE, Kemper EM, Stroes ESG, Moerland M, 
Burggraaf J. Characterization of inflammation and immune cell modulation induced by 
low-dose LPS administration to healthy volunteers. Journal of Inflammation. 2014;11:28. 
Food and Drug Administration (FDA). Guidance for Industry. Estimating the Maximum 
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. 
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER), .; 2005. Pharmacology and Toxicology. 
Guha M. Anticancer TLR agonists on the ropes. Nature Reviews/ Drug Discovery. 
2012;11:503-505. 
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.
ICH, M3 (R2), 2009 
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ry/M3_R2/Step4/M3_R2__Guideline.pdf 


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Isambert N, Fumoleau P, Paul, C, Ferrand C, Zanetta S, Bauer J, Ragot K, Lizard G, 
Jeanin J-F, Bardou M. Phase I study of OM-174, a lipid A analogue, with assessment of 
immunological response, in patients with refractory solid tumors. BMC Cancer. 
2013;13:172.
Kanzler H, Barrat FJ, Hessel EM, Coffman RL. Therapeutic targeting of innate immunity 
with Toll-like receptor agonists and antagonists. Nature Medicine. 2007;13:552-559. 
Lee DW, Gardner R, Porter DL, Louise CU, Ahmed N, Jensen M, Grupp SA, Mackall 
CL. Current concepts in the diagnosis and management of cytokine release syndrome. 
Blood, 2014 124: 188-195
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, 
Sheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, 
Levine BL, June CH, Porter DL, Grupp SA. Chimeric Antigen Receptor T Cells for 
Sustained Remissions in Leukemia. The New England Journal of Medicine. 
2014;371:1507-1517.
Taveira da Silva AM, Kaulbach HC, Chuidian FS, Lambert DR, Suffredini AF, Danner 
RL. Brief Report: Shock and multiple organ dysfunction after self-administration of 
salmonella endotoxin. The New England Journal of Medicine. 1993;328:1457-1460.
van Eijk LTGJ, Pickkers P, Smits P, Bouw MPWJM, van der Hoeven JG. Severe vagal 
response after endotoxin administration in humans. Intensive Care Med. 2004;30:2279-
2281


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AGP
Aminoalkyl glucosaminide 4-phosphate
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of variance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-last)
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration
AUC (0-t)
Partial area under the concentration-time curve to time = t 
(where t may be 24, 168 h or other as appropriate),
AUC (0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
BMI
Body mass index
BP
Blood pressure
BPM
Beat Per Minute
BUN
Blood urea nitrogen
CI
Confidence Interval
CL
Clearance
Cmax
Maximum observed drug concentration
CPK
Creatine phosphokinase
CRF
Case Report Form
CRP
C-reactive protein
CRS
Cytokine release syndrome
CV
Cardiovascular
DBF
Database freeze
DBP
Diastolic blood pressure
DC
Dendritic cell
DNA
Deoxyribonucleic acid
EC10
10% Effect Concentration
ECG
Electrocardiogram
FDA
Food and drug administration
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GCSF
Granulocyte-colony stimulating factor
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma glutamyltransferase
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HED
Human equivalent dose


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HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICU
Intensive care unit
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IFN
Interferon
IgM
Immunoglobulin M
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous
L
Litre
LFTs
Liver function tests
LPS
Lipopolysaccharide
MABEL
Minimum anticipated biologic effect level
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCP
Monocyte chemoattractant protein
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Millilitre
mm
Millimetre
mmHg
Millimetres of mercury
MPL
Monophosphoryl lipid
MSDS
Material Safety Data Sheet
msec
Milliseconds
N
Sample size
NOAEL
No observed adverse effect level
NSAIDs
Non steroidal anti-inflammatory drugs
PAMPs
Pathogen-Associated Molecular Patterns
PBMCs
Peripheral Blood Mononuclear Cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PK
Pharmacokinetic(s)
PTS-BIB
Platform Technology and Science, Bioanalysis, 
Immunoginicity and Biomarkers
PT
Prothrombin time
QTcF
QT duration corrected for heart rate by Fridericia’s formula


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RANTES
Regulated on Activation, Normal T Expressed and Secreted
RAP
Reporting and Analysis Plan
RBC
Red blood cells
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
Ro
Accumulation ratio
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SRM
Study Reference manual
t
Time of last observed quantifiable concentration
t1/2
Terminal half life
TLR
Toll-like receptor
tmax
Time of occurrence of Cmax
TNF
Tumor necrosis factor
TTS
Study Specific Technical Agreement/Memo
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UK
United Kingdom
USA
United States
Vd
Volume of distribution
Vss
Volume of distribution
WBC
White blood cells
WNCBP
Women of non child bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
SAS
WinNonlin


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12.2.
Appendix 2: FDA Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventative Vaccine 
Clinical Trials
Taken from the FDA Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
The purpose of this appendix is to provide guidance and is to be used in conjunction with 
the investigator’s judgment.  Alternative criteria for fever and tachycardia are provided in 
Section 4.2.  The scales for vital signs and laboratory abnormalities are intended to guide 
the grading of adverse events that are clinically significant and changed from a subject’s 
baseline. Similarly, the scales for systemic (general) events should take into account the 
normal range of symptom intensity and duration for the setting as well as an individual 
subject’s baseline status, in particular, when evaluating subjective criteria (e.g. “some 
interference with activity”).
Tables for Clinical Abnormalities 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate(Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity   
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity  
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness 
* 
2.5 – 5 cm
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling 
** 
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
          (°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia -
beats per 
minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats 
per 
minute***  
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 


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Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hypertension 
(systolic) -
mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or
hospitalization for 
malignant 
hypertension 
Hypertension 
(diastolic) -  
mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) –
mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate –
breaths 
per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
*Subject should be at rest for all vital sign measurements
**Oral temperature; no recent hot or cold beverages or smoking
***When resting heart rate is between 60-100 beats per minute. Use clinical judgment when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes
Systemic 
(General) 
Mild (Grade 1) 
Moderate(Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 –
2 episodes/24 
hours 
Some interference 
with activity or > 2 
episodes/24 hours  
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 – 3 loose stools 
or
< 400 gms/24 
hours
4 – 5 stools or 
400 – 800 gms/24 
hours 
6 or more watery 
stools or 
> 800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with
activity 
Repeated use of 
non-
narcotic pain 
reliever > 24 hours 
or
some interference 
with activity  
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity  
ER visit or 
hospitalization 
Fatigue 
No interference 
with
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse 
event (as defined 
according to 
applicable 
regulations) 
No interference 
with
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 


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Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters.  Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate. 
Serum * 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium –
Hyponatremia 
mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125  
Sodium –
Hypernatremia 
mEq/L 
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium –
Hyperkalemia 
mEq/L 
5.1 – 5.2  
5.3 – 5.4 
5.5 – 5.6 
> 5.6  
Potassium –
Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1  
Glucose –
Hypoglycemia 
mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45  
Glucose –
Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
100 – 110 
110 – 125 
111 – 125 
126 – 200 
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood Urea 
Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine –
mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Calcium –
hypocalcemia 
mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0  
Calcium –
hypercalcemia 
mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0  
Magnesium –
hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9  
Phosphorous –
hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6  
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin –
Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5  
--
Total Protein –
Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0  
--


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Serum * 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Alkaline phosphate 
–
increase by factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10  x ULN 
> 10 x ULN
Liver Function 
Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN
Bilirubin – when 
accompanied 
by any increase in 
Liver Function 
Test 
increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN
Bilirubin – when 
Liver Function 
Test is normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN
Cholesterol 
201 – 210 
211 – 225 
> 226
---
Pancreatic 
enzymes –
amylase, lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional
normal parameters.  Institutional normal reference ranges should be provided to demonstrate that they are
appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization
of the laboratory abnormalities as Potentially Life Threatening (Grade 4).  For example, a low sodium
value that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia
event if the subject had a new seizure associated with the low sodium value.
***ULN” is the upper limit of the normal range.
Hematology * 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin 
(Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin 
(Female) 
change from 
baseline value -  
gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0
> 5.0
Hemoglobin 
(Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin 
(Male) 
change from 
baseline value –
gm/dL 
Any decrease – 1.5  1.6 – 2.0 
2.1 – 5.0 
> 5.0
WBC Increase -
cell/mm
3
10,800 – 15,000 
15,001 – 20,000  
20,001 – 25, 000 
> 25,000
WBC Decrease -
cell/mm
3
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 


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Hematology * 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Lymphocytes 
Decrease -
cell/mm
3
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils 
Decrease -
cell/mm
3
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils -
cell/mm
3
650 – 1500 
1501 - 5000 
> 5000
Hypereosinophilic 
Platelets 
Decreased -
cell/mm
3
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
PT – increase by 
factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
1.11 – 1.20 x 
ULN 
1.21 – 1.25 x ULN 
> 1.25 ULN
PTT – increase by 
factor 
(partial 
thromboplastin 
time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x ULN 
> 1.5 x ULN
Fibrinogen 
increase - mg/dL 
400 – 500  
501 – 600  
> 600
--
Fibrinogen 
decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or associated 
with gross 
bleeding or 
disseminated 
intravascular 
coagulation (DIC) 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional
normal parameters.  Institutional normal reference ranges should be provided to demonstrate that they are
appropriate.
** “ULN” is the upper limit of the normal range.


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Urine * 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood 
(microscopic) –
red blood cells per 
high power field 
(rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or gross 
blood 
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters.  Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 


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12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to 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 I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 
Report the event to GSK within 24 hours

Complete the liver event CRF/eSource, 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, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

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, stabilise or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days post last dose4

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 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:


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Liver Chemistry Stopping Criteria – Liver Stopping Event
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

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

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 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/ 
eSource 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 3xULN and bilirubin 2xULN. 
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 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), 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.
Includes: 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 
4.
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/eSource. 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. 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


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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, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

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 


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from baseline is not considered an AE.
d.
Results in disability/incapacity
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 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* 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.

Refer to Appendix 3 for the required liver chemistry follow-up instructions


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12.4.3.
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/eSource

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/eSource 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.
12.4.4.
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 will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

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.


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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/eSource.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.


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12.4.5.
Reporting of SAEs to GSK
SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

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]

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, 2007a].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 
2007a] 
o
Injectable progestogen [Hatcher, 2007a]
o
Contraceptive vaginal ring [Hatcher, 2007a]
o
Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all inclusive list of those methods that meet the 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.


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12.5.2.
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 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. 

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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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.


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12.7.
Appendix 7: Protocol Changes
12.7.1.
AMENDMENT 1
This amendment will apply to all study sites and all countries.
List of specific changes:
SECTION 2.2 Brief Background
TLR biology
GSK1795091 is an agonist of TLR4 that induces immunologic responses in vitro and in 
vivo.  GSK1795091, as a single-agent, stimulates cytokine production (in vitro and in 
vivo), changes in immune cell populations (in vivo) and generates fever response (in 
vivo). When administered by intravenous bolus and combined with the immune 
checkpoint modulator, OX86, mouse surrogate OX40 agonist antibody, OX86 induced a 
potent immunologic response and significant tumor shrinkage in a syngeneic mouse 
model of cancer. Indeed, 30-70% of mice were tumor free for at least 2 months after 
combination treatment of 25 g GSK1795091 and 25 g OX86. Four (4) groups of 10 
Balb/c mice (with intact immune systems) were implanted with syngeneic CT-26 tumors.  
Mice received either placebo, GSK1795091, OX86, or the combination of GSK1795091 
and OX86.  While the monotherapies had modest effects on tumor growth (Figure 1), the 
combination produced durable responses.
The reduction in tumor volume translated to significant improvement in the survival of 
animals (Figure 2).  Approximately, 70% of animals that received the combination of 
GSK1795091 and survived more than 100 days.  By contrast, only 10-20% of the animals 
that received either monotherapy survived 100 days.


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Figure 2: Survival of mice
This model provides support for the evaluation of this combination in patients with 
cancer.  Additional details are available in the Investigator’s Brochure.
Healthy subject experience with TLR4 agonists
Synthetic TLR4 agonists, such as monophosphoryl lipid A (MPL), have similarly been 
studied in ascending dose studies [Astiz, 1995]. MPL is used as a vaccine adjuvant in 
Fendrix, a hepatitis B vaccine, and Cervarix, a human papillomavirus vaccine [Kanzler, 
2007]. Early in development of MPL, healthy subjects received escalating intravenous 
doses from 1 to 20 µg/kg.  The 20 uµg/kg dose was considered safe and biologically 
active.  Systemic adverse events and cytokine increases were observed after doses of 10 
uµg/kg.  At the highest doses tested, 6 of 6 subjects experienced adverse events including 
fevers, chills, headache, myalgia, and pain at the injection site.  Adverse events were mild 
to moderate in severity.  Changes in vital signs, as compared to control, included 
increases in mean temperature of 2oC and increases in mean heart rate of 30 beats/min.  
Changes in respiratory rate and blood pressure were not observed.  Vital sign changes 
peaked within 3 to 4 hours and returned to normal within 12 hours.  Total white blood 
cell count transiently increased and total lymphocyte count transiently decreased.  
Laboratory biomarkers, TNF, IL6 and IL8 peaked within 2 to 4 hours. Clinical and 
laboratory parameters returned to baseline in 6 to 24 hours.  A second cohort of subjects 
received 20 uµg /kg MPL followed by a dose of endotoxin 24 hours later.  Subjects that 
received endotoxin 24 hours after MPL experienced diminished cytokine release and 
improved tolerability consistent with drug tolerance which has been described following 
repeat dosing of TLR agonists [de Vos, 2009]. This study provides an example of a 
synthetic TLR4 agonist that was safely administered intravenous (IV) in ascending doses 
to healthy subjects and produced transient changes in clinical and laboratory 
measurements. 


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TLR4 agonist development plan
It is possible that immunotherapies acting at different steps in the cycle could have 
improved therapeutic indices over currently available monotherapies.  Thus, a TLR4 
agonist may enhance anti-tumor effects of checkpoint modulators by its actions on 
dendritic cells and antigen presenting cells. This hypothesis is supported by nonclinical 
data (Figure 1 and Figure 2).
Relevance of a healthy subject study to future development in cancer patients
Part 1 of this study in healthy subjects will provide relevant monotherapy safety, 
pharmacokinetic and pharmacodynamic information for GSK1795091 to support a 
subsequent trial in patients with cancer.  To ensure the safety of subjects in a FTIH study 
of an immune system agonist, whether the trial is performed in healthy subjects or in 
cancer patients, the starting dose is conservative and anticipated to have minimal 
biological activity.  As dose escalation progresses, pharmacologically relevant doses can 
be identified safely in healthy subjects based on monitorable and reversible, mild to 
moderate clinical effects (e.g. changes in body temperature, heart rate, and flu-like 
symptoms, etc.). Subsequently, a pharmacologically active dose could reasonably be 
explored as a starting dose in a study in cancer patients.  Thus, by beginning development 
of GSK1795091 in healthy subjects, it will be possible to conduct the FTIH study safely 
while avoiding the exposure of cohorts of cancer patients to pharmacologically inactive 
doses of the study drug.  
The pharmacodynamic markers to be measured in this FTIH study are directly relevant to 
a subsequent study to be conducted in cancer patients.  For example, we will measure IL-
1, TNFα, IL-6 cytokines as markers of TLR4 signaling and immune activation; these 
markers will also be measured in patient studies to confirm TLR4 signaling and to 
explore the relationship between the markers and clinical activity.  In study 204685, we 
will also measure immune cell activation and immune cell expression of target proteins 
of interest (e.g., OX40, ICOS, and others) in peripheral blood.  This cellular phenotype 
information will inform our understanding of the pharmacologic effects of GSK1795091 
on circulating immune cells and may suggest additional immunotherapy combinations of 
interest. By conducting study 204685 in healthy subjects, it will enable detailed PK and 
PD assessments (e.g., multiple time points to characterize time-course) that would be 
more difficult to obtain from a study in cancers due to blood-drawn volume 
considerations and the inconvenience.
A primary goal of Part 2 of study 204685 is to optimize the dosing interval for 
GSK1795091 in future studies.  Administration of TLR agonists can be associated with 
tachyphylaxis when the dosing interval is short.  Therefore, two parallel cohorts of 
subjects will receive 2 doses of GSK1795091, either 1 week apart (Part 2, Cohort 1) or 2 
weeks apart (Part 2, Cohort 2). The pharmacodynamic effects of the second dose will be 
compared to those of the first dose using biomarker endpoints.  This part of the study will 
provide a more robust assessment of the dosing interval for GSK1795091 than would be 
possible in a cancer patient study. 


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OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
GSK1795091 when administered to 
healthy subjects.

Safety data comprising adverse events, 
vital signs, laboratory tests, and 12-lead 
ECGs.
Secondary

To evaluate the systemic 
pharmacokinetics of GSK1795091 
following administration of a single 
intravenous dose to healthy subjects.

Plasma pharmacokinetic parameters 
such as Cmax, tmax, AUC(0-t), 
AUC(0-last), AUC(0-), CL, Vd, and 
t1/2.

To evaluate the pharmacodynamic 
effects of GSK1795091 following 
administration as a single intravenous 
dose to healthy subjects.

Vital signs, cytokine measurements, 
WBC and differential, immune cell 
phenotype. 

To evaluate the systemic 
pharmacokinetics of GSK1795091 
following a second intravenous dose 
administered to healthy subjects 1 week 
or 2 weeks after the first dose..

Plasma pharmacokinetic parameters 
such as Cmax, tmax, AUC(0-t) , 
AUC(0-last), and AUC(0-), CL, Vss, t1/2 
and accumulation and time invariance 
(as possible).

To evaluate the clinical and 
pharmacodynamic effects of 
GSK1795091 following a second 
intravenous dose administered to healthy 
subjects 1 week or 2 weeks after the first 
dose.

Vital signs, cytokine measurements, 
WBC and differential, immune cell 
phenotype, and laboratory tests.
Exploratory

To evaluate immune system effects 
following intravenous administration of 
GSK1795091.

To evaluate the pharmacodynamic effects 
of intravenous administration of 
GSK1795091 on gene signature analysis 
of PBMCs from part 2 healthy subjects.

To explore the relationship between 
pharmacokinetics, pharmacodynamic 
markers, and adverse events

To characterize the metabolic profile of 
GSK1795091 

Cytokine measurements in plasma and 
immune cell phenotyping of leukocytes.

Gene signature analysis

Correlation between pharmacokinetics 
and pharmacodynamic markers, such as  
vital signs and CRP, and adverse events

Collection of samples to characterize the 
metabolites in plasma and urine


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SECTION 4.1 OVERALL DESIGN
Figure 13
Part 1 study schematic
Treatment Period 
GSK1795091A 
or PBO
Day-2 Day-1 Day 1 Day 2 Day 3 Day 4 Day 5
Admission
Discharge
Day 7 
Outpatient visit
Day 30 (+/- 2)
Outpatient visit
Screening
Within 30 days
Figure 2 4
Part 2 study schematic
GSK1795091A 
Admission
Day 30 (+/- 2) 
Post 2nd Dose
Outpatient visit
Screening
Within 30 days
Cohort 1 Treatment Period 
Day-2 Day -1 Day 1 Day 2
Day 3
Day 4
Day 5
Day6
Day7
Day 8
Day 9
Day10
Day11
Day 12
GSK1795091A 
Discharge
Cohort 2 Treatment Period 2 
Day13 Day14 Day 15 Day 16 Day17 Day18 Day 19
Admission
GSK1795091A 
Discharge
Day 7 
Post 2nd Dose
Outpatient visit
Cohort 2 Treatment Period 1 
GSK1795091A 
Day-2 Day-1 Day 1 Day 2 Day 3 Day 4 Day 5
Discharge
Admission
SECTION 4.2 TREATMENT ARMS AND DURATION
Part 1
In Part 1, the Principal Investigator should pause dosing of new subjects, within a cohort, 
for review with the GSK Medical Monitor in the following cases:

If 1 or more subjects experience a Grade 3 or greater adverse event or a serious 
adverse event that can reasonably be attributed to GSK1795091 or a serious 
adverse event or QTcF >500 msec or an increase in QTcF by 60 msec or more 
compared to baseline, dosing of additional subjects within the cohort should 
stop.

If 1 or more subjects experience a Grade 2 or greater adverse event that lasts 
more than 24 hours and can reasonably be attributed to GSK1795091, dosing of 


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additional subjects within a cohort should be held until the adverse event has 
resolved to Grade 1 or less.  
In Part 1, cohorts will be opened sequentially after evaluation of adverse events, vital 
signs, laboratory tests, and 12-lead ECGs by the Principal Investigator (blinded), GSK 
Medical Monitor (unblinded), GSK statistician (unblinded).  All available safety and 
tolerability data (adverse events, vital signs, 12-lead ECG and safety laboratory 
assessments) will be reviewed from ongoing and preceding cohorts.  Safety data from 96 
hours after administration of study product must be available for a decision to dose-
escalate to be taken.  Additionally, safety data from at least 5 of the 6 subjects who were 
randomized to receive GSK1795091 must be available in order for a decision to dose-
escalate to be taken. If subjects prematurely discontinue from the study, additional 
replacement subjects may be enrolled and assigned to the same treatment at the discretion 
of the Sponsor in consultation with the Investigator. Up to 8 subjects may be replaced 
during the study.
Progression to the next higher dose level will be stopped if any of the following occur:

1 or more subjects experience a serious adverse event that can reasonably be 
attributed to GSK1795091.

1 or more subjects experience a Grade 3 or greater adverse event or a serious 
adverse event that can reasonably be attributed to GSK1795091.

1 or more subjects experience a transaminase increase 3xULN (see Section 
5.4.2).

2 1 or more subjects experience QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.

3 or more subjects in a cohort experience Grade 2 adverse events that can 
reasonably be attributed to GSK1795091.

Any other event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor. 
Following completion of Part 1, the safety data and proposed dose level for Part 2 will be 
submitted to the Ethics Committee for review. Once the Ethics Committee vote is 
received, Part 2 will begin. 
Part 2
In Part 2, on Day 1 subjects will receive intravenous study product GSK1795091at a dose 
determined by results from Part 1.  
If dose escalation in Part 1 was stopped for one of the following reasons, GSK1795091 
will be administered in Part 2 at a dose one level below the highest dose evaluated in Part 
1:

1 or more subjects experienced a serious adverse event that can reasonably be 
attributed to GSK1795091.


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
1 or more subjects experienced a Grade 3 or greater adverse event or a serious 
adverse event that could reasonably be attributed to GSK1795091.

1 or more subjects experienced a transaminase increase 3xULN.

2 1 or more subjects experienced QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.

Another event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor. 
Subjects will be observed as inpatients for at least 96 hours, after assessments have been 
performed by the investigator. Subjects in Cohort 1 will remain inpatients until Day 12. 
Subjects in Cohort 2 will be discharged after completion of the Day 5 (96 hour) 
assessments and will return to the clinical unit for a second inpatient visit on Day 13 (Part 
2, Cohort 2). If AEs attributed to the first dose of GSK1795091 have resolved, subjects 
will receive a second dose of GSK1795091 on Day 8 (Part 1, Cohort 1) or Day 15 (Part 2, 
Cohort 2).  Subjects will be followed according to the same schedule as after the first 
dose of GSK1795091. In addition, the Principal Investigator should review all available 
safety data following the second dose of GSK1795091 and interrupt subsequent dosing 
(within or between cohorts) if any of the following occur subject experiences a Grade 3 
or greater adverse event or a serious adverse event that can reasonably be attributed to 
GSK1795091.  Events that interrupt dosing should be reviewed with the GSK Medical 
Monitor.

1 or more subjects experiences a serious adverse event that can reasonably be 
attributed to GSK1795091.

1 or more subjects experience a Grade 3 or greater adverse event that can 
reasonably be attributed to GSK1795091.

1 or more subjects experience a transaminase increase 3xULN (see Section 
5.4.2).

1 or more subjects experience QTcF >500 msec or an increase in QTcF by 60 
msec or more compared to baseline.

Any other event deemed to pose an unacceptable risk to subjects by the principal 
investigator or medical monitor.
In the event that dosing is interrupted, administration of GSK1795091 in Part 2 will only 
resume after approval by the Ethics Committee and Higher Health Authority following a 
substantial amendment.
SECTION 4.3 TYPE AND NUMBER OF SUBJECTS
If subjects prematurely discontinue from the study, additional replacement subjects may 
be enrolled and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the Investigator. Up to 8 subjects may be replaced during the study.


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SECTION 4.5.1 STARTING DOSE SELECTION
CALCULATION OF MINIMUM ANTICIPATED BIOLOGICAL EFFECT LEVEL 
The proposed starting dose for the study was determined after due consideration of all 
available in vitro and in vivo preclinical data, in accordance with EMEA and FDA 
regulatory guidance for first-time-in-human studies.  
SECTION 4.5.1.1 CALCULATION OF MINIMUM ANTICIPATED BIOLOGICAL  
EFFECT LEVEL
The dose is based upon calculated using the in vivo Minimum Anticipated Biological 
Effect Level (MABEL) in the 6-week cynomolgus monkey study, and secondarily, 
supported by rabbit pyrogenicity studies and in vitro potency comparisons to LPS.  The 
cynomolgus monkey was chosen as the in vivo toxicology model based upon greatest 
sensitivity and highest the similarity to humans as determined by cytokine production 
following exposure of whole blood from several species to GSK1795091 ex vivotr. Five 
(5) cytokines selected from a panel for were measured in vivo; these cytokines were
selected for evaluation based upon high ex vivo in vitro sensitivity of whole blood to 
GSK1795091 (IL10 and IP10) or based upon increases following administration of TLR4 
agonists to healthy subjects in published clinical trials (TNFa, IL6, and IL8) [Astiz, 
1995]. Vehicle or GSK1795091, at doses of 0.05, 2, and 200 uµg/kg, was administered to 
cynomolgus monkeys.  IP10 and IL10 were the most sensitive pharmacodynamic markers 
and were detectable in all evaluable monkeys at 0.05 µg/kg.  There were minor decreases 
in lymphocytes, monocytes, eosinophils, and NK cells at doses of 0.05 uµg/kg, and 
transient increases in heart rate and body temperature at doses of 2 uµg/kg, all of which 
were considered non-adverse.  
SECTION 4.5.1.2 RABBIT PYROGENICITY
Rabbits are commonly used as models for assessing endotoxin contamination of 
parenteral formulations due to their high sensitivity. Therefore, GSK1795091 was given 
to New Zealand white rabbits at single intravenous doses of 0.1, 0.5, 1, 2.5 and 5 ng/kg in 
5% dextrose. Rabbits given single doses of 5 ng/kg had increases in body temperature of 
> 0.5oC 60 minutes post dose and generally returned to baseline temperature by 180 
minutes post dose, consistent with the expected pharmacologic actions of GSK1795091. 
Lower doses were not considered to be pyrogenic. Based on a scaling factor of 3.1, the 
2.5 ng/kg dose in the rabbit corresponds to a HED of 0.8 ng/kg, or 56 ng for a 70 kg 
subject.  Thus, the HED of the non-pyrogenic dose in rabbits is 8-fold higher than the 
proposed starting dose of 7 ng.
SECTION 4.5.2  4.5.1.3 COMPARISON TO LIPOPOLYSACCHARIDE (LPS)
The typical dose of LPS administered to healthy subjects in clinical trials is 2 to 4 ng/kg 
(approximately 140 ng to 280 ng).  Following administration, subjects experience mild to 
moderate flu-like symptoms and increases in body temperature and heart rate.  To 
confirm the safety of the proposed 7 ng starting dose of GSK1795091, the potencies of 


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GSK1795091 and E.coli-derived LPS (commonly used for clinical trials of healthy 
subjects) were compared.  Human whole blood was incubated in vitro with either 
GSK1795091 or LPS, and cytokines were measured to assess the relative potencies of the 
two TLR4 agonists. At concentrations of 0.2 ng/ml (approximating the plasma 
concentration following a 8.6 ng/kg dose of LPS for a 70 kg subject with a 3000 ml 
plasma volume), LPS was as potent or more potent than GSK1795091 by a factor of 1 to 
4 for a panel of 5 measureable cytokines.  If GSK1795091 is estimated to be of 
comparable potency to LPS, the doses of LPS routinely administered to healthy subjects 
are 20-fold to 40-fold greater than the 7 ng starting dose of GSK1795091. Thus, the 
planned starting dose is appropriately conservative.
If GSK1795091 is estimated to be less potent than LPS by a factor of 4, dose escalation 
would need to exceed 4-times the 2 ng/kg dose of LPS administered to healthy subjects 
(i.e. at least 560 ng) to achieve pharmacologic activity similar to LPS.  Thus, the top dose 
is selected to accommodate a possible range of potencies of GSK1795091, based on in 
vitro evaluations.
SECTION 4.5.2 DOSE ESCALATION
Dose escalation will proceed as follows:  7, 21, 60, 120, 180, 280, 420, 630ng.  The dose 
increments between cohorts progressively decline from 3-times to 1.5-times the previous 
dose.
SECTION 4.5.3 TOP DOSE SELECTION
The maximum proposed dose level is 630 ng. However, dose escalation may stop at a 
lower dose level based on criteria in Section 4.2. In the repeat dose intravenous toxicity 
studies in rats and monkeys, GSK1795091 was associated with expected pharmacologic, 
pro-inflammatory actions of a TLR4 agonist. Therefore, adverse events that stop dose 
escalation are likely to include mild to moderate flu-like symptoms and increases in body 
temperature and heart rate.   
The top dose is selected to accommodate a possible range of potencies of GSK1795091, 
based on in vitro evaluations.  In vitro data suggest that the relative potency of LPS is 1-
to 4-times that of GSK1795091. If GSK1795091 is equipotent with LPS, dose escalation 
is predicted to stop in accordance with Section 4.2 at 2-4 ng/kg (i.e. 140 to 280 ng). If 
GSK1795091 is less potent than LPS by a factor of 4, higher dose levels will be required 
to elicit pharmacologic effects similar to LPS; this possibility is accommodated by the 
maximum proposed dose level of 630 ng (i.e. approximately 4.5-fold greater than the 
LPS dose of 2 ng/kg). 
Based on the maximum predicted human exposure of approximately Cmax 0.09 ng/mL 
and AUC 2.6 ng.h/mL at the highest planned clinical dose of 630 ng, the margin to the 
NOAEL dose in rat (15 uµg g/kg/dose) is approximately 777X (Cmax) and 121X (AUC) 
and in monkey (200 uµg/kg/dose) is approximately 19,100X (Cmax) and 8461X (AUC). 
Thus, at the maximum proposed dose level, 630 ng, severe or irreversible toxicities are 
not expected.


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SECTION 4.5.4 SUMMARY
The starting dose of 7 ng is expected to be safe and appropriately conservative for a 
healthy subject study.  Sensitive assays in a cynomolgus monkey model were used to 
calculate the MABEL.  At the dose defining the MABEL, animals experienced neither 
adverse events nor histopathological changes.  Furthermore, the dose is 8-fold higher than 
the HED of the non-pyrogenic dose in rabbits.  Additionally, clinical experience with 
TLR4 agonists administered to healthy subjects provides a reference value against which 
the starting dose of GSK1795091 can be compared.  Since GSK1795091 has in vitro
potency similar to (or lower than) LPS, a starting dose of 7 ng is conservative in 
comparison to the 20 to 40-fold higher doses of LPS routinely administered to healthy 
subjects.  These estimates provide a high level of confidence that the starting dose of 7 ng 
can safely be administered to healthy subjects. Dose escalation is expected to stop, at or 
below 630 ng, based on mild to moderate toxicities that are reversible and readily 
monitored.  The top dose in the study, 630 ng, does not approach the Cmax or AUC at the 
NOAEL in rats or in monkeys. Thus, dose escalation proceeds from a conservative 
starting dose to a top dose unlikely to be associated with severe or irreversible effects.
Dose escalation
Dose escalation will proceed as follows: 
7, 21, 60, 120, 180, 280, 420, 630ng
SECTION 5.2 EXCLUSION CRITERIA: CONCURRENT CONDITIONS/MEDICAL 
HISTORY (INCLUDES LIVER FUNCTION AND QTcF INTERVAL
5. History of liver disease, or known hepatic or biliary abnormalities. (with the exception 
of Gilbert's syndrome).
6. AST, ALT, gamma-GT and bilirubin >1.1xULN 0xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%).
7. Creatinine >1.0 x ULN. 
SECTION 5.2 EXCLUSION CRITERIA: DIAGNOSTIC ASSESSMENTS AND 
OTHER CRITERIA
21. Subject is unable to understand and communicate in German/or native language of 
the site
SECTION 5.4 WITHDRAWAL/STOPPING CRITERIA
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, behavioural or 
administrative reasons. Furthermore, any female subject who becomes pregnant while 
participating will be withdrawn from the study [see Section 12.5.2]. 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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SECTION 6.1
Study Treatment
Product name:
GSK1795091 Injection, 
0.001mg/mL and 
0.0001mg/mL, 5mL vial with 
5.2mL fill volume
Placebo
Sodium Chloride Injection
Formulation description:
A clear solution in a 5ml vial 
with a 20mm stopper and 
overcap.
Commercial saline solution
A clear colourless solution 
containing 0.9% sodium 
chloride
Dosage form:
Solution for Injection
Solution for Injection
Unit dose 
strength(s)/Dosage level(s):
0.001mg/mL (1000 nanogram 
per mL)
0.0001mg/mL (100 nanogram 
per mL)
N/A
Route of Administration
Intravenous Injection 
Intravenous Injection
Dosing instructions:
Administered as an 
intravenous bolus slowly over 
2-5 minutes, followed by an 
intravenous bolus of 10mL of 
normal saline
To be administered in an 
identical manner to 
GSK1795091
Physical description:
A clear, colourless to slightly 
coloured solution, free from 
visible particles in a clear glass 
vial with grey stopper and 
aluminium grey brown 
overseal.
A clear colourless solution
SECTION 7.1: TIME AND EVENTS TABLE 
SECTION 7.1.2: Part 1: In-House Assessments
Row 7: Haem/Clin Chem/Urinalysis/Coagulation
SECTION 7.1.3: Part 1: Outpatient Assessments
Row 5: Haem/Clin Chem/Urinalysis/Coagulation
SECTION 7.1.4: Part 2: In-House Assessments
Row 7: Haem/Clin Chem/Urinalysis/Coagulation
Row 16: PK Metabolite urine sampling
SECTION 7.1.5: Part 2: Outpatient Assessments
Row 5: Haem/Clin Chem/ Urinalysis/Coagulation


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SECTION 7.3.6 CLINICAL SAFETY LABORATORY ASSESSMENTS
Table 2
Coagulation 
Tests

prothrombin time (or international normalized ratio)

partial thromboplastin time
Other 
Screening 
Tests

HIV

Hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc 
Ab)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum or urine hCG Pregnancy test. 

Lipids, Total cholesterol, HDL, LDL

PT (or INR)/PTT
SECTION 7.4 PHARMACOKINETICS
SECTION 7.4.1 Blood Sample Collection
Blood samples (2ml 4ml per timepoint) for pharmacokinetic (PK) analysis of 
GSK1795091 will be collected at the time points indicated in Section 7.1, Time and 
Events Table.  
SECTION 7.4.3 Sample Analysis
Once the plasma has been analyzed for GSK1795091 any remaining plasma may be 
analyzed qualitatively for other compound-related metabolites and the results reported 
under a separate PTS-BIB, GlaxoSmithKline protocol.
Plasma and uUrine may be analyzed qualitatively for GSK1795091 and other compound-
related metabolites and results reported under a separate PTS-BIB, GlaxoSmithKline 
protocol.
SECTION 12.5.2 COLLECTION OF PREGNANCY INFORMATION
Any female subject who becomes pregnant while participating: 

will be withdrawn from the study


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12.7.2.
AMENDMENT 2
SECTION 5.2 Exclusion criteria
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
13.  14. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody 
test (anti-HBc Ab) result at screening or within 3 months prior to first dose of study 
treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA PCR test is obtained.
12.7.3.
AMENDMENT 3
This amendment will apply to all study sites and all countries.
Summary of Amendment Changes with Rationale
This protocol amendment is revising Part 1 dose escalations and subject numbers 
following a halt in dosing after one subject experienced a transient heart rate increase 
from 68 bpm to 125 bpm, meeting protocol-defined stopping criteria as a grade 3 change. 
For Part 1, this protocol amendment is intended to generate additional clinical data while 
applying the available clinical data to maximize the safety of subjects enrolled in 
subsequent cohorts.  The original protocol included stopping rules that were designed to 
be more conservative than rules used in vaccine trials to ensure a pause for review of 
safety data at early signals of pharmacologic activity.  Modifying the stopping rules to, 
now, include an effect threshold as well as an increase from baseline is supported by the 
good tolerability profile of GSK1795091 in cohorts 1 – 3.  Repeating the 60 ng cohort 
will further characterize the frequency and magnitude of heart rate increases and 
temperature increases before taking any additional steps.  In turn, because clinical signs 
and symptoms are now being observed, future dose increments are smaller and the 
potential top dose has been lowered.  These modifications will provide additional data 
that further characterizes safety and dose-effect relationships to facilitate the design of 
subsequent studies of GSK1795091 in cancer patients.
Minor typographical errors and other sections have been amended for clarification.


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List of Specific Changes
TITLE PAGE
 has replaced 
 in the list of Authors. 
MEDICAL MONITOR/SAE CONTACT INFORMATION: 
Addition of the secondary medical monitor’s email address into the table:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Secondary 
Medical 
Monitor
Dr 
1250 S. 
Collegeville Road, 
Collegeville, PA 
19426
SECTION 1: PROTOCOL SYNOPSIS FOR STUDY 204685
Cross references in the summary have been deleted.  They were included in previous 
versions in error.
Treatment Arms and Duration – Part 1
Part 1 is planned to enrol up to 87 sequential cohorts of 8 subjects per cohort (at protocol 
Amendment 03, the planned number of cohorts is reduced from 8 to 7).  
Treatment Arms and Duration
If AEs attributed to the first dose of GSK1795091 have resolved, subjects will receive a 
second dose of GSK1795091 on Day 8 (Part 2, Cohort 1) or Day 15 (Part 2, Cohort 2);
(Otherwise, subjects will not receive the second dose and will be followed according to 
the schedule for Part 1).  Subjects will be followed according to the same schedule as 
after the first dose of GSK1795091.
Part 2
Part 2 is planned to enrol 2 parallel cohorts of 6 subjects per cohort.
Type and Number of Subjects
Approximately 7668 subjects may be enrolled in the study.  Between 8 and 6456 subjects 
will be enrolled in Part 1.  Twelve (12) subjects will be enrolled in Part 2.
Part 1 is planned to enrol up to 87 cohorts of 8 subjects per cohort. 
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Part 2 is planned to enrol 2 cohorts of 6 subjects per cohort.
SECTION 4.1 OVERALL DESIGN
Figure 4 
Part 2 study schematic.
SECTION 4.2 TREATMENT ARMS AND DURATION
Overview:
Part 1 is planned to enrol up to 87 sequential cohorts of 8 subjects per cohort (at protocol 
Amendment 03, the planned number of cohorts is reduced, and the dose of GSK1795091 
for cohorts 5, 6 and 7 lowered. Cohort 4 is a repeat of the 60 ng dose; refer to Section 
4.5.2).  
Part 2 is planned to enrol 2 parallel cohorts of 6 subjects per cohort.
Part 1:
The grading of adverse events will be guided by the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(Appendix 2) with the exception of fluctuations in white blood cell counts (which are 
anticipated and may be considered adverse events only after >24 hours) and fever and 
tachycardia which are graded according to also require a changes from time-matched
baseline (per table below).  
Grade 1
Grade 2
Grade 3
Grade 4
Temperature (increase 
from baseline)
>0.5 - 1.5 oC 
change
>1.5 - 3oC 
change
>3oC change
(<24 hours)
>3oC change
(24 hours)
AND
>38.0oC 
AND
>38.5oC 
AND
>39.0oC 
AND
>40oC 
Heart rate (increase from 
baseline)
>15 - 30 bpm 
change
>30 - 45 bpm 
change
>45 bpm change
Emergency 
intervention 
required
AND
>101 bpm
AND
>116 bpm
AND
>130 bpm


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SECTION 4.3 TYPE AND NUMBER OF SUBJECTS
Approximately 7668 subjects may be enrolled in the study.  Between 8 and 6456 subjects 
will be enrolled in Part 1.  Twelve (12) subjects will be enrolled in Part 2.
Part 1 is planned to enrol up to 87 cohorts of 8 subjects per cohort. 
Part 2 is planned to enrol 2 cohorts of 6 subjects per cohort.    
SECTION 4.5.2  Dose escalation
Cohort Number
Dose (ng)
1
71
2
211
3
601
4
602
5
100
6
150
7
210
1.
Cohorts completed under Protocol Amendment 2.
2.
Study restart dose following stopping criteria met in one subject 
under Protocol Amendment 2
7, 21, 60, 120, 180, 280, 420, 630ng.  The dose increments between cohorts progressively 
decline from 3-times to 1.54-times the previous dose.
SECTION 4.5.3  TOP DOSE SELECTION
The original maximum proposed dose level proposed on preclinical data is was 630 ng 
but was revised to 210 ng based on emerging clinical data cohorts 1-3 in Part 1. 
However, Dose escalation may stop at a lower dose level based on criteria in Section 4.2. 
In the repeat dose intravenous toxicity studies in rats and monkeys, GSK1795091 was 
associated with expected pharmacologic, pro-inflammatory actions of a TLR4 agonist. 
Therefore, adverse events that stop dose escalation are likely to include mild to moderate 
flu-like symptoms and increases in body temperature and heart rate.   
The original top dose of 630 ng was is selected to accommodate a possible range of 
potencies of GSK1795091, based on in vitro evaluations.  In vitro data suggest that the 
relative potency of LPS is 1- to 4-times that of GSK1795091. If GSK1795091 is 
equipotent with LPS, dose escalation is predicted to stop in accordance with Section 4.2
at 2-4 ng/kg (i.e. 140 to 280 ng). If GSK1795091 is less potent than LPS by a factor of 4, 
higher dose levels will be required to elicit pharmacologic effects similar to LPS; this 
possibility is accommodated by the maximum proposed dose level of 630 ng (i.e. 
approximately 4.5-fold greater than the LPS dose of 2 ng/kg). 


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Based on the maximum predicted human exposure of approximately Cmax 0.09 ng/mL 
and AUC 2.6 ng.h/mL at the highest planned clinical dose of a dose of 630 ng, the margin 
to the NOAEL dose in rat (15 µg/kg/dose) is approximately 777X (Cmax) and 121X 
(AUC) and in monkey (200 µg/kg/dose) is approximately 19,100X (Cmax) and 8461X 
(AUC). Thus, at the maximum proposed a dose level, of 630 ng, severe or irreversible 
toxicities are not expected.
Based on emerging clinical data from Part 1, the GSK1795091 is likely to produce effects 
similar to LPS at a dose between 140 to 280 ng.  Therefore, the top dose in the study was 
revised to 210 ng.
SECTION 4.5.4  SUMMARY
The starting dose of 7 ng is expected to be safe and appropriately conservative for a 
healthy subject study.  Sensitive assays in a cynomolgus monkey model were used to 
calculate the MABEL.  At the dose defining the MABEL, animals experienced neither 
adverse events nor histopathological changes.  Furthermore, the dose is 8-fold higher than 
the HED of the non-pyrogenic dose in rabbits. Additionally, clinical experience with 
TLR4 agonists administered to healthy subjects provides a reference value against which 
the starting dose of GSK1795091 can be compared.  Since GSK1795091 has in vitro
potency similar to (or lower than) LPS, a starting dose of 7 ng is conservative in 
comparison to the 20 to 40-fold higher doses of LPS routinely administered to healthy 
subjects.  These estimates provide a high level of confidence that the starting dose of 7 ng 
can safely be administered to healthy subjects. Dose escalation is expected to stop, at or 
below 630 210 ng, based on mild to moderate toxicities that are reversible and readily 
monitored.  The top dose in the study, 630 210 ng, does not approach the Cmax or AUC 
at the NOAEL in rats or in monkeys. Thus, dose escalation proceeds from a conservative 
starting dose to a top dose unlikely to be associated with severe or irreversible effects.
SECTION 6.1 INVESTIGATIONAL PRODUCT AND OTHER STUDY TREATMENT
On Day -1, subjects will be hydrated with approximately 1200 mL glucose/saline (2.5% 
glucose/0.45% sodium chloride) (e.g. intravenous drip 150 mL/hr). Intravenous hydration 
(sourced locally) should continue on Day 1, beginning approximately 2 hours prior to and 
continuing for 6 hours after administration of study product (intravenous drip 150 
mL/hr).
Subjects will receive GSK1795091 administered as an intravenous bolus slowly over 2-5 
minutes, followed by an intravenous bolus of 10mL of normal saline.


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SECTION 7.1.5.
PART 2 OUTPATIENT ASSESSMENTS
Procedure
Day 7
7 Days Post Dose1
Follow-up2
(23 days 2 days post-last visit) or early withdrawal
Outpatient Visit 
X
X
Urine pregnancy test (WNCBP)
X
Full physical exam including height and weight
Haem/Clin Chem/ Urinalysis/Coagulation
12 lead ECG
Vital signs (Temperature, BP and Heart rate)
PK blood sampling
X
AE/SAE review
X
X
Concomitant medication review
X
X
1.
Following first dose, Day 7 days post first dose assessments (Cohort 1 D7; Cohort 2 D14) will be conducted in house; following second dose Day 7 days post second dose (Cohort 
1 D15; Cohort 2 D22)  assessments will be conducted as an outpatient visit 
2.
Outpatient visit or Contact at FU. All subjects with (1) new AE or (2) unresolved AEs or abnormal labs at the Day 7 visit should return for a follow-up visit. Female subjects should 
return for pregnancy testing. For all other subjects a FU contact is acceptable


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SECTION 7.3.6.
CLINICAL SAFETY LABORATORY ASSESSMENTS
Per Inclusion/exclusion criteria addition of “Gamma-GT” into the table for ‘other 
screening tests’:
Other 
Screening 
Tests

HIV

Hepatitis B surface antigen (HBsAg) and core antibody (anti-HBc 
Ab)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum or urine hCG Pregnancy test. 

Lipids, Total cholesterol, HDL, LDL

Gamma-GT

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204685
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for: A 2-part randomized, double-blind 
(sponsor-unblinded), placebo-controlled, ascending dose and 
parallel group study of TLR4 agonist (GSK1795091) administered to 
healthy subjects
Compound Number 
:
GSK1795091
Effective Date 
:
19-NOV-2017 (Final Version 1.0)
Description :

The purpose of this RAP is to describe the planned analyses and output to be included in the 
Clinical Study Report for Protocol 204685.

This RAP is intended to describe the statistical analyses for safety, pharmacokinetic and 
pharmacodynamics analyses required for the study.

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:
07-NOV-2017
Principal Biostatistician (PAREXEL EP Berlin)
07-NOV-2017
QCD Scientific Director (PAREXEL Quantitative Clinical Development)
17-NOV-2017
Statistics Leader (Clinical Statistics, Oncology, GSK)
17-NOV-2017
Manager (Clinical Pharmacology, GSK)
Approved by: 
19-NOV-2017
Senior Director (Clinical Statistics, Oncology, GSK)
17-NOV-2017
Manager (Clinical Programming, Oncology, GSK)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
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TABLE OF CONTENTS
Page
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................4
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Design ................................................................................................8
2.3.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Analyses ...................................................................14
6.2.
Disposition of Subjects................................................................................14
6.3.
Protocol Deviations.....................................................................................15
6.4.
Demographic and Baseline Characteristics.................................................15
6.5.
Concomitant Medications............................................................................15
7.
SAFETY ANALYSES .............................................................................................16
7.1.
Extent of Exposure .....................................................................................16
7.2.
Adverse Events...........................................................................................17
7.3.
Deaths and Serious Adverse Events...........................................................17
7.4.
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events ........................................................................................................18
7.5.
Pregnancies................................................................................................18
7.6.
Clinical Laboratory Evaluations...................................................................18
7.7.
Other Safety Measures...............................................................................19
7.7.1.
Vital Signs....................................................................................19
7.7.2.
ECG.............................................................................................20
8.
PHARMACOKINETIC ANALYSES.........................................................................21
8.1.
Drug Concentration Measures ....................................................................21
8.2.
Pharmacokinetic Parameters......................................................................21
8.2.1.
Deriving Pharmacokinetic Parameters.........................................21
8.2.2.
Statistical Analysis of Pharmacokinetic Parameters.....................22
8.2.2.1.
Statistical Analysis of Pharmacokinetic Data ..............22
8.2.2.2.
Dose-Proportionality Analysis.....................................22
9.
PHARMACOKINETIC / PHARMACODYNAMIC AND BIOMARKER 
ANALYSES ............................................................................................................24
9.1.
Pharmacodynamic Analyses.......................................................................24
10. REFERENCES.......................................................................................................27


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204685
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11. APPENDICES........................................................................................................28
11.1.
Appendix 1: Time & Events.........................................................................29
11.1.1.
Protocol Defined Time & Events ..................................................29
11.1.1.1.
Screening...................................................................29
11.1.1.2.
Part 1: In-House Assessments ...................................30
11.1.1.3.
Part 1 Outpatient Assessments ..................................32
11.2.
Appendix 2: Treatment States and Study Phases.......................................33
11.2.1.
Study Phases ..............................................................................33
11.2.1.1.
Study Phases for Concomitant Medication .................33
11.2.1.2.
Treatment States for AE Data.....................................33
11.3.
Appendix 3: Data Display Standards & Handling Conventions....................34
11.3.1.
Study Treatment & Sub-group Display Descriptors......................34
11.3.2.
Baseline Definition & Derivations .................................................34
11.3.2.1.
Baseline Definitions....................................................34
11.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................35
11.3.3.
Reporting Process & Standards...................................................35
11.4.
Appendix 4: Derived and Transformed Data ...............................................38
11.4.1.
General........................................................................................38
11.4.2.
Study Population..........................................................................38
11.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............39
11.5.1.
Premature Withdrawals................................................................39
11.5.2.
Handling of Missing Data.............................................................39
11.5.2.1.
Handling of Missing Dates..........................................39
11.5.2.2.
Handling of Partial Dates............................................39
11.6.
Appendix 6: Values of Potential Clinical Importance ...................................40
11.6.1.
Laboratory Values........................................................................40
11.6.2.
ECG.............................................................................................42
11.6.3.
Vital Signs....................................................................................42
11.7.
Appendix 7: Abbreviations & Trade Marks ..................................................43
11.7.1.
Abbreviations...............................................................................43
11.7.2.
Trademarks .................................................................................44
11.8.
Appendix 8: List of Data Displays ...............................................................45
11.8.1.
Data Display Numbering..............................................................45
11.8.2.
Mock Example Shell Referencing ................................................45
11.8.3.
Deliverable [Priority].....................................................................45
11.8.4.
Study Population Tables..............................................................46
11.8.5.
Efficacy Tables ............................................................................47
11.8.6.
Efficacy Figures ...........................................................................47
11.8.7.
Safety Tables...............................................................................48
11.8.8.
Safety Figures .............................................................................52
11.8.9.
Pharmacokinetic Tables...............................................................53
11.8.10. Pharmacokinetic Figures .............................................................54
11.8.11. Pharmacodynamic/Biomarker Tables ..........................................55
11.8.12. Pharmacodynamic/Biomarker Figures .........................................58
11.8.13. Pharmacokinetic / Pharmacodynamic Tables ..............................63
11.8.14. Pharmacokinetic / Pharmacodynamic Figures .............................64
11.8.15. ICH Listings .................................................................................71
11.8.16. Non-ICH Listings..........................................................................74
11.9.
Appendix 9: Example Mock Shells for Data Displays ..................................77


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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose

First-time-in-human (FTIH) study to evaluate GSK1795091 for safety, 
pharmacokinetic (PK), and pharmacodynamic (PD) data in healthy subjects.
Protocol

This RAP is based on the original protocol [(dated: 11-MAR-2016) of study 
204685 (GSK Document No.: 2015N236402_03)], Protocol Amendment 
Number 03 (dated: 12-APR-2017), and ClinBase eCRF Version 4.6.07.
Primary 
Objective

To evaluate the safety and tolerability of GSK1795091 when administered to 
healthy subjects.
Primary 
Endpoint

Safety data comprising adverse events (AEs), vital signs, laboratory tests, and 
12-lead electrocardiograms (ECGs).
Study 
Design

The study will be conducted in two parts.

Part 1 will be a randomized, double-blind (sponsor-unblinded), 
placebo-controlled, single-center, single-dose escalation, sequential-group 
evaluation of intravenously administered GSK1795091 to evaluate the safety 
and tolerability in healthy subjects.

Part 2 will be an open-label, parallel-cohort evaluation of 2 doses of 
GSK1795091 administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks 
apart (Part 2, Cohort 2). GSK1795091 will be administered at a dose 
determined by results from Part 1.

Part 2 will not begin until review/approval of Part 1 safety primary endpoints and 
dose selection.
Planned 
Analyses

Safety, PK, PD
Analysis 
Populations

All Subjects Population (Safety Population)

PK Concentration Population

PK Parameter Population

PD Population
Hypothesis

No formal statistical hypotheses will be tested.


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Overview
Key Elements of the RAP
Primary 
Analyses

Safety parameters will be analysed descriptively.
Secondary 
Analyses

Descriptive summaries of PK concentrations and parameters

Dose proportionality of GSK1795091 Cmax following single dose administration 
will be evaluated graphically and using the power model, if more than two dose 
cohorts are completed and if possible.
Exploratory 
Analyses

Exploratory graphical PK/PD analyses may be performed to examine the 
relationship between GSK1795091 PK (e.g., Cmax) and response as measured 
by vital signs (e.g., body temperature, heart rate, etc.) or PD biomarkers (e.g., 
cytokines/chemokines) or other endpoints if warranted by the data (e.g., grade, 
onset and duration of AEs). The relationship(s) between PD endpoints and PK 
parameters (Cmax) initially will be explored graphically. Plots of PD endpoint 
versus PK parameters of GSK1795091 will be generated.

Descriptive summaries of biomarkers


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There was a change to the originally planned statistical analysis specified in the Protocol (dated: 
11-MAR-2016) and Protocol Amendment Number 03 (dated: 12-APR-2017).
The study team decided that Part 2 of the study would not be conducted following a review of data 
from Part 1.  Therefore, all analysis planned for Part 2 per protocol will not be performed.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and tolerability 
of GSK1795091 when administered to 
healthy subjects.

Safety data comprising adverse events, vital signs, 
laboratory tests, and 12-lead ECGs.
Secondary Objectives
Secondary Endpoints

To evaluate the systemic 
pharmacokinetics of GSK1795091 
following administration of a single 
intravenous dose to healthy subjects.

Plasma pharmacokinetic parameters such as Cmax, tmax, 
AUC(0-t), AUC(0-last), AUC(0-∞), CL, Vd, and t1/2.

To evaluate the pharmacodynamic 
effects of GSK1795091 following 
administration as a single intravenous 
dose to healthy subjects.

Vital signs, CRP measurements and WBC and differential.

To evaluate the systemic 
pharmacokinetics of GSK1795091 
following a second intravenous dose 
administered to healthy subjects 1 
week or 2 weeks after the first dose.

Plasma pharmacokinetic parameters such as Cmax, tmax, 
AUC(0-t), AUC(0-last), and AUC(0-), CL, Vss, t1/2, 
carryover, accumulation and time invariance (as possible)
1.

To evaluate the clinical and 
pharmacodynamic effects of 
GSK1795091 following a second 
intravenous dose administered to 
healthy subjects 1 week or 2 weeks 
after the first dose.

Vital signs, CRP measurements, WBC and differential, , 
and laboratory tests.


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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints

To evaluate immune system effects 
following intravenous administration of 
GSK1795091.

Cytokine measurements in plasma and immune cell 
phenotyping of leukocytes.

To evaluate the pharmacodynamic
effects of intravenous administration of 
GSK1795091 on gene signature 
analysis of Peripheral Blood 
Mononuclear CCells (PBMCs) from 
Part 2 healthy subjects.

Gene signature analysis2.

To explore the relationship between 
pharmacokinetics, pharmacodynamic 
markers, and adverse events.

Correlation between pharmacokinetics and 
pharmacodynamic markers, such as vital signs and CRP, 
and adverse events.

To characterize the metabolic profile of 
GSK1795091 in plasma and urine.

Plasma and urine may be analyzed qualitatively for 
GSK1795091 and other compound related metabolites 
and results reported under a separate GlaxoSmithKline 
protocol2.
Notes:
1
AUC(0-), CL, Vss, t1/2, carry-over and accumulation, and time invariance are not endpoints of interest due to 
cancellation of Part 2 cohort expansion.
2
Will not be explored due to cancellation of Part 2 cohort expansion.


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2.2.
Study Design
Figure 1
Part 1 study schematic
Treatment Period 
GSK1795091A 
or PBO
Day-2 Day-1 Day 1 Day 2 Day 3 Day 4 Day 5
Admission
Discharge
Day 7 
Outpatient visit
Day 30 (+/- 2)
Outpatient visit
Screening
Within 30 days
Figure 2
Part 2 study schematic
GSK1795091A 
Admission
Day 30 (+/- 2) 
Post 2nd Dose
Outpatient visit
Screening
Within 30 days
Cohort 1 Treatment Period 
Day-2 Day -1 Day 1
Day 2
Day 3
Day 4
Day 5
Day6
Day7
Day 8
Day 9
Day10
Day11
Day 12
GSK1795091A 
Discharge
Cohort 2 Treatment Period 2 
Day13 Day14 Day 15 Day 16 Day17 Day18 Day 19
Admission
GSK1795091A 
Discharge
Day 7 
Post 2nd Dose
Outpatient visit
Cohort 2 Treatment Period 1 
GSK1795091A 
Day-2 Day-1 Day 1 Day 2 Day 3 Day 4 Day 5
Discharge
Admission
Design Features

Subjects will attend the clinical unit for a screening visit and, if eligible, 
will attend the study within 30 days.

For both Part 1 and Part 2, subjects will be admitted to the clinical unit 
2 days prior to dosing (Day -2). On Day -1, adverse events and vital
signs will be recorded according to the schedule on Day 1.

In Part 1, 8 subjects in each dose cohort will be randomised to receive 
an intravenous dose of GSK1795091 or matching placebo in a 3:1 
ratio. Subjects will then be observed as inpatients until discharge on 
Day 5, after assessments have been performed. 


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
For Part 1, subjects will return on Day 7 for clinic visit and have a follow 
up contact on Day 30. 

Part 2 will not begin until review/approval of Part 1 safety primary 
endpoints and dose selection.

In Part 2, on Day 1 subjects will receive intravenous GSK1795091 
administered at a dose determined by results from Part 1. 

Subjects in Part 2 Cohort 1 will be observed as inpatients until 
discharge on Day 12.

Subjects in Part 2 Cohort 2 will be observed as inpatients until 
discharge on Day 5, after assessments have been performed. They will 
return to the clinical unit for a second inpatient visit on Day 13 

Each subject in Part 2 will receive a second dose of GSK1795091 on 
Day 8 (Part 2, Cohort 1) or Day 15 (Part 2, Cohort 2) (unless AEs 
attributable to the first dose of GSK1795091 have not resolved, in 
which case the subject will not receive the second dose). 

For Part 2, subjects will return to the clinical unit for a clinic visit 7 days 
after the second dose of GSK1795091 and have a follow up contact 30 
days after their second dose of GSK1795091.
Details of the assessments and procedures subjects will undergo are listed 
in Section 7 of the Clinical Study Protocol (CSP). The time points and visits 
are provided in the Time and Events table, (Appendix 1: Time & Events).
Dosing

Part 1: The planned dose levels for GSK1795091 are:
o
Dose Level 1: 7 ng
o
Dose Level 2: 21 ng
o
Dose Level 3: 60 ng
o
Dose Level 4: 60 ng repeat
o
Dose Level 5: 100 ng
o
Dose Level 6: 150 ng
o
Dose Level 7: 210 ng
o
or Placebo.

Part 2: Actual dosing of GSK1795091 depends on the outcomes of 
Part 1.


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Treatment 
Assignment

Part 1: In each cohort, subjects will be assigned to GSK1795091 or 
placebo with a ratio of 3:1. A sentinel group of 2 subjects will receive 
study product in a ratio of 1 GSK1795091 : 1 placebo. The remaining 
6 subjects will receive study product in a ratio of 5 GSK1795091 : 1 
placebo.

Part 1 will be double-blind, with both the investigator and subject 
blinded to study treatment. All site personnel with the exception of the 
pharmacy team will remain blinded to study treatment except as 
discussed below. The sponsor’s team will be unblinded.

Part 2: All subjects will be treated with GSK1795091.

Part 2 will be open-label where the sponsor, investigator and subject 
will be open to study treatment.
Interim Analysis

No formal interim analyses are planned for this study except for 
making dose escalation decisions (described in Section 4 of CSP).
2.3.
Statistical Hypotheses
No formal statistical hypotheses will be tested. Analysis will be descriptive and exploratory. An 
estimation approach providing point estimates and corresponding confidence intervals will be used, 
where appropriate.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analyses are planned for this study except as required for making dose 
escalation decisions or regulatory compliance. In Part 1, cohorts with next higher dose will be 
started sequentially after evaluation of adverse events, vital signs, laboratory tests, and 12-lead 
ECGs by the Principal Investigator (blinded), GSK Medical Monitor (unblinded), GSK statistician 
(unblinded).
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the following 
sequential steps:
1.
All subjects have completed the study as defined in the protocol.
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 by GSK.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All subjects who signed the informed consent 
form

Screen failure listing

Age ranges table
All Randomized

All subjects in the Screened population who 
were randomized

Exclusion of study 
populations listing
All Subjects 
Population

All subjects enrolled into the study who have 
received a dose of study medication 
(GSK1795091 or placebo) will be included in 
the safety population.

This population will be based on the 
treatment the subject actually received.

Safety/tolerability

Subject disposition
Demography
PK Concentration 
Population

All subjects in the ‘“All Subjects Population” 
for whom a pharmacokinetic blood sample 
was obtained and assayed.

Listing, summarizing 
and plotting plasma 
concentration-time
data
PK Parameter 
Population

All subjects in the ”PK Concentration 
Population” for whom, at least, one valid and 
evaluable pharmacokinetic parameter (AUC 
or Cmax) was derived.

Listing, summarizing 
and plotting of PK 
parameters
PD Population

All subjects in the ”All Subjects Population”
for whom valid and evaluable 
pharmacodynamic parameters were derived..

Listing, summarizing 
and plotting of PD 
Parameters
NOTES : 

Please refer to Appendix 8: 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, subject management or subject assessment) will be summarised and 
listed.

Protocol deviations will be tracked by the study team throughout the conduct of the study in 
accordance with the Protocol Deviation Management Plan (PDMP).
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 summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary 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 1 provides an overview of appendices within the RAP for outlining general considerations for 
data analyses and data handling conventions. 

There are no planned examination of covariates and subgroups.

There are no planned adjustments made for multiple centres in this study.

There are no planned adjustments for multiple comparisons or multiplicity.
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Time & Events
11.2
Appendix 2: Treatment States and Phases
11.3
Appendix 3: Data Display Standards & Handling Conventions
11.4
Appendix 4: Derived and Transformed Data
11.5
Appendix 5: Premature Withdrawals & Handling of Missing Data
11.6
Appendix 6: Values of Potential Clinical Importance
11.7
Appendix 7: Abbreviations & Trade Marks
11.8
Appendix 8: List of Data Displays
11.9
Appendix 9: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “All Subjects Population”, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details of data 
displays being presented in Appendix 8: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Endpoints
Data Displays Generated
Table
Figure
Listing
Randomisation
Randomisation
Y
Subject disposition
Subject Disposition
Y
Study Populations
Y
Protocol Deviations
Y
Y
Exclusion from Any populations
Y
Y
Inclusion & Exclusion Criteria Deviations
Y
Reasons for Withdrawal / Study Treatment Discontinuation
Y
Investigational Product
Investigational Product Status
Y
Y
Demographics
Demographics Characteristics
Y
Y
Concomitant medications
Concomitant Medications
Y
Y
Medical History
Medical History
Y
Y
Alcohol and Drug Screen
Substance Use
Y
NOTES :

Y = Yes display generated.
6.2.
Disposition of Subjects
A summary of the number of subjects in each of the analysis populations described in Section 4
will be provided. A listing of subjects excluded from analysis populations will also be provided.
A summary of subject status and reason for study withdrawal will be provided. This display will 
show the number and percentage of subjects who withdrew from the study, including primary 
reasons for study withdrawal. Reasons for study withdrawal will be presented in the order they are 
displayed in the eCRF. 
A listing of study treatment discontinuation will be generated. The listing will include cohort, last 
dose date, and reasons for study treatment discontinuation. 


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6.3.
Protocol Deviations
Protocol deviations will be summarized and listed and will include inclusion/exclusion deviations.
A listing of inclusion/exclusion deviations will also be provided.
6.4.
Demographic and Baseline Characteristics
The demographic characteristics (e.g., age, race, ethnicity, sex, height, and body weight) will be 
summarized and listed. Age, height and weight will be summarized using the mean, standard 
deviation, minimum, median, and maximum. In addition, age will also be categorized and 
summarized by <18, 18-64, 65-74 and >74. The count and percentage will be computed for age 
categories, sex, race and ethnicity. A separate summary table for age ranges will be provided.
Race and racial combination will be summarized.
Medical conditions present at screening will be listed and will be summarized.
Substance use will be listed.
6.5.
Concomitant Medications
Concomitant medications will be coded using GSK Drug coding dictionary, summarized, and listed. 
The summary of concomitant medications will show the number and percentage of subjects taking 
concomitant medications by ingredient. Multi-ingredient products will be summarized by their 
separate ingredients rather than as a combination of ingredients. Anatomical Therapeutic Chemical 
(ATC) classification Level 1 (Body System) information will be included in the dataset created, 
however, will not appear on the listing or summary.
In the summary of concomitant medications, each subject is counted once within each unique 
ingredient. For example, if a subject takes amoxicillin on two separate occasions, the subject is 
counted only once under the ingredient “amoxicillin”.
In the summary of concomitant medications, the ingredients will be summarized by the base only.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “All Subjects Population”, unless otherwise specified.
Table 3 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 8: List of Data Displays.
Table 3
Overview of Planned Safety Analyses
Endpoints
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Investigational Product Exposure
Exposure
Y
Y
Adverse Events
All AEs
Y
Y
AEs – Max Grade
Y
Y
AEs – Drug Related
Y
Y
AEs – Serious AE
Y
Y
AEs – Leading to 
Discontinuation
Y
Y
Laboratory Tests
Clinical chemistry
Y
Y
Y
Y
Hematology
Y
Y
Coagulation
Y
Y
Urinalysis
Y
Y
Other Screening Tests
Y
Vital Signs
Vital Signs
Y
Y
Y
Y
Vital Signs by Toxicity 
Grading Scale for 
Healthy Adult and 
Adolescent Volunteers 
Enrolled in Preventive 
Vaccine Clinical Trials
Y
Y
Y
Y
Electrocardiogram
12-Lead ECG
Y
Y
Y
Y
ECG Findings
Y
Y
QTcF Grades
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

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.     
7.1.
Extent of Exposure
The number of IV bolus injections administered to study treatment will be summarised with mean, 
median, standard deviation, minimum, and maximum. 


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Dose intensity (dose delivered per bolus injection) will be summarized by cohort using mean, 
median, standard deviation, minimum, and maximum.
7.2.
Adverse Events
An overview summary of AEs, including counts and percentages of subjects with any AE, AEs 
related to study treatment, AEs leading to permanent discontinuation of study treatment, SAEs, 
SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study treatment will be 
produced.
A summary of non-serious AEs that occurred in strictly 5% of the subjects or above will be provided 
(no rounding for the percentage will be used in terms of 5% threshold, e.g., event with 4.9% 
incidence rate should not be included in this table). The summary will be displayed by SOC and 
PT.
Adverse event (AE) grading is guided by the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
Additionally, adverse events will be coded to the PT level using the Medical Dictionary for 
Regulatory Affairs (MedDRA dictionary). 
A summary of number and percentage of subjects with any adverse events by maximum grade will 
be produced. AEs will be sorted by PT in descending order of total incidence. The summary will 
use the following algorithms for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several times with 
different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only once at the 
maximum grade no matter how many events they have.
In addition, the frequency and percentage of AEs (all grades) will be summarized and displayed in 
descending order of total incidence by SOC and PT. In the SOC row, the number of subjects with 
multiple events under the same system organ class will be counted once. 
A separate summary will be provided for study treatment-related AEs. A study treatment-related 
AE is defined as an AE for which the investigator classifies the relationship to study treatment as 
“Yes”. A worst case scenario approach will be taken to handle missing relatedness data, i.e. the 
summary table will include events with the relationship to study treatment as ‘Yes’ or missing. The 
summary table will be displayed in descending order of total incidence by PT only.
All AEs will be listed. 
7.3.
Deaths and Serious Adverse Events
In the event that a subject has withdrawn consent, no data after the withdrawal of consent date 
from this subject including death is supposed to appear in the database, which should be part of 
the data cleaning process. 


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All SAEs will be tabulated based on the number and percentage of subjects who experienced the 
event. The summary tables will be displayed in descending order of total incidence by PT only.
A study treatment-related SAE is defined as an SAE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst case scenario approach will be taken to handle 
missing data, i.e. the summary table will include events with the relationship to study treatment as 
‘Yes’.
SAEs are included in the listing of all adverse events.
7.4.
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study and Other 
Significant Adverse Events
The following categories of AEs will be summarized separately in descending order of total 
incidence by PT only and separate supportive listings will be generated with subject level details for 
those subjects:

AEs Leading to Discontinuation of Study Treatment
7.5.
Pregnancies
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol. If subjects become pregnant while on the study, the information will be 
included in the narratives and no separate table or listing will be produced.
7.6.
Clinical Laboratory Evaluations
The following laboratory tests are required: 
Hematology: Hemoglobin (HGB), Hematocrit (HCT), Red Blood Cell (RBC) count, White Blood 
Cell (WBC) count with differential (Total Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils), Platelet count, Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin 
(MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC). 
Clinical Chemistry: Sodium, Potassium, Calcium, Glucose, Urea, Creatinine, Albumin, Aspartate
aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase, C-reactive protein
(CRP), Gamma Glutamyl Transferase (GGT), Ferritin, Transferrin, Triglycerides, Total Protein, 
Total bilirubin (total) and Direct/Indirect bilirubin. 
Routine Urinalysis (Dipstick): Specific gravity, pH, Glucose, Protein, Blood and Ketones. If 
urinalysis results are abnormal, the microscopic panel (leukocytes, erythrocytes, casts, crystals, 
bacteria, and/or epithelial cells, as appropriate) will be performed.
Coagulation: Prothrombin time or International Normalized Ratio (INR), and partial thromboplastin 
time (PTT).
Other Screening Tests: Human immunodeficiency virus (HIV), Hepatitis B surface antigen 
(HBsAg), core-antibody (anti-HBc Ab), Hepatitis C (Hep C Antibody), Follicle Stimulating Hormone 


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(FSH), Estradiol, Alcohol and Drug Screening (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines), serum or urine hCG pregnancy test, Lipids, 
Total cholesterol, HDL and LDL.
Laboratory grades will be reported using the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.Summary of laboratory values 
by scheduled visits using mean, median, standard deviation, minimum and maximum will be 
provided.
Other Screening Tests are only collected at screening. Therefore these tests will be only listed.
7.7.
Other Safety Measures
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit will 
be based on the number of subjects with non-missing value at each particular visit.
7.7.1.
Vital Signs
Values of vital signs as well as the change from baseline will be summarized by scheduled visit 
using mean, median, standard deviation, minimum and maximum. At screening and pre-dose, the 
average of triplicated measurements will be summarized. Triplicated measurements and average 
will be listed.
In addition vital signs values will be categorized by Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Appendix 2 of the CSP) with 
the exception of fever and tachycardia which also require a change from time-matched baseline 
(per table below).
Grade 1
Grade 2
Grade 3
Grade 4
Temperature
>0.5oC change 
AND 
>38.0oC
>1.5oC 
change
AND 
>38.5oC
>3 oC change 
(<24 hours)
AND 
>39.0oC
>3oC change 
(24 hours) 
AND
>40oC
Heart rate
>15 bpm 
change
AND 
>101 bpm
>30 bpm 
change
AND 
>116 bpm
>45 bpm 
change
AND 
>130 bpm
Emergency 
intervention 
required
Summaries of increase in vital signs from the baseline with respect to the categories defined above 
will be performed. These summaries will display the number and percentage of subjects with any 
grade increase, increase to Grade 2 and increase to Grade 3 at each scheduled assessment time 
and in the worst case post-baseline. 


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7.7.2.
ECG
A summary of the number and percentage of subjects who had normal and abnormal (clinically 
significant and not clinically significant) ECG findings will be displayed by scheduled visits as well 
as for the worst case post-baseline. 
The QTc values based on Fridericia formula will be rounded to the integer and the values will be 
categorized into the following ranges (in “msec”): Grade 0 (<450), Grade 1 (450-480), Grade 2 
(481-500), and Grade 3 (≥501). Summaries of grade increase will be provided. These summaries 
will display the number and percentage of subjects with any grade increase, increase to Grade 2 
and increase to Grade 3 at each scheduled assessment time and in the worst case post-baseline. 
The changes in QTc values will be categorized into the clinical concern ranges which are specific 
to changes in QTc: 31-60 and >60 msec. A summary of change in QTc value will display the 
number and percentage of subjects with a change within each range at each scheduled 
assessment time point and in the worst case post-baseline. Subjects with missing baseline values 
will be excluded from this summary. The summaries for the QTc will use the calculated value 
based on Fridericia’s correction formula.
In addition, ECG interval values will also be summarized. At screening, day 1 and day 4, the 
average of triplicated measurements will be summarized. Triplicated measurements and average 
will be listed.
Listings of abnormal ECG findings and a listing of ECG values will be provided.


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8.
PHARMACOKINETIC ANALYSES
The pharmacokinetic concentration analyses will be based on the “Pharmacokinetic Concentration”
population, the PK parameter analyses will be based on the “Pharmacokinetic Parameter” 
population, unless otherwise specified.
Table 4 provides an overview of the planned analyses, with full details being presented in Appendix 
8: List of Data Displays.
Table 4
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pharmacokinetic Analyses
GSK1795091 
concentration
Y
Y
Y
Y
GSK1795091 PK 
Parameters
Y
Y
Y
Dose Proportionality
GSK1795091 dose 
proportionality
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = 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.    
8.1.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 11.3.3 Reporting 
Process & Standards).
8.2.
Pharmacokinetic Parameters
8.2.1.
Deriving Pharmacokinetic Parameters

Refer to Section 11.3: Appendix 3: Data Display Standards & Handling Conventions 
(Section 11.3.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin version 6.3.

All calculations of non-compartmental parameters will be based on actual sampling times.

Pharmacokinetic parameters described in Table 5 will be determined from the GSK1795091
concentration-time data, as data permit.


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Table 5
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-
last)
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 trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-t)
Partial area under the concentration-time curve to time (where t may be 24, 168 h or other 
as appropriate) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-last) + C(last) / lambda_z
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
CL
Clearance
CL = Dose/AUC(0-∞)
Vd
Volume of distribution
Vd = Dose/lambda_z * AUC(0-∞)
Vss
Volume of distribution where V = CL/MRTiv
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.
8.2.2.
Statistical Analysis of Pharmacokinetic Parameters
8.2.2.1.
Statistical Analysis of Pharmacokinetic Data
Except for tmax, pharmacokinetic parameters summarized descriptively to determine mean, 
standard deviation (SD), median, minimum. maximum, geometric mean, and the SD, CV% and 
95% confidence interval of loge-transformed parameters by dose cohort in Part 1,  tmax will be 
summarized descriptively as mean, SD, median, minimum, and maximum. 
8.2.2.2.
Dose-Proportionality Analysis
If data support, the PK-dose relationship initially will be examined graphically by plotting Cmax, as 
a function of the dose levels administered. Two plots of each PK parameter vs. dose will be 
produced. The first will be on a linear scale and the second will use the logarithmic scale for both 
axes. 
If more than two dose cohorts are completed and data support, dose proportionality of 
GSK1795091 Cmax following single dose administration will be evaluated graphically and using 
the power model as described below:
loge (PK parameter) = a + b * loge (dose)
where a is the intercept and b is the slope


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Assessment of dose proportionality will be conducted based on the power model described above. 
The power model will be fitted by restricted maximum likelihood (REML) using SAS Proc Mixed. 
Both the intercept and slope will be fitted as fixed effects. If there is sufficient data, the model may 
also be fit with the intercept and/or slope as random effects depending on the ability of the model to 
converge and on estimation of variance-covariance matrix. An estimate of the slope with 
corresponding 90% confidence interval will be obtained from the power model to assess the 
degree of dose-proportionality (slope b around unity indicates dose-proportionality, b near zero 
implies the response y is independent of dose), and to describe the uncertainty (width of the CI) of 
the estimate. 
If data support, plots will be provided showing individual subject values by treatment (dose) for 
each of the PK parameter Cmax, together with the predicted PK parameter value from the Power 
Model.
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection 
of residual plots. Normality will be examined by normal probability plots, while homogeneity of 
variance will be assessed by plotting the residuals against the predicted values for the model. If the 
assumptions are grossly violated then alternative analyses will be performed.
Sample SAS Code for dose-proportionality analysis using power model. Programmers will need to 
modify as appropriate to the study:
proc mixed;
  by PKParameter;  
  model lnPKParameter = lnDose / cl alpha=0.1 solution ddfm=kr;  
run;


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9.
PHARMACOKINETIC / PHARMACODYNAMIC AND 
BIOMARKER ANALYSES
9.1.
Pharmacodynamic Analyses
The Pharmacodynamics analyses will be based on the “PD” population, unless otherwise specified.
Pharmacodynamics endpoints / Biomarkers will be analysed numerically and graphically to explore 
the relationship between GSK1795091 and PD biomarkers. The PD biomarkers of interest include:

Cytokine/Chemokine:
-
IL-6
-
TNF-alpha
-
IFN-gamma
-
IP-10
-
MCP-1
-
GM-CSF
-
IL-1Ra
-
IL-10

Immunophenotyping:
-
Neutrophils
-
Lymphocytes
-
Monocytes
Table 6 provides an overview of the planned pharmacodynamic analyses, with full details of data 
displays being presented in Appendix 8: List of Data Displays.


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Table 6
Overview of Planned Pharmacokinetic / Pharmacodynamic and 
Biomarker Analyses
Display Type
Untransformed
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pharmacodynamic/Biomarker analyses
Laboratory tests (CRP, 
Neutrophil abs., 
Lymphocyte abs.)
Y
Y
Y
Y
Y
Y
Y
Y
Vital Signs (HR, Body 
temperature, Systolic 
pressure, Diastolic 
pressure)
Y
Y
Y
Y
Y
Y
Y
Y
PD Biomarkers 
(Cytokine/Chemokine, 
Immunophenotyping) 
Y
Y
Y
Y1
Y1
PK/PD analyses
Pharmacokinetics 
parameters (Cmax) vs. 
Laboratory tests 
change from baseline 
(CRP, Neutrophil abs., 
Lymphocyte abs.)
Y
Pharmacokinetics 
parameters (Cmax) vs. 
Vital signs change 
from baseline (HR, 
Body temperature, 
Systolic blood 
pressure, Diastolic 
blood pressure)
Y
Pharmacokinetics 
concentration vs. PD 
Biomarkers 
(Cytokine/Chemokine, 
Immunophenotyping)
Y
NOTES :
1 Display fold change as defined in Section 9

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 (descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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The “Change from Baseline” for cytokine/chemokine biomarkers in Table 6 specifically refers to 
fold change, which is calculated as the ratio of the difference between a value at Time T (denote as 
XT) and the baseline (predose) value X0 over the baseline value ((XT – X0)/ X0.) If a biomarker value 
is below limit of quantitation limit (LOQ), then impute ½*LOQ for the calculation of fold change for 
tables and figures. Note imputation will not be implemented for listings.
Exploratory graphical PK/PD analyses may be performed to examine the relationship between 
GSK1795091 PK and response as measured by vital signs (e.g., body temperature, heart rate, 
etc.), PD biomarkers (e.g., cytokines, /chemokines, immunophenotyping) or other endpoints if 
warranted by the data (e.g., grade, onset and duration of AEs).  The relationship(s) between PD 
endpoints and PK parameters (Cmax) initially will be explored graphically.  Plots of PD endpoint 
versus PK parameters of GSK1795091 will be generated. In addition, PD end-points versus dose 
should also be explored.
The relationship between PK concentrations and PD biomarkers, i.e. cytokines and 
immunophenotypings, will be explored graphically.
Additional exploratory analyses may be performed to further characterize the novel biomarkers, 
and may be reported separately from the main clinical study report. 
Further analysis may be conducted if the initial plots suggest a correlation between the PD and PK 
endpoints.  Models to describe the relationship(s) may include linear models and/or a maximum 
effect models.  Other more complex models may be explored if warranted by the data.  Results 
may be included in the final study report for this study or reported separately.


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10.
REFERENCES
GSK Document Number 2015N236402_03: A 2-part randomized, double-blind (sponsor-
unblinded), placebo-controlled, ascending dose and parallel group study of TLR4 agonist 
(GSK1795091) administered to healthy subjects (Protocol Amendment 03).
GUI_137354 (2.0): Information for Authors: Reporting and Analysis Plan (RAP), Global
GUI_51487 (5.0): Non-compartmental Analysis of Pharmacokinetic Data, CPMS Global
SOP_54838 (5.0): Development, Review and Approval of Reporting and Analysis Plan
(RAP), Global


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11.
APPENDICES
Section
Appendix
RAP Section 1-5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.1
Appendix 1: Time & Events
Section 11.2
Appendix 2: Treatment States and Phases
Section 11.3
Appendix 3: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.4
Appendix 4: Derived and Transformed Data
Section 11.5
Appendix 5: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Other RAP Appendices
Section 11.6
Appendix 6: Values of Potential Clinical Importance
Section 11.7
Appendix 7: Abbreviations & Trade Marks
Section 11.8
Appendix 8: List of Data Displays
Section 11.9
Appendix 9: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Time & Events
11.1.1.
Protocol Defined Time & Events
11.1.1.1.
Screening
Procedure
Screening (up to 30 days prior to
Day -1)
Informed consent
X
Outpatient visit
X
Inclusion and exclusion criteria
X
Demographics
X
Full physical exam including height and weight
X
Medical history1
X
Drug/Alcohol screen
X
Serum/urine pregnancy test ( WNCBP)
X
HIV, Hep B and Hep C screen
X
Haem/Clin Chem/PT & PTT/Urinalysis
X
12-lead ECG2
X
Vital signs (BP and heart rate)
X
Concomitant medication review
X
1.
To include substance usage, family history of premature cardiovascular disease, medication, drug/alcohol history
2.
Triplicate ECGs collected 5mins apart


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11.1.1.2.
Part 1: In-House Assessments
Procedure
Day 
-2
Day 
-1
Treatment Period Day 1
Day 2 (24h)
Day 3 (48h)
Day 4 (72h)
Day 5 (96h)
Pre dose
0h
5min
0.25h
0.5h
1h
2h
3h
4h
6h
8h
10h
12h
16h
Admission to the 
unit
X
Overnight stay
X
X
==========================================================================================================
Serum/urine 
pregnancy test 
(WNCBP)
X
Full physical exam 
including height and 
weight
X
Inclusion and 
exclusion criteria
X
X
Haem/Clin 
Chem/Urinalysis
/Coagulation
X
X
X
X
WBC with 
differential1
X
X
X
X
X
X
X
X
X
X
Drug/Alcohol test
X
12 lead ECG
X
X
X
X
X
X
Vital signs 
(Temperature, BP 
and Heart rate)
X2
X
X
X
X
X
X
X
X
X
X
X
X
Telemetry 
=======================================================================================
Dosing
X
Intravenous 
hydration
X
======================================================
PK blood sampling3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Day 
-2
Day 
-1
Treatment Period Day 1
Day 2 (24h)
Day 3 (48h)
Day 4 (72h)
Day 5 (96h)
Pre dose
0h
5min
0.25h
0.5h
1h
2h
3h
4h
6h
8h
10h
12h
16h
Cytokine 
measurements3
X
X
X
X
X
X
X
X
X
Leukocyte 
phenotyping3
X
X
X
AE/SAE review4
X
X
========================================================================================================
Concomitant 
medication review
X
X
==========================================================================================================
Discharge
X
1.
Where WBC+Differential and Haematology are scheduled for the same time, WBC+Differential may  be collected as part of the Haematology assessment
2.
Baseline Vital Signs to match Day 1  timepoints
3.
PK and Biomarker Sampling: The pre-dose blood samples should be collected within 1 hr before administration of GSK1795091. Every attempt should be made to collect 
samples within 5 min on samples up to 2 hrs, 20 min on samples up to 12 hrs, and 40 min on samples after 12 hrs. Actual date/time of sample collection and dosing must 
be recorded. Explanations are required for any deviations of >5 min from the planned time during the first 2 hrs and for deviations of more than 20 min from the planned time for 
samples collected at 3 hrs up to 10 hrs.
4.
Blood samples may be collected to explore biomarkers at the discretion of the Investigator


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11.1.1.3.
Part 1 Outpatient Assessments
Procedure
Day 7 
Follow-up
(23 days 2 days post-last visit) or early 
withdrawal
Outpatient Visit or Contact1
X
X
Serum/urine pregnancy test (WNCBP)
X
Full physical exam including height and weight
X
Haem/Clin Chem/Urinalysis/Coagulation
X
12 lead ECG
X
Vital signs (Temperature, BP and Heart rate)
X
PK blood sampling2
X
Cytokine measurements
X
Leukocyte phenotyping
X
AE/SAE review
X
X
Concomitant medication review
X
X
1.
Outpatient visit at Day 7; Outpatient visit or Contact at FU. All subjects with (1) new AE or (2) unresolved AEs or abnormal labs at the Day 7 visit should return for a follow-up visit. 
Female subjects should return for pregnancy testing. For all other subjects a FU contact is acceptable
2.
PK Sampling: Blood samples for analysis of GSK1795091 concentrations will be collected following dosing 144 hours (Day 7) after administration


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11.2.
Appendix 2: Treatment States and Study Phases
11.2.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to study 
treatment.
Study Phase
Definition
Pre-Treatment
Date/Time < Study Treatment Start Date/Time
On- Treatment
Study Treatment Start Date/Time ≤Date/Time ≤ Study Treatment Stop Date/Time
Post- Treatment
Date/Time > Study Treatment Stop Date/Time
11.2.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening 
visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 5 : Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
11.2.1.2.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date/Time < Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time ≤ AE Start Date/Time ≤ Study Treatment Stop 
Date/Time
Post-Treatment
AE Start Date/Time > Study Treatment Stop Date/Time
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.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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11.3.
Appendix 3: Data Display Standards & Handling 
Conventions
11.3.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions – Part 1
RandAll NG 
Data Displays for Reporting
Code
Description
Description
Order [1]
S1
7 ng single dose
GSK 7 ng
2
S2
21 ng single dose
GSK 21 ng
3
S3
60 ng single dose[2]
GSK 60 ng
4
S4NEW
60 ng single dose – redo[3]
GSK 60 ng
5
S5NEW
100 ng single dose
GSK 100 ng
6
S6NEW
150 ng single dose
GSK 150 ng
7
S7NEW
210 ng single dose
GSK 210 ng
8
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate (fewer groups possible, if dose escalation 
stopped).
2.
Cohorts completed under Protocol Amendment 2.
3.
Study restart dose following stopping criteria met under Protocol Amendment 2.
11.3.2.
Baseline Definition & Derivations
11.3.2.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the latest non-
missing pre-dose assessment. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and baseline 
will be set to missing.
Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety Data
Vital Signs
X
Mean of replicate 
assessments on Day 
1
ECG
X
Mean of replicate 
assessments on Day 
1
Laboratory tests
X
Day 1


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Parameter
Study Assessments Considered As Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Pharmacokinetic
GSK1795091 
concentration data
X
Day 1
Pharmacodynamic
Pharmacodynamic 
markers
X
Day 1
Biomarkers
X
Day 1
11.3.2.2.
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 time point 
   and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.3.2.1 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.

The baseline definition will be footnoted on all change from baseline displays.
11.3.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and WinNonlin software will be used.
Analysis Datasets 

Analysis datasets will be created according to AdaM IG Version 1.1.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.

Define XML Version 2.0
Generation of RTF Files

RTF files will be generated for Tables, Listings, and Figures, one RTF file per item.


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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

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

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.

RTF files will be generated for displays.
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.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

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, except when summarizing worst 
cases.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.


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Reporting Standards
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 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of logged data and [between] geometric coefficient of variation (CVb (%)) will 
be reported.
CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
tmax
Listings
Additionally, include the first point, last point and number of points used in 
the determination of lambda_z for listings. Also, list %AUCextrap.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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11.4.
Appendix 4: Derived and Transformed Data
11.4.1.
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 time window the value closest to the target day for that window 
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.
Study Day

Calculated as the number of days from randomisation date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
11.4.2.
Study Population
Demographics
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2


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11.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
11.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
subjects who completed all phases of the study including the follow-up visit or 
contact. 

Withdrawn subjects may 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.
11.5.2.
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.
11.5.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Imputation will not be implemented for partial dates or missing dates. 
Consequently, time to onset and duration of such events will be missing.

The recorded partial date will be displayed in listings.
11.5.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Imputation will not be implemented for partial dates or missing dates. 
Consequently, time to onset and duration of such events will be missing.

The recorded partial date will be displayed in listings.


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11.6.
Appendix 6: Values of Potential Clinical Importance
11.6.1.
Laboratory Values
Clinical laboratory test results within potential clinical importance range will be flagged 
in the listings. Note: a high flagged or low flagged laboratory value is not necessarily of 
clinical concern. Reference ranges included are taken from CSP, Chapter 12.2 (with a
Grading of 3 or worse).
Haematology
Laboratory Parameter
Units
Category
Potential Clinical Importance Range
Low Flag (< x)
High Flag (>x)
Haemoglobin 
g/dL
Male
10.5
Female
9.5
∆from BL
-
2.0
Lymphocytes decrease
cell / 
mm³
500
Neutrophils decrease
cell / 
mm³
1000
Eosinophils
cell / 
mm³
5000
Platelets decreased 
cell / 
mm³
100000
White Blood Cell Count (WBC) 
increase
cell / 
mm³
20000
White Blood Cell Count (WBC) 
decrease
cell / 
mm³
1500
Clinical Chemistry
Laboratory Parameter
Units
Category
Potential Clinical Importance Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/dL
2.5
Calcium
mg/dL
7.5
11.5
Creatinine
mg/dL
2.0
Glucose
mg/dL
55
125 (fasting)
200 (random)
Magnesium
mg/dL
1.1
Phosphorus
mg/dL
2.0
Potassium
mEq/L
3.3
5.4
Sodium
mEq/L
130
147
Blood Urea Nitrogen
mg/dL
31
CPK
mg/dL
3*ULN
Total Protein
g/dL
5.0
Cholesterol
mg/dL
225


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Clinical Chemistry
Laboratory Parameter
Units
Category
Potential Clinical Importance Range
Low Flag (< x)
High Flag (>x)
Amylase
2xULN
Lipase
2xULN
Liver Function
Test Analyte
Units
Category
Potential Clinical Importance Range
ALT/SGPT 
U/L
High
> 5x ULN
AST/SGOT 
U/L
High
> 5x ULN
AlkPhos 
U/L
High
> 3x ULN
Total Bilirubin when
Liver Function
Test is normal;
increase by factor
µmol/L
High
> 2xULN
Total Bilirubin + increase in Liver 
function test
µmol/L
High
1.51xULN T. Bilirubin
+
U/L
2x ULN Liver function test
Coagulation
Laboratory Parameter
Units
Category
Potential Clinical Importance Range
Low Flag (< x)
High Flag (>x)
PT – increase by factor
sec
1.20*ULN
PTT – increase by factor
sec
1.40*ULN
Fibrinogen increase
mg/dL
600
Fibrinogen decrease
mg/dL
125
Urine
Laboratory Parameter
Units
Category
Potential Clinical Importance Range
Low Flag (< x)
High Flag (>x)
Protein
1+
Glucose
1+
Blood (microscopic) – red 
blood cells per high power field 
(rbc/hpf)
50


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11.6.2.
ECG
ECG Parameter
Units
Potential Clinical Importance Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
≤ 480 
≥ 481 
≤ 500 
≥ 501 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110 
Increase from Baseline QTc
msec
msec
> 30 
≤ 60  
msec
≥ 61  
11.6.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Potential Clinical Importance Range
Lower (<x)
Upper (>x)
Systolic Blood Pressure
mmHg
80
155
Diastolic Blood Pressure
mmHg
45
100
Heart Rate
bpm
45
130
Body temperature
°C
38.9
Respiratory rate
breaths/min
25
Vital Sign Parameter
(Change from Baseline)
Units
Potential Clinical Importance Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30


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11.7.
Appendix 7: Abbreviations & Trade Marks
11.7.1.
Abbreviations
Abbreviation
Description
A&R
Analysis and Reporting 
ADaM
Analysis Data Model
AE
Adverse Event
ANOVA
Analysis of Variance
AUC
Area-under-the-curve
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity 
AUC(0-last)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUC(0-t)
Partial area under the concentration-time curve to time 
BP
Blood Pressure
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL
Clearance
Cmax
Maximum observed concentration, determined directly from the concentration-
time data.
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DLT
Dose-limiting Toxicity
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FSH
Follicle Stimulating Hormone
FTIH
First-time-in-human
GSK
GlaxoSmithKline
GUI
Guidance
HIV
Human Immunodeficiency Virus
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
INR
International Normalized Ratio
IP
Investigational Product
ITT
Intent-To-Treat
Lambda_z
Terminal Phase Rate Constant
LOCF
Last Observation Carries Forward


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Abbreviation
Description
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PT
Prothrombin Time or Preferred Term
PTT
Partial Thromboplastin Time
QC
Quality Control
LOQ
Limit of Quatitation
QTcF
Frederica’s QT Interval Corrected for Heart Rate
RAMOS
Randomization & Medication Ordering System 
RAP
Reporting & Analysis Plan
Ro
Accumulation ratio
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operation Procedure
t½
Apparent terminal half-life 
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
tmax
Time to reach Cmax, determined directly from the concentration-time data.
VD
Volume of distribution
VSS
Volume of distribution where V=CL/MRTiv
11.7.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin


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11.8.
Appendix 8: List of Data Displays
11.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.10
Not applicable
Efficacy
Not applicable
Not applicable
Safety
3.1 to 3.24
Not applicable
Pharmacokinetic
4.1 to 4.4
4.1 to 4.3
Pharmacodynamic and / or Biomarker
5.1 to 5.24
5.1 to 5.39
Pharmacokinetic / Pharmacodynamic
Not applicable
6.1 to 6.14
Section
Listings
ICH Listings
1 to 29
Other Listings
30 to 56
11.8.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example mock-up 
displays provided in Appendix 9: 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
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.8.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC [1]
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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11.8.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects
ES8
Summary of Subject Status and Reason for Study Withdrawal
Programmer to update primary reason 
for withdrawal to be study specific.
ICH E3, GSK CTR, FDAAA, EudraCT
SAC [1]
Protocol Deviations
1.2.
All Subjects
DV1
Summary of Protocol Deviations
Generated, if data permits. As required, 
refer to PDMP.
ICH E3
SAC [1]
Study Populations
1.3.
All Subjects
SP1
Summary of Study Populations
IDSL
SAC [1]
1.4.
All Subjects
SP2
Summary of Exclusions from Any Population
IDSL
SAC [1]
Demographic and Baseline characteristics
1.5.
All Subjects
DM1
Summary of Demographic Characteristics
ICH E3, GSK CTR, FDAAA, EudraCT
SAC [1]
1.6.
Screened
DM11
Summary of Age Ranges
EudraCT
SAC [1]
1.7.
All Subjects
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [1]
Prior and Concomitant Medications
1.8.
All Subjects
MH4
Summary of Medical Conditions
ICH E3
SAC [1]
1.9.
All Subjects
CM1
Summary of Concomitant Medications
ICH E3
SAC [1]
Exposure and Treatment Compliance
1.10.
All Subjects
EX1
Summary of Exposure to Study Treatment
ICH E3
SAC [1]


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11.8.5.
Efficacy Tables
Not applicable.
11.8.6.
Efficacy Figures
Not applicable.


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11.8.7.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
All Subjects
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
Sort Preferred Terms by highest 
incidence rate
Please summarize safety tables by 
dose group (placebo, 7ng, 21 ng, 
60ng, 120ng) and include a column 
for total drug-treated (7, 21, 60, 
100)
SAC [1]
3.2.
All Subjects
AE5B
Summary of Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term
ICH E3
For each SOC, sort Preferred 
Terms by highest incidence rate
SAC [1]
3.3.
All Subjects
AE1
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
For each SOC, sort Preferred 
Terms by highest incidence rate
SAC [1]
3.4.
All Subjects
AE15
Summary of Common (≥5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
For each SOC, sort Preferred 
Terms by highest incidence rate
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
3.5.
All Subjects
AE3
Summary of Serious Adverse Events by Overall Frequency
GSK CTR
SAC [1]
3.6.
All Subjects
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
For each SOC, sort Preferred
Terms by highest incidence rate
SAC [1]
3.7.
All Subjects
AE3
Summary of Drug-Related Serious Adverse Events by Overall 
Frequency
GSK CTR
SAC [1]
3.8.
All Subjects
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Preferred Term
IDSL
SAC [1]
Laboratory: Clinical Chemistry
3.9.
All Subjects
LB1
Summary of Clinical Chemistry
ICH E3
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units.
SAC [1]
3.10.
All Subjects
LB2
Summary of Clinical Chemistry data outside reference range
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units
SAC [1]
Laboratory: Hematology
3.11.
All Subjects
LB1
Summary of Hematology
ICH E3
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units.
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.12.
All Subjects
LB2
Summary of Hematology data outside reference range
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units
SAC [1]
Laboratory: Coagulation
3.13.
All Subjects
LB1
Summary of Coagulation
ICH E3
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units.
SAC [1]
3.14.
All Subjects
LB2
Summary of Coagulation data outside reference range
Order Parameters alphabetically
Includes pre-specified parameters 
repeated in conventional units
SAC [1]
Laboratory: Urinalysis
3.15.
All Subjects
LB1
Summary of Urinalysis Results
ICH E3
Order Parameters alphabetically
SAC [1]
ECG
3.16.
All Subjects
EG1
Summary of ECG Findings
IDSL
Use ECG findings categories (and 
change from baseline categories, if 
applicable).
SAC [1]
3.17.
All Subjects
EG1
Summary of ECG Findings worst case post-baseline
IDSL
SAC [1]
3.18.
All Subjects
EG2
Summary of ECG Values by Visit
IDSL
SAC [1]
3.19.
All Subjects
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
Includes Baseline values.
SAC [1]
3.20.
All Subjects
EG10
Summary of QTcF Grades by Visit
IDSL
SAC [1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
All Subjects
EG11
Summary of Change from Baseline and worst case post-
baseline QTcF Grades by Visit
IDSL
Includes Baseline values.
SAC [1]
Vital Signs
3.22.
All Subjects
VS1
Summary of Vital Signs by Visit
IDSL
SAC [1]
3.23.
All Subjects
VS1
Summary of Change from Baseline in Vital Signs by Visit
IDSL
Includes Baseline values
SAC [1]
3.24.
All Subjects
VS6
Summary of Vital Signs by Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials
IDSL
SAC [1]


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11.8.8.
Safety Figures
Not applicable.


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11.8.9.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
4.1.
PK Concen-
tration 
PK01
Summary statistics of GSK1795091 concentration data
SAC [1]
4.2.
PK 
Parameter 
PK04
Summary statistics of GSK1795091 PK Parameters
SAC [1]
4.3.
PK 
Parameter
PK13
Listing of GSK1795091 PK Parameters 
Standard listing format; include as table 
in table section
SAC [1]
Dose proportionality
4.4.
PK 
Parameter
Non-Standard
Summary of Results of Dose Proportionality Assessment for 
Cmax Using Power Model  Single dose
SAC [1]


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11.8.10.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
4.1.
PK Concen-
tration 
PK17
Mean (95% CI) PK Concentration of GSK1795091
Linear and Log Scale
SAC [1]
4.2.
PK Concen-
tration
LB11
Individual subject plots of PK Concentration for GSK1795091
Linear and Log Scale
SAC [1]
Dose proportionality
4.3.
PK 
Parameter
PK29
Individual and Box Plot of Dose-Normalized GSK1795091 PK 
Parameter by Dose following Single Dose
Cmax only, Linear and Log Scale
SAC [1]


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11.8.11.
Pharmacodynamic/Biomarker Tables
Pharmacodynamic/Biomarker : Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Cytokines/Chemokines
5.1.
PD
PD1
Summary of Concentration of IL-6
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.2.
PD
PD1
Summary of Concentration of TNF-alpha
Summarize by visit for each cohort. Exclude 
subjects administered placebo from each 
cohort, and group all placebos together
SAC [1]
5.3.
PD
PD1
Summary of Concentration of IFN-gamma
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.4.
PD
PD1
Summary of Concentration of IP-10
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.5.
PD
PD1
Summary of Concentration of MCP-1
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.6.
PD
PD1
Summary of Concentration of GM-CSF
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.7.
PD
PD1
Summary of Concentration of IL-1Ra
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.8.
PD
PD1
Summary of Concentration of IL-10
Summarize by visit for each dose level, and 
group all placebos together
SAC [1]
5.9.
PD
PD3
Summary of Fold Change of Concentration of IL-6 
from Baseline
Summarize by visit for each dose level, and 
group all placebos togetherImpute 0.5LOQ if a 
value is below LOQ. 
SAC [1]


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Pharmacodynamic/Biomarker : Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
5.10.
PD
PD3
Summary of Fold Change of Concentration of 
TNF-alpha from Baseline
Summarize by visit for each dose level, and 
group all placebos together. Impute 0.5LOQ if 
a value is below LOQ.
SAC [1]
5.11.
PD
PD3
Summary of Fold Change of Concentration of 
IFN-gamma from Baseline
Summarize by visit for each dose level, and 
group all placebos together. Impute 0.5LOQ if 
a value is below LOQ. 
SAC [1]
5.12.
PD
PD3
Summary of Fold Change of Concentration of IP-
10 from Baseline
Summarize by visit for each dose level, and 
group all placebos together.  Impute 0.5LOQ if 
a value is below LOQ
SAC [1]
5.13.
PD
PD3
Summary of Fold Change of Concentration of 
MCP-1 from Baseline
Summarize by visit for each dose level, and 
group all placebos together. Impute 0.5LOQ if 
a value is below LOQ
SAC [1]
5.14.
PD
PD3
Summary of Fold Change of Concentration of 
GM-CSF from Baseline
Summarize by visit for each dose level, and 
group all placebos together.Impute 0.5LOQ if 
a value is below LOQ
SAC [1]
5.15.
PD
PD3
Summary of Fold Change of Concentration of IL-
1Ra from Baseline
Summarize by visit for each dose level, and 
group all placebos together. Impute 0.5LOQ if 
a value is below LOQ
SAC [1]
5.16.
PD
PD3
Summary of Fold Change of Concentration of IL-
10 from Baseline
Summarize by visit for each dose level, and 
group all placebos together. Impute 0.5LOQ if 
a value is below LOQ
SAC [1]
Immunophenotyping
5.17.
All Subjects
PD4
Summary of Neutrophils
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together.
SAC [1]


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Pharmacodynamic/Biomarker : Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
5.18.
All Subjects
PD4
Summary of Lymphocytes
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together
SAC [1]
5.19.
All Subjects
PD4
Summary of Monocytes
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together
SAC [1]
5.20.
All Subjects
PD3
Summary of Neutrophils Change from Baseline
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together. Impute 0.5LOQ if a value is below 
LOQ.
SAC [1]
5.21.
All Subjects
PD3
Summary of Lymphocytes Change from Baseline
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together. Impute 0.5LOQ if a value is below 
LOQ.
SAC [1]
5.22.
All Subjects
PD3
Summary of Monocytes Change from Baseline
Summarize abs. only. Summarize by visit for 
each dose level, and group all placebos 
together. Impute 0.5LOQ if a value is below 
LOQ.
SAC [1]
Laboratory Tests
5.23.
All Subjects
PD4
Summary of CRP
Summarize by visit for each dose level, and 
group all placebos together.
SAC [1]
5.24.
All Subjects
PD3
Summary of CRP Change from Baseline
Summarize by visit for each dose level, and 
group all placebos together.
SAC [1]


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11.8.12.
Pharmacodynamic/Biomarker Figures
Pharmacodynamic/Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Cytokines
5.1.
PD
EG9
Mean Concentration of IL-6 with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.2.
PD
EG9
Mean Concentration of TNF-alpha with 95% CI over Time by 
Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.3.
PD
EG9
Mean Concentration of IFN-gamma with 95% CI over Time by 
Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.4.
PD
EG9
Mean Concentration of IP-10 with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.5.
PD
EG9
Mean Concentration of MCP-1 with 95% CI over Time by Dose
Time course. Each dose as single 
figure, placebo pooled
SAC [1]
5.6.
PD
EG9
Mean Concentration of GM-CSF with 95% CI over Time by Dose
Time course. Each dose as single 
figure, placebo pooled
SAC [1]
5.7.
PD
EG9
Mean Concentration of IL-1Ra with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.8.
PD
EG9
Mean Concentration of IL-10 with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]


CONFIDENTIAL
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Pharmacodynamic/Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunophenotyping
5.9.
All Subjects
EG9
Mean Neutrophils abs. with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.10.
All Subjects
EG9
Mean Change from Baseline in Neutrophils abs. with 95% CI 
over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.11.
All Subjects
LB11
Individual Neutrophils abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.12.
All Subjects
LB11
Individual Change from Baseline in Neutrophils abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.13.
All Subjects
EG9
Mean Lymphocytes abs. with 95% CI over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.14.
All Subjects
EG9
Mean Change from Baseline in Lymphocytes abs. with 95% CI 
over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.15.
All Subjects
LB11
Individual Lymphocytes abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.16.
All Subjects
LB11
Individual Change from Baseline in Lymphocytes abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]


CONFIDENTIAL
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Pharmacodynamic/Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.17.
All Subjects
EG9
Mean Change from Baseline in Monocytes abs. with 95% CI 
over Time by Dose
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.18.
All Subjects
LB11
Individual Monocytes abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.19.
All Subjects
LB11
Individual Change from Baseline in Monocytes abs. over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
Vital signs
5.20.
All Subjects
EG9
Mean Body Temperature values with 95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.21.
All Subjects
EG9
Mean Change from Baseline in Body Temperature values with 
95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.22.
All Subjects
LB11
Individual Body Temperature values over Time
Spaghetti plot of individual values, 
each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.23.
All Subjects
LB11
Individual Change from Baseline in Body Temperature values
over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.24.
All Subjects
EG9
Mean Heart Rate values with 95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]


CONFIDENTIAL
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Pharmacodynamic/Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.25.
All Subjects
EG9
Mean Change from Baseline in Heart Rate values with 95% CI 
over Time
Time course
All doses on a single graph, 
placebo pooled
SAC [1]
5.26.
All Subjects
LB11
Individual Heart Rate values over Time
Spaghetti plot of individual values, 
each cohort as single figure, 
placebo as pooled cohort
SAC [1]
5.27.
All Subjects
LB11
Individual Change from Baseline in Heart Rate values over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.28.
All Subjects
EG9
Mean Systolic Blood Pressure values with 95% CI over Time
Time course
All doses on a single graph, 
placebo pooled
SAC [1]
5.29.
All Subjects
EG9
Mean Change from Baseline in Systolic Blood Pressure values
with 95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.30.
All Subjects
LB11
Individual Systolic Blood Pressure values over Time
Spaghetti plot of individual values, 
each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.31.
All Subjects
LB11
Individual Change from Baseline in Systolic Blood Pressure 
values over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.32.
All Subjects
EG9
Mean Diastolic Blood Pressure values with 95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]


CONFIDENTIAL
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Pharmacodynamic/Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.33.
All Subjects
EG9
Mean Change from Baseline in Diastolic Blood Pressure values
with 95% CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.34.
All Subjects
LB11
Individual Diastolic Blood Pressure values over Time
Spaghetti plot of individual values, 
each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.35.
All Subjects
LB11
Individual Change from Baseline in Diastolic Blood Pressure 
values over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
Laboratory Tests
5.36.
All Subjects
EG9
Mean CRP values with 95%CI over Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.37.
All Subjects
EG9
Mean Change from Baseline in CRP values with 95%CI over 
Time
Time course
Each dose as single figure, placebo 
pooled
SAC [1]
5.38.
All Subjects
LB11
Individual CRP values over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]
5.39.
All Subjects
LB11
Individual Change from Baseline in CRP values over Time
Spaghetti plot of individual values, 
Each dose as single figure, placebo 
as pooled cohort
SAC [1]


CONFIDENTIAL
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11.8.13.
Pharmacokinetic / Pharmacodynamic Tables
Not applicable.


CONFIDENTIAL
204685
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11.8.14.
Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.1.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Parameters and Vital Signs 
Maximum Changes from Baseline
Scatterplot (X-axis: PK parameter, 
Y-axis: Maximum change, pair X 
and Y by SubjID) Individual figure.
Use different colors or symbols to 
distinguish dose levels. Draw linear 
trending line for each dose level.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. X: 
Cmax only.
Y: HR, Body temperature, Systolic 
blood pressure, Diastolic blood 
pressure
SAC [1]
6.2.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Parameters and WBC incl. 
differential Maximum Changes from Baseline
Scatterplot (for each subject, X-
axis: PK parameter, Y-axis: 
Maximum change, pair X and Y by 
SubjID) Individual figure. Use 
different colors or symbols to 
distinguish dose levels. Draw linear 
trending line for each dose level. 
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together.
X: Cmax only.
SAC [1]


CONFIDENTIAL
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Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.3.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Parameters and Laboratory 
Tests Maximum Changes from Baseline
Scatterplot (for each subject, X-
axis: PK parameter, Y-axis: 
Maximum change, pair X and Y by 
SubjID) Individual figure. Use 
different colors or symbols to 
distinguish dose levels. Draw linear 
trending line for each dose level. 
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together.
X: Cmax only
Y: Laboratory tests (CRP,
Neutrophil abs., Lymphocyte abs.)
SAC [1]
6.4.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and IL-6
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
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Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.5.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and TNF-alpha
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]
6.6.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and IFN-
gamma
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
204685
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Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.7.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and IP-10
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]
6.8.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and MCP-1
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
204685
68
Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.9.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and GM-CSF
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]
6.10.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and IL-1Ra
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
204685
69
Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.11.
PD
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and IL-10
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]
6.12.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and 
Neutrophils abs.
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
204685
70
Pharmacokinetic / Pharmacodynamic : Figures
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
6.13.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and 
Lymphocytes abs.
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]
6.14.
All Subjects
Non-
Standard2
Relationship of GSK1795091 PK Concentrations and 
Monoocytes abs.
Scatterplot with trending lines ( X-
axis: PK concentration, Y-axis: 
Biomarker, pair X and Y by SubjID 
and Time) Use distinct colors or 
symbols to distinguish dose levels.
Exclude subjects administered 
placebo from each cohort, and 
group all placebos together. Draw 
linear trending line for each dose 
level
SAC [1]


CONFIDENTIAL
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71
11.8.15.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reason for Screening Failure
Journal Guidelines
SAC [1]
2.
All Subjects
ES2
Listing of Reasons for Withdrawal
ICH E3
SAC [1]
3.
All Subjects
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [1]
4.
All Subjects
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC [1]
5.
All Subjects
TA1
Listing of Planned and Actual Treatments
IDSL
SAC [1]
Protocol Deviation
6.
All Subjects
DV2
Listing of Protocol Deviations
ICH E3
Listing also includes analysis 
population exclusions.
SAC [1]
7.
All Subjects
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC [1]
Populations Analysed
8.
All 
randomised
SP3
Listing of Subjects Excluded from Any Population
ICH E3
SAC [1]
Demographics and Baseline Characteristics
9.
All Subjects
DM2
Listing of Demographics Characteristics
ICH E3
SAC [1]
Prior and Concomitant Medication
10.
All Subjects
CM3
Listing of Concomitant Medications 
IDSL
SAC [1]
Exposure and Treatment Compliance
11.
All Subjects
EX3
Listing of Exposure Data
ICH E3
SAC [1]


CONFIDENTIAL
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72
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Medical History
12.
All Subjects
MH2
Listing of Medical History
IDSL
SAC [1]
13.
All Subjects
SU2
Listing of Substance Use
IDSL
SAC [1]
Adverse Events
14.
All Subjects
AE8
Listing of All Adverse Events
ICH E3
SAC [1]
15.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [1]
16.
All Subjects
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC [1]
17.
All Subjects
AE8
Listing of Serious Adverse Events
ICH E3
SAC [1]
18.
All Subjects
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [1]
19.
All Subjects
AE8
Listing of Adverse Events Leading to Withdrawal from Study /
Permanent Discontinuation of Study Treatment
ICH E3
SAC [1]
All Laboratory
20.
All Subjects
LB5
Listing of Clinical Chemistry for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
Include a normal range column in 
the listing
SAC [1]
21.
All Subjects
LB5
Listing of Hematology for Subjects with Any Value of Potential 
Clinical Importance
ICH E3
SAC [1]
22.
All Subjects
LB5
Listing of Coagulation for Subjects with Any Value of Potential 
Clinical Importance
ICH E3
SAC [1]
23.
All Subjects
UR2A
Listing of Urinalysis for Subjects with Any Value of Potential 
Clinical Importance
ICH E3
SAC [1]
24.
All Subjects
LB5
Listing of Laboratory Values of Potential Clinical Importance
ICH E3
SAC [1]


CONFIDENTIAL
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73
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
25.
All Subjects
EG3
Listing of All ECG Data for Subjects with Any Value of Potential 
Clinical Importance
IDSL
SAC [1]
26.
All Subjects
EG3
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC [1]
27.
All Subjects
EG5
Listing of Abnormal ECG Findings
IDSL
SAC [1]
Vital Signs
28.
All Subjects
VS4
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC [1]
29.
All Subjects
VS4
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC [1]


CONFIDENTIAL
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11.8.16.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic 
30.
PK Concen-
tration
PK07
Listing of GSK1795091 Concentration-Time data
Sort by subject, treatment, day, and 
time
SAC [1]
Laboratory Tests
31.
All Subjects
OLB7
Listing of Selected Laboratory Tests
IDSL
CRP, Neutrophils abs., 
Lymphocytes abs.
SAC [1]
32.
All Subjects
OLB7
Listing of Change from Baseline in Selected Laboratory Tests
IDSL
CRP, Neutrophils abs., 
Lymphocytes abs.
SAC [1]
Vital Signs
33.
All Subjects
OVT7A
Listing of Selected Vital Signs with Values Potential Clinical 
Importance
IDSL
HR, Body temperature, Sys BP, 
Dias BP
SAC [1]
34.
All Subjects
OVT7A
Listing of Vital Signs Change from Baseline with Values 
Potential Clinical Importance
IDSL
HR, Body temperature, Sys BP, 
Dias BP
SAC [1]
Pharmacodynamic
35.
PD
PD16
Listing of Concentration of IL-6
Sort by subject, treatment, day, and 
time
SAC [1]
36.
PD
PD16
Listing of Concentration of TNF-alpha
Sort by subject, treatment, day, and 
time
SAC [1]


CONFIDENTIAL
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75
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
37.
PD
PD16
Listing of Concentration of IFN-gamma
Sort by subject, treatment, day, and 
time
SAC [1]
38.
PD
PD16
Listing of Concentration of IP-10
Sort by subject, treatment, day, and 
time
SAC [1]
39.
PD
PD16
Listing of Concentration of MCP-1
Sort by subject, treatment, day, and 
time
SAC [1]
40.
PD
PD16
Listing of Concentration of GM-CSF 
Sort by subject, treatment, day, and 
time
SAC [1]
41.
PD
PD16
Listing of Concentration of IL-1Ra
Sort by subject, treatment, day, and 
time
SAC [1]
42.
PD
PD16
Listing of Concentration of IL-10 
Sort by subject, treatment, day, and 
time
SAC [1]
43.
PD
PD16
Listing of Fold Change of Concentration of IL-6 from Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
44.
PD
PD16
Listing of Fold Change of Concentration of TNF-alpha from 
Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
45.
PD
PD16
Listing of Fold Change of Concentration of IFN-gamma from 
Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
46.
PD
PD16
Listing of Fold Change of Concentration of IP-10 from Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
47.
PD
PD16
Listing of Fold Change of Concentration of MCP-1 from Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
48.
PD
PD16
Listing of Fold Change of Concentration of GM-CSF from 
Baseline
Sort by subject, treatment, day, and 
time
SAC [1]


CONFIDENTIAL
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76
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
49.
PD
PD16
Listing of Fold Change of Concentration of IL-1Ra from Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
50.
PD
PD16
Listing of Fold Change of Concentration of IL-10 from Baseline
Sort by subject, treatment, day, and 
time
SAC [1]
51.
PD
PD16
Listing of Neutrophils
List both % and abs.. Sort by 
subject, treatment, day, and time
SAC [1]
52.
PD
PD16
Listing of Lymphocytes
List both % and abs.. Sort by 
subject, treatment, day, and time
SAC [1]
53.
PD
PD16
Listing of Monocytes
List both % and abs..  Sort by 
subject, treatment, day, and time
SAC [1]
54.
PD
PD16
Listing of Neutrophils abs. Change from Baseline
List abs. only. Sort by subject, 
treatment, day, and time
SAC [1]
55.
PD
PD16
Listing of Lymphocytes abs. Change from Baseline
List abs. only. Sort by subject, 
treatment, day, and time
SAC [1]
56.
PD
PD16
Listing of Monocytes abs. Change from Baseline
List abs. only. Sort by subject, 
treatment, day, and time
SAC [1]


CONFIDENTIAL
204685
77
11.9.
Appendix 9: Example Mock Shells for Data Displays
Example 
: Non-Standard 2
Page 1 of 1
Protocol
: 204685
Population
: All Subjects
Figure 6.16
Relationship of GSK1795091 PK Parameters and Vital Signs Maximum Changes from Baseline